Electronic copy available at: http://ssrn.com/abstract=2394599

Electronic copy available at: http://ssrn.com/abstract=2394599

Descrierea CIP / Description of CIP – Biblioteca Națională a României Conferința Internațională Educație și Creativitate pentru o Societate Bazată pe Cunoaștere – MEDICINĂ, MEDICINĂ DENTARĂ ŞI FARMACIE, București, Universitatea Titu Maiorescu, 2013 ISSN 2248-0048 Österreichische Nationalbibliothek Wien The International Conference Education and Creativity for a Knowledge – based Society – MEDICINE, DENTAL MEDICINE AND PHARMACY, Vienna, Osterreichish Rumanischer Akademischer Verein, 2013 ISBN 978-3-9503145-7-1 134 p.; 21 cm.

Referenți științifici / Reviewers: Dan-Florin Ungureanu Cristian-Adrian Stan Doina-Lucia Ghergic Otilia Cinteză © Universitatea Titu Maiorescu ISSN 2248-0048 Osterreichish Rumanischer Akademischer Verein, 2013 ISBN 978-3-9503145-7-1 Bun de tipar / Signature for the press: 27.12.2013 Format: 21/29,7×100

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Electronic copy available at: http://ssrn.com/abstract=2394599

CONTENT STUDY REGARDING THE ROLE OF MELATONIN IN “CHRONIC FATIGUE SYNDROME”, Constantin BĂLĂEŢ, Mirela RADU, Elena RUSU...........................................5 STUDY REGARDING HOMOCISTEIN AS MARKER IN PATIENTS WITH STROKE, Constantin BĂLĂEŢ, Mirela RADU, Simona VLAIC, Viorel POALELUNGI, Elena RUSU…………………………………………………………………………………….11 THE CURRENT PERSPECTIVES AND PRINCIPLES OF MODERN SURGICAL TREATMENT IN STRESS URINARY INCONTINENCE IN WOMEN, Florentina BEALCU, Jessica Maria POPESCU……………………………………………………………………….14 MULTIRESISTANT TO ANTIBIOTICS OF S. TYPHIMURIUM STRAINS PRODUCING EXTENDED SPECTRUM BETA-LACTAMASES (ESBLs), Bogdan-Ioan COCULESCU, Andi-Marian PALADE, Manole COJOCARU…………………………………………………18 EXPERIMENTAL AND THEORETICAL EVALUATION OF VSB POSITIONING AT THE INCUS, Horia MOCANU, Matthias BORNITZ, Niokoloz LASURASHVILI, Thomas ZAHNERT....................................................................................................................................21 A CASE OF TRACHEO-OESOPHAGEAL FISTULA CAUSED BY LONG TERM IPPV, Horia MOCANU..........................................................................................................................24 INCIDENCE AND ANTIBIOTIC DRUGS RESISTANCE OF SOME BACTERIA SPECIES IN URINARY TRACT INFECTIONS, Elena RUSU, Silviu EPURAN, Manole COJOCARU …………………………………………………………………………27 PLACENTAL PATHOLOGY IN ANTIPHOSPHOLIPID SYNDROME, Iulia SAVU, Monica CIRSTOIU, Raluca TULIN, Luminiţa CEAUŞEL, V. HORHOIANU, M. TANASI…………………………………………………………………………………….…30 CLINICAL ENT ASPECTS OF RARE DISEASES– GAUCHER DISEASE, Carmen STAN…………………………………………………………………………………..39 CLINICAL CONSIDERATIONS ON AN OESOPHAGEAL CANCER CASE WITH ATYPICAL DEBUT, Carmen STAN…………………………………………………………..42 THE JURISTIC CONNOTATIONS OF EAR TRAUMA, Carmen STAN……………………44 ATTRACTING EUROPEAN FUNDS – A NEED FOR THE SUSTAINABLE DEVELOPMENT OF HIGHER EDUCATION AND RESEARCH IN HEALTH, Cristian STAN, Otilia CINTEZĂ, Camelia PETRESCU, Carmen STAN ……………………47 DELIBERATE HYPOTENSION – OLD AND NEW INTRAANAESTHETIC METHOD FOR HEAD AND NECK ONCOLOGICAL SURGERY, Cornelia TÎRÎȘ………………………..58 CLINICAL AND ENDOSCOPIC LONG TERM SURVEY AFTER LAPAROSCOPIC SURGERY IN HIATAL HERNIAS, Florin-Dan UNGUREANU, Laurenţiu U., Cosmin M., Mădălina T., Gabriel LOPEZ-COBENA……………………………………………………….60 ASSESSMENT OF AVAILABLE BONE IN SINGLE-TOOTH IMPLANT TREATMENT IN LATERAL AREA, Claudia Florina ANDREESCU, Oana SMĂTREA, Doina Lucia GHERGIC…………………………………………………………………………69 ASSESSMENT OF THE AVAILABLE BONE IN ORDER TO INSERT DENTAL IMPLANTS, Ane-Mary ANGHELINA, Costin COMAN, Raluca Monica COMĂNEANU, Horia BARBU, Doina Lucia GHERGIC, Mihai TÂRCOLEA……………….………………..74 THE INFLUENCE OF THE SALIVARY PH ON THE MATERIALS USED IN THE METALCERAMIC TECHNOLOGY, Monica COMĂNEANU, Violeta HÂNCU, Costin COMAN, Doina Lucia GHERGIC…………………………………………………………………………80

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A CLASS II DIVISON 2 MALOCCLUSION TREATED WITH REMOVABLE TWIN BLOCK FUNCTIONAL APPLIANCE - A CASE REPORT, Delia Elena DARAGIU, Doina Lucia GHERGIC…………………………………………………..……………………………85 TOTAL EDENTATION OCCURRENCE IN A YOUNG PATIENT, Elena Gabriela DESPA, Graziella Emilia CÂNDESCU, Anca Iuliana POPESCU, Ana Maria PANGICĂ, Raluca Anca GIURESCU……………………………………………………………………………………..94 ORAL REHABILITATION WITH CERAMIC-FUSED-TO-METAL RESTAURATIONSCASE STUDY, Anca Monica DOBRESCU, Costin COMAN, Raluca Monica COMĂNEANU, Oana SMĂTREA, Doina Lucia GHERGIC.................................................................................98 TREATMENT PLANNING IN SEVERE OPEN BITE, Viorel IBRIC CIORANU, V. Nicolae, Sorin IBRIC CIORANU……………………………………………………………………….103 AESTHETIC OPTIMIZATION BY VENEERS TECHNIQUES, Anca_Iuliana POPESCU, Raluca_Anca GIURESCU, Anna Maria PANGICĂ, Alina Gabriela FILIPESCU, Cătălin Sorin DUMITRESCU, Elena Gabriela DESPA……………………………………………………..106 INTERDISCIPLINARY AND COMPLEX ORAL REHABILITATION – CASE REPORT, Oana ROŞU, Doina Lucia GHERGIC, Mihaela RĂESCU……………………………………111 PERIIMPLANTITIS, COMPLICATION IN ORAL REHABILITATION WITH DENTAL IMPLANTS, Oana SMĂTREA, Doina Lucia GHERGIC, Claudia Florina ANDREESCU..................................................................................................118 NEW TREND IN THE NANO-BASED PHARMACEUTICAL FORMULATION FOR THE TREATMENT OF OSTEOPROROSIS, Ioana AILIESEI, Ludmila Otilia CINTEZĂ, Ana Maria SACHELARIE...........................................................................................................................124 ATTRACTING EUROPEAN FUNDS – A NEED FOR THE SUSTAINABLE DEVELOPMENT OF HIGHER EDUCATION AND RESEARCH IN HEALTH, Cristian STAN, Ludmila Otilia CINTEZĂ, Ioana AILIESEI, Camelia PETRESCU………………….130

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STUDY REGARDING THE ROLE OF MELATONIN IN “CHRONIC FATIGUE SYNDROME” Constantin Bălăeţ1, Mirela Radu2, Elena Rusu3 Lecturer PhD., Preclinic Department, Faculty of Medicine, Titu Maiorescu University, Gheorghe Petrascu Street, no. 67A, sector 3, Bucharest Romania 2 Assistant, Faculty of Medicine, Titu Maiorescu University, Gheorghe Petrascu Street, no. 67A, sector 3, Bucharest Romania 3 Lecturer PhD., Preclinic Department, Faculty of Medicine, Titu Maiorescu University, Gheorghe Petrascu Street, no. 67A, sector 3, Bucharest Romania *Corresponding author: Lecturer PhD. Constantin Balaet: [email protected] 1

ABSTRACT Dosing melatonin in healthy patients without symptomatology and in an equal number of patients having sleep disturbances, headaches, migraines, “chronic fatigue” status. Methods and materials Melatonin dosage during routine analysis for 60 clinical healthy patients who did not present any symptoms and for 60 patients who presented “chronic fatigue syndrome”. Melatonin dosage was determined in the laboratory after processing the collected samples. Discussion. The quantitative variations of melatonin for subjects tested with “t-Student test” (the subjects with chronic tiredness syndrome), were considered to be highly statistically relevant. Conclusions For the patients with chronic fatigue, the melatonin dosage in their blood is useful for their diagnosis, in order to ferret out how advanced their condition is (physiopathologic and therapeutic factors). Key words: melatonin, chronic fatigue syndrome, patients (subjects).

INTRODUCTION Melatonin can be synthetised by other mammal tissues and it is ubicuitary. Except the regulatory role in the circadian/seasonal rhythm, melatonin is involved in modulating immune response, body weight, cardiovascular regulation especially blood pressure and reproduction [2, 3]. Nowadays, more and more patients come to doctors’ offices and hospitals, patients whose anamnesis holds as causes sleep disturbances, fatigue, stress, migraines, headaches [8]. “Chronic fatigue syndrome”, remains more than often without a known cause [7]. Recently, several studies carried out on melatonin seem to help in decoding this syndrome [11, 6]. In our study, we are analysing dosing melatonin in healthy patients without symptomatology and in an equal number of patients having sleep disturbances, headaches, migraines, “chronic fatigue” status. MATERIALS AND METHODS Cooperating with family physician and internal medicine physician, we have selected 60 patients healthy clinically and paraclinically, aged 20-65 who came to doctor’s office for routine blood tests and an equal number of patients, aged 20-65 who presented during anamnesis insomnias, headaches, fatigue, migraines. The study has had a length of three years, researched batches being carefully chosen, sampling being carried out according to a well-defined protocol in order to observe melatonin variations dynamically. Melatonin determination was carried out in the two batches in November and December, when theoretically, melatonin values during night should be to a maximum level, the day-light being 9-10 hours. Samples were taken in the morning, “a jeun”, at 8 o’clock and in the evening, at 9 o’clock with a break of 4 hours after the last meal, water being the only allowed. Samples did not contain hemolysed serum and were not lipemic. Some of the samples were processed immediately, others were kept in 2-8 degrees C for 24 hours, other samples were frozen to -20 degrees C (Re-freezing samples was not allowed!) We dosed melatonin in serum through Elisa method, using the reactive Melatonin ELISA (EIA-1431), both in the witness batch and in the researched one. RESULTS, DISCUSSIONS Standard values of melatonin in the laboratory are 4.5 pg/ml by day – 77.8 pg/ml at night. Average values of the melatonin obtained in our laboratory in the witness batch were within the reference range (4.6 pg/ml during the day and 77.6 pg/ml during the night). 5

Healthy patients (the witness batch) represented 50% women (30) and 50% men (30) The researched batch was represented by 50% women (30) and 50% men (30) In the researched batch we obtained the following melatonin values: Aged 20 – 35 (10 patients, five men, five women) the average value at 8 o’clock in the morning was of 4.0 pg/ml and during night, at 9 o’clock was of 76.0 pg/ml.

Valorile medii la lotul martor si valorile medii la lotul de cercetat obtinute la grupa de varsta 20-35 ani

80 70 60

77.6

50 76

pg/ml 40 30 20 10

Melatonina

4.6

0 4

interval de referinta ziua

Melatonina interval de referinta noaptea femei. barbati (20-35 ani)- ora 8.00 (pg/ml)

femei. barbati (20-35 ani)- ora 21.00 (pg/ml)

Aged 36 - 50 (30 patients,15 men and 15 women) the average value at 8 o’clock in the morning was of 4.1 pg/ml and during night, at 9 o’clock, was of 74 pg/ml.

Valorile medii la lotul martor si valorile medii la lotul de cercetat obtinute la grupa de varsta 36-50 ani

80 70 77.6

60 50

74

pg/ml 40 30 20 10

Melatonina 4.6

0 4.1

interval de referinta ziua

Melatonina interval de referinta noaptea femei. barbati (36-50 ani) - ora 08.00 (pg/ml)

femei. barbati (36-50 ani)- ora 21.00 (pg/ml)

Aged 51 – 65 (20 patients, 10 men and 10 women) the average value at 8 o’clock in the morning was of 3.5 pg/ml and during night, at 9 o’clock, was of 69pg/ml.

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Valorile medii la lotul martor si valorile medii la lotul de cercetat obtinute la grupa de varsta 51-65 ani

80 70 60 50 pg/ml 40

77.6

30 20 10

Melatonina

69 4.6

0 3.5

interval de referinta ziua

Melatonina interval de referinta noaptea femei. barbati (51-65 ani) - ora 08.00 (pg/ml)

femei. barbati (51-65 ani)- ora 21.00 (pg/ml)

Our study shows that melatonin changes during sampling, night/day are in an obvious physiopathological dynamics. We have noticed that melatonin values have suffered changes that is they decreased along with aging, fact which proved the decrease of sleeping hours, especially in the elderly. As a result of our study, we can draw the conclusion that melatonin decrease can be correlated with occurrence of fatigue, insomnia, headaches and appearance of “chronic fatigue syndrome”. Melatonin is a hormone secreted rhythmically by the pineal body, involved in regulating circadian rhythm and seasonal one. Maximum levels are reached at night, its secretion being suppressed by light. Melatonin can be synthetised by other mammal tissues and it is ubicuitary [10, 22] . For the first time, it was isolated in the cattle pineal body and it was identified by Lerner and associates in 1958. Except the regulatory role in the circadian/seasonal rhythm, melatonin is involved in modulating immune response, body weight, cardio-vascular regulation especially blood pressure [18, 27, 28] and reproduction. Other properties that it has are: antioxidant and aging prevention process [9]. Melatonin is biosynthetised from tryptophan and serotonin. It can be collaterally formed at the retina level, cochleal membrane level, mononuclear leukocytes level, skin, kidney and GI tract. Extra-pineal locations contribute to a low extent and only after specific stmuli to the circulant melatonin levels [10]. Melatonin follows several metabolising pathways. It is oxidised at the level of Cit. P450 at 6-hydroxy melatonin (CYP1A1, YP1A2 and CYP1B1 are involved) which conjugate with 6-sulfate oxi melatonin and it is eliminated by renal pathway (it is dosed in urine by ELISA method using the reactive Melatonin-Sulfate EIA-1432) [17]. Other possible metabolites of melatonin are 3- hydroxy melatonin, 2- hydroxy melatonin, nitrosated metabolites [26]. In our study we have noticed that circulant melatonin is decreased during day and increased at night, raising its level during dark, the plasmatic peak level being reached at the middle of darness period [19]. In humans, the highest melatonin concentration is reached in childhood. It starts decreasing at the beginning of puberty and continues to decrease significantly in the elderly. This trend was also noticed through our study, by comparing the witness batch with the researched one (the 2035 group of age) [12, 13, 14]. Melatonin plays an important part in the life cycle, that means in growing up, development and maturity as well as in the ageing process [18]. Thus, melatonin action mechanisms are: Role in circadian rhythm regulation with effects on NS being efficient in treating neuro-degenerative diseases in patients with Alzheimer, Parkinson, Huntington or lateral amyotrophic dystrophy. It inhibits Aβfibrogenesis [32]. In patients with autism there are abnormalities in melatonin production and release and by treating with melatonin there was observed in 3 children out of 107 sleepiness in the morning or enuresis [16]. Melatonin acts through the gamma-aminobutyric acid receptors and benzodiazepinic acids which explains its

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success in treating convulsions in children and adults. Melatonin administration reduced pain, sleep disorders and depression in fibromialgia and bulimia [24, 30]. Effects at the cardio-vascular level, melatonin decreases blood pressure but in the treatment with beta blockers for 10 weeks determined decrease of melatonin levels in 42 patients [20]. Effects on gonads- melatonin is involved in regulating gonads function by influencing the hypothalamic-pituitary-gonadal axis. Melatonin regulates reproduction in animals [24]. By controlling hormones production at the gonads level, melatonin can inhibit hormone-dependent tumors [19]. Antioxidative properties: melatonin inter-reacts efficiently with different reactive species of oxygen and azoth as well as organic radicals, having the role of a trap for free radicals [15]. At intracellular level it protects sub-cellular structures, including mitochondriae and DNA against oxydative stress directly on the place of its production [9]. Immuno-modulating effects: melatonin activates both the innate response and the adaptative immune response. It activates T,B, NK cells and monocytes, determines thymocyte proliferation, cytokines release, metenkephalin release and other immuno-opioids release, stimulates phagocytosis and it has anti-apoptotic effects including glucocorticoid antagonism. Thus, melatonin regulates positively immune responses and negatively inflammation [25]. Oncostatic effects- certain onco static effects of melatonin have been demonstrated in studies on cells cultures (malignant cells and/or breast tumors and prostate tumors) and in vivo studies on pineal atomised animals, after inducing cancer with different chemical substances or on viral pathwat. Melatonin has antimitotic action by direct effect on hormone-dependent proliferation, interacting with nucleal receptors [19]. It diminishes estrogen receptors express [10] and it inhibits aromatase, enzime involved in estradiol production [31]. It affects the cellular cycle control and incraeses tumor suppressor gene p53. It has antiangiogenic activity [31]. Several clinical studies suggest that melatonin, alone or in association with the standard treatment has a favourable response in treating human cancer. It was also noticed that melatonin suppresses linoleic acid capture by mchanism depending on MT1/MT2 receptors [19]. It inhibited in vivo mutagenesis and clastogenic effects of several chemical substances mutagenic indirectly [1]. In Northen countries, indigenous populations suffer less from breast and prostate cancer. The darkness during winter seems to protect. Assumed increased levels of melatonin created the “melatonin assumption”. Epidemiological studies support this assumption [24]. In workers who work at night, night levels of melatonin are lower. Case studies and the prospective cohort ones associate constantly labour in the night shift with the increased of breast cancer and, more recently, with endometrial cancer, another type of cancer very sensitive to estrogens [31]. Effects on the glucidic metabolism: effects of melatonin on insulin secretion are mediated by MT1 and MT2 receptors which inhibit adenylyl cyclase/AMPc. Insulin secretion has a circadian rhythm being influenced by melatonin. Recent genomic studies revealed a tight connection between the mt2 receptor polymorphism and high risk of type 2 diabetes [21, 23]. Effects at the GI level- secretion is periodical, connected to ingestion and digestion of foods and by prevention of tissue damage caused by clorhidric acid and digestive enzymes. At the GI level, melatonin exerts an endorine, paracrine, autocrine and luminal action. Melatonin administration can prevent or treat pathologies such as esophageal and gastric cancer, pancreatitis, colitis, irritable colon syndrome, colon cancer [4, 5]. Effects at the skin level - the skin represents the main target organ of melatonin.Melatonin and its metabolites intervene in the skin and hair biology/pathology exerting damage at the skin level induced by pressure and heat. In our study, we have noticed that plasmatic levels of melatonin decrease with ageing. Exogenous melatonin substitution therapy can lead to partial normalisation of damage associated to old age at the skin architcture/functions [9]. Nowadays, it is more and more spread the idea of “chronic fatigue syndrome” caused by exposure to blue light before going to sleep which produces changes in the melatonin secretion [29, 30]. In our study, statistical processing of data shows that melatonin changes in “chronic fatigue syndrome” declared during anamnesis and supported by laboratory results is significant leading to the following conclusions: CONCLUSIONS Melatonin is synthetised especially in the pineal body having a special role in circadian regulation, in maintaining sleep in children with autism, in diminishing high blood pressure, in regulating reproductive function and stimulation of the immune response. We have noticed that in the „chronin fatigue syndrome” melatonin has drecreased values. CONFLICT OF INTERESTS: We declare that there is no conflict of interests regarding the publication of this study. 8

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STUDY REGARDING HOMOCISTEIN AS MARKER IN PATIENTS WITH STROKE Constantin Bălăeţ1, Mirela Radu2, Simona Vlaic3, Viorel Poalelungi4, Elena Rusu5 1

Lecturer PhD., Preclinic Department, Faculty of Medicine, Titu Maiorescu University, Gheorghe Petrascu Street, no. 67A, sector 3, Bucharest Romania 2 Assistant, Faculty of Medicine, Titu Maiorescu University, Gheorghe Petrascu Street, no. 67A, sector 3, Bucharest Romania 3 Alfred Rusescu Institute for Mother and Child’s Protection Bucharest 4 Floreasca Emergency Hospital 5 Lecturer PhD., Preclinic Department, Faculty of Medicine, Titu Maiorescu University, Gheorghe Petrascu Street, no. 67A, sector 3, Bucharest Romania *Corresponding author: Lecturer PhD. Constantin Balaet: [email protected]

Abstract Recently, there has been reported in the literature more and more the role of homocysteine in humain pathology. Our study proves that homocysteine has had high levels in blood in patients with recent stroke (1-5 days). High level of homocysteine in these patients marks severe prognosis. It is necessary to institute urgently an adequate treatment, its efficacy being proven by decreased levels of homocysteine. INTRODUCTION Several studies showed that hyperhomocysteinemia is usually associated with high risk of cardiovascular diseases, venous thrombosis, pregnancy complications, neural tube defects [1, 10, 15]. In our study, we are analysing homocysteine values, studied in blood and their importance to patients requiring emergency care with stroke diagnosis, regardless of their clinical status (mild or severe). PATIENTS AND METHODS For two years, according to a working protocol we have monitored patients requiring emergency care with recent stroke diagnosis [2,4,11]. The researched batchconsisted of 71 patients, aged 60-70, 20 women, 51 men with diagnosis: mild clinical stroke (30 patients), avrage clinical stroke (17 patients)and severe clinical stroke (24 patients). In all patients, apart from current blood tests (hemoleucogram, ESR, INR, bilirubin, GPT, SGT, HDL cholesterol, LDL cholesterol, triglycerides, creatinin, urine tests) homocysteinewas measured in blood, right after hospitalization [9]. The method is based on a series of enzymatic reactions. The sample was plasma, processed right after vacutainer centrifugation in which was sampled the simple blood on anticoagulant [8]. If centrifugation takes place immediately, the samples have to be processed immediately,if not, the vacutainer can be kept on ice. Hemolyzed or hyperlipemic plasma is not processed. After plasma separation, homocysteine is stable in room temperature for 4 days, for 4 days in 2-8 degrees Celsius and for 12 months in temperatures of -20 degrees C. Note that, if a whole sample of blood is kept in room temperature, the level of homocysteine can increase with 10% because it is synthetised by erythrocytes[14]. Reference values: after NIST: ≤ 15µmol/l, after CLIA ≤ 12µmol/l, in our laboratory ≤ 14µmol/l. The witness batch had the same structure on ages and sex and was represented by normal patients clinically and paraclinically, average value of homocysteinebeing11 µmol/l. RESULTS In all patients we obtained increased values of homocysteine: - In patients with mild clinical stroke (30 patients) average values of homocysteine were 16µmol/l; - In patients with avrage clinical stroke (17 patients) average values of homocysteine were 17µmol/l; - In patients with severe clinical stroke (24 patients) average values ofhomocysteine were 18µmol/l; 11

NOTE: Sampling blood to analyse homocysteine was performed within 1-5 days after stroke. After 6 weeks samples were taken to determine homocysteine, average values obtained in all three batches were 14.5 µmol/l. DISCUSSIONS Results regarding homocysteine dosage in patients’ blood with recent stroke (1-5 days) proved to have a variation between 1 and 4 µmol/l compared to the reference laboratory values. It is to be noticed that patients received a diet with adequate calories, received antihypertensive, antithrombotic symptomatic medication and especially therapy based on vitamins (vitamin B6, folic acid and vitamin B12 in perfusions) [6]. After 6 weeks of treatment, average values of homocysteine decreased in all patients reacing to be 14.5 µmol/l, close to our laboratory reference values; decreases in all three batches are proportional to the severity of the condition (in the batch with mild clinical stroke the values came back to normal after pathologic and vitamin treatment). In our study, we have noticed,by analysing values of homocysteine in different situations, from the starting point of strokes and along the treatment period-6 weeks, that this aminoacid (homocysteine) can be considered a marker of this pathology. Homocysteine is an aminoacid which contains a thiol group formed by methionine intracellular demethylation (alpha amino gama methylthio butyric). In plasma, homocysteine is found free in oxidized or disulphidic form, linked to proteins [13]. Homocysteine has two ways to be metabolised, a metabolic path is represented by transsulfuration to cysteine through cystatin synthetasis, enzymes which need vitamin B6 as cofactor (proving the need of vitamin B6 administration during the treatment). Another metabolic pathis remethylation to methionine in the presence of methylentetrahydrofolate reductase (MTHFR) and methionine synthesis in the presence of folic acid as an under layer for vitamin B12 as co-enzyme (proving the need of folic acid and vitamin B12 administration during the treatment) [7]. Therefore, we prove that the level of homocysteine in blood is inversely proportional with folate levels, vitamin B12, vitamin B6 and oxygen intake induced by these vitamins. Therefore, hyperhomocysteinemia (>14µmol/l) occurs when one of these ways of metabolisation is blocked, due to inadequate intake of folic acid, vitamin B12, vitamin B6 or an inadequate intake of all these at the digestive tract level [16]. In the literature, there is also a physiopathologic criterion of researching homocysteine and a certain severe hyperhomocysteinemia leading to homocysteinuria (in urine) induced by genetic defects most frequently by homozygous CBS deficiency with occurrence of 1 to 300,000 births [3]. These patients have mental retardation, arterial thromboembolism and precocious atherosclerosis [5]. The same manifestations are found in the case of methylenetetrahydrofolate reductase (MTHFR) deficiency. At the level of methylenetetrahydrofolate reductase (MTHFR) there is a mutation which generates a thermolabile enzymatic variant; patients who are heterozigot for this do not have hyperhomocysteinemia or increased risk for thrombosis while homozigotic ones can develop it [18]. In the literature, there are theories regarding the mechanism through which hyperhomocysteinemia increases the risk of atherosclerosis occurrence, probably dislipidemia and the sulfhydryl group becomes oxygenated which makes homocysteine to behave as a real free radica [12]. There are theories through which there is a justification for homocysteine increased level in blood and favouring of platelet adhesion, development of endothelial lesions especially in the „vasculo-sanguin” organ, alteration of fibrin affinity of lipids and lipoproteins, of smooth muscular cells proliferation and increase of oxygen reactive species, increasing the oxydative stree for the body. In our study, we have noticed that a well-managed treatment, including therapy with vitamins (B6, B12, folic adid) improved the patients’ status with stroke, fact proven by decrease of homocysteinemia which, probably, marks an improvement of endothelial function. It is often emphasised that homocysteine is involved in several pathologies: strokes – which was proven by our study as well, atherosclerosis, colon cancer, breast cancer, colopathies, senile dementia, depression, diabetes, heart attack, neuroasthenia, parkinson disease, thrombosis, sleep disorders, congenital malformations etc [16, 19,20].

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CONCLUSIONS Our study proves that homocysteine is a marker, an indicator of good health and a risk factor, as well, in strokes. Pathology related to homocysteine level in blood is a genetic one (very severe) and a nutritional one representing the patients’ way of living and diet. There occur and we propose new ways of approaching homocysteine in blood, especially as screening tests of certain groups of population with high risk for different forms of the condition, in which homocysteine is involved. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.

Eikelboom JW, et. Al. Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Intern Med 131:363-75.1999 EU-Dir 1999/11 Commission Directive of 8 March 1999 adapting to technical progress the principles of good laboratory practice as specified in Council Directive 87/18/EEC. Faure-Delanef et al. Am. J. Hum. Genet. 60: 999- 1001. 1997. Frances Fischbach. Chemistry Studies. In A Manual of Laboratory and Diagnostic Tests. Lippincott Williams & Wilkins, USA, 8 Ed., 436-438. 2009 Francesco Dentali, Mark Crowther, and Walter Ageno. Thrombophilic abnormalities, oral contraceptives, and risk of cerebral vein thrombosis: a meta-analysis. Blood, vol l07, 2766-2773. 2006 Guttormsen AB et al. J Nutr. 124(10):1934-41. 1994 H. Paunescu, I. Ghita, D. A. Coman, I. Fulga. Vitaminele ca factori protector cardiovasculari. Medicina Moderna, nr A, 2006. Laborator Synevo. Referintele specific tehnologiei de lucru utilizate.. Ref Type: Catalog. 2010 Laboratory Corporation of America. Directory of Services and Interpretive Guide. Homocysteine, Plasma. www.labcorp.com Ref Type: Internet Communication. 2010. McLean R. et al. Homocysteine as a Predictive Factor for Hip Fracture in Older Persons N. Engl. J. Med. 350: 2042-2049. 2004 NCCLS Document, "Procedures for the collection of arterial blood specimens", Appr. Std., 3rd Ed. 1999 Nygard O. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med. 337(4):230-6.1997 Popescu A., Cristea E., Zamfirescu-Gheorghiu M., BiochimieMedicală, Ed. Medicală, 1980. Refsum H. Clinical laboratory News May. 2-14. 2002 Scott J, Weir D. Homocyteine and cardiovascular diseases. Q J Med 89: 561- 3.1996 Seshadri S. et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N. Engl. J. Med. 346:477-483.2002 Vilaseca et al. Total Homocysteine in Pediatric Patients. Clin. Chem. 43: 690-692.1997 Willianne L.D.M. Nelen and Henk J. Blom. Pregnancy Complications. In MTHFR Polymorphisms and Disease. Edited by: Per MagneUeland, 2005. www.med.uiuc.edu. University of Illinois. Hematology Resource Page. Hyperhomocysteinemia. Ref Type: Internet Communication. www.synevo.ro/homocisteina/

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THE CURRENT PERSPECTIVES AND PRINCIPLES OF MODERN SURGICAL TREATMENT IN STRESS URINARY INCONTINENCE IN WOMEN *Bealcu Florentina Assistant Univ. Drd. Titu Maiorescu University, The Main Licensed Nurse, Center of Uronephrology and Renal Transplantation, Fundeni Clinical Institute, Bucharest, *Popescu Jessica Maria, Faculty of Medicine student,Titu Maiorescu University Abstract: The stress urinary incontinence (S.U.I.)-affects 16% of global population it's a public health problem, can be embarrassing and can affects the patient's self-confidence. Stress urinary incontinence can be detected at any age, specially elderly adults and it most commonly urinary incontinence case (I.U.) in women. The Fair Management assume an evaluation with tests and procedures (specific tests+urodynamic. Surgical treatment represents the alternative considered the highest chances of healing. The Alternative treatments available currently for stress urinary incontinence have just a partially effect; The autologous implant treatment investigated in this study (in progress) follows to treat the cause stress urinary incontinence ensuring a long-term effect. Stress urinary incontinence is treated with ''tissue engineering'': is harvested a biopsy from the patient's tissue seceding immature muscle cells-myoblasts; it is cultivate in specialized laboratories, are injected para-urethral between the muscular fibers and the colagen ones; There are 2 centres in Romania, the patient being distributed to the closest centre of her home. The described treatment aims to treat external urethral sphincter insufficiency, time ensuring a good result according to the existing studies Key words: stress urinary incontinence, urodynamic, tissue engineering, autologous implant; INTRODUCTION: The stress urinary incontinence (S.U.I )-affects 16% global population (10 million patients, and in U.S.A is spent annually 20 billions of dollars). It is a public health problem, can be embarrassing and can affect the patient's self-confidence. S.U.I can be detected at any age, specially elderly adults and it most commonly urinary incontinence case (I.U) in women. DEFINITION: Urinary incontinence( U.I)-the involuntary loss of urine The stress urinary incontinence (S.U.I) - the loss of urine assumed : the cough, the laught, physical exercise' other movements which rise intra-abdominal pressure, rising the pressure of the bladder too; S.U.I occurs in women ( men too ). It is characterized through function of the damaged sphincter urethral. This weakened, takes to a insufficient closing of urethra in abdominal pressure so the loss of urine. U.I mixted -S.U.I +Detrusorion hyperactivity(O.A.B) RISK FACTORS: -the cought -menopause (hormonal changes-the lack of the estrogen hormone) -smoking -obesity -natural birth (ex:multipare) -performance sport -constipation -respiratory disorders -radiation therapy -structural abnormalities of the urinary tract -subvezical lock The diseases that can produce urinary incontinence are: -chronic cough(smoking, chronic bronchitis) -diabetes mellitus -The Parkinson -The Alzheimer 14

-multiple sclerosis -superficial bladder cancer -spinal cord trauma (A.V.C) DIAGNOSIS -THE MAKING REAL OF SYMPTOMS: -properly run history -mictional calendars -clinic exam: It shall examine: the perineal area, cough, with the objectivity of the loss of urine -abdominal examination -valve exam -specific tests: the short test of the cotton ball ,the cough test in upright position, the loss of urine test -the Q type test: stricture hypermobility, Marshall/Bonney maneuver or Ulmsteen maneuver -calendar, log 7days; ingested fluids quantity, urination eliminated quantity, mictions number, the involuntar loss of urine -blood tests -urinalysis -uroculture -imaging examinations and urodynamic test (cistometers filler-for the determination of the bladder muscle ,of the detrassor) TREATMENT: A right treatment includes a real diagnosis of the incontinence type; As a first intention, before abording the invassive, are tried: behavioral methods, Kegel exercises, medication THE STRESS URINARY INCONTINENCE MANAGEMENT: 1. Lyquids management: - lyquids moderate consumation - elimination for ever of :drinks with caffeine,alcohol ,carbonated 2. Reeducation of the bladder: Mictional journal (going point) - allows the obiectivity : liquids, mictions ,the moments and conditions of loss of urine, programed urine ,at one or two hours every moment in the day; 3. Protection systems: urethral valves, pesare 4. Pelvic muscle reeducation: - pelvic floor exercises (Kegel) - toning perineale muscle and external urinary sphincter through kineo, biofeedback and electro-magnetic stimulation; 5. Drug treatment: - Pseudoefedrina, Imipramina-rise the smooth muscles of the urinary sphincter - Duloxetina-the last drug appeared in S.U.I - Oxibutin, Tolterodine, Diciclomine -relax the bladder and rise bladder capacity 6. Minimally invasive surgical treatment: - It has the highest success rate in S.U.I - Requires a very short period of postoperative recovery - It is more expensive, but the benefits are as - Increase urethral resistance==>prevent loss of urine - Micro-balonate of silicon containing saline - Bandelete T.V.T and T.O.T inferior the bladder place a ''hairpiece'', which mentain the other one like a hammock assuring it/him a normal position 7. Other therapeutic methods: - Static pelvic defects (cistocel, rectocel, prolaps uterin) - Injections of pelvic static parauretrale(colagen, teflon, macroplastic) - The implant with its own muscle tissue 8. Autologous implant: - The treatment investigated in this study( still loading ) , follows to treat the cause of S.U.I ,ensuring a long time effect - S.U.I treated through tissular enginering - Take a biopsy of the patient's tissue and separate immature muscle cells-myoblasts - Grown in the laboratory specialty - are injected para-urethral ,among muscle fibers of collagen and existing - there are 2 centres in Romania, the patient being distributed to the closest centre of her home. 9. Mioblasth therapy procedures: (Muscular Byopshy): 15

- It explains the patient's maneuvers are made - Prepares equipment and surgical instruments - The patient sits in the dorsal position, with the extension arm; - Desinfected with betadine - Perform local anesthesia with xilin 1% - Perform an incision 2 cm long,take 1-2 pieces of muscle tissue - Suture with absorbable threads Vicryl 0 Vicryl 3/0 - Placing the sample in a special container with Fixer - local dressing - procedure takes 15-20 minutes - if you need take some drugs for pain - get out of hospital the same day - avoiding sport ( 1-2 weeks) - local ice - hospitalization for a day

Fig. 1- Injection of cells – autologous implant; Collection Uronefrologie and Renal Transplantation Center, CI Fundeni Bucharest 10. Injecting cells - General anesthesia with laryngeal mask - The patient sits in the gynecological position - Pubic hair is removed' - Desinfected with betadine - Fill the bladder with saline syringe using Guyon (100 ml) and a uretro vesical semple - Wiggles with sterile Gynecologic field - Through the use of ultrasound, a special device will be routed through the urethra for detection of external urethral sphincter - At this level, inject the patient's allocated solution-2 levels of administration - Duration of procedure: 15'-20 'up to 30' - Final leaned a hairpiece pessaries, which will take off with the first urination - The patient shall be checking out the next morning and it is recommended that periodic checks CONCLUSIONS: Urinary Incontinence of effort represents a public health problem,can have profound impact on patient quality of life: - Correct Management requires an assessment with tests and procedures (specific tests + urodynamic) - Surgical treatment is considered the alternative with the highest chance of healing -Alternative Treatments currently available for urinary incontinence of effort have only a partial effect -The treatment described aims to treat the external urethral sphincter insufficiency, ensuring over time according to existing studies, a good result.

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REFERENCES • Chibelean C, Surcel C, Cerempei V, Postolache E, Iliescu L, Sinescu I. - IVS – procedură tip TVT în tratamentul incontinenţei urinare de efort – optimizarea rezultatelor utilizând datele clinice şi urodinamice. Revista Română de Urologie, 2005, vol.4, nr.1, p.9-14, ISSN: 1223-0650 • Sinescu I., Glück G., Chibelean C.. Surcel C, Vezica hiperactivă ,Tratat de Urologie, vol. IV, cap 41,pag.2921-2938), Vol. IV - ISBN: 978-973-39-0655-1 / 978-973-39-0659-9 • Sinescu I., Glück G., Surcel C. Examenul clinic al aparatului urogenital, Tratat de Urologie Vol. I, cap3, pag.115-138, Editura Medicală, Bucureşti 2008,- ISBN: 978-973-39-0655-1 / 978-973-39-0656-8 • Surcel C, Chibelean C, Mirvald C, Gîngu C, Sinescu I. Epidemiologia incontinenţei urinare în România - studiul OMNIBUS. Revista Română de Urologie, serie noua, vol.1, 2009.ISSN: 1223-0650 • Surcel C., Cerempei V., Postolache E., Chibelean C., Iliescu L.and Sinescu I.. Avoiding tape erosionafter TVT and TVT-like – Small detail, good results. European Urology Meetings, nr.33, vol.1, nr.1,ISSN: 1872-7174.Al IV-lea Congres Central European, Bucureşti, 2004.

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MULTIRESISTANT TO ANTIBIOTICS OF S. TYPHIMURIUM STRAINS PRODUCING EXTENDED SPECTRUM BETA-LACTAMASES (ESBLs) Lecturer PhD COCULESCU Bogdan-Ioan1, CS III biol. PhD student PALADE Andi-Marian2, Associate Professor PhD COJOCARU Manole1 1 Preclinic Department, Faculty of Medicine, “Titu Maiorescu” University Bucharest 2 National Institute for Research and Development in Microbiology and Immunology "Cantacuzino" Bucharest Abstract Introduction Gastrointestinal infections caused by gram-negative amounts ESBL-producing special problems in medical practice by decreased sensitivity to antibiotics due to the acquisition of various ways of achieving strength, including the production of ESBL. Appropriate use of antimicrobial therapy in cases of antibiotic-resistant enteric pathogenic strains each isolated and its correlation with acute diarrheal disease progression, namely food poisoning is mandatory. Materials and methods We have studied 54 strains of Salmonella sent for further investigation to NIRDMI "Cantacuzino" Bucharest. Antibiotic sensitivity was tested by disc diffusion antibiogram method (Kirby -Bauer), according to CLSI recommendations 2009. Results and Discussion Statistical analysis was based on the interpretation pathogen susceptibility and analyzed according to CLSI 2009 revealed that of the 54 strains of Salmonella tested antibiotic of 8 (14,81%) identified as S. enterica serovar Typhimurium group presented phenomenon of multiresistant to antibiotics (MDR), which while being resistant to beta-lactams, aminoglycosides, quinolones (nalidixic ac.), tetracycline and sulfonamides. Conclusions S. Typhimurium strains producing ESBL showed resistance mechanisms associated with beta-lactam resistance to aminoglycosides, quinolones, sulfonamides and tetracyclines. In this context, the increasing prevalence of Salmonella enterica serovar Typhimurium strains resistant to antibiotics, and mainly those resistant betalactams is worrying for the treatment of human salmonellosis. Introduction Gastrointestinal infections caused by gram-negative amounts ESBL-producing special problems in medical practice by decreased sensitivity to antibiotics due to the acquisition of various ways of achieving strength, including the production of ESBL. Given that intestinal infections themselves are a public health problem, etiological involvement of microorganisms resistant to antibiotics increases their severity. Continue monitoring the emergence and spread of strains producing extended-spectrum beta-lactamases (ESBLs) is one of the major objectives of health programs that address infectious disease control. The purpose of the study Given the rising incidence of Salmonellosis and continuous decrease of sensitivity Salmonella to a range of antibiotics, the prime importance of the choice of optimal anti-infective chemotherapy in order to prevent the selection of multidrug-resistant strains (MDR). Appropriate use of antimicrobial therapy in cases of antibiotic-resistant enteric pathogenic strains each isolated and its correlation with acute diarrheal disease progression, namely food poisoning is mandatory. Materials and methods We have studied 54 strains of Salmonella sent for further investigation to NIRDMI "Cantacuzino" Bucharest. Antibiotic susceptibility testing Antibiotic sensitivity was tested by disc diffusion antibiogram method (Kirby -Bauer), by plating each inoculum on Mueller- Hinton medium according to CLSI recommendations 2009 (Clinical and Laboratory Standards Institute) using microtablets supplied by Oxoid Ltd. (Basingstoke, UK) or Mast Diagnostics (Bootle, UK) using an inoculum of 0,5 McFarland turbidity. E. coli ATCC 25922 and E. coli ATCC 35218 (for combinations of β 18

lactam beta- lactamase inhibitor) were used as control strains of pathogen susceptibility performed (ref. no. 0335P, MicroBioLogics). The following antibiotics were tested: Ampicillin (10 mg), Amoxicillin (10 mg), Amoxicillin/Clavulanic acid (20/10 mg), Cefoxitin (30 mg), Cefotaxime (30 mg), Ceftazidime (30 mg), Imipenem (10 mg), Nalidixic acid (30 mg), Ciprofloxacin (5 mg ), Gentamicin (10 mg), Kanamycin (30 mg), Streptomycin (10 mg), Sulfonamide/Sulfadiazine (300 mg), Trimethoprim (5 mg), Cotrimoxazole (Trimethoprim 1,25/Sulfamethoxazole 23,75 mg), Tetracycline (30 mg), Chloramphenicol (30 mg). Phenotype test for the confirmation of beta-lactam production - DDST (double disk synergy test). Identification producing extended-spectrum beta-lactamase (ESBL) was performed using the double disc (Jarlier et all., 1988). Phenotypic confirmation of S. serovar Typhimurium strains producing ESBLs suspected was achieved by simultaneous testing by Kirby-Bauer disc diffusion method, the synergy between ceftazidime discs, disc cefotaxime and amoxicillin with clavulanic acid. We used Oxoid discs containing combination amoxicillin/clavulanic acid (20 μg/10 mg), ceftazidime (30 mg) and cefotaxime (30 mg), placed at a distance of 2 cm (measured between centers disks) on Mueller-Hinton medium. Plates were incubated for 18-20 hours at 37°C. Results and Discussion Prevalence of Salmonella strains studied is the Enteridis serotypes (51,85%) and Typhimurium (27,78%) - see table no. 1. Table no. 1. Prevalence of enteropathogenic strains of Salmonella serovar group after characterization. Species

Group

Serovar

S. enterica

D1

Enteritidis

28

S. enterica

B

Typhimurium

15

S. enterica

B

Agona

7

Saintpaul

4

S. enterica B ADD = Acute Diarrheal Disease FBD = Foodborne Desease

No strains

Source of isolation 21 ADD 7 FBD 12 ADD 3 FBD 7 ADD (isolated) 3 ADD (isolated) 1 FBD

Percent (%) 51,85 27,78 12,96 7,41

Statistical analysis was based on the interpretation pathogen susceptibility and analyzed according to CLSI 2009 revealed that of the 54 strains of Salmonella tested antibiotic of 8 (14,81%) identified as S. enterica serovar Typhimurium group presented phenomenon of multiresistant to antibiotics (MDR), which while being resistant to beta-lactams, aminoglycosides, quinolones (nalidixic ac.), tetracycline and sulfonamides. High rates of resistance (> 70%) were recorded to ampicillin, cefotaxime, ceftazidime, gentamicin, kanamycin and streptomycin, sulfonamide, trimethoprim, respectively nalidixic acid. The highest level of resistance to tetracycline was obtained (87,5%). Instead, he showed a sensitivity of 100% to cefoxitin, imipenem, and ciprofloxacin. Only 25% of the strains were sensitive to semi-synthetic penicillins and cephalosporins (3rd generation). In addition, a number of 7 strains showed resistance to chloramphenicol (87,5%). The same eight strains were resistant to amoxicillin + clavulanic acid, showing on one side of the substrate specificity of beta-lactamases and, on the other hand, the possible adaptation of S. typhimurium in clavulanic acid (a beta-lactamase inhibitor remains active the ESBLs therefore will enhance the action of cephalosporins). Antimicrobial test results by the method of double diffusion synergy test showed that the 8 strains tested produced beta-lactamase. Strains belonging to this phenotype (ESBLs) were characterized by cross-resistance to most beta-lactam tested. All 8 strains showed ESBLs phenotype associated with phenotypes of resistance to aminoglycosides, cotrimoxazole and tetracycline, and of these, seven showed ESBLs phenotype associated with chloramphenicol resistance phenotype. Conclusions This indicative study on the characterization of antibiotic resistance by phenotypic methods strains of S. Typhimurium identified as producing beta-lactamases showed that: 19

• All isolates were resistant to amoxicillin/clavulanic acid and ceftazidime. Not identified any strain sensitive to these antibiotics. Carbapenems (imipenem) are beta-lactam antibiotics that were susceptible to all strains of S. Typhimurium producing ESBLs (100% of cases). Similarly, there was no resistant strains isolated cefamicine (cefoxitim). • Most active quinolone antibiotic ciprofloxacin proved, all 8 strains of S. Typhimurium tested showing sensitivity. All of these antimicrobials may be used as antibiotics of choice in the gastrointestinal infections caused by Salmonella serovar Typhimurium. • In contrast, a high percentage of isolates showed resistance to tetracycline (87,5%), ampicillin, cefotaxime, gentamicin, kanamycin, streptomycin, sulfonamide, trimethoprim or nalidixic acid (the same percentage, 75%). • In addition, the study phenotypes of acquired resistance to anti-infectives chemotherapies revealed that a 100% strains (8 of 8 selected) of S. Typhimurium showed ESBL-producing multidrug-resistant phenomenon at medication (MDR) as diffusion antibiogram. Multiresistant to antibiotics of strains producing ESBLs was defined by the presence of concomitant resistance to aminoglycosides, fluoroquinolones and sulfamethoxazoletrimethoprim. • S. Typhimurium strains producing ESBL showed resistance mechanisms associated with beta-lactam resistance to aminoglycosides, quinolones, sulfonamides and tetracyclines. • In this context, the increasing prevalence of Salmonella enterica serovar Typhimurium strains resistant to antibiotics, and mainly those resistant betalactams is worrying for the treatment of human salmonellosis. Bibliography 1. Arjyal A., Basnyat B., Koirala S. et al., Gatifloxacin versus chloramphenicol for uncomplicated enteric fever: an open-label, randomised, controlled trial, Lancet Infect Dis, 2011; 11:445-454. 2. Baucheron S., Le Hello S., Doublet B., Giraud E., Weill F-X, Cloeckaert A., ramRmutations affecting fluoroquinolone susceptibility in epidemic multidrug-resistant Salmonella enterica serovar Kentucky ST198, Front. Microbiol., 2013; 4:213, doi: 10.3389/fmicb.2013.00213. 3. Clinical and Laboratory Standards Institute (CLSI), Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard -Tenth Edition (M02-A10), and Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard - Eighth Edition (M07-A8), 2009. 4. Koirala J., Multidrug-resistant Salmonella enterica, The Lancet Infectious Diseases, 2011, 11 (11):808 – 809. 5. Nagshetty K., Channappa S.T., Gaddad S.M., Antimicrobial susceptibility of Salmonella Typhi in India, J Infect Dev Ctries., 2010; 4 (2):070-073.

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EXPERIMENTAL AND THEORETICAL EVALUATION OF VSB POSITIONING AT THE INCUS *Mocanu Horia, †Bornitz Matthias, †Lasurashvili Niokoloz, †Zahnert Thomas †Department of Medicine, Clinic of Otorhinolaryngology, Technische Universität Dresden, Germany *Faculty of Medicine, Department of Otorhinolaryngology, Titu Maiorescu University Bucharest, Romania ABSTRACT: The Vibrant Soundbridge (VSB) is an implantable hearing aid whose floating mass transducer (FMT) is attached to the long process of the incus if the device is used for pure sensorineural hearing loss with an intact middle ear. Variations of attachment may occur. Knowing of the impact of such variations on the overall device performance may guide towards optimal transducer attachment during surgery. INTRODUCTION: Implantable hearing aids, initially developed against sensorineural hearing loss, are recently becoming more important with the extension of indication towards mixed hearing loss. This might also revive the application for pure sensorineural hearing loss. Advantages of implantable hearing aids against conventional ones are: no ear canal closure, higher possible gain at the high frequency range and no visible parts (in case of totally implantable systems)1. The Vibrant Sound Bridge is an implantable middle ear hearing device to treat sensoneurinal hearing loss which involves damage to the inner ear (aging, pre-natal and birth-related problems, viral and bacterial infection, heredity, trauma, exposure to loud noise, fluid backup, benign tumor of the inner ear) and represents 60% of all hearing loss. In the case of a VSB, defining the optimal position for transducer attachment during surgery could mean optimisation of functional results. The VSB directly drives the ossicular chain, bypassing the ear canal and tympanic membrane. MATERIAL AND METHODS: Investigations were performed by help of a Finite Element (FE) Model of the middle ear which consists of the ear canal (acoustic fluid with matched impedance at the canal entrance to the surrounding air), the eardrum (orthotrop-elastic shell with constant damping ratio), the ossicles (rigid bodies with mass and inertia properties), ligaments (elastic bars), joints (elastic bodies with constant damping ratio) and a spring-mass-damper model of the cochlea1 (Fig.1,2,3). We investigated the VSB connected to the long process of the incus in 3 different conditions: • FMT vibrating freely in the middle ear in direction of the longitudinal stapes axis, without contact to the stapes. • FMT in contact to the stapes suprastructure, vibrating in direction of the longitudinal stapes axis. • FMT in contact to the stapes suprastructure, vibrating in a direction of 45-60 degree off the longitudinal stapes axis. The 3 situations were investigated experimentally on temporal bone specimen and theoretically by means of a Finite Element simulation model of the middle ear. The displacement of the stapes footplate was measured using LDV and calculated with the simulation model. The Polytec LDV (OFV-302 sensor head, OFV-3000 vibrometer controller; Polytec PI, Waldborn, Germany) is mounted onto a Zeiss microscope (Zeiss Co., Jena, Germany) and is used to focus a helium-neon laser on the target (squares of foil of 0.5 mm2 with reflective polystyrene microbeads). The sound generator (insert earphone, eartone 3A) was inserted into the ear canal and the probe microphone (ER7c; Ethymotic Research Inc., IL, USA) positioned through an extra opening in the external ear canal next to the eardrum for reference measurements2. We compared the results obtained from these measurements and simulations in order to determine the influence of variations of coupling of the FMT.

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Fig.1

Fig.2

Fig.3

RESULTS: The measurements on human temporal bones, as shown in Fig.4, 5 and 6 for each of the studied positions, yielded a graphic representation depicted for comparison in Fig.7.

Fig.4

Fig.5

Fig.6

Fig.7 The FEM experiments for FMT coupling with contact to the stapes parallel to it’s long axis and tilted at a 15°, respectively 45° angle showed the similar changes in METF to those obtained on temporal bone. (Fig.8,9)

Fig.8

Fig.9

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CONCLUSIONS: Experimental investigations and simulations with the model yield the same main results. The first fitting situation, the FMT floating freely in the middle ear provides by far the worst possible results. Contact to the stapes suprastructure of the FMT is necessary for optimal performance of the FMT. Tilting the FMT off the longitudinal axis of the stapes reduces the vibration of the stapes footplate. But this reduction is less than for the first situation of the freely floating FMT.

REFERENCES: 1. BORNITZ, M. et.al.: Evaluation of implantable actuators by means of middle ear simulation model. Hear.Res. 2010; 263, 145-51. 2. NEUDERT, M. et.al.: Partial ossicular reconstruction: Comparison of three different prostheses in clinical and experimental studies. Otol.Neurotol. 2009; 30: 332-38. Fig. 1,2,3 - Schematic representation of the FEM. Fig. 4,5,6 – Positioning of the FMT (3 different positions) in regard to the stapes structure during the temporal bone experiments. Fig.7 – Change in transfer function when direction of excitation changes from no contact to the stapes to 0° and 45°60° (on temporal bone). Fig.8,9 - Change in transfer function when direction of excitation changes to 15° and 45° (on FEM).

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A CASE OF TRACHEO-OESOPHAGEAL FISTULA CAUSED BY LONG TERM IPPV Mocanu Horia Titu Maiorescu University, Faculty of Medicine – Bucharest, Romania Ilfov County Clinical Emergency Hospital, E.N.T. Department – Bucharest, Romania ABSTRACT: Non-malignant tracheo-oesophageal fistula (TEF) after Intermittent Positive Pressure Ventilation (IPPV) treatment is a rare entity with an incidence of 0,5% of all cases. The classical presentation is swallow-cough sequence (Ono’s sign), although not present in all cases. Artificial ventilation through a tracheotomy tube with inflated cuff is effective in prolonging the life of critical patients but can also create complications. To maintain an airtight fit between the cuff and the trachea, the cuff inflation pressure must exceed the pressure required for adequate inflation of the lungs (usually 3050 cm.H20) which exceeds the capillary pressure.1 Our case report, a 58 year female patient with chronic respiratory insufficiency and acuteG (-) pneumonia depicts a totally atypical evolution. INTRODUCTION: A tracheo-oesophageal fistula (TEF) represents an abnormal connection between the trachea and the oesophagus via which air can pass into the stomach or gastric content can pass into the airways and lungs. It can often lead to severe and fatal pulmonary complications.3 This pathology can be congenital or acquired.4 TEF occurring after the institution of tracheostomy and intermittent positive pressure ventilation (IPPV) can, in turn, be classified under three headings: traumatic (accidental), surgical (iatrogenic) and ulcerative.4 This paper is concerned solely with ulcerative fistulae. The large majority of the fistulae occur at the level of the inflated cuff. Relative to the lower margins of the tracheal stoma, the sites vary from just below the stoma to 4-5 cm. below the stoma. Most are located at 1-3 cm. below the stoma, just under the upper margin of the manubrium sterni or about half way between the cricoid cartilage and the carina, the site at which cuff stenosis occur. The size of a TEF greatly varies and tends to be underestimated at endoscopy. Associated lesions caused by tracheostomy and IPPV are tracheal stenosis and perforation of the innominate artery. Ulcerative TEF caused by tracheotomy and assisted ventilation occurs at the site of the cuff or tip of the tracheostomy tube, usually the former, and their aetiology is the same as that of tracheal stenosis occurring at these sites. Damage to the trachea is initiated mechanically by pressure and movement of the inflated cuff or tip of the tracheostomy tube and is aggravated by the infection which inevitably follows ulceration of the mucosa. The importance of the infection cannot be over-emphasized. Other factors such as chemical irritation, hypotension and anti-inflammatory agents (steroids) may further add to the damage. If ulceration extends through the whole thickness of the membranous wall of the trachea before a fibrotic reaction leading to stenosis has had time to occur, then a TEF may result. In regard to the mechanism of oesophageal damage, opinions vary. Some authors consider that a fistula is caused by a ulceration of the trachea spreading into the oesophagus; however other authors consider the oesophagus as the initiating site of a fistula (decubitus ulcers occur in tracheotomized patients, sometimes near the upper end of the oesophagus). 2, 5, 6 Once the membranous wall of the trachea yields and ulcerates, the anterior wall of the oesophagus become vulnerable to compression between the cuff or tip of the tube and the vertebral column, to the shearing stress of the movements of deglutition or of the tracheostomy tube, to infection and to the other factors previously enumerated. The inflammatory reaction welds the trachea and oesophagus together so that ulceration can spread from the former to the latter without diffuse mediastinitis or pneumomediastinitis. 2 Most authors consider the inflated cuff as the main injury factor although some believe the tip of the tracheostomy tube to be the principal cause. The inflated cuff may distend the membranous wall of the trachea into a sac, like a diverticulum, in which it fits. If chronic irritation and infection weld the trachea and oesophagus together, the end of the tracheostomy tube, or of an aspirating catheter, may damage or perforate the lower margin of the “diverticulum”. (Fig.1&2) In conclusion, the initiating factor is the ischemia and pressure caused by the cuff, followed by repeated trauma from the end of the tracheostomy tube and aspirating catheters. Other factors may be considered as very important in leading to oesophageal damage. Resident nasogastric tubes which are frequently used for feeding patients treated by assisted ventilation, especially if they are large and hard, may compress, together with a tracheotomy tube, the walls of the trachea and oesophagus for long periods of time. Care should be taken to select the smallest and softest tubes consistent with adequate function. Fragility of the tissues is thought to be of aetiological importance, especially by French authors. 4 24

Fig.1

Fig.2

MATHERIAL AND METHODS: B.E. a 58 year old female patient suffering from Chronic Obstructive Pulmonary Disease under treatment with Long-term Oxygen Use at home was admitted on January 6th 2012 in the I.C.U. of the Ilfov County Clinical Emergency Hospital with Gram (-) Pneumonia, Acute Respiratory Insufficiency and Respiratory Encephalopathy. The patient also suffered from numerous chronic afflictions such as: Ischemic coronary heart disease, Aorto-coronary by-pass, Unbalanced diabetes, Hypertension risk group C, Third degree obesity, Chronic depression. The patient was immediately connected to the ventilator via oro-tracheal intubation and treated with multiple antibiotics. During the next ten days the patient remained connected to IPPV but several attempts to disconnect her were made. Every time she had to be re-intubated, at times under precipitated emergency conditions which we suspect was the traumatic factor that created a fistula at the site of the inflated cuff where the walls were already ischemic and necrotic. On January 15th a permanent tracheostomy was performed. After the operation the patient could not be ventilated via the normal-size tracheotomy tube, which at the time should have been considered a clue to the problem. Therefore a longer, oro-tracheal tube was inserted into the tracheostoma. The post-operative evolution of the patient was apparently positive, with good general status, spontaneous breathing and normal alimentation. No gastric reflux through the tracheostomy or Ono’s sign were documented. On January 26th during the usual change of the ventilation tube, the patient went into acute respiratory distress with bronchospasm. This event raised the question of a possible tracheo-oesophageal fistula although all the classical signs were not present. A bronchoscopy from February 2nd revealed a larynx with maintained dynamics, oedema and granulation tissue above the tracheostomy tube, a small fragment of necrotic tracheal cartilage that was extracted and a large TEF of approximately 1,5-2 cm./ 6-7 mm. located 4 cm. above the carena. On February 7th, one month after admission, the patient was discharged with a good general status, hemodynamically stable, with spontaneous breathing through the ventilation tube and intermittent use of oxygen, in order to be admitted by the Surgical Department to be fitted with a gastrostoma and consequently transferred to the Thoracic Surgery Department for surgical treatment of the TEF. CONCLUSIONS: The case we reported was especially difficult to diagnose since the patient showed no typical signs of TEF, no regurgitation through the tracheostoma or swallow-cough sequence. The only clue we had were the extremely high ventilation volumes required when ventilating through the normal-sized tracheostoma tube. The longer, orotracheal tube surpassed the site of the TEF an encountered resistance no longer. In other aspects, the evolution of the case was text book. A chronic respiratory insufficiency patient that required long-term assisted ventilation; the pressure exerted by the cuff on the trachea walls and the repeated and probably violent attempts of intubation caused the TEF as described before. Ulcerative tracheo-oesophageal fistula during treatment by IPPV is a rare entity (0,5%). To maintain an airtight fit between the cuff and the trachea, the cuff inflation pressure must exceed the pressure required for adequate inflation of the lungs (usually 30-50 cm.H20) which exceeds the capillary pressure.2 If ischemic damage to the trachea is to be avoided, circulation of blood in the mucosa and submucosa must not be impeded for more that brief intervals. The inflation of the cuff must be just enough to make an airtight seal but not cause mucosal ischemia. Prevention of such fistulae includes: use of minimal occlusion volume, avoiding frequent deflation, using thin walled cuffs of suitable size and shape, avoiding movement of the tracheotomy tube and omitting assisted ventilation as soon as possible. The classical presentation is swallow-cough sequence or hallmark (Ono’s sign). Although spontaneous healing has been reported, direct surgical repair should be the procedure of choice. In the last decades, mortality has been greatly reduced thanks to improved surgical techniques but it is still dramatically influenced by the co morbidities of IPPV patients. 25

Being a benign disease with fatal complications, early diagnosis and early surgical intervention are the key to successful management of ulcerative tracheo-oesophageal fistulae. REFERENCES: 1.FLEGE, J.B.JR.: Tracheoesophageal Fistula Caused by Cuffed Tracheostomy Tub. Annals of Surgery 1967; 153-56. 2.HARLEY H.R.S.: Ulcerative trachea-oesophageal fistula during treatment by tracheostomy and intermittent positive pressure ventilation. Thorax 1972; 27: 338- 52. 3.http://emedicine.medscape.com/article/186735-overview 4.MOCANU, H. et.al.: Non-Malignant Tracheo-Oesophageal Fistula Caused By Tracheostomy Tube During Long Term Intermittent Positive Pressure Ventilation, The International Conference Education and Creativity for a Knowledge– based Society – Medicine And Dental Medicine, Osterreichish Rumanischer Akademischer Verein, 2012; 186-92. 5.NICOLAS, F. et al.: Fistules trachea-oesophagienne après tracheotomie. A propos de trois observations. Ann.Chir.Thorac.Cardiovasc. 1967;6:1159. 6.TOTY, L. et al.: Cinq cas de fistules tracheo-oesophagiennes après tracheotomie. Ann.Chir. Thorac. Cardiovasc. 1967 :1155, Fig. 1 - Distension of trachea by inflated cuff to form a diverticulum adherent to the oesophagus; the tip of the tracheotomy tube may damage the TEF.2, 6 Fig. 2 – Damage to lower margin of diverticulum and oesophagus by aspiration cannula. 2, 6

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INCIDENCE AND ANTIBIOTIC DRUGS RESISTANCE OF SOME BACTERIA SPECIES IN URINARY TRACT INFECTIONS Rusu Elena1, Epuran Silviu2, Cojocaru Manole3 Lecturer PhD., Preclinic Department, Faculty of Medicine, Titu Maiorescu University, Gheorghe Petrascu Street, no. 67A, sector 3, Bucharest Romania 2 Assistant, Preclinic Department, Faculty of Medicine, Titu Maiorescu University, Gheorghe Petrascu Street, no. 67A, sector 3, Bucharest Romania 3 Associate Professor PhD., Preclinic Department, Faculty of Medicine, Titu Maiorescu University, Gheorghe Petrascu Street, no. 67A, sector 3, Bucharest Romania *Corresponding author: Lecturer PhD. Rusu Elena: [email protected] 1

ABSTRACT The aim of our study was to determine the urinary infection incidence caused by different microbial species and the sensitivity to the different antibiotics classes. We observed a lot of 638 patients which were hospitalized in Gerota Hospital from Bucharest during six weeks for different pathologies (gastroenteritis, cardiovascular disease, pneumonitis, and urinary tract infections). From the total number of patients, 100 were done positive for urinary tract infections. The predominant species was E. coli (65%) followed by Enterococcus species (15%), Proteus species (10%), Enterobacter species (6%), Pseudomonas aeruginosa (3%) and Staphylococcus aureus (1%). The incidence E. coli species was 57% for women and 23% for men. Six strains were susceptibility only to imipenen and resistant to all antibiotics used (four E. coli strains and two Enterobacter strains). Five of these were from men and one from a woman. Incidence of antibiotic drugs resistance was 45% for gentamicin, 43% for cefaclor, 43% for tetracycline, 21.5% for ciprofloxacin, and 26% for amoxicillin and clavulanic acid for E. coli strains. Most of identified strains belong to Escherichia coli species and have a great resistance to antibiotic drugs. Keywords: E. coli, Antibiotics, Resistance INTRODUCTION Although the spread of pathogens has been hindered by the discovery and widespread use of antimicrobial agents, antimicrobial resistance has increased globally. The emergence of resistant bacteria has accelerated in recent years, mainly as a result of increased selective pressure. E. coli and other commensally intestinal flora of mammals often form a beneficial symbiotic relationship with their host, providing nutrients, key signals for developmental and immune regulation, and protection against foreign pathogens [1]. Antibiotics currently represent the most commonly prescribed treatment for urinary tract infection, and patient who had suffer from recurrent infection, having three or more infections a year, may be prescribed antibiotics prophylactically. Antibiotic therapy may deleteriously affect patients commensally microbiota and lead to secondary infections post-treatment, such as vaginal yeast infection and gastrointestinal infection. It is being increasingly recognized that multiple drug resistance commensally bacteria in the gut of animals and humans are an important source of bacteria causing opportunistic infections or act as resistance gene reservoirs forming a source of spread to bacteria infecting humans [2]. The predominant pathogen species isolated from urine sample remain Escherichia coli which is also responsible for asymptomatic bacteriuria and for recurrent cystitis. The pathogens traditionally associated with urinary tract infection are changing many of their features, particularly because of antimicrobial resistance. The aim of our study was to determine the urinary infection incidence caused by different microbial species and the sensitivity to the different antibiotics classes. MATERIALS AND METHODS We observed a lot of 638 patients which were hospitalized in Gerota Hospital from Bucharest during six weeks for different pathologies (gastroenteritis, cardiovascular disease, pneumonitis, and urinary tract infections). They were under medical observation; urine culture and antimicrobial susceptibility tests for different antibiotics classes were done for positive cultures. A quantitative urine cultures were collected from all patients. Organisms present at ≥103 CFU/ml in a urine sample were identified by standard microbiological techniques. Antibiotic resistance test of all strains was determinate by using patterns of antimicrobial susceptibility (antibiogram).

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RESULTS From the total number of patients, 100 were done positive for urinary tract infections. The predominant species was E. coli (65%) followed by Enterococcus species (15%), Proteus species (10%), Enterobacter species (6%), Pseudomonas aeruginosa (3%) and Staphylococcus aureus (1%) (figure 1). The incidence E. coli species was 57% for women and 23% for men. Six strains were susceptibility only to imipenen and resistant to all antibiotics used (four E. coli strains and two Enterobacter strains). Five of these were from men and one from a woman. Incidence of antibiotic drugs resistance was 45% for gentamicin, 43% for cefaclor, 43% for tetracycline, 21.5% for ciprofloxacin, and 26% for amoxicillin and clavulanic acid for E. coli strains (figure 2).We observed one E. coli strain from a patient (75 years woman) which was resistant for all classes of antibiotic drugs used in this study. Figure 1. Number of uropathogens isolated for each age group

Figure 2. Incidence of antibiotic drugs resistance of isolated bacteria strains

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DISSCUTIONS Surveillance data show that resistance in E. coli is consistently highest for antimicrobial agents that have been in use the longest time in human medicine. A retrospective analysis of E. coli from urine specimens collected from patients during 1997–2007 showed an increasing resistance trend for ciprofloxacin, trimethoprim/sulfamethoxazole, and amoxicillin/clavulanic acid [3]. It is commonly accepted that patients with symptoms attributable to the urinary tract and who have a positive culture are most likely to benefit from antibiotics. The uropathogens isolated in this study were similar to those in other studies, however, significant changes were found with increasing age of the patients tested [4, 5]. Escherichia coli remains the most often isolated (65%) followed by Enterococcus species (15%) then by Proteus species (10%). These data confirm other studies that shown a higher incidence of E. coli species in urine cultures [6]. Another study found that previous prescribing of amoxicillin and trimethoprim for 7 days or more in general practices is associated with an increased risk of ampicillin and trimethoprim resistance in urinary tract infections in the following 3 months and that in the case of ampicillin a higher prescribed dose may reduce this risk [7]. The tetracyclines are a class of antibiotics discovered more than 50 years ago. They are relatively inexpensive drugs with a broad spectrum of activity. Consequently, they have been extensively used in the prophylaxis and therapy of human infections. The dramatic increase in the number of species and genera that have acquired tetracycline resistance since the 1950s has led to a reduction in the efficacy and use of current tetracycline therapy for many diseases [8]. Amoxicillin–clavulanic acid is one of the most consumed antimicrobial agents in many countries, principally for respiratory and urinary tract infections. Increased AMC resistance coincided with growing AMC consumption at the community level [9]. In urinary infections, previous treatment with AMC is a risk factor for the development of AMC resistance. CONCLUSIONS Our study showed incidence and antibiotic drugs resistance of bacterial strains in hospitalized patients. Most of these belong to Escherichia coli species and have a great resistance to antibiotic drugs. REFERENCES 1.1.Yan F, Polk DB. Commensal bacteria in the gut: learning who our friends are. Curr Opin Gastroenterol. 2004;20:565–571. 2.Hawkey PM, Jones AM. The changing epidemiology of resistance. J Antimicrob Chemother. 2009 Sep; 64 Suppl 1:i3-i10. 3.Blaettler L, Mertz D, Frei R, Elzi L, Widmer AF, Battegay M, Secular trend and risk factors for antimicrobial resistance in Escherichia coli isolates in Switzerland 1997–2007. Infection. 2009;37:534–9. 4.Gupta K, Hooton TM, Stamm WE. Increasing antimicrobial resistance and the management of uncomplicated community-acquired urinary tract infections. Ann Intern Med 2001; 135: 41–50. 5.Arredondo-Garcia JL, Figueroa-Damian R, Rosas A et al. Comparison of short-term treatment regimen of ciprofloxacin versus long-term treatment regimens of trimethoprim/sulfamethoxazole or norfloxacin for uncomplicated lower urinary tract infections: a randomized, multicentre, open-label, prospective study. J Antimicrob Chemother 2004; 54: 840–3. 6.Ferjani A, Mkaddemi H, Tilouche S, Marzouk M, Hannechi N, Boughammoura L, Boukadida J. Epidemiological and bacteriological characteristics of uropathogen bacteria isolated in a pediatric environment. Arch Pediatr. 2011 Feb;18(2):230-4. Epidemiological and bacteriological characteristics of uropathogen bacteria isolated in a pediatric environment 7.Hillier S, Roberts Z, Dunstan F, Butler C, Howard A, Palmer S. Prior antibiotics and risk of antibioticresistant community-acquired urinary tract infection: a case-control study. J Antimicrob Chemother. 2007 Jul; 60(1):92-9. 8.Chopra I., Roberts M. Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol. Mol. Biol. Rev. 2001; 65, 232–260 9.Oteo J, Campos J, Lázaro E, Cuevas O, Garcia-Cobos S, Pérez-Vazquez M, et al. Increased amoxicillin-clavulanic acid resistance in Escherichia coli blood isolates, Spain. Emerg Infect Dis. 2008 Aug; 14 (8): 1259-62.

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PLACENTAL PATHOLOGY IN ANTIPHOSPHOLIPID SYNDROME Iulia SAVU, MD PhD Student, Dept. of Obstetrics-Gynecology, Life Memorial Hospital, Bucharest, Monica CIRSTOIU, Associate Professor MD PhD, UMF ”Carol Davila” Bucharest, Raluca TULIN, Assistant Lecturer MD PhD, UMF ”Carol Davila” Bucharest, Luminita CEAUSEL, MD, Dept. of Pathology, Filantropia Hospital, Bucharest, V.HORHOIANU, Professor MD PhD, UMF ”Carol Davila” Bucharest, M. TANASI, Associate Professor MD PhD, UTM Bucharest ABSTRACT Antiphospholipid antibody syndrome represents an aquired autoimmune thrombophilia, mediated by antibodies directed against plasmatic phospholipid binding proteins. The most notorious of these PL-binding proteins are beta2-glycoprotein I and prothrombin. This syndrome is a well-known cause of recurrent pregnancy loss. In pregnant patients the main target of antiphospholipid antibodiesis is the placental tissue. The most frequent histopathological microscopy findings in placentae from aPL antibody positive patients are thrombosis, acute atherosis, a decreased number of syncytio-vascular membranes, an increased number of syncytial knots and obliterative arteriopathy. The biological effects of these injuries on trophoblast culture are mediated by aPL antibodies. These antigen – autoantibody complexes inhibit the expression of human chorionic gonadotrophin in the throphoblast tissue, induce apoptosis, alter expression of cell adhesion molecules, decrease trophoblast fusion and limit trophoblast invasiveness. Therefore the mechanism of pregnancy failure in antiphospholipidic antibody syndrome is very complex and involves impaired decidualisation, alterations of the physiological trophoblast function, local inflammation and apoptosis. In this article we review the pathological mechanisms that are involved in the etiology of the antiphospholipid antibody syndrome, facing the associated placental histopathological findings. KEYWORDS: antiphospholipid syndrome, placenta, thrombosis, aPL antibodies, recurrent misscariage Antiphospholipid syndrome, also known as Hughes syndrome, is a complex multisystem disorder that reunits a great variety of medical and obstetric complications. It is an autoimmune disease characterized by a hypercoagulable state. This appears after the immune system develops antibodies that are targeted against anionic phospholipids on plasma membrane or phospholipid binding proteins . These antibodies, called antiphospholipid antibodies, are: lupus anticoagulant (LA), anticardiolipin antibodies (aCL) and anti-beta 2 glycoprotein I antibodies. The antiphospholipid syndrome has two clinical entities:the primary form, which includes patients with no underlying disease state, and the secondary form, in patients who associate an underlying disease state, such as lupus erythematosus disease. The main phenomena that lead to the clinical manifestations of the antiphospholipidic antibody syndrome are thrombosis and vasculopathy, and consequently infarction. These pathological changes can occur in in any artery as well as any vein or small vessel, thus potentially affecting any major organ system [4]. The thrombotic risks are usually exaggerated during pregnancy because of the underlying changes that are well-known: susbstantially increase in plasma volume (about 45 percent above the nonpregnant state), an increase of concentration in mostly all coagulation factors (except factor XI and factor XIII), with the concomitant increase in fibrinogen complexes levels (factor I). All these physiological changes are counterbalanced by many fibrinolytic mechanisms that are augmentated during pregnancy, in order to maintain the hemostatic balance. Antiphospholipidic antibody syndrome is virtually the most frequent acquired thrombophilia that is to be found in pregnant women. This syndrome may cause a series of obstetrical events, which can be diveded in two major classes: maternal complications, as well as embyonic or fetal complications. The embryo-fetal complications which are to be found in antiphospholipidic antibody syndrome include [8,12,15]: ● ● ● ● ●

Early recurrent pregnancy loss: three or more consecutive spontaneous abortions, which can be either preembryonic (before the 6th week of gestation) or embryonic (between the 6th and the 9th week of gestation) Fetal loss, which can occur early (beyond the 10th week of gestation, during the first trimester) or late in pregnancy Placental abruption, eventually leading to stillbirth in case of acute onset of a massive retroplacental hematoma Uteroplacental insufficiency, thus causing early intrauterine growth restriction (starting even from the 15th week of gastation) Oligohydramnios 30

● Preterm delivery, before the 34th week of gestation Maternal pathology may be either pregnancy related or general thromboembolic diseases, such as: ● Gestational hypertension ● Severe pre-eclampsia, eclampsia, or HELLP syndrome with early onset (hemolysis, high liver enzymes, low platelets count associated to preeclampsia) ● Postpartum catastrophic antiphospholipidic syndrome (Asherson’s syndrome), which can be lethal; it involves at least three organs in less than a week ● Deep vein thrombosis (DVT) ● Pulmonary embolism (PE), ● Transient ischemic attack (TIA), stroke ● Heart attack ● Thrombocytopenia with associated vascular thrombosis ● Failures of IVF attempts The recurrent fetal loss virtually relays on placental vascular thrombosis. This is a certain mechanism, but it is not always detectable and cannot explain the clinical effects all by itself. The vascular pathology is determined by the antiphospholipidic antibodies, which compete with the natural placental anticoagulants for the phospholipidic sites. This is how they cause activation of the coagulation cascade at the placental site [14]. Both the tissular factor and the intrinsec pathways are activated. The latter is due to a pathological endothelial activation by the anti-endothelial cell antibodies. Thrombosis that occurs during the vascular development af the feto-maternal circulation in early pregnancies may also explain the etiopathogeny of the recurrent abortions. The etiopathogenic mechanisms implied in the antiphospholipidic antibody syndrome are depicted in Figure 1 [9].

Fig.1. Pathogenic mechanisms in antiphospholipid antibody syndrome [9]. The complement cascade is activated by the linkage of the antiphospholipidic antibodies to the endothelial cell surface [23]. This exerts endothelial lesions, which activates thrombosis cascade and promotes further placental disease. Beta2- glycoprotein I (also known as apolipoprotein H) binds to many phospholipids in the cellular wall. The most important bounds are the ones it makes to lupus anticoagulant and to cardiolipin. Beta2-GP I is the most important protein cofactor in patients with antiphospholipidic antibody syndrome, playing an important antithrombotic role in vivo. It interacts with the intrinsec pathway, altering the contact activation of the clotting cascade. It inhibits the conversion of prothrombin to thrombin and it also has a regulatory effect on platelets and protein S [21]. On the surface of the syncytiotrophoblastic cells, beta2-GP I binds as well as it does on the endothelial cells [6]. This complex is easily recognised by the specific aPL antibodies, thus leading to downregulation of 31

trophoblastic hormone production at this site. As a result of the decreased secretion of human chorionic gonadotropin in the first stages of pregnancy, the invasion of the uterine wall by the embryonic placental villi is therefore defective, altering placental formation. It’s a mechanism known to be responsible for the recurrent fetal loss. The aPL antibodies target the negatively charged phospholipides on the surface of the cell membrane, but also phospholipid binding proteins, such as beta2-glycoprotein I. Other phospholipid-binding proteins include tissue factor, prothrombin, protein C, protein S, prostacycline, factor VIII, and annexin V. These protein cofactors play an important role in coagulation cascade regulation. After aPL antibodies bind to these cofactors, the normal function of the cascade is afected and a procoagulant state is established. Annexin V, also known as annexin A5, is a phospholipid-binding protein that forms a bidimensional shield around negatively-charged phospholipid molecules in the cell membrane, thus reducing their availability for coagulation. It competes for phosphatidylserine binding sites with prothrombin and also inhibits the activity of phospholipase A1. It therefore exerts a potent antithrombotic role at the interface between the blood stream and trophoblastic cells and endothelial cells. This protein which - among the members of the annexin family - has the highest affinity for phospholipid, is expressed on the external surface of the syncytiotrophoblast since 7th week of gestation until birth time. Its anatomic disposal is perfect for mentaining optimal blood viscosity in the intervillous space. The shield of annexin V, which clusters on the phospholipid surface of the cell walls, exerts an anticoagulant effect in two ways. The first one is achieved through the inhibition of the binding of coagulation-factor complexes to the phospholipids in the cell membrane. The second way to inhibit thrombosis is by limiting the lateral diffusion of those coagulation factors that are already bound to the phospholipids [17], as shown in Figure 2. Antibodies directed against annexin V that are present in pregnant women with antiphospholipidic antibody syndrome destroy the above mentioned protective shield. This is how an increased quantity of phospholipid molecules are revealed on cell membranes, leading to a speeding up of coagulation reactions and causing the characteristic clotting of the antiphospholipidic antibody syndrome.

Fig. 2. Antiphospholipid antibodies inhibit the clustering of annexin V; this consequently favors both the binding of coagulation-factor complexes and their lateral diffusion [17]. Levels of annexin V are markedly reduced on trophoblast cells of these patients. The physiological hypercoagulability in these pregnancies is therefore enhaced due to the reduction of surface-bound annexin V by aPL antibodies. The consecutive thrombosis that develops in the itervillous space leads to reduced oxygen and nutrients passage in the feto-maternal unit. This autoimmune recognition also represents a pathologic mechanism that leads to apoptosis of the trophoblastic cells and reduces the gonadotrophine secretion, thus causing defective placentation and consecutive spontaneous abortions before the 10th week of gestation. Anti-annexin V antibodies are also involved in failures of IVF and embryo transfer attempts in the assisted reproductive techniques. Another mechanism implied in aPL antibodies formation is centered upon phosphatidyl-serine. This is a component of the phosppholipidic wall of the human cells. It lies on the inner surface of the cell membrane, where is being kept by an enzyme known as flippase. Phosphatidyl-serine acts as a potent prothrombotic factor. 32

High concentrations of this anionic lipid result in an accumulation of negative surface charge to which polycationic proteins can bind. In platelets, membrane vesicles are are formed after the activation of these blood cells. They transport the phosphatidyl-serine mollecules from the inner cytosolic leaflet to the outer surface of the platelets. Here, the phosphatidyl-serine mollecules enhance the activation of prothrombin to thrombin in two mays: either directly or by binding to specific sites on two key regulatory factors [7]. In apoptotic cells, a great number of phosphatidyl-serine molecules are exposed to the surface of the cell membrane. Two fenomena are then stimulated: direct activation of the coagulation cascade and immunogenic stimulation. The latter generates antibodies that are targeted against this lipidic structure as a single molecule or as a complex between phosphatidyl-serine and prothrombin. There is an interconnection between annexin V and phosphatidyl-serine: after binding to the latter, annexin V acts as an anticoagulant factor. Antiphospholipidic antibodies inhibit this binding, stimulating clotting processes. Moreover, anti-annexin V antibodies can lead to apoptosis, exposing the phosphatidyl-serine molecules. There is growing evidence that indicates the fact that oxidized phospholipids are among the targets of anti-phospholipid antibodies [10]. A significant proportion of aPL antibodies are directed at neoepitopes of oxidized phospholipids., Other neoepitopes that are targeted by the aPL antibodies are the ones generated by complex molecules that develop after the breakdown products of oxidized phospholipids combine with the associated proteins. Each cardiolipin molecule contains four unsaturated fatty acids and is therefore highly susceptible to oxidation, particularly when exposure to air takes place. Thrombosis alone cannot sustain the obstetric complications that are associated with the antiphospholipidic antibody syndrome, mediated by the aPL antibodies. An alternative pathogenic mechanism for recurrent fetal loss is thought to be the acute placental inflammation [20], mediated by aPL antibodies. β2GPI-dependent aPL antibodies target the placenta directly by binding to beta2-GP I expressed on the surface of trophoblast cells. Thus, they inhibit the proliferation and differentiation of trophoblasts, and eventually cause defective placentation. Anti beta2-GP I antibodies trigger an inflammatory response at the trophoblastic site, characterized by an up-regulation in secretion of inflamatory agents such as IL-8, IL-1beta, MCP-1and GRO-alpha [16]. The mechanism of action of lupus anticoagulant and anticardiolipin antibodies has been the object of in vitro studies, for elucidating the pathogenesis of the antiphospholipid antibody syndrome in pregnant women. It has been stated that LA antibodies recognize the prothrombin bound to the anionic lipid mollecules in the outer cellular wall, therefore they inhibit plasmatic coagulation cascade. On the other hand, aCL antibodies require beta 2-GP I mollecules as a cofactor in order to bind to phospholipids. In the presence of their cofactors, LA and aCL antibodies interact with specific structures on the membrane of activated platelets and platelet-derived microvesicles [1]. This immunologic reaction is quite similar to their interaction with phospholipid surfaces. In response, platelets aggregate and thus contribute to thrombosis, which plays the leading role in the antiphospholipidic antibody syndrome. In normal early pregnancies, the trophoblast invades the decidual stroma and the decidual vessels at the same time. Iinitially the endovascular trophoblast is to be found in small aggregates within the vessel walls. These small inserts subsequently dissociate and spread. Therefore, through trophoblastic invasion, the branches of the uterine arteries are converted to low resistance uteroplacental vessels. Defective trophoblast invasion of the uteroplacental arteries is a well known cause of later pregnancy complications, such as intrauterine growth restriction and pre-eclampsia. Defective trophoblast invasion is also associated with early pregnancy loss. Hence, defective endovascular trophoblast invasion may explain both the occurrence of early pregnancy loss and later pregnancy complications in antiphospholipidic antibody syndrome pregnant pacients [3]. Histopathologic microscopy analyses of placentae in pacients with antiphospholipidic antibody syndrome showed the following lesions: o villous infarcts o excessive perivillous thrombosis o decidual necrosis o acute decidual atherosis (with intimal foamy macrophages in arterioles) o obliterative arteriopathy o retroplacental hematomas o increased syncytial knots o excessive villous maturity o avascular terminal villi o decreased number of syncytio-vascular membranes o deciduitis o chronic villitis o uteroplacental vasculitis o decidual vasculopathy 33

A few microscopic aspects of the aforementioned are also present in the placental tissue obtained after delivery from a term pregnant patient diagnosed with antiphospholipid antibody syndrome, as can be seen in Figure 3.

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Fig.3. Photomicrographs of placenta showing areas of villous infarction, arteriolar fibrinoid necrosis, decidual arterial atherosis, placental dysmaturity (increased syncytial knotting, decreased villous size) (hematoxylin and eosin). Pathologists have found a great variety of placental disfunctions, which can range from minor changes to placental infarction. Usually, the placenta weights less than normal, might have ischemic and hypoxic lesions and decidual vasculopathy. The microscopical findings include calcium deposits, white infarcts, red infarcts, 35

diminished placental surface and thickness. Decidual vasculopathy consists of persistence of smooth muscle inside the vascular wall, associated with fibrinoid necrosis of the same structure, thrombosis and atherosis [20]. There is an increased risk of maternal floor infarction or massive perivillus fibrin deposition development in patients with antiphospholipidic antibody syndrome. Maternal floor infarction is to be distinguished from placental infarction. The former process results from the deposition of fibrin in the decidua beneath the placenta and does not result from arterial occlusion and ischemic necrosis. The fibrin in maternal floor infarctions extends into the intervillous spaces and results in villous atrophy. The latter is a localized area of ischemic tissue necrosis that is due to an obstruction of the villous blood supply. There are three main possibilities to explain the mechanism by which the presence of aPLs may affect this process of trophoblastic invasion. Firstly, aPL antibodies bind to the surface of sincytiotrophoblast cells, causing trophoblast damage. This requires complement activation in the first place. Secondly, circulating aPL antibodies bind to the endothelium of maternal vessels, including those within the decidua. This way either the correct interaction between endothelium and trophoblast is prevented, or direct endothelial damage is done, thus impeding normal trophoblast invasion. Thirdly, aPL antibodies bind directly to the trophoblast cells that lie inside the vascular wall, leading to dissolution of these endovascular trophoblast aggregates [19]. In the end, the antiphospholipidic antibodies prevent normal trophoblast implantation and invasion, leading to defective development and eventually to placental insufficiency. Alongside with thrombosis, extensive necrosis and infarction, pathologists have described another ethyology of the clinical events consistent with antiphospholipidic antibody syndrome. This is targeted upon the uterine spiral artery. There are some frequent aspects to be found in these arteries. They consist of intimal thickning, narrowing of the arterial lmen, acute atheromatosis and fibrinoid necrosis. The spiral artery vasculopathy is the main organic mechanism that explains the recurrent pregnancy loss. This pathologic process is much more evident at the miometrial site of the spiral arteries, thus leading to lesser blood flow in the intervillous space. Anti-phospholipid antibodies and complement activation are associated in triggering a local inflammatory process, characterized by neutrophil infiltration. This cooperation eventually cause placental thrombosis and hence hypoxia. Histological analyses of human placenta tissues from antiphospholipidic antibody syndrome patients show small inflammatory injuries rather than widespread ones. Recent studies have identified autoreactive T lymfocytes that recognize the peptide which contains the major phospholipid-binding site of the beta2 – GP I mollecules [11]. After the immune recognition, these CD4+ T cells promote the synthesis of the antiphospholipid antibodies, which are responsible for the pathogenesis of antiphospholipidic antibody syndrome. The role of complement in the induction of placental tissue injury in patients with antiphodpholipidic antibodies syndrome has been the objet of study for many years. It has been shown by some in vitro studies of human placentae that trophoblastic cell membranes are targets for aPL antibodies [18]. However, in placentae from patients with antiphospholipidic antibody syndrome pathologists have found microscopical images of lesions that are commonly associated with malperfusion [2]. Hence, the factors that stimulate inflammation firstly activate complemen cascade, eventually leading to ischemia, tissular injury and fetal loss. There has been found a significant correlation between the presence of placental pathologic lesions and the deposition of C4d complement component discovered in the trophoblast cytoplasm and cellular and basement membranes, which are increased in these patients compared to control pregnancies. Researchers correlated the microscopic pathologic findings to C4d deposition in the extravillous trophoblast of decidua. The direct contact between maternal blood and fetal tissue exposes the mother to paternal antigens that are expressed on the trophoblastic surface [22]. Therefore, the placenta provides a highly stimulating substrate for complement activation. At the trophoblastic site, fetal tissue becomes susceptible to complement activation and damage. The relative hypoxic conditions existing in a normal placenta generate trophoblast differentiation, but on the other hand initiate activation of the complement cascade. Complement activation products can also be found in normal placentae. There are a series of complement regulatory proteins expressed on the cytotrophoblast that prevent the excessive complement deposition at these sites. Therefore, tissue damages are prevented in normal placentae. In antiphospholipidic antibody syndrome pacients the amount of aPL antibodies is overwhelming compared to the action of these regulatory proteins. These antibodies form many antigen-antibody complexes that directly activate the complement cascade [5]. The complement depositions in the antiphospholipidic antibody syndrome placentae ar hence much more detectable than in normal placentae, without a decrease in number of the regulatory proteins in the former. Placental histopathological lesions in pregnant pacients are coherent with these findings. Another mechanism involved in the pathogeny of the antiphospholipidic antibody syndrome is centerd upon the endothelial cell [13]. After aPL antibodies bind to endothelial cells, they induce the activation of these vascular wall cells and hence promote expression of cytokines and metabolism of prostacyclins. Activation of endothelial cells induces thrombosis.

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There are certain aPL antibodies that are proved to reduce vascular prostacyclin production, especially those antibodies which are associated with arterial thrombosis. Antiphospholipid antibodies decrease the activity that phospholipase A2 has upon phospholipid substrates. This way, the prostaglandin cascade is downregulated and the prostacyclin (PG I2) production decreseas. This leads to a prothrombotic state within the vessels. In antiphospholipidic antibody syndrome, the rate of recurrence of similar thrombotic events is very significant. In order for thrombosis to occur, a "second hit" or other non-immunologic procoagulant factors are necessary [24]. The "second hit" theory states that in the presence of another thrombophilic condition, aPL antibodies increase the risk of thrombotic events that potentially take place. Some promoters are therefore needed, such as an infection - which turns on the cytokine production, or a traumatic injury to the endovascular cells – thus leading to endothelial activation and blood flow turbulences. The etiopathogenic mechanisms described in this article explain the thrombotic events that are the hallmark of the atiphospholipidic antibody sindrome. The theme is of great interest for many medical disciplines that face its challenges, such as internists, hematologists and obstetricians. The more thoroughgoing their study, the more therapeutical pathways arise. REFERENCES 1. 2. 3. 4. 5. 6.

7.

8. 9. 10.

11. 12. 13.

14. 15.

16.

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Abdel-Monem H, Dasgupta SK, Le A, Prakasam A, Thiagarajan P. Phagocytosis of platelet microvesicles and beta2- glycoprotein I. Thromb Haemost. 2010 Aug;104(2):335-41. Baergen RN. Manual of Benirschke and Kaufmann’s pathology of the human placenta. New York: Springer; 2005. pp. 81–90. Bischof, P., Meisser, A.,Campana, A. Mechanisms of endometrial control of trophoblast invasion. J. Reprod. Fertil. Suppl. 2000; 55, 65–71. Branch DW, Eller AG. Antiphospholipid syndrome and thrombosis. Obstet Gynecol. 2006;49:861-874 De Groot PG, Derksen RHWM. Pathophysiology of the antiphospholipid syndrome. J Thromb Haemost. 2005;3:1854–60. Di Simone N, Raschi E, Testoni C, Castellani R, D'Asta M, Shi T, Krilis SA, Caruso A, Meroni PL. Pathogenic role of anti-beta 2-glycoprotein I antibodies in antiphospholipid associated fetal loss: characterisation of beta 2-glycoprotein I binding to trophoblast cells and functional effects of anti-beta 2-glycoprotein I antibodies in vitro. Ann Rheum Dis. 2005 Mar;64(3):462-7 Galli M, Bevers EM, Comfurius P, Barbui T, Zwaal RF. Effect of antiphospholipid antibodies on procoagulant activity of activated platelets and platelet-derived microvesicles. Br J Haematol. 1993 Mar;83(3):466-72. Gambetta Margarita, Chu Valery L.. The Antiphospholipid Syndrome. US Pharm. 2008;33(1):HS-23HS-30. Hanly John G.. Antiphospholipid syndrome: an overview. CMAJ June 24, 2003 vol. 168 no. 13 16751682 Hörkkö S, Miller E, Dudl E, Reaven P, Curtiss LK, Zvaifler NJ, Terkeltaub R, Pierangeli SS, Branch DW, Palinski W, Witztum JL. Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids. Recognition of cardiolipin by monoclonal antibodies to epitopes of oxidized low density lipoprotein. J Clin Invest. 1996 Aug 1;98(3):815-25. Kuwana M. Beta2-glycoprotein I: antiphospholipid syndrome and T-cell reactivity. Thromb Res. 2004;114(5-6):347-55. Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med. 2002;346:752-763 López-Pedrera C., Buendía P., Barbarroja N., Siendones E., Velasco F., Cuadrado M.J. Antiphospholipid-Mediated Thrombosis: Interplay Between Anticardiolipin Antibodies and Vascular Cells. Clin Appl Thromb Hemost January 2006 vol. 12 no. 1 41-45 Meroni P.L., Borghi M.O., Raschi E., Tedesco F. Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nature Reviews Rheumatology 7, 330-339 (June 2011). Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, Derksen RHWM, de Groot PG, Koike T, Meroni PL, Reber G, Shoenfeld Y, Tincani A, Vlachoyiannopoulos PG, Krilis SA. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4 : 295–306. Mulla MJ, Brosens JJ, Chamley LW, Giles I, Pericleous C, Rahman A, Joyce SK, Panda B, Paidas MJ, Abrahams VM. Antiphospholipid antibodies induce a pro-inflammatory response in first trimester trophoblast via the TLR4/MyD88 pathway. Am J Reprod Immunol. 2009 Aug;62(2):96-111. Pierangeli S., Rand JH. Chapter 3 Laboratory Heterogeneity of Antiphospholipid Antibodies Handbook of Systemic Autoimmune Diseases, Volume 10, 2009, Pages 35–53. Salmon JE, Girardi G, Volers VM. Complement activation as a mediatory of antiphospholipid antibody induced pregnancy loss and thrombosis. Ann Rheum Dis. 2002;61:46–50. 37

19. Sebire N.J., Fox H., Backos M., Rai R., Paterson C., Regan L.. Defective endovascular trophoblast invasion in primary antiphospholipid antibody syndrome-associated early pregnancy failure. Hum. Reprod. (2002) 17 (4): 1067-1071. 20. Shamonki JM., Salmon JE, [...], Baergen RN. Atherosis with fibrinoid necrosis of vessel walls. Am J Obstet Gynecol. 2007 February; 196(2): 167.e1–167.e5. 21. Sikara MP, Routsias JG, Samiotaki M, Panayotou G, Moutsopoulos HM, Vlachoyiannopoulos PG. {beta}2 Glycoprotein I ({beta}2GPI) binds plateletfactor 4 (PF4): implications for the pathogenesis of antiphospholipid syndrome. Blood 2010;115:713-23. 22. Stone S, Pijnenborg R, Vercruysse L, et al. The placental bed in pregnancies complicated by primary antiphospholipid syndrome. Placenta. 2006;27:457–67. 23. Tincani A., Cavazzana I., Ziglioli T., Lojacono A., De Angelis V., Meroni P. Complement Activation and Pregnancy Failure. Clinical Reviews in Allergy & Immunology, December 2010, Volume 39, Issue 3, pp 153-159. 24. Vlachoyiannopoulosa PG, Routsias JG. A novel mechanism of thrombosis in antiphospholipid antibody syndrome. J Autoimmun. 2010, 35(3):248-55.

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CLINICAL ENT ASPECTS OF RARE DISEASES– GAUCHER DISEASE Stan Carmen Ilfov County Clinical Emergency Hospital, ENT Department, Bucharest, Romania ABSTRACT: Rare diseases represent a constant preoccupation within the scientific community, both because of the difficulty in diagnosis and of the researches made in order to find effective treatments that require multidisciplinary studies: human genetics, biochemistry, cellular biology, and sometime involves surgical approaches. Gaucher disease is one of the rare diseases that in Romania is diagnosed and documented once in a dozen cases. This study presents the case of a patient diagnosed with Gaucher disease admitted in the ENT clinic for massive epistaxis. INTRODUCTION: Gaucher disease is part of the Thesaurismosis (Sphingolipidosis) group. The enzyme deficit is of glucocerebrosidase and the abnormal cerebrosides accumulate (glucocerebrosides). The study presents the case of a patient diagnosed with Gaucher disease 27 years ago, admitted in the ENT Clinic for massive epistaxis,. MATERIAL AND METHODS: A 58 years old male patient was admitted in the ENT Clinic for massive bleeding from the right naris, pre-cordial pain, bone pain in the lower limbs, dyspnea and gingival bleeding. The most significant facts from the patients’ personal history are: stage 2 high risk group arterial hypertension and stage I untreated Gaucher disease. The ENT exam highlights active bleeding in the right nasal fossa. At the general clinic examination, the patient is found with: stage II obesity, teguments with hyperpigmentation lesions, tegumentary disseminated hematomas, distended abdomen, rigid and painful when palpated. The abdominal echography shows a major hepatosplenomegaly, homogenous structure of the liver, enlarged in volume, RL 42cm, LL 26cm, long axis of the spleen approximately 35cm, ascending diaphragm. The cardiologic exam: stage 2 arterial hypertension and ischemic cardiac disease. The laboratory examination emphasizes moderate anemia (WBC 3.090000U/L, HGB 12,4g/dl, HCT 34, 6%) and significant thrombocytopenia (PLT 46000/uL), and the EKG shows terminal phase nonspecific modifications. Therapeutic approach: Right anterior nasal packing with bleeding control was performed during hospitalisation. After 24 h the patient had begun bleeding from the left naris also, therefore bilateral anterior nasal packing was necessary. Simultaneously a general antibiotic, antihypertensive, analgesic, haemostatic, diuretic and sedative treatment was established. 2u PPC were administrated. The packing was maintained for another 48h until the bleeding stopped. After 72 h the patient was transferred at Fundeni Institute of Hematology, where he had been registered as a patient for 27 years, in order to establish the specific enzymatic replacement treatment. DISCUSSIONS: Gaucher disease is a monogenic disorder, which is transmitted in an autosomal recessive pattern and is caused by a gene mutation situated on chromosome 1 which encodes the glucocerebrosidase enzyme (β– glucosidase acid, glucosylceramidosis). The lysosome localized enzyme has the role of decomposing the glucosylceramides in glucose and ceramides. The enzymatic deficit leads to the accumulation of undegraded metabolic substrate in the reticulo-endotelial system lysosomes (macrophages). These large size cells, with eccentric nucleus, which presents glucosylceramide deposits in the cytoplasm, have been referred to as Gaucher cells and they represent the disease markers. (fig1)

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Fig.1 Clinical aspects : Type I of Gaucher disease is diagnosed around the age of 20. It is the most frequent form of the disease, characterized by: Bone lesions, proven both clinically and radiological, are present in 70-100% of the persons that carry the Gaucher disease – asymptomatic osteopenia to lithic outbreaks or sclerotic lesions and osteonecrosis. (fig.2) The splenomegaly is impressive; the volume of the organ can grow from 15-200 cm3, in normal conditions, to 1500-3000 cm3 (Fig.3). It is associated with hypersplenism with the apparition of pancytopenia (anemia, leukopenia and thrombocytopenia). The liver can also grow (hepatomegaly) 8 times its normal volume .

Fig.2

Fig.3

Thrombocytopenia, the most frequent hematological modification (in 75% of patients), causes cutaneous and mucous hemorrhage. The patients can present petechiae, bruising, epistaxis, spontaneous gingival bleeding or while brushing their teeth, menometrorrhagia, and posttraumatic hemorrhage, occurred during prolonged surgical interventions or pregnancy. These can be stopped only by administrating platelet mass.

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Diagnosis : The confirmation test for the Gaucher disease is represented by measuring the glucocerebrosidases enzyme activity in the leukocytes or other nucleus cells from the peripheral blood. Specific examination includes: dosing of leukocytes β–glucosidase acid, which in patients with GD I has a value ≤ 30% of the healthy subjects, (in type II and III the activity decreases even under 10%) and DNA analysis, for mutation deceleration( in type I the N370S mutation overbears). [1] Treatment : Symptomatic : - Splenectomy for the cases where the hematological complications come first (hypersplenism, hemorrhagic syndrome, massive splenomegaly that gives compression effects). Currently the splenectomy is avoided because the substitution symptomatic treatment has also the role to decrease the spleen dimensions, and the splenectomy exacerbates the bone lesions - the bone crises requires immobilization and the usage of level I and II analgesics, sometimes even morphine - biphosphonates have been proposed in order to prevent the skeletal (bone) complications. Enzyme replacement therapy (ERT) is performed with a product obtained by recombinant DNA (Imiglucerase) [3]. Imiglucerase – commercial name Cerezyme- represents a targeted therapy [4]. It is administrated in perfusion i.v. every 2 weeks, in variable dosage, depending on the age of the patient and the severity of the disease; for the majority of the patients the dosage is 30-60 UI/ kg in type I and 100 UI/kg in type III of the disease. The therapeutical results are spectacular, and the side effects practically absent. The substrate reduction therapy targets the reduction of the glycosyl-ceramide synthesis, substance that has to be metabolized by β–glucosidase acid. For this purpose it is utilized Miglustat- commercial name Zavesca- in the treatment of Gaucher disease type I mild and moderate, administered orally, dosage 3x 100mg/ day. Improvement is only partial and slower than the one with ERT. Gene therapy hasn’t shown until now notable results. Genetic aspects: The gene that codifies the synthesis of β–glucosidase acid is localized on the long arm of chromosome1 (1q.21.), where there is an active gene and a pseudogene.[2] At the gene level formed by 11 exons, the most frequent recorded mutations are: two point mutations (N370S; L444P) and a splice- junction mutation (84 GG). Gaucher disease type 1 in Romania: The National Health House statistics show that, at the entire country level, 41 persons have Gaucher disease. For a single patient, the monthly cost of the treatment with Cerezyme varies between 84000 lei and 140000 lei, depending on the stage of the disease. For a Gaucher patient, stopping the treatment with Cerezyme, can lead to death. So far, in Romania, there has been only one death recorded among the Gaucher patients. The specific diagnosis of GD in our country is possible since 1997. CONCLUSIONS: Type 1 Gaucher disease remains undiagnosed in our country, especially among men. There is a high frequency of the N370S/L444P genotype and a severe phenotype in the majority of patients. ERT has proven its efficacy in hematological manifestations and organomegaly (visceromegaly) but not in bone mineral density. In order to obtain the optimum therapeutical results it is essential to start the therapy as close as possible to the clinical onset of the disease with a posology adapted to the severity of the disease. REFERENCES: 1. BEUTLER E, GRABOWSKI GA. Gaucher disease. In: Scriver C, Beaudet AL, Sly WS, Valle D, eds.The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill; 2001:3635-3668. 2. MISTRY P, GERMAIN DP. Phenotype variations in Gaucher disease. Rev Med Interne 2006;27(Suppl 1):S3– S10. 3. CHARROW J, DULISSE B, GRABOWSKI GA, WEINREB NJ. The effect of enzyme replacement therapy on bone crisis and bone pain in patients with type 1Gaucher disease. Clin Genet 2007;71:205–211. 4. SIMS KB, PASTORES GM, WEINREB NJ, et al. Improvement of bone disease by imiglucerase (Cerezyme) therapy in patients with skeletal manifestations of type 1 Gaucher disease: Results of a 48-month longitudinal cohort study. Clin Genet 2008;73:430–440.

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CLINICAL CONSIDERATIONS ON AN OESOPHAGEAL CANCER CASE WITH ATYPICAL DEBUT Stan Carmen Ilfov County Clinical Emergency Hospital, ENT Department, Bucharest, Romania ABSTRACT: The paper presents the case of a patient for which the correct diagnosis required a complex investigational algorithm since the main lesions was masked by neighboring organs (larynx, pharynx, oral cavity). INTRODUCTION: Oesophageal cancer represents circa 1% of all cancers and 6% of all gastrointestinal cancers. Amongst the risk factors we count: smoking, alcohol, some gastrointestinal diseases such as Barett’s oesophagus, gastro-oesophageal reflux, peptic oesophagitis.1 The most frequent site for the disease is the inferior third of the oesophagus (43%), followed by the medial third (37%) and the superior (20%). The most frequent histological type is the epidermoid carcinoma (95%), whilst the adenocarcinoma represents circa 5% of cases.1 The loco-regional extension takes place by invading the neighboring organs (mediastinum, laryngeal recurrent nerve etc.) and via the lymphatic nodes, — supra-clavicular, tracheo-bronchial and the lymphnodes of the small gastric arch. Distance metastasis is rare since the death occurs relatively quick.2 The symptomatology is dominated by the oesophageal syndrome, second to oesophageal stenosis (pathologic reduction of lumen caliber by share volume of tumor). The first sign is the dysphagia, initially for solid food and than for liquids. On occasion , the dysphagia can disappear for a period of time if the tumor becomes ulcerated. The extension of the inferior oesophageal cancer produces permanent retro-sternum or dorsal pain. Usually, it takes approximately 5-6 months from the first clinical signs which are not too suggestive, until establishing a diagnosis. Regurgitation appears in small quantity, possibly containing blood. The general status of the patient decays rapidly and he becomes pale, anemic, weak. The patients loses 1520 kg in a few months by loss of appetite and cancerous intoxication. The curative treatment for situations which still allow it, is multimode and has the purpose of prolonging the patient’s life as much as possible. This treatment comprises surgery, chemotherapy and radiotherapy. The surgery with the least morbidity is the transhiatal oesophagotomy with anastomosys of the stomach to the cervical oesophagus. For the lower third of the oesophagus, the surgical treatment has the best results while for the superior 2/3 the radiotherapy is indicated. 2 The 5 year survival rate for oesophageal cancer is lower that 15%. Since the patients require medical assistance very late, the prognostic of the disease has not been improved in the recent years. MATERIAL AND METHODS: The paper presents the case of a 44 year old patient, admitted in our clinic for persistent dysphonia and weight loss and a dysphagic syndrome of far lesser importance. From the patient’s history we mention an intricate pectoral angina, obliterative arteriopathy and 3rd degree liver steatosis. The patient, great smoker and alcohol consumer, mentions a delirium tremens episode about 6 months back. The ENT clinical examination reveals asimetry of the larynx lumen, paralysis of the left vocal cord and no other signs of larynx tumor. The CT-scan of the cervical region shows nonspecific hypertrophy of the lateral neck lymph nodes and arises the suspicion of gloto-subglotic tumor. The endoscopic larynx examination reveals no trace of tumor in the gloto-subglotic region of the larynx nor in the hypofarynx regions (piriform sinus or valecula) (Fig2). The flexible fibroscopy of the nose, farynx and larynx reveals diminished laryngeal mobility and left vocal cord paresis but no tumors that could account for the symptoms in the investigated regions. The lab exams reveal medium leucocitosys (WBC 11,5%) and an inflamatory syndrome (ESR 18mm/h). The ecographic abdominal examination shows moderate hepatomegaly. Lung Xray examination: accentuated peribronhovascular patterns, no signs of lesions. Since none of the investigation can establish a diagnosis, a superior digestive endoscopy is required. This discovers a friable, cauliflower-like tumor, over the inferior 2/3 of the distal oesophagus, situated at 30-35 cm(Fig2). from the superior dental arcade. A biopsy is taken. 42

Fig1

Fig2

The histopathology exam establishes a diagnosis (moderate differentiated squamos cell carcinomaof the oesophagus – tumor proliferation with plates and islands of large, polygonal, tumor cells with eozinophile cytoplasm, pleomorphic nucleii with protruding nucleolei, atypical mytosis and keratine pearls) DISCUSSIONS: The presented case does not represent a rule for the pathological evolution of the oesophageal cancer. We underline the fact that the patient presents minimal dysphagia, his main symptoms being dysphonia and progressive weight loss (circa 15 kg in the past 3 months). None of the symptoms affect the digestive or respiratory function which determines the patient to present himself very late for a medical examination. By masking the oesophageal syndrome, the treatment can no longer have a curative purpose and the patient is directed towards our oncology service for chemotherapy, the only treatment that can moderately improve the biological status. The chemotherapy yields questionable results. A bronchopneumopathy episode, probably related to tumor complications, occurs. In the mean time, the patient’s alimentation is not physiologic, done via a silicone oesophageal stent which limits the extent of the weigh loss. The patient’s general state and the late presentation do not support surgical treatment which would otherwise be elective for this pathology.

CONCLUSIONS:

The oesophagial cancer still represents a challenge for the clinician, in correlation to a minimal initial symptomatology and slow progression of the disease. These are usually the reasons why the diagnosis is very late established and in a faze that does not indicate curative surgical treatment. The case was special because the debut symptoms were mainly respiratory and the differential diagnosis to a chronic laryngitis was difficult. That is why we consider useful a digestive superior endoscopy for all cases of unexplained weight loss. This exam, together with the histopathology are the only exams capable to establish a diagnosis.

REFERENCES: 1. Miron L. Cancerul esofagian. In: Bild E., Miron L., eds. Terapia Cancerului – ghid terapeutic. Iasi: Editura Tehnopress, 2003: 105-13 2. Robustelli della Cuna G, Bonnadonna G. Carcinoma dell esofago. In: Bonnadonna G, ed. Medicina Oncologica. Tma ed. Milano: Mason, 2003: 847-954 3. Stahl M, Kataja VV, Oliveira J. ESMO Minimum clinical recommendations for diagnosis, treatment ad follow-up of oesophageal cancer. Ann.Oncol. 2005; 16(suppl.1):i26-i28.

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THE JURISTIC CONNOTATIONS OF EAR TRAUMA Stan Carmen Ilfov County Clinical Emergency Hospital

INTRODUCTION: The location of the ear in close vicinity to the skull base increases it’s vulnerability to external aggressions, whether by direct involvement or by infection which is a feared complication and favours functional impairment that most of the time can no longer be solved by surgical treatment and require a prosthesis. MATERIAL AND METHOD: The present work represents a review of clinical diagnosis aspects regarding external ear trauma doubled by considerations on their medico-legal impications. It is based on the study of a cohort of 47 patients which suffered cranio-facial trauma that included lesions of the acustico-vestibulary analizor with involvment of the external ear. These were only part of the otic injuries, the rest being lesions of the middle and inner and also lesions to neighbouring organs (facial bones, cerebral but not deadly lesions). DISCUSSIONS: Trauma of the pavilion Excoriation and Ecchymosis – usually a clinical diagnosis presents no problems and they do not require treatment. Deep excoriation require cleaning and local antibiotic treatment, no longer than 4-5 days, in order to avoid infection. Ecchymosis can occur both by direct trauma or by falling and hitting a hard surface, associating skin and bone lesions. Pavilion wounds. From a clinical and forensic point of view these can be: • Cracked wounds – irregular margins, frequent cartilage involvement by compression between the hard object and the bone surface of the skull. Inflicted by direct trauma or by falling (excoriated margins and dilacerated tegument). A particular aspect are the torn wounds with partial or total pavilion amputation. The wounds require more than 12 days of medical care and constitute mutilation. • Bitten wounds – present lesion polymorphism from small straight wounds with a semicircular distribution on both sides of the pavilion to complete sever that mimics the dental records. • Cut wounds – when hitting with a cutting object, the margins align well and favour quick healing and aesthetic scars. These injuries usually necessitate 6 to 8 days of medical care if the cartilage is not involved and if no complications arise. They usually apear after agressions or car crashes with large fragments of glass. Based on the way that the elastic and conjuctive fibres intersect, the final scar could be aesthetic or unsound. • Stabbed and cut-stabbed wounds – can have various morphology based on the characteristics of the patogenic agent. They are most frequently transfixiant and associated to retro-auricular and external era canal lesions. • GSW – most frequent in suicide attempts (close range shot or absolute discharge) in which the supplementary factors are found on the skin or inside the EAC and can determine an anfractuos, star-like aspect of the entry wound and associate skull and brain legions that could provoke instant death. In the particular case of a distance shot, a stabbed-like wound can appear whilst the projectile can ricoche of the cranium and provoke seton wounds or can remain inside the soft tissues. The lesions that affect the cartilage need over 12 days of medical care, healing frequently taking place with deformity of the pavilion. Infection generates skin and cartilage necrossis followed by vicious scarring, pavilion mutilation and maiming with a treatment lengh of over a month. Othematoma is a sero-haematic collection between the pericondrium and cartilage. It appears following a hard trauma in which the pavilion is compressed between the pathogenic agent and the skull. Treatment most frequently surgical and antibiotherapy. Best cases require 8-10 days of treatment. Pericondritis requires over 20 days. The scarring is iniquitous with irreversible pavilion deformities.

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Frostbite frequent due to the exposed positioning of the pavilion and lack of subcutaneous and fatty tissue. Lesions concern the superior edge of the pavilion, with secondary deformity and sometimes necrosis of the entire pavilion. Burn wounds associated to cranio-facial burns, rarely located just on the pavilion, provoked by flame, hot liquid or vapour or even prolonged exposure to sun. Chemical burns by chemical agents, acid or base. The cartilage can be affected or even deformed. Electric trauma by lightning or high or low voltage electric current. At the ear level electric current can provoke primary direct lesions of the pavilion, tympanic membrane or Corti’s organ; primary indirect lesions by hemorage or vasomotoric lesions; secondary and late lesions with trophic, neuropsichiatric, sensorial lesions or transmission, perception or mixt deafness. In the case of fulguration, blast lesions appears at the level of the auditory aparatus, acompagnied by burns and sound trauma. It can interest the tympano-auricular system or it can provoke ireversible cohlear and facial injuries. Cohlear and vestibular signs appear imediatly. Deafness is mixt or perception, mild or severe and frequently involves the tympanic membrane. The electric current never affects the tympanic membrane. There are also associated types: burns with bone necrosis and infectious complications, lesion of the mucosa, hemiplegy and afasis, psychiatric afflicions, progressive cerebrale lesions Treatment addresses the general status, otic and associated lesions. The neurologist’s cooperation is required. If the patient does not die the functional deficite can lead to permanent disability. External Ear Canal Trauma Relatively frequent, accidental or iatrogenic. Escoriation of the EAC tegument as a consequence of inserting sharp objects for scratching or removing ear wax or it can be produced actively with an elongated object (needle, wire). Treatment disinfection of EAC and sterile packing, no longer than 3-4 days of medical treatment. EAC wounds by direct trauma, accidental or iatrogenic. It can affect the soft tissue and/or the cartilage. Due to the anatomic shape of the EAC, lesions can be caused by sharp objects or projectiles. Evolution usually simple but it requires supervision to prevent infection and secondary stenosis. Simple wounds require 5-6 days of treatment. Infection requires over 12 zile. Stenosis needs plastic surgery which prolongues the period of medical care. EAC Fracture rarely direct (projectile, metalic shafts). Usually indirect by the mandibular condil, by falling on the chin or hiting the mandibula with a hard object and pushing the condil towards the inferior wall of the EAC. It can also be the consequence of a iradiated cranial fracture, associated to mastoid fracture, temporal bone fracture or tympanic bone fracture. Simptoms dominated by pain exacerbated by mandibula movement. Otoscopy: deformation of anteroinferior wall of the EAC, tegument lesions, protruding condil. In EAC fracture with concomitent condile, the ladder protrudes in the wound. An abnormal rotatory movement of the mandibula on the oposite side and alteration of the corect overlay of the dental arcades appears. A feared complication is facial nerve paralysis by mastoid trauma which requires surgical treatment. EAC fractures require 30-50 days of medical care, unless associated to meningo-cerebrale lesions and complications. Ear trauma is frequent in the „Beaten child’ Syndrome descibed by Kempe in 1962. Although half of the lesions provoked by abuse, involve the head, there are relatively few reports concerning ENT trauma. A pavilion trauma can be sometimes a superficial manifestation of a neurologic lesion, a so called „Metal sheet Syndrome” is described: ear haematoma, haemoragic retinopathy, subdural ipsilateral haematoma with severe cerebral oedema. Grace reports repeted lesions of the EAC and tympanic membrane in abused children. Leavitt et.al., reports that 18 % of all abused children have various forms of otitis media. A medico-legale examination in the case of these children must take under consideration the role of the trauma upon the future development of the middle ear and of psychic, requering both traumatologic evaluation and forensic psychiatric evaluation. Simulation of hipoacusis brings special diferencial dyagnosis problems with the so-called „functional deafness”, without organic cause which contains the psichogenic deafness. Audiometric studies for simulants are varied and will be done by an experimented examiner. The most utilized methodes are: - Liniar tonal audiometry on various skipping frequencies. - The lack of parallelism between tone audiometry results and vocal audiometry.

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-

-

Stenger test, based on the bilateral deafness phaenomenon. Usually, if concomitently present, in both ears, a sound of the same tonality, but which in one ear has a 10 dB higher intensity shall be the one perceved. Azzi test, in which the subjects voice is played as a backround noise, whilst the simulant can no longer continue reading. Lombard test – increasing gradually the intensity of sound in the earphones, the simulant will raise his voice. Dowfler-Stewart test based on the masking effect that an artificial backround noise has on the perception of the human voice that has an intensity of 10-15 dB lower than the sound. Transcranial lateralization ccheck. Objective audiometry (impedansmetry, electrofiziologic methods).

CONCLUSIONS:

Pavilion wounds necessitate up to 10 days of medical care whilst cartilage lesions require 14-16 days. Septic complications prolong treatment, suppurated pericondritis determines cartilage deformities up to mutilation, necessitating even more than 60 days in case of sepsis. Lack of pavilion constitutes mutilation and pavilion deformity represents permanent aesthetic prejudice. Evaluation of posttraumatic infirmity and mutilation can be done shortly after the trauma in cases of irreversible functional affliction or amputation, respectively after exhaustion of plastic surgery or functional microsurgery methods.

References: 1.Ataman T.-‘’Otologie’’-Ed.Tehnica-2002 2.Belis V. - Tratat de medicina legala - ed. Medicala Bucuresti,1995. 3.Belis V. ,Nanes C.- Traumatologie mecanica in practica medico-legala si judiciara- ed.Academiei RSR Bucuresti, 1985. 5.Derobert L. - Medicine legale - ed. Flammarion, Paris, 1974. 6.Dragomirescu V.T.- Tratat de Medicina Legala Odonto-stomatologica- ed.All Bucuresti,1996 . 7.Garbea St. ,Moga I. - Rinologie- Ed.Stiintifica si Enciclopedica, Bucuresti,1985. 8.Garbea St.,Dimitriu V.Al., Firica D.,- Chirurgie ORL- Ed.Didactica si Pedagogica, Bucuresti,1983. 9.Garbea St.Milosescu P.Olariu B, Stefaniu Al,- Patologie ORL - Ed. Didactica si Pedagogica- Bucuresti,1980.

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ATTRACTING EUROPEAN FUNDS – A NEED FOR THE SUSTAINABLE DEVELOPMENT OF HIGHER EDUCATION AND RESEARCH IN HEALTH Cristian Stan1, Otilia Cinteza1, Camelia Petrescu1,Carmen Stan2 1

University Titu Maiorescu

2

Ilfov County Hospital

The Structural Funds are financial instruments through which the European Union acts in order to eliminate the economical and social disparities between the regions, towards achieving an economical and social cohesion. The structural funds are post-adherence funds supplied through the European Union budget whose purpose is to support the member countries. Are supported the investments in education, research, agriculture, substructure, SMEs development and measures for the development of the rural areas. A special attention is given to the less developed regions in order to consolidate the economical and social cohesion in the European Union. The main objectives of the Structural Funds for the period 2007-2013 are: Convergence Objective: facilitates the development and the structural adjustments of the regions that report developing delays. Regional Competitiveness and Employment Objective: supports the regions that are not eligible for the Convergence objective. European Territorial Cooperation Objective: supports cross-border regions, counties and areas. These structural funds are allowed by reason of the convergence standard, standard that stipulates the elimination of the disparities that exist between the regions of the country, the correspondence with the european standards economically and socially, the improvement of the life and nature quality. The structural funds can be accessed through instruments named operational programmes, that at their turn contain a series of subprogrammes that stipulate a high number of activities that can be financed with grants.

THE STRUCTURE OF THE RESEARCH DEVELOPMENT INNOVATION SYSTEM At present the scientific research in Romania evolves under the National Research Development and Innovation Strategy 2007-2013 and the management levels of the Research Development and Innovation system (CDI system) in Romania are:  The National Authority for Scientific Research (ANCS)  The Executive Unit for Financing The Higher Education of Research Development and Innovation (UEFISCDI)  National Advisory Bodies: - The National Council of The Scientific Research (CNCS) - The National Council for Development and Innovation (CNDI) - The Advisory Body for the Research Development and Innovation (CCCDI) THE PLAN AS MAIN DEPLOYMENT INSTRUMENT. THE NATIONAL RESEARCH DEVELOPMENT INNOVATION STRATEGY The national plan is structured on six component programmes:  Human Resources with the increment of the number of researcher and their professional performance as purpose,  Capacities, for the development of the research substructure and of the pan European and international cooperation ,  Ideas, for international eminence and visibility,  Partnerships in foreground fields for solving complex problems and transferring the solutions to the business environment,  Innovation, for the support of the pre-competitive and competitive research led by economic operators and  Support of the institutional performance, for encouraging the activity of the national institutes in their own activity field. 47

As a EU member Romania adopted the economical growth principles of the EU member countries, namely intelligent, sustainable and favorable to the social inclusion economical growth. Within the Europe Strategy 2020 the priority for the scientific research, technological development and innovation is announced as one of the seven emblematic resolutions, namely an innovation Europe, that stipulates a coherent action set for the performance increment for CD&I. The new European programme Orizont 2000 (Horizon 2000) integrates all the programmes dedicated to research and innovation with the announced purpose of ensure the continuous financing of the innovative processes based on the scientific research and the technical knowledge defined by the phrase “from idea to market”. For the period 2014-2020 the foundation of the political decisions for establishing the objectives and for resources assignment will be done according to the recommendations of the National Research Development and Innovation Strategy for the period 2014-2020 and the Sectoral Operational Programme financed from structural funds with the thematic objective “Research, technological development and innovation consolidation” for the period 2014-2020, The National Council of The Scientific Research initiated the elaboration of the Potential of economical growth based on CD&I Analysis – Intelligent specialties identification. At present there are three strategic orientations for the National CD&I System that regards the capacity and performances of the CD&I System, economical competitiveness growth through innovation and international funds absorption. Capacity and performances growth for CD&I System The investments in the CD&I System focused on human resource development resulting in the growth of the quality and number of the researchers and their results, as well as on offering an appropriate environment for supporting their activity by building or updating the research substructure. Economical competitiveness growth by stimulating the innovation for the Research Development investments in the private field The national economy competitiveness growth claims mainly two aspects: a number as high as possible of companies capable of penetrating into the international markets and the existence of an inner open market functionally compatible with the EU market. Emphasis of the international dimension of the CD&I policies and programmes for the community funds absorption growth The Romanian research internationalization policy, sustained at this time by several instruments for financing and cooperation at bilateral level with other countries (Bilateral programmes, at multilateral level, through the Main Programme Research Development and Innovation of the European Community, EUROATOM Programme, other pan European programmes and resolutions EUREKA. NATIONAL RESEARCH DEVELOPMENT INNOVATION PLAN PROGRAMME UEFISCDI is and acts as an institution that finances the higher education, development and innovation and the main action lines, according to the attributions are:  providing logistical, financial and informational support required by the national councils National Scientific Research Council (CNCS), National Development and Innovation Council(CNDI), National Higher Education Financing Council (CNFIS), National Council of Statistics and Forecast of the Higher Education (CNSPIS) in order to perform their responsibilities;  coordination of the programmes Ideas, Capacities, Human resources, Partnerships in foreground fields, Innovation from the National Research Development Innovation Plan 20072013 (PNCCDI II) under the scientific guideline of the national councils;  accomplishment and implementation of projects regarding institutional and system development for higher education as well as research, development and innovation. IDEAS Programme The purpose of the programme is to obtain top scientific and technological results, comparable with the European level ones, reflected by the international visibility and accreditation growth of the Romanian research. Exploratory Research Projects – PCE The purpose of the projects is the support and promotion of the basic, interdisciplinary and/or exploratory scientific research from Romania. The Ideas programme targets the researchers with proved performances by the quality and by the international recognition of the scientific journals, including those researches that are activating in foreign countries and want to conduct researching projects of higher scientific level in institutions from Romania.

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Complex Exploratory Research Projects – PCCE The purpose of the programme is the support and promotion of the multidisciplinary and interdisciplinary scientific research from Romania. Within this programme several researchers teams from the same institution or from different institutions are contributing at the development of some complex researching tendencies. The programme targets the researchers with experience and special scientific performance, proved by the originality and by the major international impact of their scientific journals and the personalities recognized as leaders in research domain. The programme is also targeting researchers from other countries. Exploratory Workshops The purpose of the programme is the initiation of scientific partnerships between Romanian and foreign researches in order to start and promote some new research lines and to involve students, Ph. D. student and young researchers in present –day scientific activities at international level. Advanced academic courses – SSA The purpose of the programme is the approach of exploratory research themes/ explicit defined subjects which are included in one of the priorities sustained by the National Strategy for Research Development and Innovation Strategy for the period 2007-2013 and report of further progresses regarding these themes/subjects, yet unexposed at international course level. CAPACITIES Programme The purpose of the programme is the development of the National Research Capacity and the integration of the CDI system in Romania in the international scientific environment. The programme supports projects for the foreground fields stipulated in the CDI National Strategy for the period 2007-2013. BILATERAL COOPERATION Programmes The purpose of the programme is to ensure the development of the scientific and technical collaboration between excellence research teams in Romania and the countries with which there exists bilateral cooperation agreements through scientific and technological exchanges. MAIN PROGRAMME 7 The purpose of the programme is the support of the participation of the CDI organizations in Romania through the European Committee Main Research Programme – FP7. With this instrument is ensured the financing needed for covering to the highest level of the participation rate of the Romanian partner in the project. European Research Council Programmed (ERC) The purpose of the programme is the support of the Romanian researchers with excellent results in the competitions organized by European Research Council (ERC) for the implementation of the projects in Romania. There are financed two types of projects:  Projects type 1 Grant Support (“Bridge support”) – projects that obtained at least the score of the imposed quality threshold needed for passing into the II stage of evaluation, for the Principal Investigator as well as for the Research Project;  Projects type 2 Excellence Grant – projects that in the II stage of ERC evaluation obtained the excellent score, but due to the ERC budget limit did not receive financing. HUMAN RESOURCES Programme The purpose of the programme is the growth of the researchers number, the improvement of their professional performances, attracting foreign researchers in Romania as well as the growth of the attractiveness of a research career. There have been initiated competitions under the scientific coordination of CNCS for the following financing instruments. Prize award for the research results – type JOURNAL The purpose of the programme is the growth of the quality, impact and international visibility of the Romanian research through the accreditation and prizing the significant results published in prestige magazines from the main international scientific flow. Postdoctoral research projects – PD The purpose of the programme is to sustain young researchers and science doctors with exceptional results which want to develop an independent professional research career in research institutions from Romania, in order to encourage scientific excellence in Romanian research. The programme targets too researches that are working in foreign countries and want to conduct research projects.

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Research projects that encourage the creation of independent young researchers teams –TE The purpose of the programme is to sustain young researchers and science doctors which are in a period of development or consolidation of a research team, with an independent research programme, in order to obtain relevant results. The programme targets too researches that are working in foreign countries and want to conduct research projects. Programme PARTNERSHIP IN MAIN FIELD The purpose of the programme is to create conditions for a better collaboration between different research development innovation entities, economical agents and/or public administration units in order to solve the identified problems. The research lines are:  Information technology and communication  Energy  Environment  Health  Agriculture, food safety and security  Biotechnologies  Innovative materials, processes and products  Space and security  Social-economical and humanist research. Collaborative Applied Research Projects – PCCA The purpose of the programme is to sustain and promote the applied research in main fields inter- and transdisciplinary relevant for the competitiveness growth in CDI at national level and according to the global economy based on knowledge. There are financed experimental research and technological development projects made in partnership and finalized by making innovative products, technologies and services, with the purpose of solving and implementing solutions for complex socio-economical problems of national priority and international actuality. In the programme there are two types of projects:  PCCA – Type 1 – the partnership structure: on this type of projects is not mandatory the participation of a company and the financing from the state budget can be 100% of the project value.  PCCA – Type 2 – the partnership structure: on this type of projects is mandatory the participation of at least one company. INNOVATION Programme The purpose of the programme is the growth of the capacity of innovation technological development and assimilation in manufacture of the research results in order to improve the competitiveness of the national economy and to raise the life quality. There have been initiated competitions under the scientific coordination of CNDI for the following financing instruments:  Products – Systems – Technologies development Purpose: Stimulation of the technological and economical performances of Romanian companies by financing those entities that have history, maturity and the capacity to transform ideas into products and innovative technologies with real market potential.  HIGH – TECH Export Stimulation Purpose: Growth of the competitiveness of the Romanian high-tech products and technologies.  Support Services for Innovation – Innovation Circles Purpose: The insurance of a flexible instrument for sustaining the SMEs from the productive field in order to update the technology and to improve the innovation rate. The SMEs and the authorized natural persons – PFA are encouraged to develop partnerships with research innovation institutions to create innovative products and services based on advanced technologies. Subprogram – European Cooperation EUREKA – EUROSTARS The programme targets the economic agents SMEs, Romanian legal persons interested to develop projects inside EUREKA initiative, namely Romanian economical competitiveness growth, mainly the industry, by obtaining new products, technologies and services. It is an innovative instrument which, by collaboration between economic agents and research institutions for advanced technologies, technological development, technology and innovation transfer, has the purpose to help the member countries of the EUREKA Initiative to obtain and exploit new technologies for the growth of the economy competitiveness and of the improvement of the quality of life. 50

The EUROSTARS Programme represents an European initiative for helping the supporting of the realization of research – development activities by the SMEs with innovative specific. A necessity for the sustainable development of the higher education and research is to attract European funds which develop by the following programmes:  Regional Operational Programme – POR  Economical Competitiveness Growth Sectoral Operational Programme – POS CCE  Human Resources Development Sectoral Operational Programme – POS DRU  Environment Sectoral Operational Programme – POS MEDIU  Transport Sectoral Operational Programme – POST  Administrative Capacity Development Sectoral Operational Programme –PO DCA  Technical Assistance Operational Programme – POAT  Rural Development National Programme – PNDR  Fishing Operational Programme – POP  Cross-border, Transnational and Interregional Territorial Cooperation Programme. Regional Operational Programme – POR The main objective of POR consists of supporting an economical, social, territorially balanced and sustainable development of the Romanian Regions, corresponding to their needs and specific resources, by concentrating on the urban growth pole, by improving the conditions of the substructure and of the business environment in order to make the regions of Romania, especially the less developed ones, more attractive places for living, visiting, investing and working. The specific objectives are:  The growth of the economical and social role of the urban centers by adopting a polycentric approach in order to stimulate a more balanced development of the Regions  The improvement of the accessibility of the Regions and particularly of the accessibility of the urban centers and the connections with the surrounding areas  The growth of the social substructure quality of the Regions  The growth of the competitiveness of the Regions as business locations  The growth of the contribution of the tourism to the development of the Regions. Economical Competitiveness Growth Sectoral Operational Programme – POS CCE The main objective of the POS CCE is the growth of the productivity of the Romanian companies for the decrease of the disparities to the medium productivity at the Union level. The taken measures will generate by 2015 a medium productivity growth of approximately 5,5% annually and will allow Romania to achieve a level of approximately 55% of the EU average. Specific objectives:  The consolidation and sustainable development of the productive sector;  The building of a favorable environment for the sustainable development of the companies;  The growth of the research development capacity (C&D), the stimulation of the cooperation between research development innovation institutions (CDI) and companies, as well as the growth of the companies access at CDI;  The exploitation of the information and communication technology and its application in the public sector (administration) and the private one (companies, citizens);  The growth of the energetic efficiency and the sustainable development of the energetic system by promoting the renewable energy sources. Human Resources Development Sectoral Operational Programme – POSDRU The main objective of POS DRU is the development of the human resources and the growth of the competitiveness by correlating education and learning during the whole life with the labor market and the insurance of an increased opportunity for a future participation to a modern, flexible and inclusive labor market for 1.650.000 people. Specific objectives:  Promoting of the quality of the education system and initial and continuous professional development system, including the higher education and research;  Promoting of the entrepreneurial culture and improvement of the work quality and productivity;  Facilitating the insertion of the youth and long term unemployed in the labor market;  Development of a modern, flexible and inclusive labor market;  Promoting of the (re)insertion in the labor market of the inactive persons, including the rural areas;  Improvement of the public employment services;  Facilitating of the access to education and to the labor market of the vulnerable groups. 51

Environment Sectoral Operational Programme – POS MEDIU The main objective of POS Mediu is to reduce the existing imbalance between European Union and Romania regarding qualitatively and quantitatively environmental substructure. This should materialize in effective public services, taking into consideration the sustainable development principle and of the principle “the pollutant pays”. The specific objectives are:  Improvement of the quality and of the access to the water and waste water substructure by ensuring the services of water supply and canalization in the majority of the urban areas until 2015.  Development of the sustainable systems of waste management by improving the waste management and by decreasing the number of long term polluted areas in at least 30 counties until 2015.  Decrease of the negative impact caused by the urban heating systems in the most polluted towns until 2015.  Protection and improvement of the biodiversity and of the natural heritage by supporting the management of the protected areas, including the implementation of the network Natura 2000 (Nature 2000).  Decrease of the risk of natural disasters that affect the population by implementing precautionary measures in the most vulnerable areas until 2015. Transport Sectoral Operational Programme – POS Transport The main objective of POS Transport is the promoting in Romania of a sustainable transport system that would allow the fast, effective and safe circulation of people and goods, services at a level according to the European standards, at national level, inside Europe, between and inside the regions of Romania. The specific objectives are:  update and development of the TEN-T priority axis by applying the measures needed for the environment protection  update and development of the national transport networks according to the sustainable development principles  promoting of the railway, naval and intermodal transport  supporting the development of the sustainable transport by the minimization of the side effects of the transport on the environment and the improvement of the traffic safety and human health. Administrative Capacity Development Sectoral Operational Programme –PODCA The main objective of PO DCA is to contribute to creating a more effective and efficient public administration to the socio-economical benefit of the Romanian society. Specific objectives:  Obtaining structural and process improvements of the management of the public policies cycle.  Improving the quality and performance of the public services, insisting on the decentralization process. Technical Assistance Operational Programme – POAT The main objective of the Technical Assistance Operational Programme is to ensure the support needed for the healthy, efficient, efficacious and transparent coordination and implementation process of the structural instruments in Romania. The specific objectives are:  Providing the support and adequate instruments in order to coordinate and efficient and effective implementation of the structural instruments for the period 2007-2013 and prepare for the next period the programming of the structural instruments.  Providing a nationally coordinated dissemination of the general messages regarding the structural instruments and the implementation of the Action Plan of ACIS for communication, connected to the National Communication Strategy for Structural Instruments. Rural Development National Programme – PNDR The European Agricultural Fund for Rural Development (FEADR) is an instrument for financing, created by the European Union in order to support the member countries in the implementation of the Common Agricultural Policy. The Common Agricultural Policy is a set of rules and mechanisms that controls the production, processing and commercialization of the agricultural products in the European Union and pays special attention to the implementation of the rural development.

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FEADR represents a financing opportunity for the Romanian rural space, with a value of approximate 7,5 milliards EURO, beginning with 2007 until 2013. FEADR is based on the principle of co-financing the private investments projects. The European funds for agriculture may be accessed based on the key- document Rural Development National Programme (PNDR ). Fishing Operational Programme – POP The Fishing Operational Programme of Romania ( POP) contributes to the accomplishment of the strategic vision formulated in the National Strategic Plan for Fishing, namely: ”A competitive fishing sector , modern and dynamic, based on sustainable activities of fishing and aquaculture that takes into account the aspects regarding the environmental conservancy, the social development and the economic welfare”. The specific objectives are:  The development of the competitiveness and sustainability of the primary fishing sector ;  The development of the specific market for the fishing sector products;  The support of the sustainable development of the fishing areas and the improvement of the life quality in those areas;  The support of an adequate implementation of OP inside of the Common Policy for Fishing,  Inside the Economical Competitiveness Growth Sectoral Operational Programme – POS CCE there are: The priority axis 2 – Competitiveness by research, technological development and innovation Major intervention domain 2.2.- Investments for the Research Development Innovation infrastructure. Operation 2.2.2.: Developing poles of excellence Inside the Human Resources Development Sectoral Operational Programme – POSDRU there are: The priority axis 1 :” Education and professional training to support the economic growth and society development based on knowledge”  Major intervention domain 1.1 “Doctoral and postdoctoral programmes to support the research” aims to support the development of a flexible way of learning during all life and to improve the access to education and learning by providing modern and good quality education and training, including the university learning and research.  Major intervention domain 1.2 “Quality in university learning” The programme priorities are: the reorganization and modernization of the university learning as a system and also regarding the universities;  the development and implementation of the National Qualification Frame in University Learning;  the development and implementation of a national system to assurance and management of quality; the development and implementation of the national qualifications system and assurance of the quality in university learning;  the improvement of the university management;  the increasing of the relevance of the university learning for the labour market and for the society based on knowledge, by better university study programmes. Territorial Cooperation Programme These are:  Cross-border Territorial Cooperation The cross-border cooperation programmes are programmes that finance accesibility projects, environment, risk prevention, economic and social development projects and activities “people to people at the internal and external borders of UE”.  Transnational Territorial Cooperation The transnational cooperation programmes have as main objective the financing of activities and developing of networks that are able to lead to integrated territorial development in fields as environment, urban development, innovation and accessibility.  Interregional Territorial Cooperation The Interregional Territorial Cooperation programmes support the cooperation between the public authorities regarding common interest issues, through experience and good practice transfer between the regions of the European Union, by establishing networks between the UE towns and also between the EU researchers.

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   

For the development of the university learning an research funds may be accessed also through projects financed inside the International Programme FP7 – Frame Programme 7. This programme is structured in following subprograms: Cooperation; Ideas; Human resources; Capacities. The attraction of European funds, of national dedicated funds CDI and of national programmed inside funds represents a necessity for the sustainable development of the Romanian university learning and research.

Bibliography: http://uefiscdi.gov.ro/articole/1559/SCOP.html http://uefiscdi.gov.ro/articole/1560/SCOP.html http://uefiscdi.gov.ro/articole/1561/SCOP.html http://uefiscdi.gov.ro/articole/2597/SCOP.html http://uefiscdi.gov.ro/articole/2980/Proiecte-de-cooperare-bilaterala.html http://uefiscdi.gov.ro/articole/3031/Proiecte-de-cofinatare-a participarii-Romanieli-la PC-7.html http://uefiscdi.gov.ro/articole/3005/Proievte-ERC-uri.html http://uefiscdi.gov.ro/articole/1772/Articole.html http://uefiscdi.gov.ro/articole/1967/Proiecte-de-cercetare-postdoctorală-tip-PD.html http://uefiscdi.gov.ro/articole/1966/Proiecte-de-cercetare-pentru –stimularea-constituirii-de-tinereechipe-de-cercetare-independente-ti.html http://uefiscdi.gov.ro/articole/2992/Proiecte-colaborative-de-cercetare-aplicativa.html http://uefiscdi.gov.ro/articole/2325/INOTECH.html http://uefiscdi.gov.ro/articole/3118/Stimularea-Exportului-HIGH-TECH.html http://uefiscdi.gov.ro/articole/2859/Cercuri-de-inovare.html

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NASAL POLYPOSIS – A LIFE TIME EVOLUTION TO MALIGNANCY. CASE REPORT Stoica Cristina, Zainea Viorel Institute of Phono-Audiology and Functional ENT Surgery “Prof. Dr. D. Hociota” - Bucharest, Romania. Abstract: Nasal Polyposis represents a frequent pathology in the ENT daily practice requiring complex and combined medical and surgical treatment, often with many surgical interventions for the same case. Presenting this case we underline the importance of the following-up every case of Nasal Polyposis, the significance of Hystopathological exam – multiple samples at every surgery, the ability to adapt the treatment, including new surgical technics and technologies to every stage of disease evolution. “As a doctor you must be always one step in front of the illness” Introduction: Having in mind EPOS - Evidence-based management scheme for adults with Nasal Polyposis for ENT-Specialists and EPOS Evidence – based surgery for rhinosinusitis, the aim of the paper is to present "life time evolution" of a nasal polyposis case to an extensive and invasive malignant tumor of the sinuses and skull base during 22 years. Method consists in a clinical selected case. A male patient presented himself in our clinic for Chronic Rhinosinusitis with Nasal Polyposis, after multiple surgical interventions in other ENT clinics. After his last surgery the Hystopathological and IHC result was Inverted Papilloma. Preoperative CT scan revealed the extension of the tumor lesions to the ethmoid, maxillary, sphenoid sinuses, nasal fossa with the invasion of orbit on the right side - fig. 1: First surgery in our clinic consisted in combined approach - lateral rhinothomy and endoscopic control using new technologies as Radiofrequency in order to control and clean all tumor lesions preserving ocular globe (the periostum was intact) - fig. 2:

Fig. 1

Fig. 2

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Hystopathological result was Islands of Epidhermoid carcinoma in inverted papilloma mass. The patient went for Radiotherapy with follow-up at every 6 months. After 18 months the patient was admitted in our clinic for a tumor lesion on the external part of the lateral bone of the nose on the right side (fig. 3). CT scan identified tumor lesions in ethmoid, maxillary, sphenoid sinuses, nasal fossa with external extension to lateral bone of the nose and skin and invasion of the right orbit and skull base.

Fig. 3

The last surgery in our clinic consisted in combined approach - lateral rhinothomy and endoscopic control using new technologies as Radiofrequency preserving again the ocular globe, followed by reconstruction surgery on irradiated field - fig. 4 and fig. 5:

Fig. 4

Fig. 5

CT scan 6 months after final surgery revealed tumor free sinus cavities - fig. 6:

Fig. 6

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Discusions: New research data shows that it is most likely that stem cells are directly involved in the developmental processes. There are studies that focus on the identification and characterization of potential stem cells in nasal polyposis and the molecular regulation of growth and regeneration. Among them is one held in Department of Otorhinolaryngology, University of Lübeck, Germany (A. Hagge, S. Reers, R. Pries, B. Wollenberg). These researchers analyzed by flow cytometry single cell suspensions of polyposis nasi concerning their surface characteristics as well as their proliferation and self-renewal capacities. They identified different cell subsets in polyposis nasi that show different expression levels of potential stem cell markers CD44 and CD59 and strong similarities to solid HNSCC tissue samples. Their data provide novel insights in the origin of polyposis nasi as well as in the role of stem cells in benignant and malignant neoplasm of the head and neck. Conclusions Recurrence of nasal polyposis is higher from second surgery. Recurrence of papillomatos lesions has high risk for malignancy. Risk of evolution to malignancy underline the significance of patient follow-up in nasal polyposis and ethmoidal papillomatos lesions. This paper emphasize also the impotance of preoperative CT +/-MRI in showing the extension of the lesions and helping the surgeon to choose the best approach. Hystopathological exam is very important – at every surgery – multiple samples in order to have an early diagnosis when methaplasia took place (take care in endoscopic sinus surgery with shaver). The ability to adapt the treatment, including new surgical technics and technologies to every stage of the disease evolution is a value instrument for the doctor in order to control this pathology. We have the hope of developing research – to identify different markers – as those from stem cells - in polypoid tissue with high risk of recurrence and evolution to malignancy. References A. HAGGE, S. REERS, R. PRIES, B. WOLLENBERG - A185 Stem cell characteristics of polyposis nasi European Archives of Oto Rhino Laryngology and Head and Neck vol 266/Number 7 July 2009 BALLANGER J.J. and col. Disease of the Nose Throat Ear Head and Neck Lea & Febiger, Philadelphia 1991 BECKER W. NAUMANN H. PLATZ C. - Ear, Nose & Throat Diseases – A Pocket Reference Georg Thieme Verlag Stuttgart. New York 1989 Prof. Dr. R. CALARASU, Prof. Dr. T. ATAMAN Conf. Dr. V. ZAINEA - Manual de patologie otolaringologica si chirurgie cervicofaciala – Editura Universitara “ Carol Davila” 2002 CHARLES W. CUMMINGS M.D. Otolaringology – Head and Neck Surgery – second edition.

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DELIBERATE HYPOTENSION – OLD AND NEW INTRAANAESTHETIC METHOD FOR HEAD AND NECK ONCOLOGICAL SURGERY Tîrîș Cornelia Ilfov County Emergency Clinical Hospital, Anaesthesiology and Intensive Care Department, Bucharest – Romania

Abstract Surgery for head and neck malignancies often involves long, laborious dissections and/or major facial reconstructions. The aim of this study was to evaluate the blood volume loss during surgery for normovolemic patients, who suffered total laryngectomy for malignant tumors under the conditions of normal blood pressure values by comparison with deliberate hypotension. 76 adult patients that underwent total laryngectomy and “radical neck dissection” were included in the study. The achievement of the deliberate hypotension was realized by pharmacological means using greater doses of opioid to maintain general anaesthesia or by adding direct vasodilatation drugs. 4 patients from the studied group presented electrical disturbances on the EKG. 8 patients presented with post-operative anuria for 6 hours.

Key – words: Deliberate hypothension, head and neck oncologic surgery, opioids, tissue perfusion.

Introduction Surgery for head and neck malignancies often involves long, laborious dissections and/or major facial reconstructions. The consequent blood loss can be rapid, considerable and life – threatening. The deliberate anaesthetic reduction of blood pressure has the purpose both to diminish the blood transfusion necessity with it’s own implied risks and complications and to improve the surgeon’s visibility. It is a well known fact that the mechanism of circulatory auto-regulation allows for blood flow preservation within the vital organs for medium blood pressure values of 50-150 mmHg due to the decrease of the vascular resistance in a linear correlation with the blood pressure diminution. The major risk of a deliberate hypotension, that can overcome the potential benefits at any time, is represented by hypo-perfusion of the vital organs with transitory or permanent functional effects. That is why a safe, minimal working value for this technique is 65 mmHg for the medium arterial blood pressure, as recommended in the literature. The aim of this study was to evaluate the blood volume loss during surgery for normovolemic patients, who suffered total laryngectomy for malignant tumors under the conditions of normal blood pressure values by comparison with deliberate hypotension. Material and methods After obtaining the Ethics Committee Approval and the written informed consent, 76 adult patients that underwent total laryngectomy and “radical neck dissection” were included in the study. The exclusion criteria were: age over 70 years and conditions which severely modify the relationship between the provided oxygen and tissue oxygen consumption such as: coronary and carotid stenosis, cerebral oedema, policitemia, hypovolemia, and serious anaemia, decompensated liver cirrhosis, medular compression, chronic renal insufficiency. Before surgery, haemoglobin value was established at the 8 g/dl mark and the haematocrit value at about 40%. The complex intra-operative monitoring implied the standard parameters ( EKG, pulsoximetry, central venous blood pressure, urinary output, non-invasive BP) and invasive determination of mean blood pressure by arterial catheter (fitted up at radial or femoral artery level). In this way, the arterial blood gases (paO2 and paCO2), the blood glucose, electrolytes and serum lactate level, known as early and proper inadequate cellular perfusion marker, were determined. The achievement of the deliberate hypotension was realized by pharmacological means using greater doses of Opioid to maintain general anaesthesia or by adding direct vasodilatation drugs (Nitroglycerine, Sodium Nitroprusside) or β – adrenergic receptor blocking drugs (Esmolol). Additionally, the patients benefited from a correct placement on the operation table, with the head elevated to 15 degrees as well as mechanical intra-op. ventilation with PEEP in order to reduce the venous return. 58

A number of 38 patients were scheduled for deliberate hypotension, the rest represent the reference group to which standard general anaesthesia was administrated. The average surgical operation time was approximately 3 hours and the intra-operatively fluid replacement was realized at the maximum level (4 – 8ml/kg/h). Just before wound closure, the deliberated hypotension reversion was initiated in order to verify the haemostatic efficiency. The blood loss was evaluated by comparing the serum values of the haemoglobin and the haematocrit before and after surgery. At the myocardium level, the diminished cardiac output (CO) can temporarily compromise certain territories (tributary to some blood vessels already modified by atheroma plaque). By this physiological effect, myocardium ischaemia can be dangerously initiated or worsened. The correct volume replacement maintains the preload within normal limits and plays a protective role. At the kidney level, the severe hypo-perfusion, even for short periods (a few hours) especially at elderly persons with vascular disease, can lead to irreversible functional alterations (nitrous oxide retention). Results The blood loss was insignificant (a medium decrease of 0,5 g/dl postoperatively compared to the reference value) during surgery within the studied group. It was noticed that for patients with normal blood pressure under general anaesthesia, haemoglobin value diminished by approximately 2 g/dl. The relative myocardium hypo-perfusion had no clinical correspondence (angor pectoris, dyspnoea) after surgery at any of the patients. 4 patients from the studied group presented electrical disturbances on the EKG (abnormalities of the ST segment) which spontaneously disappeared and were not accompanied by growth of myocardium enzymes. The long lasting surgery (over 4 hours) may play a role. The kidney response at both groups was minimal oliguria (urinary output of 0,2 – 0,4 ml/kg/h). 8 patients presented with post-operative anuria for 6 hours. They did not respond to additional volume infusion and they benefited from diuresis stimulation with Furosemide (repeated doses of 20 mg/h). Serum Creatinine level was not influenced. Short confusional episodes, as a result of the cerebral hypo-perfusion appeared at the older patients (over 60 years) and at some chronic ethanol abusers and were probably intensified by the “tactical” ligature of a carotid branch caught within the tumor. Ischemic optic atrophy, quoted by literature and manifested by variable visual field deficits was not reported. Although arterial blood gases were in normal ranges at both groups, for 10 patients of the hypotension group, the serum lactate level was slightly elevated (over 2,5 mmol/l). Conclusions Hypotension is not synonymus with inadequate tissue perfusion as long as organ vascular resistance decreases parallel to blood pressure (BP). The reduction of the blood loss is not directly related to the degree of the deliberate hypotension. The transfusion necessity does not appear if the preoperative haemoglobin value is higher than 8 g/dl and the surgery time remains under 3 hours. Even though “old“, the deliberate hypotension technique can return in the actual anaesthetic practice under safer conditions, for carefully selected patients with strong indication (very rare blood type, blood transfusion refusal or anticipated surgical difficulties). The present level of the technical evolution allows the slow reversion of the deliberate hypotension induced by Opioids. The patients can be mechanically ventilated until complete disappearance of the respiratory depression, fully using the residual analgesic effect of long – lasting Opioids (Fentanyl, Sufentanyl).

References: 1. HUMPHREY Y., Deliberate hypotension. Anesthesia Secrets, In: DUKE Y., Ed. Mosby 2006, 3rd Edition, 77: 484 – 487. 2. GURMAN G.: Deliberate hypotension – What is for and what is against using it?, In: Recomandari si protocoale in Anestezie, Terapie Intensiva si Medicina de Urgenta sub redactia SANDESC D., BEDREAG O., PAPURICA M. Ed. Mirton : 685 – 688 3. MORGAN E. G., MICKHAIL M. S., MURRAY M. J., LARSON PH. C., Clinical Anesthesiology, Ed. Mc. Graw – Hill, 2002, 3rd edition; 39: 771 – 780.

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CLINICAL AND ENDOSCOPIC LONG TERM SURVEY AFTER LAPAROSCOPIC SURGERY IN HIATAL HERNIAS Florin-Dan Ungureanu., Witing Clinical Hospital – General Surgery Department, Titu Maiorescu University – Faculty of Medicine. Laurentiu U., Witing Clinical Hospital – General Surgery Department Cosmin M., Witing Clinical Hospital – General Surgery Department, Titu Maiorescu University – Faculty of Medicine. Madalina T., Witing Clinical Hospital – General Surgery Department, Titu Maiorescu University – Faculty of Medicine. Gabriel Lopez-Cobena, Oral and Maxilo-Facial Surgery, Targu Mures Clinical Emergency Hospital Abstract: The authors discuss 281 coelioscopic antireflux procedures, carried out for transhiatal hernia accompanied by gastro-esophageal reflux, during a period of 16 years, between 1996 and 2012. The aim of this research is a clinical and technical comparative study between the posterior total or partial fundoplication and the anatomical procedures. In order to have a complete evaluation of the risks and results, the authors discuss the indications of each procedure, a series of specific intra and post-operatory complications, including conversions and secondary reinterventions for each procedure. The authors also refer to the difficulty degree, the time required for each procedure in order to find out the ways of improving these parameters. Although the number of patients is quite small, in this experience posterior fundoplication seems easier and safer, whenever possible. The Nissen procedure, of which technique is more laborious seems to offer a better post-operatory evolution and more long - lasting results in time. Key words: transhiatal hernia, laparoscopic repair, surgical strategy. Introduction Our research carried on for an approximate period of 16 years, 1996 – 2012, and it integrates a number of 281 cases of which 200 cases have been operated by the same team, some in The Digestive Surgery Clinic of The Caritas Clinic Hospital, Bucharest and the others in The Surgery Clinic of the CF Witing University Hospital from Bucharest. Even though operated in two different clinics, the casuistic beneficiated of an unitary conception, both under the aspect of imagistic explorations and surgical strategy as well as technical execution and post-operatory control. In the before mentioned period of time 281 cases have been laparoscopically approached, of which only 279 cases have been finalized laparoscopically, this study excluding the three conversions as being surgically unadvisable cases or gastro-esophageal reflux cases without hiatal hernia, respectively patients that are under medical treatment and continuous observation. One of the objectives of this study is the principle laparoscopic approach of each case, excepting those expressly unadvisable of pneumoperitoneum which if classically approached would have been excluded. The reasons for adopting this approach are first of all the magnitude of the laparoscopic image of the esophageal hiatus region and the surgical comfort given by the laparoscopic technique in an anatomic area of depth where both visibility as well as surgical maneuvers are more restricted using the classical approach. Maybe another reason of equal importance for choosing the laparoscopic technique is the mirage of postsurgical evolution which can be appreciated only by a surgeon having experienced both techniques. Furthermore, even the few secondary reinterventions that have been approached laparoscopically have also had great results. Actually, this research begins from the fact that once the surgical indication is established, no matter the anterior stipulated surgical tactic, intra-operatory we will confront with the anatomic particularities or anomalies of each single case, so that adapting each case to a standard technique is actually impossible. Hence various options of surgical procedures, surgery being adapted during dissection or rather being prefigured by preoperatory investigations and decided by local anatomic conditions, the final montage decision being the result of true pre- and intra-operatory strategy. This adaptation of surgical technique to local conditions however had a limit, indicated by the volume of the hiatal hernia as well as by the severity degree of the esophagitis. As the esophagitis lesions aggravated, it was more necessary to carry out a montage type of total or partial posterior fundoplication which has greater antireflux efficiencies. At the opposite side we have giant or type III hiatal hernias, sometimes even without gastro-esophageal reflux, where of maximum importance was the hernia reduction in the abdomen and the recalibration or prosthesis of the hiatal imperfection/flaw, considering the antireflux montage being a compliance measure [1].

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Another limit would be established by pre-operatory imagistics, which if correctly interpreted may definitely contraindicate the celioscopic approach in favor of the thoracic approach intervention as shortesophage or paraesophageal giant upside-down type hernias. In the following notes we will try to systematize the multitude of factors which are to be considered in completing the antireflux montage, preferably for the laparoscopic approach. Material and method From the 281 cases under observation, during 1996 – 2012 a number of 279 cases have been operated and finalized laparoscopically, cases being diagnosed with hiatal hernia of different types, with different degrees of acid gastro-esophageal reflux and different stages of reflux esophagitis. From the 279 cases approached laparoscopically : the Nissen – Rossetti procedure in 127 cases, respectively 46%; the Floppy – Nissen procedure in 115 respectively 41%; the Toupet procedure in 22 cases, respectively 8%; the Dor or Nonnaile procedure in 8 cases, respectively 3%; and the Lucius Hill procedure in 5 cases, respectively 2%. A number of 3 cases (1.06%) needed conversion, we performed laparoscopic reintervention in two cases (0,7%), performing associated interventions in 7 cases, respectively 9,8%. Here follows the anatomic and functional classification of the hiatal hernias from our series, taken over from Ackerlund and modified by Cadiere:  Type I (sliding), with three evolutionary stages: • St. I (Hiatal Hernias+/- , gastro-esophageal reflux +) = 12 cases; • St. II (Hiatal Hernias +, gastro-esophageal reflux +/-) = 35 cases (2 without reflux signs); • St. III (Hiatal Hernias+, gastro-esophageal reflux +) = 5 cases;  Type II (para-esophageal), 12 cases (8 without reflux signs);  Type III (mixt), 4 cases. Esophageal pathology evaluated by superior digestive endoscopy was as follows:  Esophagitis : • I-st degree - 11 cases; • II-nd degree - 29 cases; • III-rd degree - 12 cases; • IV-th degree - 0 cases;  Barrett Esophagus - 6 cases;  Without esophagitis signs: 10 cases; The pathology associated with operated hiatal hernias was represented as follows: vesicular litiasis (8 cases), obesity (22 cases), operated abdomen (in 5 cases), ischemic cardiopathy/heart disease (in 12 cases) and varicose (vein) disease (in 6 cases). The following operatory procedures have been used in this series: 1. The Nissen – Rossetti operation, the total fundoplication of 360 degrees respecting the gastro-splenic ligament, has been carried out in a number of 127 cases, respectively 46%, representing the surgical technique we prefer whenever montage was imposed by the severity of the esophagitis and local conditions allowed the avoidance of short vein sectioning. The rationality of this preference, especially at the beginning of an experience, consists of the avoidance as possible of complications inherent to short vein sectioning, whether this technique is carried out through clipping, using the ultrasound scissors or using the Liga-Sure® device. As long as the dissection of the abdominal esophagus on the right and left margin assures the easy attainment of a wide retroesophageal window, and the gastric material of the greater curvature allows the easy sliding of the posterior valve and a tensionless anterior contact between the two valves, has enough arguments that can support avoiding the sectioning of the gastro-splenic ligament. After placing the two valves in anterior contact, the condition of a wide and unobstructive disposition is the stability and the lack of displacement of the valves, these being left loose after removing the clamps [1]. The procedure of this montage is identical with the Floppy- Nissen procedure, the height of the valve being of maximum 2 cm, being fixed with two different non-absorbable sutures, of which the first also passes the esophagus for avoiding telescoping. (Fig. 1).

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Fig. 1 2. The Floppy-Nissen procedure represents a laparoscopic adaptation of a classic operation, slightly different in the modern variant. The base principle of the original technique described by Nissen in 1956 consists of bending of the gastric fundus around the abdominal esophagus, thus leaving the short vessels and esophageal hiatus intact. Numerous adaptations have been added in time to this technique, as: esophageal hiatus recalibration, a wider or limited mobilization of the greater gastric curvature through short vessel sectioning, modifying the width or height of the valve or reducing the number of suture points of the two valves. Dallmagne recommends the technique he practices and its principles stipulated by Donahue, Bombek and De Meester [2], consisting of: • short vessel sectioning with the mobilization of the great gastric curvature; • recalibration of the esophageal hiatus; • narrow total fundoplication, of maximum 2 cm.; • wide montage, Floppy – Nissen procedure; • montage fixing with 2 – 3 suture points, the first being fixed in the esophagus. We have applied the same procedure in 115 cases, respectively 41%, and its final indications were established intra-operatory, conditioned by the anatomic and technical loco-regional data. One of the fundamental principles of the mechanic antireflux interventions, fundoplication type is the absence of tension in montage realization, which must perfectly fit, a principle that is poles apart to anatomic procedures that require tension in montage realization such as Lucius Hill procedure or fixation with round ligament, both requiring intra-operatory manometric determination [3]. For this precise purpose of avoiding montage tension there is a series of conditions that must be satisfied, such as: having a convenient length of the abdominal esophagus of over 3 cm after dissection, having a wide o retro-esophageal window and sufficient gastric material of the great tuberosity for accomplishing a complete and wide bending of the abdominal esophagus [4]. The first objective is accomplishing the retro-esophageal window and the dissection of the abdominal esophagus. After sectioning the small epiploon until the diaphragm, we continue the dissection towards the right diaphragmatic arch, descending until the convergence of the arches, next liberating the left arch on its anterior side, upwards in order to avoid the dissection slipping in the mediastin. Then we continue dissecting the anterior side of the esophagus sectioning through the freno-esofageal membrane and the Gregoire gastrofrenic ligament, progressing to the left side of the esophagus where we will reach the anterior liberated side of the left diaphragmatic arch. We make a traction using a string or plastic tube passed retro-esophageal, moment in which we will be able to appreciate by traction both the length of the abdominal esophagus as well as the width of the retro-esophageal window. A length between 3 and 5 cm of the abdominal esophagus supposes a wide breach in the retroesophageal space, which we will continue enlarging through blunt dissection in order to avoid vascular or esophageal lesions. 62

From this moment, our montage depends on the generosity of the gastric material of the great stomach tuberosities. Sometimes the anterior side of the stomach easily yields to a total fundoplication, reason why short vessel sectioning is no longer necessary and fundoplication realization as Nissen-Rossetti procedure is easy attainable. If somehow the posterior valve comes with difficulty, the gastric material of the anterior side obviously being insufficient and the traction of the valve opposing a considerable tension, the sectioning of short vessels becomes necessary in order to accomplish a total wide and short fundoplication which will now use the posterior gastric side, the manner of montage this time being in the short variant of Floppy-Nissen. In the moment when not even after sectioning the short vessels and mobilizing the great gastric tuberosities, the posterior valve doesn’t allow a complete fundoplication because of insufficient gastric material and the montage tension at tractioning the posterior valve, that is when the procedure to be done is to be listed among the posterior partial fundoplication, between 180, 270 and 300 degrees, respectively the Toupet procedure. In the conditions of a small stomach, with all the liberation of the abdominal esophagus and of the cardioesophageal junction for expanding the retro-esophageal portii, there is the risk of misplacing the valve around the superior gastric pole and not around the esophagus, with all the possible consequences (suture cession, valve rupture, thoracic herniation, high gastric stenosis or even a small post-operatory stomach) [1]. We believe that in these cases the choosing of an anatomic procedure would be more appropriate. The recalibration of the esophageal hiatus is an imperative gesture of the Nissen surgery because of the extension of the dissection into the abdomen, thorax, towards the greater gastric curvature so that achieving a wider retro-esophageal window also requires a better hiatal recalibration. Usually we carry out this recalibration each time with two or at most three separate sutures, the limit being marked by an open Babcock® device, which would indicate the limit of the maximum opening of the new hiatal orifice [1]. Another modality of recalibration control would be the minimum distance of a Babcock® device, between the esophagus and the margins of the reconstructed hiatal orifice [4]. 3. The Toupet Procedure. Imagined in the conditions of a diminished esophageal propulsion force, because of an old advanced and untreated esophagitis, accompanied by the scar alteration of esophageal musculature, this operation remains for the cases that have precarious esophageal contractility and don’t allow normal deglutition in front of a 360 degree valve, respectively of a complete fundoplication, implying an increased degree of postoperatory dysphagia [5]. Main diagnosis criteria of esophageal propulsion force decrease, it belongs unquestionable to manometry, which can even offer concrete pressure values, even though radiology as well as endoscopy can approximately estimate this contraction capacity according to the amplitude of the peristaltic waves and the configuration of the thoracic esophagus. Another surgical indication of this procedure has been reported at the lack of sufficient gastric material to obtain a complete fundoplication with all the ample mobilization of the greater gastric curvature when having a small stomach. Every time we observed that the posterior valve tensions or the two valves loose contact after device removal, and the loosened posterior valve retracts through the retro-esophageal breach along with the entire sectioning of short vessels, we preferred a Toupet type montage. (Fig. 3).

Fig. 2

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However when the esophageal contractility is compromised, if the retro-esophageal window allows it and the gastric material is generous, we regularly renounce at short vessel sectioning – which would have no extra contribution in the surgical comfort. Actually none of the original Nissen or Toupet procedures include short vessel sectioning or the mobilization of the greater gastric curvature [6]. This technical artifice has been adopted in time so as to allow an easier mobilization of the great tuberosities, without being indispensable and without blocking the function of the gastric material we dispose of, thus obtaining a partial posterior fundoplication in the 180, 270 or even 300 degree manner, even if it only uses the anterior gastric side. The same considerations refer to the recalibration of the esophageal hiatus that we apply each time according to the principle of repairing what we damaged during dissection. In the case of the Toupet procedure, fixing the posterior valve to the right diaphragmatic arch and then to the right and left margin of the esophagus is so firm and complex that the recalibration of the esophageal hiatus can be made optionally, the migration or telescoping of the montage being excluded. 4. The Dor procedure is technically placed at the limit between mechanic and anatomic procedures. This operation supposes both reestablishing the normal anatomic reports of the cardio-esophageal region between the stomach, esophagus and diaphragmatic arches as well as obtaining of an antireflux anterior gastric hemivalve fixed on the right arch [1]. By principle we continue by completing it with a gastric fixation of the anterior valve at the cranial contour of the esophageal hiatus. (Fig. 4).

Fig. 3

Simple enough to realize both classic as well as laparoscopic, the Dor procedure represents for us an exceptional solution in sometimes extremely delicate situations. Some of the objectives of antireflux interventions are: they have the virtue of bringing back the eso-gastric junction, respectively the esophageal sphincter in the abdomen in order to suppose it to abdominal pressures , they reduce hiatal hernia, they reconstruct the angle of Hiss and implicit the valve of Gubaroff, being controversial enough in reestablishing the sphincterian and valve mechanisms. It seems that the anterior hemivalve doesn’t oppose such a great antireflux resistance as to determine in all the cases its definitive suppression. The procedure yields to solving voluminous or even giant hiatal hernias that have no acid/gastro-esophageal reflux, where we consider that the antireflux montage would only be made for compliance and realize the retroesophageal window faces difficulties without at least one concrete motif. In these cases first of all matters the reduction of the hiatal hernia and its contents in the peritoneal cavity and the recalibration or the closing of the diaphragmatic breach of the herniated orifice [1]. We haven’t used substitution textile material in any case, but in exchange have often performed a posterior and anterior recalibration as tight as possible, and after fixing the anterior valve to the right arch we continued fixing the great gastric tuberozity at the margin of the herniated orifice, anterior of the esophagus, from the right arch to the left one, realizing in addition a gastric fixation of the anterior valve. We mention that the suture of both arches is not part of the original technique described by Dor, this actually being the Nonaille procedure that realize an anterior hemivalve after the reconstruction of the Hiss angle, followed by the posterior recalibration of the esophageal hiatus [1]. 64

If the key to antireflux interventions total or posterior fundoplication type lies in the realize of the retroesophageal window, any severe impediment in accomplishing this goal automatically leads to choosing another procedure, as the Dor, Nonaille or Hill procedures. Here are some hypostases: a. Short esophagus. We have chosen this procedure whenever the abdominal esophagus with the entire performed advanced transhiatal dissection didn’t allow the maintaining of the cardio-esophageal junction in the abdomen, which immediately retracted in the mediastinum once the traction ceased. In such situations, dealing with a possible brahi-esophagus, our entire attention was directed towards the dissection of the esophagus in the mediastinum, in order to allow an ample esophageal mobilization that will allow keeping the cardia in the abdomen. Yet sometimes, with all the persistence, a more ample mobilization of the abdominal esophagus seemed impossible and the progression of the intra-mediastinal dissection was risky. Even though we succeeded in placing the cardia under the diaphragm, being impossible to partially reestablish the length of the abdominal esophagus for realizing a retro-esophageal window capable of allowing the easy sliding of the posterior valve, given the conditions we relinquished in performing a total or posterior fundoplication. b. Vascular anomaly. We have encountered anomalies or variants of the left hepatic artery coming from the left gastric artery, crossing the small epiploon directly in front of the right arch, thus not allowing the posterior dissection approach of the esophagus neither cranial nor caudal of this vein. For sectioning it, a super-selective arteriography of the celiac trunchi was required; it would attest the possibilities of bypassing the hepatic vascularization. Being known that in 23% of the cases, this artery represents the only arterial ram destined to the left liver. Not being able to beneficiate of any arteriographic control, we preferred realizing of an anterior fundoplication. In another case we encountered a high emergence of the celiac branch, in the immediate proximity where the two diaphragmatic arches split, completely occupying the access towards accomplishing of the retro-esophageal window, which lead to the same solution. c. Periesophagitis, lateral but especially posterior, sometimes consisted a severe impediment in approaching the arches and the retro-esophageal window, because of a prolonged evolution of a severe reflux esophagitis. Because of the peri-esophageal sclerosis tissue the dissection was blocked by excessive bleeding or by the risk of some lesions of the nearby organs, impossible to separate from the esophagus, as arches, aorta or even the freno-esophageal membrane. d. Extreme obesity, represented another huge handicap in approaching the esophageal hiatus of whose dissection in some of these situations was also limited by the lack of adequate relaxation or by rather superficial anesthesia, due to time extension of the surgical act. None of these cases allowed a posterior fundoplication type montage, in exchange we will get back in this direction also with other observations in which being unsatisfied with the Dor procedure in surgery we have resorted to gastric fixation of the arched ligament, respectively the Lucius Hill procedure. 5. The Lucius Hill Procedure. Along with the Lortat – Jacob or Narbona procedure is one of its anatomic prototype procedures, targeting the reestablishment of normal anatomic reports between the cardio-esophageal junction and the diaphragmatic arches, and also targeting to restore the abdominal esophagus its normal physiological length based on the report between length and tension enounced by Starling’s law [3]. The esophagus and cardia are reintegrated in the peritoneal cavity, the next step being the reconstruction of the Hiss angle and the recalibration of the esophageal hiatus, while the cardiopexia of the arched ligament and the preaortic fascia are using the anterior section and partially the distal lateral sectioning of the frenoesophageal membrane under the control of manometry. The suture of the arches and an anterior gastric fixation complete the accomplish of this procedure. We have accomplished this procedure in 5 cases without being able to exceed the maximum pressure of 20 mm Hg from the moment of making the extra-corporal knots and thus establishing the montage tension (Fig 2).

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Even though simple to accomplish, it has certain risks correlated with discovering the pre-aortic fascia from the convergence of the arches to the celiac branch, risks that are also correlated with the passing of the sutures through the pre-aortic fascia or even through the distal margin of the freno-esophageal membrane , thus risking to intercept the vagus nerves. Intra-operatory manometry represents the final test that names the efficiency of the intervention, after finishing the suture the pressure from the inferior esophageal sphincter level being appreciated at over 20 mm Hg [6]. Gastric fixation with the reconstruction of the Hiss angle and the Gubaroff valve has been performed under intra-operatory endoscopic control. Even though we have performed the Lucius Hill procedure in only five cases, the good results obtained in time determine us to prefer it instead of the Dor procedure that it tends to substitute as often as accomplishing of the retro-esophageal window implies impassable difficulties. Results This chapter of unexpected intra-operatory events that we wish to be as short as possible has nevertheless had some moments worth taking notice despite our concern and attention for a most delicate and less aggressive dissection as possible. First of all we must point out 3 hemorrhagic accidents that all lead to the conversion of the laparoscopic intervention. A hematoma of the gastrosplenic ligament visibly increasing, case in which we unsuccessfully tried bipolar haemostasis devices, and two cases in which bleeding began in the angle accomplished by the left margin of the esophagus and the left arch sting, probably having as source the left inferior diaphragmatic artery that lead to immediate conversion [7]. All these three hemorrhagic accidents took place during dissections on the left side of the esophagus or at gastrosplenic ligament level, preliminary to perform of a Floppy – Nissen montage that was accomplish by necessity in classical manner after obtaining haemostasis. In three other cases we have encountered ruptures of the right arch during the suture moment at people over 70 years old, probably because of the extreme fragility of tissue and especially of musculature. There have also been efractions of the gastric mucosa due to sustained tractions or in conditions of greater tension, most of them after applying the Babcock® device and have been laparoscopically sutured or included in the final montage suture. In the end, the apparition of the subcutaneous emphysema during surgery in 7 cases can be due to some intra-operatory unattended high pressures of the gas above 12 mm Hg, or due to the effort of advanced intrathoracic dissection, in the cases of brahiesophagus or giant hiatal hernia. Generally this has been a benign incident that was delivered in maximum 48 hours from surgery. A first and extremely unpleasant post-operatory complication was a case of esophageal stenosis due to an over tight Nissen-Rossetti type montage, that occurred to a young 24 year-old and shown from the first week of post-operatory evolution, first by pronounced dysphagia to solid food, then liquids, requiring a secondary intervention in the 21st day after surgery. We have reintervened laparoscopically with a first intention of evaluation and laparoscopic diagnosis. On this occasion we have taken notice of the two sutures on the anterior side of the montage that have been sectioned and extracted. Then followed the difficult detachment of the two valves from the anterior side of the esophagus, difficult because of the adherences that overcame in time. Finally the two valves have been detached through blunt dissection, thus resulting a Toupet type posterior fundoplication montage, extremely stable, fixed by the same adherences that overcame in time. The post-operatory evolution was favorable and without unpleasant side effects and especially without any relapse of the acid reflux/gastro-esophageal reflux [8]. In 1 case we have encountered a periesophageal sclera-lipomatosis atmosphere, post-operatory exuberant after a Nissen-Rossetti procedure; it manifested clinically through permanent, invalidating pain in the absence of reflux or dysphagia, that in the end lead to a laparoscopic secondary reintervention. After a difficult dissection we have by surprise noticed the complete retraction of the montage with the disappearing of the posterior valve in exchange leaving place for a perfect reestablishment of the normal anatomic reports between the region and anatomic elements of the gastro-esophageal junction and the arches, without any sign of relapse of the hiatal hernia. Post-operatory the pain ceased. Post-operatory dysphagia has been remarked after the Nissen-Rossetti procedure in a number of 25 cases, followed by the Floppy-Nissen with 17 cases and Toupet with no cases reported which was also the case with Dor or Hill procedures. Noticeable is the fact that these deglutition disorders appeared immediately postoperatory and disappeared in the first two or three weeks from the intervention without having any consequences. None of these cases presented any relapse of the acid reflux/gastro-esophageal reflux as well as any sign of post-operatory esophagitis [9]. Here we mention the syndrome of the over tight positioning, respectively the gas-bloat syndrome, present in two of the five cases registered dysphagia after the Nissen-Rossetti procedure, cases that also rendered in time. The persistence of the acid reflux/gastro-esophageal reflux also represents an unpleasant consequence that denotes an imperfection of the performed montage without having chances of remission in time or other 66

therapeutic solution except secondary reintervention. Nevertheless secondary reintervention in these hypostases isn’t the best solution because of certain impassible difficulties represented by the accomplish of the initial montage. A favorable fact may be represented by the intermittent presence of post-operatory reflux, hence by its incapacity of perpetuating esophagitis and avoiding its consequences. Sampling the types of practiced interventions, it is noticeable the presence of post-operatory intermittent reflux in 7 cases after the Dor procedure, in 8 cases after Toupet and 18 cases after Nissen-Rossetti procedures, and in 3 cases after the Floppy-Nissen and Hill procedures. If by percentage these relapses are to be reported to the number of operated cases using a single procedure, we notice that the rate of relapses is much greater in the case of anatomic procedures having an almost insignificant incidence for the majority lot of mechanic interventions total or posterior fundoplication type. In exchange the persistence of Ist degree esophagitis was remarked after 6 months from the intervention in a single case after the Dor procedure and also in a single case after the Toupet procedure. Thus resulting the fact that for as long as there isn’t any post-operatory relapse of the esophagitis, the idea of a relapsed intermittent reflux can be accepted, this reflux being easy to therapeutically and nutritionally control without having considerable esophageal side effects. In the cases that esophagitis persists, even for those of Ist or IInd degree, after a new period of test treatment we nevertheless believe that these would beneficiate of a surgical reevaluation. Finally a last unpleasant finding is the massive weight loss of a 62 year-old female patient, at which even though we observed a less generous conformation of the stomach, we risked making a complete fundoplication type montage after sectioning the first short vessels and mobilizing the great gastric tuberosities. This extremely obvious weight loss may be related with the diminishing of the gastric reservoir, and it went along with the precocious and late post-operatory evolution. The patient went off record. Appreciating our results on a Visik scale, we had the best registered results using the Floppy – Nissen procedure, followed by the Toupet procedure, then Hill, paradoxically on the last places being the NissenRossetti procedure and then Dor; though it is true that these results are reported for an extremely different number of surgeries. Discussions The idea of operatory strategy in the surgery of hiatal hernias begins with a pre-operatory plan elaborated according to the imagistic, endoscopic, pH-metric and manometric findings that according to the amplitude of the lesions and their functional impact would require accomplishing of a certain surgical procedure, as it was before laid out in the pre-operatory evaluation. On the other hand, intra-operatory findings may lead to the modification of the pre-operatory plan, in trying to adapt the surgical procedure to the particular anatomic conditions of each case, in the tendency of accomplishing a montage as similar as possible to the one recommended by the premises of pre-operatory investigations. A first element of surgical strategy would be the thoracic approach in all cases in which pre-operatory investigations contour the brahiesophagus supposition. It is certain the fact that total 360 degree fundoplication represents the ideal surgery towards which any surgical attempt should tend to because it is the most efficient antireflux construction and its results in time are the most stable and without relapses [3]. Strategically this type of intervention would be imposed especially in advanced esophagitis lesions or in major acid reflux/gastro-esophageal reflux, radiologic, pH-metric or manometric highlighted. In our statistics total or partial funduplication is found in almost 80% of the cases. Almost as efficient and lacking the complications of total fundoplication is the posterior Toupet fundoplication that we reserved for the cases in which the esophageal propulsion force was obviously diminished or for the cases in which even though sectioning the short vessels, the lack of enough gastric material in the great curvature wouldn’t have allowed a total fundoplication without the risks of a over-tight disposition. Regarding our favourite procedure, the Nissen-Rossetti operation, we believe that if the dissection of the abdominal esophagus on the right and left side assure the easy accomplish of a wide retro-esophageal window, and the gastric material of the greater curvature allows the easy sliding of the posterior valve and obtaining an anterior contact without tension between the two valves, the sectioning of the gastro-splenic ligament is no longer necessary. Nevertheless is total fundolication imperative or necessary in all forms of hiatal hernia and may it be applied in any situation? It would be necessary in all hiatal hernias accompanied by acid reflux/gastro-esophageal reflux, but not imperative and practically impossible in all situations. Thus for example it is unnecessary in hiatal hernias without acid reflux/gastro-esophageal reflux and is quite unadvisable in hiatal hernias accompanied by diminishing propulsion force of the esophageal musculature. We have thus encountered 8 cases of voluminous para-esophageal hernias, unaccompanied by reflux in which after stomach reduction in the abdomen we applied a posterior recalibration of the esophageal hiatus accompanied by an anterior fundoplication and gastrodiaphragmatic fixation, having great results. There is a series of situations in which even though the esophagitis lesions are advanced and a 360 degree montage is required, it cannot be performed because of the anatomic conditions or technical deficiencies. In such cases we have done a posterior fundoplication or an anatomic montage in the situations when not even this last variant of a retro-esophageal montage was possible. 67

Regarding anatomic montages such as the Lucius Hill procedure or anterior fundoplication, the Dor procedure, weaker results impel us to avoid them on principle as possible in forms of hiatal hernias accompanied by acid reflux/gastro-esophageal reflux or in advanced reflux esophagitis. Unfortunately we must admit from the beginning that the results of these last procedures – under the aspect of reflux phenomena control – is not up to the level of antireflux montages posterior, total or partial fundoplication type of whose valve effect is more efficient. These interventions have only been adapted by necessity when local anatomic conditions didn’t allow the perform of the retro-esophageal window. Conclusions 1. In laparoscopic antireflux surgery of total or partial fundoplication procedures, one of the basic principles is avoidance of any stress of montage, responsable for the appearance of dysphagia; 2. Detrimental local anatomical conditions, as extreme adiposity, small stomach or short esophagus, demand the effectuation of an anatomical procedure or antrior fundoplication, with the condition of fixing the cardia in the abdomen, to reduce the hiatus hernia and to recalibrate the esophageal hiatus; 3. In the conditions of an insufficient gastric material, effectuation of a total fundoplication, may lead to the bending of the stomach or to postoperative appearance of a small stomach when we recommend the effectuation of a Toupet posterior fundoplication; 4. Although we consider that the total fundoplication is the major objective of the antireflux interventions, in necessity we adopted a nuanced attitude according to the local conditions of each case (78% retroesophageal approach, 22% anterior approach); 5. Floppy-Nissen and Nissen-Rossetti procedures reprezent antireflux fitting with excellent results which however involve a range of convenient anatomical conditions and a flawless execution; 6. Toupet surgery receives the same rating, although more laborious, being better tolerated and with less stable time results; 7. Anatomical surgery, seems to be followed by weaker results than mechanical surgery as total or posterior fundoplication and thereupon have been uesd in a much more limited number of cases, only in need; 8. Choosing for a procedure or another, is decisive for the patient’s future, as long as reinterventions are loaded with an extremly important degree of difficulty. References 1. DUCA S., Chirurgia laparoscopica, editura Paralela 45, editia a 2-a, 2001; 2. K.-H. FUCHS, S.M. FREYS, M. FEIN, A. THEIDE, Treatment of gastroesofageal reflux disease by laparoscopic fundoplication, Department of Surgery, University Clinic Wurtburg, Germany. 2003, Published by Endo-Press, Tuttlingen; 3. FIRTION O., N. DE MANZINI, ROHR S.,THIRY C.L., MEYER CH., La chirurgie laparoscopique du reflux gastro-oesophagien: quel procede utiliser ?, Le journal de Coelio-Chirurgie, Nr. 25, pag. 5 – 10, Mars 1998; 4. LANZAFAME J.F., Prevention and Management of Complications în Minimally Invasive Surgery, Igaku-Shoin Medical Publishers, 1996; 5. CHIPPONI J.,SLIM K., Traitement chirurgical du reflux gastro-oesophagien. Quelle technique choisir ?, J.CHIR. (PARIS), 1998, 135, Nr. 1., pag. 31-36; 6. BALLANTYNE G.H., Atlas of Laparoscopic Surgery, 2000 by W.B. Saunders Company, printed în USA. 7. UNGUREANU D., DAHA C., DOGIOIU C., UNGURIANU L.,GADEA A.,PRICOP M., Comparative study between laparoscopic gastroesofageal antireflux procedures. Romanian Journal of Gastroenterlogy, June 2001, Vol. 10, Nr. 2, pag. 154. 8. UNGUREANU F.D., UNGURIANU L., IOACHIMESCU M., ALEXANDRU S.C., CUCU S, PRICOP M., GADEA A., TUDORACHE A., MIRCEA G., DRAGOESCU D., MOLDOVAN A.C. Strategie operatorie în chirurgia laparoscopica a herniilor hiatale şi a refluxului gastro-esofagian. Revista Medicochirurgicală Vol 107, Mai 2003, Supliment Nr. 1, pag. 22. Comunicare, cel de-al IV-lea Congres al Societatii romane de chirurgie laparoscopica şi suturi mecanice, Iasi, 24- 25 sept. 2003. 9. UNGUREANU F.D., UNGURIANU L., IOACHIMESCU M., S. CUCU, PRICOP M., MIRCEA G., TUDORACHE A., GADEA A., MOLDOVAN A.C., Rezultate la distanta dupa chirurgia laparoscopica a herniilor hiatale şi a refluxului gastro-esofagian. Chirurgia Vol 99 Supliment 1 - Septembrie 2004, S20. Comunicare la cel de-al doilea Congres al ARCE, 15 – 17 sept. 2004. Cluj. Captions Fig. 1 : Postoperative radiological control after Nissen-Rosetti surgery. Fig. 2 : Postoperative radiological control after Toupet surgery Fig. 3 : Gastro-diaphragmatic fixation of the greater gastric tuberosity at the hernia’s breach. Fig. 4 : Vascular anomaly – emerging of the celiac trunk blocks the approach path towards the retroesophagus breach.

68

ASSESSMENT OF AVAILABLE BONE IN SINGLE-TOOTH IMPLANT TREATMENT IN LATERAL AREA Lecturer, PhD Claudia Florina Andreescu MD, Lecturer, PhD Oana Smătrea MD, Professor, PhD. Doina Lucia Ghergic MDM Faculty of Dental Medicine, Titu Maiorescu University of Bucharest Corresponding author: Claudia Florina Andreescu, DDS, PhD, Professor Assistant, Faculty of Dental Medicine, University Titu Maiorescu, Bucharest, 67A Gheorghe Petraşcu Street, sector 3, Bucharest, cod 031593, telephone/fax: +4021.325.14.16, e-mail: [email protected] Abstract: Introduction. Restoration of single tooth loss with dental implant is a modern treatment that helps patient to feel better, eat better, speak better and look better. In the same time this method of treatment protects the neighboring teeth which will not require grinding and root canal therapy. Objective of study. Objective of this study is evaluation of available bone in single-tooth implant treatment in lateral area. Material and method. This study was done on a group of 42 subjects that address to a private office for restoration of single tooth loss in lateral area. The following protocol was done for each subject before surgery: filled in general health questionnaire, clinical examination, study cast, imagistic examination (ortopantomography and/or computed tomography), general health assessment through blood tests, discussion of treatment plan, signed informed consent. For subjects where the exact limits of available bone could not established with ortopantomography was performed CT examination. Conclusion. The exact anatomical limits of available bone for dental implant should be precisely defined. Conventional X-rays (retroalveolar, ortopantomography) are limited due to their bidimensional character. Orthopantomography is a simple, fast, inexpensive and produces a low dose of radiation. It is considered routine preoperative examination in oral implantology. CT scanning has an important role in treatment planning because defines the exact limits of available bone and confirms the need for additional treatments (bone graft, sinus lift). In this study for 28.57% subjects was necessary to perform computed tomography. Key words: Orthopantomography, CT scanning, computed tomography, dental implants 1. Introduction. Restoration of single tooth loss with dental implant is a modern treatment that helps patient to feel better, eat better, speak better and look better. In the same time this method of treatment protects the neighboring teeth which will not require grinding and root canal therapy. 2. Objective of study. The objective of this study is evaluation of available bone in single-tooth implant treatment in lateral area. 3. Material and method. This study was done on a group of 42 subjects (22 men and 20 women) with the age between 25 and 45 years old that address to a private office for restoration of single tooth loss in lateral area (Figure 1). All subjects have a good general health and do present any diseases that contraindicate surgery.

47,62%

52,38%

men

women

Figure 1: Distribution of studied batch.

69

The following protocol was done for each subject before surgery: filled in general health questionnaire, clinical examination, study cast, imagistic examination (ortopantomography and/or computed tomography), general health assessment through blood tests, discussion of treatment plan, signed informed consent. For subjects where the exact limits of available bone could not be established with ortopantomography was performed CT examination. 4. Results Tooth loss in lateral area for subjects require treatment is (Figure 2): 10 cases of upper premolar, 2 cases of lower premolar, 8 cases of upper molar and 22 cases of lower molar. Repartition of tooth loss for male subjects is: 6 cases of upper premolar, 0 cases of lower premolar, 4 cases of upper molar and 12 cases of lower molar. Repartition of tooth loss for female subjects is: 4 cases of upper premolar, 2 cases of lower premolar, 4 cases of upper molar and 10 cases of lower molar. 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%

23,81%

4,76%

20%

19,05%

52,38%

20%

50%

18,18%

54,55%

MS

MI

10% 27,27%

PMS

0% PMI men

women

total

Figure 2: Distribution of tooth loss in studied batch. PMS = superior premolar, PMI = inferior premolar, MS = superior molar, MI = inferior molar.

From all 42 subjects, in 30 cases (71.43%) the limits of available bone could be measured after radiological examination (orthopantomography) in addition with clinical examination and study cast analysis (Figure 3-5). In all these situations dental implants were placed without bone augmentation techniques. In 12 cases (28.57%) there was necessary a supplementary examination: computer tomography in order to measure the exact limits of available bone. These cases are represent by second upper premolar (4 cases), upper first molar (4 cases) and lower first molar (4 cases). In one single case, the orthopantomography showed an inadequate bone density for implantation (Figure 6-8).

5. Discussion Nowadays, the best option for replacing single missing tooth is dental implant due its longevity, preserving of bone support and respecting of neighboring teeth. The main disadvantage of cemented implant-supported crown is loosing of abutment screw. In this case crown is still cemented, but restoration is mobile. When is used a longterm cement the crown is cut in order to have access to abutment screw and a new crown is made. When an implant-supported restoration is planned is mandatory a thorough clinical examination and complementary examinations, represented by: blood test, study cast and imagistic examination. In lateral area available bone is limited by the floor of maxillary sinus for upper jaw and by the superior margin of canal of inferior alveolar nerve for lower jaw. In order to place dental implants inside safety area and ensure the success of implant treatment, the exact limits of available bone must be measured with accuracy. These limits are established with the help of dental X-rays and CT-exam.

70

Figure 3: Clinical aspect of edentulous span left (first lower molar).

Figure 4: Study cast – lateral view.

71

Figure 5: Radiological aspect (ortopantomography) of the same patient with single missing tooth on lower arch.

Figure 6: Single missing upper tooth (left second upper premolar) orthopantomography

Figure 7: Single missing upper tooth (left second upper premolar) - computer tomography 72

Figure 8: Summary of computer tomography, which shown insufficient bone volume for implantation

CT-examination is the most accurate imagistic examination and has the best and dimensional precision. In addition, CT has the advantage of achieving a three-dimensional simulation of the maxillary bones. With this exam can be analyzed bone structure can be located accurately and distances to major anatomical landmarks and their topography. A study done by SCHROPP et al. [1] compares implant dimensions chosen after clinical and radiological examination (ortopantomography) for treatment of single missing teeth. These dimensions are compared with sizes of implants selected after CT examination for the same subjects. In 70% cases size of implant is change after CT measurement of available bone. This study proves that CT exam is useful for evaluation of available bone volume for correct treatment planning in single missing tooth. In another study KIM YK et al [2] found modifications in sizes of implant selected after orthopantomography and CT at the same subjects. The main variation was discovered at diameter of implant. The vertical dimension had an acceptable accuracy for lateral area [3] Orthopantomography can be considered a simple, cheap and considerably precise pre-operative assessment instrument in establishment of vertical dimension for dental implant therapy, but in more difficult cases CT scan should be used to determine the volume of available bone [4]. 6. Conclusion.  The exact anatomical limits of available bone for dental implant should be precisely defined.  Conventional X-rays (retroalveolar, ortopantomography) are limited due to their bidimensional character. Orthopantomography is a simple, fast, inexpensive and produces a low dose of radiation. It is considered routine preoperative examination in oral implantology.  CT scanning has an important role in treatment planning because defines the exact limits of available bone and confirms the need for additional treatments (bone graft, sinus lift).  In this study for 28.57% subjects was necessary to perform computed tomography. 7. References 1. Schropp L., Stavropoulos A, Gotfredsen E, Wenzel A. Comparison of panoramic and conventional cross-sectional tomography for preoperative selection of implant size. Clin Oral Implants Res. 2011 Apr;22(4):424-9. 2. Kim YK, Park JY, Kim SG, Kim JS, Kim JD. Magnification rate of digital panoramic radiographs and its effectiveness for pre-operative assessment of dental implants. Dentomaxillofac Radiol. 2011 Feb;40(2):7683. 3. Vazquez L, Nizamaldin Y, Combescure C, Nedir R, Bischof M, Dohan Ehrenfest DM, Carrel JP, Belser UC. Accuracy of vertical height measurements on direct digital panoramic radiographs using posterior mandibular implants and metal balls as reference objects. Dentomaxillofac Radiol. 2013;42(2):20110429. 4. Pertl L, Gashi-Cenkoglu B, Reichmann J, Jakse N, Pertl C. Preoperative assessment of the mandibular canal in implant surgery: comparison of rotational panoramic radiography (OPG), computed tomography (CT) and cone beam computed tomography (CBCT) for preoperative assessment in implant surgery. Eur J Oral Implantol. 2013 Spring;6(1):73-80. 73

ASSESSMENT OF THE AVAILABLE BONE IN ORDER TO INSERT DENTAL IMPLANTS Assistant PhD. Candidate Anghelina Ane-Mary1, MD. Coman Costin1, Lecturer MD. Comăneanu Raluca Monica1, Lecturer MD. Barbu Horia1, Professor MD. Ghergic Doina Lucia1, Professor PhD. Eng. Târcolea Mihai2 1 Faculty of Dental Medicine, Titu Maiorescu University of Bucharest 2 Faculty Materials Science & Engineering, Politehnica University of Bucharest Abstract: Assessment of the available bone inorder to insert dental implants in the lower jaw has a paramount importance in pre-operative planning and in selecting the type of implant to be used. Starting from 8 CBCT examinations of partially edentulous patients, of both genders, with the help of Mimics®, we carried out measurements of the height and width of the mandibular bone as well as an assessment of the distance from the mandibular canal to the edentulous crest. From the data analysed we can conclude that the configuration and dimensions of the mandible are different, depending on the patient’s gender, degree of post-extraction osseous atrophy, teeth loss cause and the physician has to take all these factors into consideration when accomplishes the individual surgery planning which, in the end, shall lead to the best choice of the implant and a successful surgical intervention. Key words: edentation, dental implant, CBCT, Mimics® Introduction: For pre-operative planning, in order to insert dental implant within the mandible, it is very important to accomplish a precise assessment of the bone dimension and of its morphology. The implant dimension which is to be used depends on the height and width of the available bone and on the mandibular canal placement. Material and method: We carried out a comparative study on the height and width of the available bone on 8 CT examinations of hemimandibles of 4 patients, 2 females and 2 males. The information achieved through CT were processed in MIMICS®. MIMICS® (Materialise’s Interactive Medical Image Control System) is a software used in processing medical images as well as in creation of 3D scaffolds. Mimics uses 2D medical images, in cross section, as well as those obtained by computerised tomography (CT) of nuclear magnetic resonance (NMR) in order to build up 3D scaffolds which can be directly linked to rapid prototyping CAD, surgical simulations and advanced engineering analyses. [2], [3], [4] In achieving measurements for all eight hemimandibles, we respected the following steps: importing images in Mimics®, setting the space orientation parameters, accomplishing the initial tridimensional model (Fig. 1) which, afterwards, is processed in order to separate the aimed osseous area on which measurements shall be carried out (Fig. 2).

Fig. 1 – The initial 3D model

74

Fig. 2 – The aimed osseous area Obtained results : Measurements were achieved by using order Measure Distance withing Measurements menu. For all eight hemimandibles studied, the measurements were accomplished on 6 sections (Fig. 3)

Section 1

Section 2

Section 3

75

Section 4

Section 5

Section 6 Fig. 3 – Sections on which the measurements were accomplished The data obtained were centralised in four tables. Table 1. Comparative width of analysed mandibular bones Section

Analysed

zone,

Case 1

Case 2

Case 3

Case 4

Case 5

Case 6

Case 7

Case 8

5

9,03

8,98

9,85

9,36

8,73

9,24

10,61

9,84

10

9,63

9,62

11,85

10,61

7,87

9,64

11,88

10,96

15

8,88

8,29

12,18

7,36

9,36

8,27

12,01

10,75

20

9,43

7,46

12,55

8,83

8,44

8,50

11,47

9,64

5

8,76

8,92

9,77

9,50

8,99

8,38

10,64

10,15

10

8,49

9,31

11,58

11,05

8,70

9,12

11,80

12,58

15

10,63

10,42

13,83

9,64

9,53

10,28

13,90

12,83

20

11,41

7,41

13,18

7,56

7,03

10,36

13,30

10,67

5

8,47

9,35

9,82

9,71

9,59

8,20

11,08

10,76

10

8,88

10,27

11,40

11,07

9,60

8,72

12,39

12,62

15

10,28

11,33

14,46

12,98

9,62

10,61

14,71

14,65

20

11,66

9,04

14,93

8,56

1,85

10,90

15,93

12,42

mm 1

2

3

76

4

5

6

5

8,47

9,38

9,90

10,41

8,79

8,85

10,60

12,11

10

9,35

11,20

11,73

12,26

10,48

9,10

11,88

14,06

15

11,35

12,03

14,49

15,09

10,50

12,01

13,64

15,27

20

13,41

7,79

16,48

12,76

9.23

13,11

15,15

14,23

5

8,48

8.43

8,53

8,19

8,33

8,24

9.61

11,55

10

8,62

9,64

10,01

10,63

9,34

9,01

9,46

12,78

15

10,29

10,97

11,81

11,48

11,56

10,38

10,90

14,67

20

12,67

12,53

13,62

14,20

10,11

13,69

12,90

15,15

5

6,78

7,03

7,58

6,04

6,70

6,65

8,72

8,25

10

6,86

7,29

8,62

6,37

6,28

7,12

9,29

9,55

15

7,37

6,96

8,77

6,84

8,52

7,04

8,96

10,47

20

8.69

7,83

9,42

8,42

10,01

8,99

9,52

12,18

Table 2. Comparative height of analysed mandibular bones Section

1

2

3

4

Zone

M1

M2

M3

M4

M5

M6

M7

M8

A

1,74

4,37

5,37

3,11

Mental

Mental

foramen

foramen

3,18

3,49

B

1,90

1,25

3,52

2,63

2,53

1,81

3,97

4,14

C

15,73

17,70

14,35

12,24

12,14

16,43

19,00

14,84

D

4,32

7,65

9,64

5,32

9,73

11,30

10,18

11,04

E

10,53

10,43

13,10

10,68

10,55

11,18

11,56

11,09

F

29,71

31,26

27,22

25,52

25,05

31,86

32,78

29,36

A

1,03

3,01

3,06

3,07

2,87

1,72

6,62

8,31

B

2,19

4,46

6,02

3,80

1,52

2,18

2,79

3,65

C

8,69

16,84

14,18

8,36

12,32

16,24

16,94

14,09

D

4,48

7,78

8,27

5,50

3,82

8,55

6,46

9,29

E

11,43

10,94

14,10

11,45

10,05

11,64

14,12

13,05

F

26,48

27,40

25,08

25,12

23,14

29,77

27,32

27,35

A

0,85

3,12

1,80

1,97

1,81

4,25

6,39

4,68

B

2,21

5,33

6,92

3,17

2,50

1,09

2,06

3,67

C

10,77

13,81

13,05

9,97

2,42

10,81

14,18

14,85

D

4,73

6,31

6,28

5,10

4,85

8,29

6,55

6,79

E

12,59

12,39

16,01

13,18

10,31

11,88

16,78

14,63

F

27,80

24,84

26,64

22,53

20,21

27,49

25,51

24,17

A

1,35

2,92

1,89

2,65

8,36

4,26

7,61

6,95

B

2,09

4,58

7,82

3,33

2,25

2,15

1,88

3,68

C

9,38

11,65

14,26

4,49

4,44

3,35

15,26

13,88

D

3,95

4,81

6,45

4,84

6,01

11,61

6,90

6,52

E

13,20

13,12

16,81

15,20

11,79

12,72

16,02

15,89

77

5

6

F

27,36

25,76

25,34

23,54

18,49

26,88

29,48

23,25

A

0,92

3,47

1,98

2,45

3,13

4,51

8,91

10,48

B

2,69

3,42

6,17

3,31

1,31

2,22

1,10

2,37

C

16,89

13,16

15,26

-

3,43

12,29

16,43

5,68

D

7,08

5,76

11,19

4,93

4,95

9,99

9,99

9,07

E

13,29

12,49

15,82

13,97

12,52

13,21

14,96

15,25

F

29,11

25,00

29,94

25,92

19,74

29,32

33,20

23,85

A

0,53

1,50

2,20

1,64

5,25

5,26

4,63

2,13

B

2,38

2,01

5,30

2,44

0,64

0,83

1,34

2,79

C

2,52

14,65

19,44

5,47

10,97

16,59

17,36

9,98

D

11,89

11,37

12,80

8,28

11,21

14,22

14,70

17,51

E

10,09

7,86

11,34

10,00

10,34

10,76

10,56

12,48

F

33,95

30,34

37,60

34,05

26,87

36,85

37,68

32,34

Table 3 – The average variation of the mandibular bone height, of its width, as well as the average of the distance from the mandibular canal to the alveolar crest for each patient Average

Average

Average of the distance

variation of

variation of

from the mandibular canal

height

width

to the alveolar crest

M1

29.07

11.86

10.66

M2

27.43

11.21

M3

28.64

M4

Age

Left /

(year)

Right

F

27

L

14.64

F

38

L

14.53

15.09

M

52

L

26.11

12.41

8.11

M

39

L

M5

22.25

10.93

7.62

F

32

R

M6

30.36

11.90

12.62

F

27

R

M7

31.00

14.00

16.53

M

52

R

M8

26.72

13.73

12.22

M

49

R

Patient

Sexe

Table 4 – The average variation of the mandibular bone height, of its width, as well as the average of the distance from the mandibular canal to the alveolar crest for each section Average variation

Average variation of

Average of the distance from the

of height

width

mandibular canal to the alveolar crest

1

29.095

11.14

15.30375

2

26.4575

12.0975

13.4575

3

24.89875

13.47125

11.2325

4

25.0125

14.34375

9.58875

5

27.01

13.93875

11.87714286

6

33.71

10.42875

12.1225

Section

78

Discussion In tables 5 and 6 are presented the values of mean dimensions of the mandible calculated in the literature [1], [5] and the values recorded in our study. Table 5 – Mean dimensions of the mandible calculated in the literature Literature [1], [5]

Dates

Men

Women 26,9 ÷ 29,8

Average variation of height

27,6 ÷ 31,0

28,0 ÷ 31,6

Average variation of height with standard

27,6±3,8 ÷

28,0±3,9 ÷

deviation, mm

34,0±3,8

31,6±3,7

Average variation of width, mm

10,5 ÷ 15,8

10,9 ÷ 16,1

Average variation of width with standard

10,5±1,3 ÷

10,9±1,3 ÷

deviation, mm

15,8±1,9

16,1±2,1

Average of the distance from the mandibular

26,9±3,5 ÷ 29,8±3,8 9,7 ÷ 15,1 9,7±1,1 ÷ 15,1±1,4

15,3 ÷ 17,4

canal to the alveolar crest

Table 6 – Mean dimensions of the mandible calculated in our study Our study

Dates

Men

Women 22,3 ÷ 30,4

Average variation of height

22,25 ÷ 31,0

26,1 ÷ 31,0

Average variation of height with standard

22,25±3,3 ÷

26,1±4,09 ÷

deviation, mm

31,0±4,4

31,0±4,4

Average variation of width, mm

10,9 ÷ 14,5

12,4 ÷ 14,5

10,9 ÷ 11,9

Average variation of width with standard

10,9±1 ÷

deviation, mm

14,5±2,1

12,4±2 ÷ 14,5±2,1

10,9±0,9 ÷ 11,9±0,9

Average of the distance from the mandibular

22,3±3,3 ÷ 30,4±3,6

7,6 ÷ 16,5

canal to the alveolar crest

Conclusions: In the studied case we noticed: - a progressively increased width of the mandible, more pronounced in the case of sections 4,5 and 6. - a decrease, in sections 2 and 3, of this width in the area of 20 mm compared to the mandibular basilar. The distance from the mandibular canal to the alveolar crest varies very much because the inferior alveolar nerve has branches and the mandibular canal differs very much from one individual to another and from one section to another. Analysing the mean variation of the heights depending on the section, we noticed that the mandibular bone has a smaller height in sections 2 and 5 because of post-extraction atrophy. References: [1] Kilic C., Kambutoglu K., Ozen T., Balcioglu H. A., Kurt B., Kutoglu T., Ozan H., The Position of the Mandibular Canal and Histologic Feature of the Inferior Alveolar Nerve, Clinical Anatomy, 2010 [2] Mimics 10.0 Help Pages [3] Mimics 13 Help Pages [4] Târcolea M., Mimics Student Edition Course Book, 2010 [5] Watanabe H., Abdul M.M., Kurabayashi T., Aoki H., Mandible size and morphology determined with CT on a premise of dental implant operation, Surgical and Radiologic Anatomy, 2010.

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THE INFLUENCE OF THE SALIVARY PH ON THE MATERIALS USED IN THE METAL-CERAMIC TECHNOLOGY Lecturer PhD Comaneanu Monica, Assistant PhD Candidate Hancu Violeta, PhD Candidate Coman Costin, Professor PhD Ghergic Doina Lucia Faculty of Dental Medicine, Titu Maiorescu University of Bucharest Abstract: The partial edentation is one of the most frequent pathologies the dentist is confronted with. Globally, an increase of patients with partial edentations is revealed at all ages, which determines a higher interest for the treatment of this condition. The condition of edentation induces a series of changes in the stomatognathic system, having effects on all its functions: physiognomy, phonation, mastication, but, at the same time, it also generates effects at locoregional or general level. In order to achieve individualized prosthetic treatments for each one of the patients, we selected different biomaterials used in the execution of metal-ceramic restorations. The choice of the biomaterials was made regarding the pH-level of the oral cavity, which is determined by the general health and the local hygiene level of the patients. The pH-level measurements were made during the preprosthetic and proprosthetic treatment sessions by using litmus indicator paper, which is colored differently after immersion in saliva. By using metal alloys adapted to each one of the clinical situations, the long-term prognosis will be improved. This will help to achieve a higher satisfaction standard of the patients and also to the saving of natural resources used in the execution of the prosthetic restorations, according to the bioeconomic principles. Keywords: salivary pH, edentation, prosthesis, biomaterials.

Introduction: The partial edentation is one of the most frequent pathologies the dentist is confronted with. Globally, an increase of patients with partial edentations is revealed at all ages, which determines a higher interest for the treatment of this condition. The condition of edentation induces a series of changes in the stomatognathic system, having effects on all its functions: physiognomy, phonation, mastication, but, at the same time, it also generates effects at locoregional or general level. The multitude of prosthetic restoration treatments of the partial edentation must maintain the harmony between teeth, periodontal, mucosa and the skeletal system. The individualized treatment of the partial edentation requires a thorough knowledge of the edentulous prosthetic field components, so that the whole morpho-physiological capacity offered by the residual dental arch is used. Currently the most widely used prosthetic treatments in solving the partial edentation are fixed metal-ceramic restorations, partially or fully physiognomic. Dental materials interact with living tissues they come into contact with and produce local or systemic host responses. At the same time, the properties of the materials used can be influenced by the biological environment which can have destructive effects on them, effects known as biodegradation.1 The biocompatibility2 is a complex concept that takes into consideration all processes that occur between the biomaterial and the living organism. Biocompatibility means the property of a material to be compatible with living organisms, so to be definitively accepted by the organism, without causing side effects and without chemical or mechanical damage.

Prosthetic treatment success depends on developing a complete diagnosis, on the elaboration of a correct treatment plan, properly phased and individualized for each clinical case, as well as the rigorous execution of all clinical-technical phases that are included in the technology of prosthetic metal-ceramic reconstructions.3 Material and method: In order to achieve individualized prosthetic treatments tailored to each patient, we decided to select biomaterials used in the manufacturing of metal-ceramic restorations, depending on the pH of the oral cavity, pH caused by the patient's general health and its local hygiene level. pH measurements were made during the treatment sessions by using litmus indicator paper, which is colored differently after the immersion in saliva, from pH = 0.5 to pH = 13, with the division of pH 0.5 (Fig. 1). 80

Fig. 1 – The indicator paper used for the salivary pH determination By using metal alloys adapted to each clinical case, the long term prognosis will be improved, which will help to achieve a higher satisfaction level of the patient, as well as the saving of natural resources used in manufacturing these prosthetic restorations, according to the bioeconomic principles. Patient D.C., age 53, came into the dental office requiring specialized consultation and treatment. The clinical and radiological examination revealed the presence of multiple, simple and complicated, carious lesions, partially treated, as well as the presence of class II edentations with two modifications, partially treated, on both maxilla and mandible. During anamnesis the patient said he was diagnosed with gastro-esophageal reflux, which explains the many injuries at the cervical level. Obtained results: In order to achieve a complex oral rehabilitation through fully physiognomic metal-ceramic restorations, we conducted during treatment sessions, determinations of the salivary pH with pH indicator paper and registered the values in table 1. Table 1 - Values registered at the measurement of the salivary pH for patient 1

Salivary pH

Session 1 5

Session 2 4,5

Session 3 5

Session 4 5,5

Session 5 5

Session 6 5

The average salivary pH of patient 1 had the value of 5, so that for the manufacturing of the metal-ceramic restorations we selected a alloy which has the lowest corrosion rate at this pH value, respectively the Girobond CoCr alloy. The esthetic component was represented by the ceramic Hera Ceram.

Fig. 2 – Initial clinical appearance – from the front 81

Fig. 3 – Initial clinical appearance of the maxillary arch

Fig. 4 – Initial clinical appearance of the mandibular arch

Fig. 5 – Initial radiological appearance

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Fig. 6 – The two metal-ceramic restorations, viewed from the front, in occlusion

Fig. 7 – The two metal-ceramic restorations, viewed from right laterality, in occlusion

Fig. 8 – The two metal-ceramic restorations, viewed from left laterality, in occlusion

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Fig. 9 – The two metal-ceramic restorations, viewed from the front, no occlusion

Fig. 10 – Final esthetic appearance

Conclusions: 1) From a bioeconomic point of view, we can appreciate that the use of biocompatible materials with superior qualities, reduces the number of complications which appear over time, by using less natural resources when making the restorations. 2) In order to produce metal-ceramic restorations with a long-time prognosis, we propose a individualized selection of metal alloys, based on the salivary pH and any associated pathologies of each patient. References: 1) Baciu C., Alexandru I., Popovici R., Baciu M., Știința Materialelor, Iași, Ed. Gh. Asachi, 1996. 2) Voicu G., Georgescu M., Lianţi anorganici şi organo-minerali cu utilizare în stomatologie, Ed.Politehnica Press, Bucureşti, 2009. 3) Bechir A., Comăneanu R.M., Barbu H.M. şi colab. (sub coordonarea Ghergic D.L.) Tehnologia metalo-ceramică, Ed. Printech, Bucureşti, 2011.

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A CLASS II DIVISON 2 MALOCCLUSION TREATED WITH REMOVABLE TWIN BLOCK FUNCTIONAL APPLIANCE - A CASE REPORT Ass. Prof. PhD. Delia Elena Daragiu MD, “Titu Maiorescu” University, Faculty of Dental Medicine Professor PhD Doina Lucia Ghergic MDM, “Titu Maiorescu” University, Faculty of Dental Medicine Abstract: This case report shows the treatment effects of class II division 2 malocclusion in a 10 years old boy with twin block functional appliance. The treatment consists of two stages: First stage- treatment with removable twin block functional appliance followed later by second stage: fixed appliances to correct the position, the torque of upper central incisors, detailing the occlusion Key words: class II divison 2 malocclusion , class II skeletal base, functional appliance, Twin Block, retrognathic mandible Introduction: Class II division 2 malocclusion presents difficulty in the provision of stable results (Selwyn Barnett, 1991). Correction of the antero-posterior, transvers and vertical discrepancies are important for a successful treatment. Selwyn Barnett (1991, 1996) demonstrated the need for expansion and limited proclination of lower incisors during treatment and recommended early treatment in the mixed dentition using removable appliances to begin buccal segment correction and reduce the overbite. Later, in a second phase , upper and lower fixed appliances are placed , usually with no extractions. Treatment of a class II division 2 malocclusion in an actively growing patient consists of proclining the upper incisors by using an upper removable appliances, trying to convert it in a class II division 1 malocclusion. This is then followed by functional treatment in order to correct sagital discrepancy. The twin block developed by William Clark is popular and clinically successful appliance. It is worn 24/24 hours , and because of increased daily wear and patient cooperation the correction of sagital discrepancy is achieved in approximately 9 months of wear. Studies comparing treated cases with twin block and control groups (Trenmouth, 2000; Lund and Sandler 1998, Mills and McCullouch 1998) showed small, but significant increases in mandibular length. The majority of overjet correction occurs because of dentoalveolar compensations. Studies comparing Twin Block with other functional appliances showed that Twin Block is the best in producing sagittal modifications. These changes are due to skeletal mandibular changes, dentoalveolar changes and normal growth changes. This paper shows that a modified Twin Block appliance can be used successfully to treat a Class II division 2 malocclusion from the beginning, thus avoiding the initial stage of upper removable appliance to align the upper labial segment. Sagittal correction of the malocclusion and the correction of the retroclined upper incisors are done together, at the same time. Patient selection and bite registration: The patient treated with modified Twin Block has a class II division 2 malocclusion on a moderate class II skeletal base with an ANB of 6-9 degrees. The buccal segment relationship should ideally be at least half of unit Class II and the patient has potential for further facial growth. The axial inclination of the upper incisor is corrected initially by labial tipping and this corrected inclination is maintained during further correction of the malocclusion. (Dyer, McKeown, Sandler, 2001) The bite registration is taken with the buccal segment relationship in an overcorrected relationship , this may result in an edge to edge incisor relationship. It is important to have sufficient hight of the blocks so the patient is comfortable in posturing forward the mandible instead of closing centric occlusion and we should have 7-8 mm of separation in the buccal segments and no incisal interference as the upper labial segment proclines. The appliance design: Both appliances are a modified Twin Block appliance (Clark 1982). They have Stahl clasps on the buccal segments, and ball ended clasps on the lower labial segment. The upper appliance contains a midline expansion screw and two “S” springs on upper central incisors and no vestibular arch . The lower appliance also contains a midline expansion screw and a vestibular arch. The inclined planes are constructed at 70 degrees to the occlusal plane. Advancement , if required ,is carried out by the addition of small acrylic tablets to the upper block.

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Case report: A 10 years old boy was reffered by his dentist. He presented with a class II division 2 incisal relationship on a moderate class II skeletal base , with mandibular retrognathia . He is in mixed dentition. The upper central incisors are retroclined and the upper lateral incisors are proclined. There was mild crowding in the labial segments, in occlusion the overbite was complete. The buccal segment relationship was half unit class II on the right side and almost full unit class II on the left side. The mandible shifts to the left side on closure (Figure 1, 2).

Fig.1 Before treatment

Fig. 2 Before treatment

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The cephalometric tracing confirmed that the patient had a moderate Class II skeletal base relationship with an ANB value of 7.5 degrees, the mandibular plane angle was 23 degrees. The upper incisors were retroclined at 95 degrees, incisor mandibular plane angle 96 degrees, inter-incisal angle was 142.5 degrees. (Figure 3) Treatment involved correction of class II skeletal relationship with a Twin Block appliance and simultaneously proclining the upper labial segment.

Fig. 3 Superimopsition on SN line: Black line- before treatment, Red line- after treatment with Twin Block Twin block appliances were fitted and instructions given to turn the midline screws both once a week. The buccal blocks were trimmed posteriorly to allow buccal eruption and reactivate anteriorly to continue anteroposterior correction. After a year of treatment the lateral cephlogram indicated correction of the mandibular position (Figure 3 and 5), the molar relationship was corrected, the overbite was reduced, the interjaw relationship was corrected and confirmed by the superimpositions (Figure 3,4,5) and lateral cephalograms analysis before and after Twin Block therapy (Table 1 )

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Fig.4 Superimposition on the maxilla,black line- before treatment, red line- after treatment with Twin Block

Fig. 5 Superimposition on mandibleblack line-before treatment, red line-after treatment with Twin Block Aesthetic improvements were observed with correction of the convex profile, the reduction of the mentolabial sulcus, the protrusion of the upper lip (Figure 3,5,7) Results and Discussion: Mandibular base length increased by 6.5 mm , which was measured from Ar-Pog, SNA reduced with 0.50, the SNB increased by 2 0, ANB decreased by 2.50, anterior facial hight (AFH) increased by 5 mm, and posterior facial hight (PFH) increased by 3.5 mm. The patient was instructed to turn the maxillary and mandibular midline screws one turn per week. The treatment duration lasted for 12 month. The pre and post treatment lateral cephalometric radiograph were obtained in centric occlusion under standard conditions and traced manually on matte acetate paper using a 0.5 mm pencil. The angular parameters measured were SNA, SNB, ANB , upper central incisor to palatal plane 88

(NL), lower incisor to mandibular plane (IMPA). The liniar parameters included mandibular length, anterior facial hight, posterior facial hight. Class I molar relationship was achieved partly because of the mandibular growth and partly because of the mesial movement of the mandibular first molar, and slight distal movement of upper molars.(Figure 6)

89

90

Figure 6 After treatment with Twin Block Antero-posterior correction was achieved after 1 year full time wear, the ANB reduced by 2.5 degrees. Superimpositions revealed mandibular changes in horizontal and vertical directions, with increase in anterior face hight (AFH) of 5 mm and increase in posterior facial hight (PFH) of 3.5 mm, the SNB angle increased with 2 degrees. Following treatment the patient’s facial appearance improved with the mandible appearing less retrognathic and the lower anterior face hight increased (Figure 7).

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A

C

B

D Figure 7: Facial profile: A,B- before treatment, C,D- after treatment

By using Twin Block functional removable appliances in treating class II division 2 malocclusion treatment time is reduced significantly by eliminating a pre-functional phase of treatment. The advancement of upper labial segment occurs simultaneously with the sagittal correction. Table 1. Pre-treatment and post-treatment cephalometric readings Variable Pre-treatment TB Post treatment TB Inter-incisal angle 142.50 134.50 0 FMA 23 250 0 SNA 76.5 760 0 SNB 69 710 0 ANB 7.5 50 0 1/-NL 95 102.50 AFH 55 mm 60 mm 92

Changes -80 20 -0.50 20 -2.50 7.50 5 mm

PFH IF ML-NL Ar-A Ar-Me ArA-ArMe Ar-B Ar-Pg Go-Me Wits AO-BO Ocluzal plane angle IMPA

37.5 mm 0.68 260 83 mm 92 mm 9 mm 87 mm 92 mm 68 mm 5.5 mm 12 mm 96 0

41 mm 0.68 25.50 85.5 mm 97.5 mm 12 mm 92 mm 98.5 mm 70 mm 1 mm 14.50 98 0

3.5 mm 0 -0.50 2.5 mm 5.5 mm 3 mm 5 mm 6.5 mm 2 mm 4.5 mm 2.50 2 0

Conclusion: Modification of Twin Block appliance to provide proclination of the upper incisors, has eliminated the need of a phase of pre-functional upper appliance. This technique has proved to be efficient and effective in the treatment of Class II division 2 malocclusion.

References: 1. Clark, W.J., The twin block traction technique, European Journal of Orthodontics, 4, 129-138, 1982 2. Dyer FMV, McKeown HF, Sandler PJ, The modified Twin Block Appliance in the treatment of class II division 2 malocclusions, Journal of Orthodontics, vol.28, 217-280, 2001 3. Illing H.M., Morris DO, Lee RT, A prospective evaluation of Bass, Bionator and Twin Block appliances, Part1-the hard tissues, European Journal of Orthodontics,20, 501-516, 1998 4. Lund DI, Sandler PJ, The effects of Twin Blocks: a prospective controlledstudy, American Journal of Orthodontics and Dentofacial Orthopedics, 113, 104-110, 1998 5. Mills CM, McCullouch KJ, Treatment effects of the Twin Block appliance: a cephalometric study, American Journal of Orthodontics and Dentofacial Orthopedics, 114, 15-21, 1998 6. Selwyn Barnett BJ, Rationale of treatmentfor Class II division 2 malocclusion, British Journalof Orthodontics, 18, 173-181, 1991 7. Selwyn Barnet BJ, Class II division 2 malocclusion: a method of planning and treatment , British Journal of Orthodontics, 23, 29-36, 1996 8. Trenmouth MJ, Cephalometric evalution of the Twin Block appliance in the treatment of Class II division 1 malocclusionwith matched normative growth data, American Journal of Orthodontics and Dentofacial Orthopedics, 117, 54-59.

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TOTAL EDENTATION OCCURRENCE IN A YOUNG PATIENT Despa Elena Gabriela, Cândescu Graziella Emilia, Popescu Anca Iuliana, Pangica Ana Maria, Giurescu Raluca Anca Titu Maiorescu University of Bucharesti, Faculty of Dental Medicine, Medicine Speciality Department Abstract: Edetation treatment is frequently characteristic for patients aged 65±5. Nowadays, in society, due to the social status, we might say that this state can characterise other age groups, too. The present paper proves the occurrence of total edentation in yound patients, socially assisted, with income under the average on economy. Key words: young patient, late prosthesis, removable prosthesis, biological integration Introduction According to different authors define the total edentation as being characterised by loss of all teeth, after their eruption [1,2,3]. This occurs most frequently in women over the age of 70, according to speciality literature [1]. Currently, clinical activity proves that this state can occur both in elder patients and in young patients, aged 32±5. Prosthetics of young patients has a greater success, as the biological and psychic integration of the total prosthesis is accomplished much more easily and faster. Objective of the study The case presentation represents an example of late prosthesis with a removable prosthesis in a young patient through the social assistance programme. Material and method Patient D.C, aged 34, came to the social assistance department within the Multifunctional Complex Caraiman, requesting restoration of the dento-maxillary functions, especially the physiognomy. As a result of the oral examination (fig.1) and of the complementary examination of orthopantomography (fig.2), the prosthetic treatment consisted in realising a late prosthesis, 30 days after remaining teeth extraction. As preprosthetic treatment, there were chosen serial extractions with post extraction suture (fig.3), having the role of alveolar crest guidance without exostoses occurrence, which might inflence negatively the prosthesis [4,5].

Fig.1. Oral examination

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Fig.2.Radiological examination - orthopantomography

Fig.3. Serial extractions with post extraction suture

Results Late prosthesis for the totally edentulous patient was carried out 30 days after extractions. Phases of treatment respected their sequencing [1,3,4]: preliminary impression (fig.4), functional impression (fig.5), intermaxillary relationship determination (fig.6), probation of models (fig.7), application of prostheses on the prosthetic field (fig.8).

Fig.4. Preliminary impression of the totally edentulous prosthetic field

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Fig.5. Functional impression of the totally edentulous prosthetic field

Fig.6. Determining the intermaxillary relationships

Fig.7. Probation of models

Fig.8. Introduction of removable prostheses within the oral cavity

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The patient put up very well with the removable prostheses, as they re-established everything as the patient requested. The patient was monitorised for 2 months, following up the biological and the psychological integration of the prostheses having in view the age of the patient. Discussions Having in view the patient’s age when this total edentation occurred, state that is characteristic of elder patients, we could state that, nowadays, especially in the socially assisted patients, the edentation age decreased. The patients having removable prostheses got acquainted very well, as these prostheses are biologically and psychologically integrated, re-establishing successfully both the patient’s wishes and the dento-maxillary system functions. Conclusions Late prosthesis in a totally edentulous patient was successful ; it was carried out 30 days after teeth extraction and the good biological and psychological integration of the removable prostheses was due to the patient’s young age. References 1. Hutu E. Edentaţia totală, Publishing House Naţional, Bucharest, 2005. 2. Păuna M, Preoteasa E. Aspecte practice în protezarea edentaţiei totale, Publishing House Cerma, Bucharest, 2002. 3. Bratu D and co. Bazele clinice și tehnice ale protezării edentației totale, Publishing House.Sigma 2003. 4. Despa E.G and co. Tratamentul edentaţiei totale clinică și tehnică de laborator, Publishing House Printech, Bucharest2012 5. Cândescu G.E, Despa E.G, Mihai C, Moise G. Intervenţii chirurgicale preprotetice în edentaţia totală. International Congress SRS-GAO 13-15 May 2010, Romanian Journal of Dentistry 2010; (1) vol.LVI: 63-64.

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ORAL REHABILITATION WITH CERAMIC-FUSED-TO-METAL RESTAURATIONS-CASE STUDY Assistant PhD. Candidate Dobrescu Anca Monica, PhD. Candidate Coman Costin, Lecturer MD. Comăneanu Raluca Monica, Lecturer MD. Smătrea Oana, Professor MD. Ghergic Doina Lucia Faculty of Dental Medicine, Titu Maiorescu University of Bucharest Abstract: Nowaadays, fixed ceramic-fused-to-metal prosthetic restaurations are used more and more frequently in reabilitating teeth with crown lesions or in order to re-establish continuity of dental arches. Essentially, ceramic-fused-to-metal systems combine the advantages of alloys (increased endurance to tension) with the ones offered by dental ceramics (physiognomy, endurance, chemical stability, biocompatibility). The present paper is aimed at presenting the case of a patient with interlaid, bimaxillary endentulous spaces, with partial prosthesis who was rehabilitated with ceramic-fused-to-metal prosthetic restaurations Key words: edentation, fixed prosthesis, ceramic-fused-to-metal prosthetic restaurations Conjunct prosthetic restaurations are entities made up of alloplastic materials (foregn to the body, such as metallic alloys, ceramics, zirconium, polymers) which are inserted on a specially treated prosthetic field in order to reconstruct morpho-functionally dento-parodontal units lost or modified pathologically.2 Fixed prosthetic restaurations are favoured to movable or mobilising dental restorations5 because they have a volume similar to the tissues they replace, have a fixed character throughout their functioning and transmit dento-parodontal or implant-bone mastication forces. Fixed prostheses are relatively easily accepted and yield special satisfaction to the patient. They can change an unaesthetic and unfunctional dentition into a pleasant, confortable one that re-establishes altered morphology and functions.2 Case study: Patient M.V., aged 49, came to the dental office, with class III Kennedy edentation with a prosthetic modification and lower jaw class III Kennedy with partial prosthesis, asking for treatment. The patient was unsatisfied with his maxillary frontal teeth aesthetics which had dento-alveoalar incongruence with crowding as well as dyschromia due to odontal received treatments. Moreover, maxillary ceramic-fused-to-metal prosthetic restaurations which the patient had did not have an adequate integration within dento-maxillary system context. The treatment plan at the upper arch level consisted in ablation of the existing ceramic-fused-to-metal prosthetic restaurations, correction of the abutment from the rear segments of the dental arches, polishing the maxillary frontal group and manufacturing of a total ceramic-fused-to-metal prosthetic bridge. At the mandibular level, dental interventions were carried out within the third quadrant, in order to apply ptosthesis on the six-year molar through a total ceramic-fused-to-metal prosthetic appliance.

Fig. 1 – Initial clinical aspect from right lateral view

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Fig. 2 – Initial clinical aspect of the maxillary arch

Fig. 3 – Initial clinical aspect of the mandibular arch

99

Fig. 4 – Final clinical aspect of the patient from left lateral view

Fig. 5 – Mandibular prosthetic restauration aspect from the occlusal perspective

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Fig. 6 –Clinical final aspect in occlusion frontal view

Fig. 7 – Clinical final aspect in occlusion right lateral view

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Fig. 8 – Clinical final aspect in occlusion left lateral view Discussion Dental medicine has a fundamental role in inproving aesthetic appearance as the oral cavity is one of the most exposed areas of the body.3,11 A smile lacking harmony reduces the human beauty and can cause discomfort within social relationships because the face expression can show friendship, pleasant sensation and assessment.10,11 Aesthetic value of a dental restauration is influenced by factors such as: line of smile, agreement between medial line of the upper and lowe arches, gingival architecture.4,6,7 Dentists have to understand the beauty, harmony, balance and proportion as they are perceived by society when planning their patients’ treatment.8 Dento-facial attractiveness is very important for the individuals’ psycho-social wellness.11 People with dental occlusion within normal limits are considered by society as attractive compared with those having malocclusions.1,9 Conclusions Re-establishing aesthetics and functionality of the dento-maxillary system are absolute concerns of the dentists. Prosthetic restaurations with conjunct character have to be executed in such a way that dental, both static and dynamic, aggregation is not disturbed according to the TMJ mandibular-meniscal-condilian cinematics. References 1) Anderson KM, Behrents RG, Mckinney T, Buschang PH. Tooth shape preferences in an esthetic smile. Am J Orthod Dentofacial Orthop. 128: 458-65, 2005. 2) Bechir A., Comăneanu R.M., Barbu H.M., Dumitrescu C.S., Ghergic D.L., Giurescu R.A., Popescu A.I., Rădulescu D.E., Smătrea O., Tehnologia metalo-ceramică, Ed. Printech, Bucureşti, 2011. 3) Cavalcante LMA, Pimenta LA. Princípios estéticos para um sorriso harmônico. Rev ABO Nac. 13: 81-5, 2005. 4) Chiche GJ, Pinault A. Esthetics of anterior fixed prosthodontics. Chicago: Quintessence Publishing Co; p.13, 61-4, 68, 180, 1994 5) Ghergic D.L., Comăneanu R.M., Andreescu C.F., Bănăţeanu A.M., Roşu O.A., Filipescu A.G., Smătrea O., Barbu H.M., Restaurarea edentaţiei parţiale prin protezare fixă, Ed. Printech, Bucureşti, 2013. 6) Goldstein RE. Esthetic principles for ceramo-metal restorations. Dent Clin North Am.; 21: 803-22, 1977. 7) Levin EI. Dental esthetics and the golden proportion. J Prosthet Dent.; 40: 244-52, 1978. 8) Peck H, Peck S. A concept of facial esthetics. Angle Orthod. 40: 284-318, 1970. 9) Shaw WC, Rees G, Dawe M, Charles CR. The influence of dentofacial appearance on social attractiveness of young adults. Am J Orthod. 87: 241-3, 1985. 10) Simon J. Using the golden proportion in aesthetic treatment: a case report. Dent Today. 23: 82- 84, 2004. 11) Soares GP, Valentino TA, Lima DANL, Paulillo LAMS, Silva FAP, Lovadino JR. Esthetic analysis of the smile, Braz J Oral Sci. 6(21):1313-1319, 2007. 102

TREATMENT PLANNING IN SEVERE OPEN BITE

Authors: Ibric Cioranu Viorel¹, V. Nicolae², Ibric Cioranu Sorin³ 1- Professor, Head of Maxillofacial Surgery Dept, ULBS 2- Assistant professor, Head of Implantology Dept, ULBS 3- Medical resident, Maxillofacial surgery Dept, ULBS

Abstract Open bite is a rare vertical maxillary deformity. Orthodontic treatment has uncertain prognosis. When this treatment fails as well when there are relapses, the patient is instructed to seek a maxillofacial surgeon. We analyzed a group of 15 patents (9 with complete open bite and 6 with partial open bite). After a careful diagnosis involving photographic, x-ray exams and analysis of the diagnostic casts, time of surgery and type of osteotomy was planned. The team consisted of surgeon, orthodontist, and prosthodontist. Results were good and no relapses were noted. Orthodontic treatment is associated to correct deficiencies in transversal and sagittal plans but also to stabilize the post operative result. We utilized the piezosurgery device when we needed accurate osteotomy lines between teeth. Keywords: open bite, surgical treatment, mandible osteotomy Introduction Open bite is a maxillary disorder concerning the vertical space. It is rarely encountered. It is thought to be caused by local factors such as: infection, tumor mass, trauma, interposition, teeth with a high potential for eruption, TMJ disorders, early loss of teeth, keloid scars. Also it has been encountered in systemic disorders such as metabolic pathologies, genetic disorders (Down syndrome, cranial synostose). It can be classified from a clinic view in frontal and lateral and from a surgeon point of view in lateral and partial anterior. It can cause a series of functional problems in chewing, swallowing, speech, esthetic, periodontal and TMJ. If there is a severe space between the bone bases and the orthodontic treatment has failed then surgical treatment remains the best option for the patient. Material and methods We considered for analysis a group of 15 patients diagnosed with open bite between 2010 and 2012. 6 patients had partial anterior type and 9 complete open bite. Male to female ratio favored the male 8 to 7. The group age ranged form 15 to 29 years. At clinical exam we noticed: enlarged inferior facial level, open labial passage, blurred labial menton groove, severe convex facial profile, downwards inclined and retruded menton, oblique horizontal ramus, shorten vertical ramus. At the oral exam there could be noted: enamel dysplasia, modified arches, deep and narrow palatine arch and open bite. Patients diagnosed with complete open bite had also severe forms of the above symptoms. In order to reach a more accurate diagnosis and a more rigorous treatment plan, we utilized photographic exams, orthodontic x-rays, study casts, blood tests. (Pic1). We were then able to predict the final outcome, to explain to the patients the osteotomy lines, the type of immobilization. All the patients were subjected to surgical treatment (Pic2). Results and discussions A team comprised of OMF surgeon, orthodontist, prosthodontist established the suitable moment for surgery and the type of osteotomy. When we planned the treatment we utilized the photographic exam. This type of exam allowed us to study facial symmetry, the soft tissues, and the proportion of the facial levels, the position of the mouth in relation with the inferior level of the face, the shape and width of the nose, the thickness and position of the lips (9). Teleradiography exam is a very important factor in establishing the path of osteotomy and its direction. It allows us to measure the Goniac angle, the Tweed angle, the Tigelkamp and Margolis index, the Tweed and Merrifield analysis. Diagnostic casts are useful in highlighting initial occlusal view, osteotomy lines and final occlusal prognosis. Only after a careful analysis we could planned the surgical treatment regarding the amount of bone needed to augment or resect. Also pre-operative orthodontic or post-operative orthodontic treatment and prosthetic methods can be planned. Depending on the localization, evolution and the severity of the pathology a specific surgical technique is regarded as the best for each case in part (10). When dealing with complete open bite, ood results can be achieved with methods that imply an intervention on the vertical ramus (Obwegesser, Caldwel103

Letterman). These techniques also when we had to correct not only the occlusion but also bone deficiency in transverse plane (maxillary hyperplasia or micrognatia). In these severe cases a LeFort I osteotomy (horizontal osteotomy above the alveolar process) was needed to. (11). The etiology of these afflictions usually had systemic cause: rickets, trauma or infections or sequels after clefts (12). When we dealt with anterior open bite we utilized alveolar osteotomy which allowed us a better prognosis with occlusal stability even at 3 years follow-up. In the space left after lifting the alveolar-teeth complex we usually placed a bone graft taken from the chin; in this manner we corrected the protruded menton usually seen in these cases. This allowed a better aesthetic outcome (Pic3). With the help of piezosurgery we were able to make very accurate osteotomies between the apexes of the teeth when the disorder was situated at the incisive block (13). Piezosurgery device allowed a good bleeding control, a good cooling during the bone cut and protection of soft tissues. Conclusions After a careful planning and with strong indication surgical treatment in severe open bites provides a very good outcome for the patients.

References 1.

2. 3.

4. 5.

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9. 10. 11.

12. 13.

Bourzgui F, Sebbar M, Hamza M, Lazrak L, Abidine Z, El Quars F, Prevalence of malocclusions and orthodontic treatment need in 8- to 12-year-old schoolchildren in Casablanca, Morocco, Prog Orthod. 2012 Sep;13(2):164-72 Ize-Iyamu IN, Isiekwe MC, Prevalence and factors associated with anterior open bite in 2 to 5 year old children in Benin city, Nigeria, Afr Health Sci. 2012 Dec;12(4):446-51 Jones ML, Mourino AP, Bowden TA, Evaluation of occlusion, trauma, and dental anomalies in African-American children of metropolitan Headstart programs, J Clin Pediatr Dent. 1993 Fall;18(1):51-4. Burford D, Noar JH. The causes, diagnosis and treatment of anterior open bite, Dent Update. 2003 Jun;30(5):235-41 Discacciati JA, Lemos de Souza E, Vasconcellos WA, Costa SC, Barros Vde M., Increased vertical dimension of occlusion: signs, symptoms, diagnosis, treatment and options, J Contemp Dent Pract. 2013 Jan 1;14(1):123-8. Jung MH, Baik UB, Ahn SJ., Treatment of anterior open bite and multiple missing teeth with lingual fixed appliances, double jaw surgery, and dental implants, Am J Orthod Dentofacial Orthop. 2013 Apr;143(4 Suppl):S125-36 Otuyemi OD, Noar JH. Anterior open bite: A review. Saudi Dent J. 1997;9:149–157 Glenn E. Lello, Skeletal open bite correction by combined Le Fort I osteotomy and bilateral sagittal split of the mandibular ramus, 1987, Journal of Cranio-Maxillo-Facial Surgery Vol. 15Complete, Pages 132-136 Wriedt S, Buhl V, Al-Nawas B, Wehrbein H., Combined treatment of open bite - long-term evaluation and relapse factors, J Orofac Orthop. 2009 Jul;70(4):318-26. Van Sickels JE, Wallender A, Closure of anterior open bites with mandibular surgery: advantages and disadvantages of this approach, Oral Maxillofac Surg. 2012 Dec;16(4):361-7 Swinnen K, Politis C, Willems G, De Bruyne I, Fieuws S, Heidbuchel K, van Erum R, Verdonck A, Carels C, Skeletal and dento-alveolar stability after surgical-orthodontic treatment of anterior open bite: a retrospective study, Eur J Orthod. 2001 Oct;23(5):547-57 Sandler PJ, Madahar AK, Murray A, Anterior open bite: aetiology and management, Dent Update. 2011 Oct;38(8):522-4, 527-8, 531-2 Millet C, Duprez JP., Multidisciplinary management of a child with severe open bite and amelogenesis imperfecta, J Contemp Dent Pract. 2013 Mar 1;14(2):320-6.

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Pictures

Pic 1

Pic 2

Pic 3

Captions to illustrations

Pic1: Study cast mounted

Pic2: Severe open bite A. Preoperative view; B. Post operative view

Pic3: Severe open bite A. Preoperative view; B. Chin graft; C. Post operative view 105

AESTHETIC OPTIMIZATION BY VENEERS TECHNIQUES Lecturer Dr. Popescu_Anca_Iuliana, , Lecturer Dr. Giurescu_Raluca_Anca, Lecturer Dr. Pangică Anna Maria, Assist. University Filipescu Alina Gabriela, Assist. University Dumitrescu Cătălin Sorin, Associate Professor Dr. Despa Elena Gabriela Faculty of Dentistry, University Titu Maiorescu, Bucharest

Abstract Physiognomy dysfunction occurs when there are changes localized to the anterior teeth, resulting in a deterioration of harmony dental dental-dental dental- alveolar and dental-facial, with negative consequences for their self-image, as well as the perceived environment. This study is to highlight the terapeutic solutions morpho-functional teeth in the previous patients who have physiognomy dysfunctions. Material and methods. For the study were examined 158 patients, 100 women and 58 men, aged between 20 and 40 years who had physiognomy dysfunction. Results and discutions. Phiz dysfunctions treatment with porcelain veneers revealed a number of advantages. Conclusions. The choice and application of treatment should be tailored for each particular patient. Keywords: aesthetics, teeth previous, physiognomy dysfunctions, veneers.

Introduction Physiognomy dysfunction occurs when there are changes localized to the anterior teeth, resulting in a deterioration of harmony dental dental-dental dental- alveolar and dental-facial, with negative consequences for their self-image, as well as the perceived environment (Popa Brândușa, 2002). The purpose of this study is to highlight the therapeutic solutions morpho-functional teeth in the previous patients who have dysfunctions phiz (Popescu Anca et all, 2009). Material and methods For the study were examined 158 patients, 100 women and 58 men, aged between 20 and 40 years who had physiognomy dysfunction. The study was performed by applying treatment techniqes such as: composite resin veneers and porcelain veneers. The choice for each particular treatment was made according to the clinical requirements, local factors and patient financial means. CLINICAL CASE NO. 1 Patient B.V., aged 22 years, F.O. no. 110/2011 presented to the dental office for specialist advice. Subjective. Of history that patient is unhappy by esthetic appearance, as amended by palatinizarea of 1.2. On physical examination it was found (Fig. 1): - dento-maxillary disharmony with dental crowding; - good hygiene degree; - free periodontal status; - no injuries neighborhood; - color front teeth is unchanged; - the proportion of gold is correct; - type of occlusion: normal occlusion. From an aesthetic point of view I watched: - coincidence of top line and bottom line between the two central incisors - incisal edge is unchanged - free gingival margin is normally outlined Treatment plan recommended that indirect veneering with porcelain veneers, eatching technique. 106

Fig. 1. Initial clinical appearance

Protocol involved the following: teeth were cleaned with brushes and abrasive pastes to highlight the actual color of the teeth; impression with synthetic elastomers in two consistencies in universal spoon; checking facet regarding coloring appearance; demineralization of 1.2 (Fig. 3); washing, drying; applying strips of celluloid; facet fixation with Kerr Premise flowable composite (Fig. 4).

Fig. 2. Porcelain veneers adapted the model

Fig. 3. Demineralization of 1.2.

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Fig. 4. Final clinical appearance

CLINICAL CASE NO. 2 Patient I. B., aged 22 years, FO no. 370/2010, are presented in the dental office to restore physiognomic appearance. On physical examination was observed (Fig. 5): - the patient has suffered an injury of the upper front teeth; - lack of hard substance of the tooth 1.1.,enamel and dentin what interests; - good hygiene degree; - good periodontal status; - color unchanged; - occlusion butt. From an aesthetic point of view: - incisal edge is changed As a treatment plan: it is recommended to carry out a direct veneering.

Fig. 5. Clinical case presentation in the office

Working protocol included the following steps: tooth preparation; the color; toilet dentin surface; drying; etching (Fig. 6); applying adhesive system - SINGLE BOND; application of composite materials in the color chosen (Fig. 7) and curing; finish.

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Fig. 6. Etching

Fig. 7. Application of composite materials

Fig. 8. Final clinical situation

Results and discutions Phiz dysfunctions treatment with porcelain veneers revealed a number of advantages: improved aesthetics due to playing shape and proportion of the tooth, sustainability over time, abrasion resistance, color strength over time, biocompatibility with soft tissues. Were found and disadvantages: can not be achieved in practice, can not be repaired, are more expensive, requires more than working is difficult, changing color after cementation. Advantages of porcelain veneers: 1. Porcelain veneers are very durable. \although porcelain veneers are very thin, usually between 0,5-0,7 mm and inherently brittle, once bonded to healthy tooth structure it becomes very strong. Porcelain veneers can last for many years, usually 10-15 years, if the patience takes good care of them using good oral hygiene and avoiding using them to crack or chew hard objects like ice. 2. Porcelain veneers create a very life-like and natural tooth appearance. The translucent properties of the porcelain allows the venners to mimic the light handling characteristics of enamel giving it a sense of depth which is not possible with other cosmetic bonding materials such as composite resin. 3. Porcelain veneers resist staining. Unlike other cosmetic dental bonding materials, porcelain is a smooth, impervious ceramic and therefore will not pick up permanent stain from cigarette smoking or from dark or richly colored liquidis or spices. 4. Porcelain veneers are conservative. Only a small amount of tooth structure is removed, if any during of procedure. Disadvantages of porcelain veeners: 1. Porcelain veneers are not made at chairside. Porcelain veneers are fabricated in a dental laboratory and therefore require at least two visits. Composite resin veneers are accomplished in one visit. An adequate amount of tooth structure is removed to allow for placement of composite resin in the desired shape without added tooth bulk. Bonding agent is applied. Composite resin is then added, light cured, then finished and polished. 2. Porcelain veneers are more expensive than composite veneers. The placement of veneers requires more time, expertise and resourses in order to fabricate and bond and therefore cost more. 3. Porcelain veneers cannnot be repaired. If the patiences breack porcelain veneers must be replaced. 109

Conclusions. Aesthetic restoration is a component of clinical dentistry, variables are only techniques . The choice and application of treatment should be tailored for each particular patient. Good treatment results are assured through a proper analysis of each case, through a correct choice of treatment and through a good patient monitoring activity.

References 1. Anca Iuliana Popescu, Valeriu Cherlea - Disfuncţia fizionomică – aspecte clinice şi de tratament Conferinţa comună de stomatologie SRS – GAO, Italia, Bucureşti, 29-31 mai 2008. 2. Faez N., Hatab – Dental Discoloration: an overview, Journal of Esthetic and Restorative Dentistry, Vol.11, issu 6, published online: 1 july 2006. 3. Popa Brândușa Mariana – Estetica in odontoterapia restauratorie, Ed. Univ. “C.D.” Bucuresti, 2002. 4. Popescu Anca Iuliana, Giurescu Raluca Anca, Bîcleșanu Cornelia – Porcelain veneers vs. composite resin veneers, The VII- th Congres of Oral Health and Dental Management in the Black Sea Countries, Istanbul, Turkey, 23-27 May 2009. 5. Ș. L. Drd. Anca Iuliana Popescu – Studiul clinic și statistic al disfuncției fizionomice, Revista Română de Stomatologie, vol. LVII, nr. 3, 2011, pag. 181-184, cod CNCSIS 756, cotat B+.

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INTERDISCIPLINARY AND COMPLEX ORAL REHABILITATION – CASE REPORT A. Oana Roșu, Phd., Assistant, Department of Prosthodontics, “Titu Maiorescu” University, School of Dental Medicine Bucharest, Romania Doina L. Ghergic, Professor, Department of Prosthodontics, “Titu Maiorescu” University, School of Dental Medicine Bucharest, Romania Mihaela Raescu, Assistant Professor, Department of Preventive Dentistry, “Titu Maiorescu” University, School of Dental Medicine Bucharest, Romania Aim: To present an approach of a complex case choosing an interdisciplinary and conservative solution. Materials and methods: The chosen approach is just one of the methods that can be applied in cases like this. After a detailed discussion with the patient, an extensive treatment plan was elaborated. The removal of the crowns and old fixed partial dentures was followed by root canal treatments / retreatments of the teeth. Only the reconstructable teeth have been kept. The teeth with advanced carious lesions, were extracted and , if necessary, replaced with an implant.Temporary long-term prosthodontic restaurations were used. The endodontic treated / retreated teeth became the temporary long-term prosthodontic abutments. The final restaurations have been made out of full ceramic in the frontal area and metalo-ceramic in the lateral areas. Results: Most of the teeth that were under the old bridges could be used as new abutments. The final results came only after the bone-integration of all the implants.The patient was very satisfyed with the results. Conclusions: The modern oral rehabilitation of complex cases demands a very good treatment plan discussed with and approved by the patient, a good interdisciplinary approach and cooperation for high therapeuthical results. Key words: complex oral rehabilitation, conservative- interdisciplinary approach, bridges. INTRODUCTION An important category of patients that come in the dental office today is the one with extensive and multiple endentulous spaces. Usually, most of this patients present a complex pathology due to the lost of teeth, which can be followed by a lot of complications. These complications can be easy or very difficult to solve especially if the extractions have been made long time ago. The pathologic conditions induced by the alteration of the dental-maxillary apparatus (due to the lost of teeth), can also alter the adjacent bone, oral mucosa, temporal-mandibulary joint, the perioral and masticatory muscles, and also the nervous system of the patient even at young ages. Therefore, restoration of the dental-maxillary functions has to be made as soon as possible. In all cases, establishing and conducting a good treatment plan is very important. An interdisciplinary approach is recommended and also the teamwork of several specialists. Most of this patients will opt for fixed prosthodontic restorations, regardless the age. This is a “must do” especially in young patients. According to the Glossary of Prosthodontic Terms 1999, Fixed Prosthodontic is that part of Prosthodontics that deals with restoration and / or replacement of teeth with artificial substitutes or materials which cannot be removed from the oral cavity. These can be divided in two large categories: • single prosthodontic restorations (single crowns) • fixed partial restorations (bridges) A successful prosthodontic restoration needs an elaborated and correct treatment plan, the therapeutical act of making it (preprosthodontic treatment, impression and tehnical stages) followed by thorough periodontal therapie which could be needed for maintaining tissues with other characteristics but natural teeth ( the prosthodontic restorations made of different materials ), prevention of possible ulterior damages and especially a specific oral health education.

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Classification of the fixed partial restorations This kind of restoration can be classified after many criteria: topography, relation with the abutments, fixing, denture retainers, relation of the interloper with the ridge, abutments and topographic areas, tehnology, support. In order to be able to chose the appropriate fixed prosthodontic solution, we must first analyse a multitude of factors and make a very detailed clinical examination. It is recommended also to make a few complementary exams such as: radiographic exam,ocluzal exam,the examination of the study models. Planning and choosing the appropriate treatment plan must take the following factors into consideration: • the expansion and the topography of the edentolous spaces; • position on the arch and the periodontal support of the adjacent teeth; • age and health state of the patient; • lab and office endowment; • professional experience of doctor-tehnician team; • financial possibilities of the patient. CASE REPORT The patient E.T., 35 years came in the office unsatisfied with the esthetic appearance of her prosthodontic restorations (fig 1).

Fig.1.

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Clinical examination revealed that, besides the esthetic deterioration of the prosthodontic restorations, these had also lost their adaptability on the prosthodontic field(both in the gingival area as well as what the occlusal plan was concerned) (fig 2).

Fig.2. The panoramic X-ray showed inadequate root canal treatments, teeth with deep decays, teeth that needed extractions and teeth that needed prosthodontic restorations due to the lost of hard tissue(fig 3). The final treatment plan was made only after the examination of the panoramic radiograph and all costs establishment.

Fig. 3 In the first step, the patient was sent to an orthodontic exam, due to the fact that the median line was deviated 3 mm to the right. The orthodontist established that the median line can be adjusted only with an extraction in the second quadrant (preferable the first or the second premolar), and the duration of the treatment will be for about 1 year and a half.Because the teeth in the left quadrant could be retreated and kept the working team decided that the orthodontic treatment will not be applied. The patient also agreed. 113

After the cleaning, the removal of the prosthodontic restoration in the first quadrant (11-15) was performed. Also the metal posts from teeth 11, 12, 13 had been removed (11 and 13 in the same time with the bridge removal).The same restoration was kept as a temporary one until the root canal re-treatments and the fiber post build-ups on teeth 11,12,13,17 were completed. Tooth 16 also needed a root canal treatment. Tooth 15, after the removal of the post and after trying to perform a root canal re-treatment it was decided that it cannot be kept. An extraction and bone augmentation (0.5 grams of BioOss mixed with 0.5 grams of MinerOss) was performed by the implantologist in the first session and then, after 6 months of healing, an internal sinus lift and an implant was placed in the 15 position. The prosthodontist prepared the endodontic treated teeth and also teeth 21 and 22, performed a gingivectomy on teeth 11, 12 and 13 and a temporary long-term acrylic baro-polimerysed restoration 22 - 16 was manufactured. Tooth 17 received a single prosthodontic restoration. Tooth 21 remained vital and tooth 22 was retreated. Since the connection between teeth and implants is not recommended (even contraindicated), when operating the internal sinus lift in the first quadrant, a bucal bone graft (with 0.7 grams of MinerOSS and an Extended Bio Mend Zimmer membrane) was performed preparing the area for an implant on 14 position). This was inserted after 5 months of the bone-graft integration (fig 5). In the third quadrant tooth 34, being the only one in that quadrant without a prosthodontic reconstruction was the first in this quadrant retreated and fiber-post restored. During the treatment, the permanent 35-37 fixed prosthodontic restoration (metal-ceramic) detached and it was temporary re-cemented. In the second quadrant the old metal-ceramic fixed prosthodontic restoration was removed, teeth 24 and 25 were retreated. First, tooth 26 was left vital (fig 4), but due to the painful symptoms that followed the polishing, a vital extirpation had to be performed on this tooth. Fiber-post restorations on 24, 25 and 26(Anatomic fiber post no1 from Micro-Medica and Opaceous White Build-It from Pentron Clinical) (fig 5). The 4th quadrant received 2 implants in the same session with the extraction of radicular remnant of tooth 45(on 45 an Alpha Bio 3,75/10mm DFI implant and on 46 an Alpha Bio 3,75/10mm DFI implant with a vestibular autogenous and 0.5 Bio Oss and Bio Gide bone-graft mixture). Tooth 47 received a root canal retreatment and a fiber-post restoration. Also all the old fillings which suffered a seal-lost, fracture or marginal infiltration or decay were replaced (fig 4).

Fig. 4 After bone-healing of bone-graft in the 14 position, an Alpha Bio SPI 3.3/11.5mm was inserted. The implantologist decided that more vestibular bone-graft is needed, so 0.3 grams of Bio Oss and ORAMEM Sustained membrane. During the same visit the 15, 45 and 46 cover screws of the implants had been removed and an impression for 2 acrylic temporary bridges was taken (14-15, 45-46). This was cemented after one week (fig 5).

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Fig. 5 In the 3rd quadrant teeth have been retreated and fiber-post reinforced. Extraction of the wisdom teeth 23, 38 was recommended. For the final prosthodontic restoration full ceramic crowns were chosen on teeth 15, 14, 13, 12, 11, 21, 22, 24, 25, and a porcelain veneer on 23. On teeth 16, 17, 26, 34 and 47 the prosthodontist chose ceramic on zirconium oxide support and on the implants 14-15, 45-46 full ceramic bridges. On teeth 35-37 a fixed prosthodontic restoration ceramic on zirconium oxide was made. The prosthodontic restorations were fixed to the natural teeth or implants through cementation.They will transmit the masticatory forces to the bone only through the parodontal ligament of the abutments (teeth or implants). The final result came after almost 1year and a half (fig. 6, 7, 8).

Fig. 6

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Fig. 7

Fig. 8 Discussion Reconstruction of the morphological, functional and esthetic integrity of the dental arches means improving the functional conditions of the entire dental-maxilary apparatus.Fixed prosthodontic restorations will be profilactic for the periodontal tissue, will establish the ocluzal-functional equilibrum.All functions of dentalmaxilary apparatus will be much more improved compared to any other mobile or movable prosthodontic solution. Disadvantages had also been described in what the fixed prosthodontic restoration is concerned. The hygiene is more difficult to be performed compared to the mobile or removable prosthesis. All kind of bridges, no matter the shape and size, could have some areas where the alimentary rests can be deposited and from where this rests cannot be easily removed through brushing or soft-parts movement. This alimentary retention is more 116

voluminous at fixed prosthodontic restorations where we have big mucosal surfaces. Special hygene rules have to be established and the patient has to be instructed for using special dentalfloss and the waterpick. As for the frontal or frontal-lateral bridges, replacing 2,3 or 4 teeth is mandatory not just to be extremely natural and esthetic, but also resistant to breakage, and capable to hold incisal-oclusal pressure of the antagonist teeth. The fisical resistance of the restorations is given by the resistance of the metal alloy from which the bridge is manufactured. The alloy, in order to be adequate from esthetic point of view, is covered with 1-1,5 mm of material of the same aspect and color as the natural teeth. Unfortunately these materials have a high risc of breakage and high rate of transparency. This means that the color may be influenced by the color of the alloy underneath, and the form and the volume of the natural teeth could not be easily restored. The volume that the prosthesis is occupying in the mouth of the patient is smaller or at least as big as the natural teeth which are replaced. Conclusion The clinical-technical execution of the fixed prosthodontic bridges, preparation of the abutments and impression of the prosthodontic field enforces the dentist and dental-technician to pay a lot of attention, to consume a lot of energy and time. No matter how functional a fixed prosthodontic restoration is, if the esthetical integration in the physiognomy and personality of the patient is not perfect, it can be considered a failure. For the patient, the good general health condition is the main condition to manufacture a good fixed prosthodontic restoration. Treating and preparing the abutments can represent for some patients traumatizing treatments. Sometimes the administration of sedatives, which can have adverse noxious reactions, is necessary. Regardless of all this the fixed prosthodontic solution shloud be the first option in any of the cases, especially at young ages.

References: 1.

BAET,SFE,NEF- Endo Practice Today, Volume 7, Issue 2, Quintessence Publishing Co. Inc, Summer 2013,

2.

Bratu D. and R. Nussbaum – Clinical and tehnical bases of fixed prosthodotic reconstructions.ed Signata, Timisoara, 2001 3. Bratu D. – Dental materials in the dental practice,2 nd edition, Editura Helicon, Timişoara, 1998. 4. Bratu D., Fabricky M. – Full ceramic sistems, Editura Helicon, Timişoara, 1998. 5. Bratu D. - Mixed crown, 2nd edition, Editura Helicon, Timişoara, 1998. 6. Bratu D., Negruţiu M. - The dental-maxilary aparatus simulator. Lito U.M.F.T., 1994. 7. Burlui V. – Dental prosthodontics. Curs UMF laşi 1988. 8. Ene L., lonescu Pogăceanu Irina – Crown leasions and their prosthodontic treatment.Curs UMF Bucureşti 1979. 9. Ene L., loniţă S. – The treatment with fixed prosthodontic restorations in small edentoulous spaces.Curs UMF Bucureşti 1982. 10. Ghergic D. şi colab. – Restoration of the partial edetolous spaces through fixed prosthodontics. Ed. Printech, Bucureşti, 2013 11. Raescu M., Manu R. –Actualități în prevenția oro-dentară, ED. Printech, București 2012 12. SSER - Cosmetic dentistry, SSER publishing, September 2013.

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PERIIMPLANTITIS, COMPLICATION IN ORAL REHABILITATION WITH DENTAL IMPLANTS Smătrea Oana professor assistant, Faculty of Dentistry University Titu Maiorescu Bucharest, Ghergic Doina Lucia professor, Faculty of Dentistry University Titu Maiorescu Bucharest, Andreescu Claudia Florina professor assistant, Faculty of Dentistry University Titu Maiorescu Bucharest. Corresponding author: Claudia Florina Andreescu, DDS, PhD, Professor Assistant, Faculty of Dental Medicine, University Titu Maiorescu, Bucharest, 67A Gheorghe Petraşcu Street, sector 3, Bucharest, cod 031593, telephone/fax: +4021.325.14.16, e-mail: [email protected]

Abstract. Introduction. Dental implants are widely use in dental practice. High rate of success on long term promoted dental implant as election therapy for replacement of teeth lost. However, widespread use of endosseous implants increase the incidence of complications in oral rehabilitation with dental implants despite initial high success rate initially reported. One of the most common complications is periimplantitis, soft tissue inflammation accompanied with bone loss around implant. Objective of study. Objective of this study is analysis of periimplantitis frequency and causes associated with this complication in oral rehabilitation with dental implants. Material and method. For this study was assessed a batch of 186 subjects, where a number of 403 implants were placed. All implants are restored and in use for at least 6 months. Majority of prosthetic rehabilitation is represented by bridges and crowns (94.61%). Conclusion. Frequency of periimplantitis at studied batch is 22.58%. Periimplantitis could be treated without compromising prosthetic work survival, but this implies a good to reserved prognosis. Recommended therapeutic approach for bone defects is general antibio-therapy (amoxicillin with metronidazole), removing prosthetic work, cleaning of prosthetic work mechanical and in ultrasonic bath, opening the bone defect, removal of granulation tissue, cleaning and decontamination of dental implant, bone defect filling and optional coverage resorbable membrane. Also is mandatory to check occlusal load on prosthetic work. 1. Introduction. Dental implants are widely use in dental practice. High rate of success on long term promoted dental implant as election therapy for replacement of teeth lost. However, widespread use of endosseous implants increase the incidence of complications in oral rehabilitation with dental implants despite initial high success rate initially reported. One of the most common complications is periimplantitis, soft tissue inflammation accompanied with bone loss around implant. 2. Objective of study. Objective of this study is analysis of periimplantitis frequency and causes associated with this complication in oral rehabilitation with dental implants. 3. Material and method. For this study was assessed a batch of 186 subjects, where a number of 403 titanium endosseous implants were placed (Figure 1). SINGLE CROWN BRIDGE OVERDENTURE TOTAL 38 48 2 88 maxillary (38 implants) (143 implants) (2 implants) (183 implants) 32 58 8 98 mandible (32 implants) (168 implants) (20 implants) (220 implants) 70 106 10 186 total (70 implants) (311 implants) (22 implants) (403 implants) Figure 1. Distribution of group according to prosthetic restoration and number of implants.

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Majority of prosthetic rehabilitation is represented by bridges and crowns (94.61%). 47.31 of prosthetic restored maxillary missing teeth and 52.69% restored mandibular missing teeth. All implants are restored and in use for at least 6 months. For all the subjects examination included: anamnesis, examination of peri-implant soft tissues through inspection and palpation, percussion of implant, inspection of prosthetic restoration and X-ray. 4. Results From all 186 subjects examined clinical and radiological, 138 subjects have no pain or sensitivity, implants do not have mobility, there is no history of periimplant exudate and bone loss around implant from first surgery is less than 4 mm. The other 48 subjects present periimplant soft tissues inflammation with or without bone loss. 6 subjects present inflammation of periimplant soft tissues without bone loss and this type of inflammation can be observed during clinical examination (Figure 2), implant has no mobility, there is no pain during mastication and bone loss from first surgery is less than 4 mm. Inflammation of periimplantar soft tissues without affecting bone around implant are called perimucositis and usually point to prosthetic problem like: mobilisation of crown, mobilisation of retain screw, fracture of prosthetic abutment etc. These kind of complications is more frequent for single crown supported by implant. 42 subjects present inflammation of periimplant soft tissues with bone loss more than 4 mm from first surgery, during exploring with a periodontal probe there is a depth more 7 mm (Figure 3-5). Anamnesis could reveal some signs like sensitivity during mastication or presence of exudate. In 2 cases bone loss around implant exceeded implant length and lead to implant loss and consecutively of failure of treatment. In studied group frequency of perimucositis is 3.22% and frequency of periimplantitis is 22.58%. From all 48 cases 2 (4.17%) were found for mobile prosthetic work, 19 (39.58%) were found for single crown implant and 27 (56.25%) were found for bridges supported by implants. This type of complication is common associated with poor oral hygiene (Figure 6), antecedent of periodontal disease found in 16 cases from all 48 subjects, smoking (29 subjects with these complication are smokers) and with overload of implant due to excessive occlusal forces that occur due to incorrect placement of implant or due to an incorrect prosthetic work (cantilever prosthetic work, small number of implants according to size of edentulous span etc.). 5. Discussion Periimplantitis is defined as an inflammatory reaction with the loss of supporting bone in the tissues surrounding a functioning implant[1]. Periimplant mucositis describes an inflammatory lesion that resides in the mucosa, while periimplantitis also affects the supporting bone[2]. Although of excellent long term prognosis of dental implant treatment, recent studies show a high prevalence of periimplantitis (48%) and perimucositis (6.6%)[3]. Lindhe J and Meyle J[2] find that periimplant mucositis occurs in about 80% of subjects (50% of sites) restored with implants, and peri-implantitis in between 28% and 56% of subjects (12–40% of sites). Fransson C. 2009[4] reports perimplantitis at 28% of 1346 subjects with fixed implant supported prosthesis with medium life of 10 years, and Norton M. 2009[5] describes 29.5% prevalence of periimplantitis in patients with partial edentulism. Risk factors for periimplantitis are: poor oral hygiene, history of periodontal disease and cigarette smoking[2]. Roughness of implant surface, bone augumentation at implant site and type of prosthetic restoration has no influence over the soft tissues inflammation around implant[6]. There is no study that indicates treatment of choice in case of bone defects[7], but is recommended following attitude: systemic antibiotics (Amoxicilin in combination with Metronidazol), removal of supra-structure, prosthetic abutments are removed cleaned and sterilised, open a flap to fully access periimplant defects, carefully removing of granulomatous tissue, decontamination of implant, filled the osseous defects with bone substitute. Guided tissue regeneration therapy has different degree of success, but does not address to the cause of the disease just fill a bone defect. As regards decontamination technique, there is no significant difference in efficiency of method: chemical, air abrasion, laser[8]. Currently, there is insufficient evidence to support the superiority of one method of managing periimplant mucositis or periimplantitis over another. The most effective therapy is prevention: daily home care, control and regular professional maintenance[9]. 6. Conclusion. -

Frequency of periimplantitis at studied batch is 22.58%. Periimplantitis could be treated without compromising prosthetic work survival, but this implies a good to reserved prognosis. 119

-

-

Recommended therapeutic approach for bone defects is general antibio-therapy (amoxicillin with metronidazole), removing prosthetic work, cleaning of prosthetic work mechanical and in ultrasonic bath, opening the bone defect, removal of granulation tissue, cleaning and decontamination of dental implant, bone defect filling and optional coverage resorbable membrane. Also is mandatory to check occlusal load on prosthetic work.

Figure 2: Perimucositis - 2.1.with modified aspect of gingival around implant supported crown.

Figure 3: Periimplantita in funnel shape (narrow and deep) – radiological aspect.

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Figure 4: Periimplantitis in cup shape (large bone defect, less deep, easy to clean) - radiological aspect.

Figure 5: Bone defect that leads to failure of implant.

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Figure 6. Patient has neglected oral hygiene at anterior mandibular implants for 6 years. Radiograph of the anterior region in the same patient.

7. References [1] [2] [3]

Albrektsson T., Isidor F. Concensus report of session IV. In: Lang NP, Karring T, editors. Proceedings of the 1st European Workshop on Periodontology. London: Quintessence Publishing; 1994. p. 365–9. Lindhe J., Meyle J. Peri-implant diseases: Consensus Report of the Sixth European Workshop on Periodontology. J Clin Periodontol 2008; 35 (Suppl. 8):282–285. Roos-Jansĺker A-M., Lindahl C., Renvert H., Renvert S. Nine- to fourteen-year follow-up of implant treatment. Part II: presence of peri-implant lesions. J Clin Periodontol 2006; 33: 290-295. 122

[4] [5] [6] [7]

[8] [9]

Fransson C. Prevalence, extent and severity of peri-implantitis. University of Gothenburg, Sweden 2009. Norton M. The decontamination and treatment of peri-implant mucositis and peri-implantitis. Implant practice May 2009 Volume 2 Number 2:1—17. Karbach J., Callaway A., Kwon Y.D., d'Hoedt B., Al-Nawas B. Comparison of five parameters as risk factors for peri-mucositis. Int J Oral Maxillofac Implants. 2009 May-Jun; 24(3):491-6. Esposito M., Grusovin M.G., Coulthard P., Worthington H.V. The efficacy of interventions to treat periimplantitis: a Cochrane systematic review of randomised controlled clinical trials. European Journal of Oral Implantology 2008, 1(2):111-25. Claffey N., Clarke E., Polyzois I., Renvert S. Surgical treatment of peri-implantitis. J Clin Perio.dontol. 2008 Sep; 35(8 Suppl):316-32. *** British Society for the Study of Prosthetic Dentistry Royal College of Physicians and Surgeons of Glasgow Consensus Statement – 2010.

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NEW TREND IN THE NANO-BASED PHARMACEUTICAL FORMULATION FOR THE TREATMENT OF OSTEOPROROSIS Ioana Ailiesei, Ludmila Otilia Cinteza, Ana Maria Sachelarie * University “Titu Maiorescu”, Pharmacy Department Abstract The present study had the purpose to formulate new colloidal vectors containing bisphosphonates, synthetic analogs of pyrophosphate, used as a good approach in the treatment of osteoporosis. Because of their high polarity bisphosphonates like Alendroanate and Clodronate have a poor bioavailability after oral administration following a poor absorption, rapidly excretion and weak penetration into the cells. The aim of the research was to obtain a more efficient formulation for the oral administration with a higher bioavailability even in bone, a site of action hard to reach. Two models of liposomes were obtained by using different lipidic film, one using only lecithin and the other a mixture of lecithin and cholesterol. The analysis of the formulations using Dynamic Light Scattering technique showed good properties: liposomes are resistant and stable even after 3 months of storage. The study also wanted to validate a specific method for the evaluation of the encapsulation efficacy, based on the bisphosphonates’ property to form complexes with Cu (II), which determine a specific absorbance in UV/Vis at a path length of λ=234nm (alendronate) and λ=235nm (clodronate). The experiment revealed that Clodronate is more effective than Alendronate. Increasing the rigidity of the molecule given by the components of the lipid layers, especially because of the cholesterol, theoretically higher results were obtained. INTRODUCTION With the technological progress over the years some innovations were developed with the aim of improving different aspects about the drug administration. In this attempt, the drug delivery systems are used because of their pharmacokinetic and pharmacodynamic properties which can allow new formulations with selective activity, low toxicity and high efficiency. [1] The modern pharmaceutical technology focused its attention on the possibility of using alternative administration in order to improve these parameters with the aim of obtaining a specific action, even in areas hard to reach. In this attempt, certain attention was given to the bone. There is no standard treatment given to all patients with osteoporosis. Treatment is tailored for the specific needs of the individual. Generally speaking, the patient’s overall risk of fracture helps to determine the best course of treatment. A common approach for the treatment of osteoporosis is the use of Bisphosphonates.[25]. Bisphosphonates are pyrophosphate analogs in which the two phosphorus atoms are linked with carbon atom. Bisphosphonates inhibit the resorption of bone matrix by osteoclasts and they have been used in treatment of osteoporosis.[5-9] They may also interfere directly with some cancer mechanisms (at epidermoid carcinoma, bone tumors and other cancer cells proliferation). [10] The bisphosphonates act directly on bone multicellular unit, with their storage in osteoclasts. This way the process of resorption is diminished, with visible effects in the evolution of the bone erosion during a detailed examination. After therapy with these compounds, the risk of bone fracture is reduced by the protection of the bone trabeculae. [5-9] This group of drug include among others: alendronate (4-amino-1-hydroxybutane-1,1-bisphosphonic acid) sodium salt and clodronate (dichloromethylene1,1-bisphosphonic acid) disodium salt. The inhibition capacity varies from one compound to another, and clodronate proved to be one of the most effective. Because of their polarity, bisphosphonates have a poor bioavailability after oral administration due to their poor absorption, rapidly excretion and weak penetration into the cells. The drugs are used parentallyconcentrate for infusion ground (high doses administered intravenuos are more efficient in the malignant therapy) and more frequently by oral administration- capsules, tablets, oral solutions (used for the treatment of hypercalcemia and osteolytic bone metastases due to malignant pathology), even their efficacy is very low. [1114]. The purpose of this thesis is to describe the preparation methods, stability and characterization of a new formulation, the liposomes, a drug delivery system containing alendronate or clodronate sodium salt as a possible way to improve their oral bioavailability. [15,16] Liposomes are small, spherical vesicles which consist of amphiphilic lipids, arranged concentrically, which includes an equal number of aqueous spaces or compartments. Depending on the processing conditions and the chemical composition, liposomes are formed with one or several concentric bilayers, with various dimensions from 30-50 nm to several mm. [17,18] Liposomes are drug delivery systems which release the active substance at the target place by their interaction with the biological membranes. [19-21] For this reason, there is not possible to determine their release profile in vitro.

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MATERIALS AND METHODS: Materials: Clodronate (Actavis Group), Alendronate ( Teva LTD API Division, Israel), Chloroform solution (Fluka, Sigma-Aldrich Chemie, Germany), Phosphatidylcholine, Cholesterol (AppliChem), Apparatus Stuart, for heat and stir, Microscope Motic, Zetasizer NanoZS90 apparatus, Solution 1.5mmol/L of Cu (II) (NO3)2 *3 H2O/HNO3, Distilled water, Supelclean Cartridge (LC-WCX SPE Tube, code 57061), Millipore ultracentrifugation cells. Assay: 1. Liposome Synthesis: The bisphosphonate was encapsulated in liposomes composed of 10mg/ml lipids and aqueous solution containing the drug.Two types of liposomes were formulated, the first one with phosphatidylcholine in the lipid film and the second one with phosphatidylcholine and cholesterol, in a molar ratio of 4:1, for the lipid film. The lipid was dissolved in chloroform under continuous agitation. The lipid film resulted after the evaporation of the residual organic solvent was hydrated with an aqueous solution containing sodium alendronate heated at 60°C (using the Stuart apparatus). The suspension was sonicated for about 15 minutes and then analyzed using a microscope (10x, 40x and 100x). [22-27] 2. Characterisation and Stability of new formulations The molecules of the active substances were generated and then characterized in comparison with other class members using HyperChem program. The stability of our new formulations was evaluated by following the modification in time of the size of the particles after 3 months since their preparation. The measurement of the size was made using Dynamic light scattering (also known as photon correlation spectroscopy or quasi-elastic light scattering), a technique in physics, which can be used to determine the size distribution profile of small particles in suspension or polymers in solution. The experiment was conducted on Zetasizer NanoZS90 apparatus.[28] It was seen that at the beginning of the trial, the samples included a single population of monodisperse liposomes. The Zetasizer device has registered the average diameter of the dispersion.After 3 months of storage in a warm place, the Zetasizer has registered a different value for the average diameter, as a result of the previous agglomeration of the liposomes particles. 3. Quantitative determination of active substance: It is based on the bisphosphonates property to form complexes with Cu (II), which determine a specific absorbance in UV/Vis at a path length of λ=234nm (alendronate) and λ=235nm (clodronate). [29] Preparation of the calibration curve:From aqueous solution of 1.5 mmol / L Cu(II)(NO3)2 *2H2O /HNO3, pH≅2, and various proportions of the examined drug ( liposomes with alendronate sodium salt, clodronate disodium salt, conc. 1mg/ml), were prepared the future solutions to be analyzed. Spectra of these solutions were recorded against water and then against blank (1.5mmol/L Cu (II)(NO3)2*2H2O/ HNO3). The calibration curves were set up by plotting direct absorbance against the drug concentration. The equations of calibration line were estimated using linear regression y=a*x + b. SAMPLE Blank Sample1 Sample2 Sample3 Sample4 Sample5

EXAMINED DRUG (mL) DISTILLED WATER (mL) COMPLEXANT AGENT (mL) 0 1mL 2mL 1mL 0 2mL 0.8mL 0.2mL 2mL 0.6mL 0.4mL 2mL 0.4mL 0.6mL 2mL 0.3mL 0.7mL 2mL

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1 0.9

y = 3.4887x + 0.1628 R2 = 0.9964

0.8

Absorbance

0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0.05

0.1

0.15

0.2

0.25

Alendronate concentration (mg/ml)

Encapsulation efficiency of liposomes with bisphosphonates Our study wants to validate a specific method for the evaluation of the liposomes content in active substance, the spectrophotometric quantification of the embedded biphosphonate. Principle of the method: It is based on the bisphosphonates’ property to form complexes with Cu (II), which determine a specific absorbance in UV/Vis at a path length of λ=234nm (alendronate) and λ=235nm (clodronate). [29] Initial attempts revealed that the complex agent has its own capacity of absorption in the UV light and it interferes with bisphosphonates determination. Due to this experimental observation, we realized that the capacity of encapsulation of the prepared liposomes needs to be determined as a difference between the initial concentration of active substance in the liposomes and the concentration detected in the remained solvent before a previous phase of liposomes separation. Liposomes were separated using the method of separation with solid phase extraction. The Supelclean Cartridge (LC-WCX SPE Tube, code 57061) it proved to be inefficient, the filtrate wasn’t clear and gave no valid result. Previous trials showed that the most effective method of separation was the centrifugation on Millipore ultracentrifugation cells. RESULTS AND DISCUSSION: The colloidal vectors embedding bisphosphonates revealed that the size is at the ratio of nm and the particles were able to be observed with the Motic Microspore ( 100x ). The analysis of the formulations showed good properties: liposomes are resistant and stable. They do not lose the active substance because of the rigidity of the molecule given by the components of the lipid layers (especially because of the cholesterol). With these properties, these drug carriers can circulate for a long time in blood until they find the target organ. The DLS experiment provided a good stability of our formulations. Even if after 3 months of storage the particles tend to agglomerate, the solution can be reversed into monodisperse using sonication. a). Representation of the liposomes after preparation

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b). Representation of the liposomes after 3 months of storage with the two populations resulted because of the aggregation of the particles

The quantitative evaluation of the content in active substance using the method of Spectrophotometry showed that the new formulation with drug delivery systems of incorporated bisphosphonates is more effectively in the case of Clodronate respect to Alendronate.

The experiments showed also that the ratio of incorporation of the drugs is bigger if the lipid layer contains the combination of two lipids, Phosphatidylcholine and Cholesterol, than only one lipid, Phosphatidylcholine. The reason is that Cholesterol inserted into liposomal membranes due to the rigid steroid nucleus, provides a close packing of lipid double layer and it reduce / avoids the leakage of the active substance embedded in bilayer lipid or aqueous compartment. 127

The capacity of encapsulation revealed that Clodronate is better incapsulated into liposomes respect to Alendronate; the ratio of encapsulated drug was 11%, respectively 5.8%.

There is not possible to evaluate the drug release from the system, because they are formulated to release the active substance after the interaction with biological membranes. CONCLUSION: The Alendronate and Clodronate formulated as liposomes proved a higher theoretical absorption along with the vehicle. The quantitative determination showed that the lipid layer containing Phosphatidylcholine and Cholesterol is more effective than the layer made only with Phosphatidylcholine in which concerns the entrapment capacity of water soluble drugs. Subsequent attempts will be focused on research of the behavior of liposomes “in vivo”, after the oral administration and formulation of new liposomes with different sources of lipids for the bilayer synthetic lipids with functional groups, as ligands for targeting. References: Hîrjău Victoria, Lupuliasa D., Hîrjău M., Sisteme cu eliberare la ţintă a substanţelor medicamentoase în Tehnologie Farmaceutică, (Iuliana Popovici, D. Lupuliasa), Editura Polirom, vol. 3, 682-686 (2009) 2. Gass M, Dawson-Hughes B., Preventing osteoporosis-related fractures: an overview. Am J Med. 119:S3-S11 (2006) 3. Management of osteoporosis in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause., 17(1):25-54 (2010 Jan-Feb) 4. Gehlbach, S.H., R.T. Burge, E. Puleo, J. Klar. Osteoporosis International. 14, 53-60. (1 Jan. 2003) 5. Fleisch H., Bisphosphonates in bone diseases, from the laboratory to the patient, 2nd edition. San Diego: Academic Press. (1995) 6. Roelofs A.J., Thompson K., Gordon S., Rogers M.J., Molecular mechanisms of action of bisphosphonates: current status, Clin. Cancer Res. 12 (20 Pt 2), 6222s–6230s (2006) 7. Fisher J.E., Rogers M.J., Halasy J.M., Luckman S.P., Hughes D.E., Masarachia P.J., Wesolowski G., Russell G., Rodan G.A., Reszka A.A., Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro, Proc. Natl. Acad. Sci. USA 96 (1),133–138 (1999) 8. Akishige Hokugo, Sun Shuting, Park Sil, McKenna Charles E., Nishimura Ichiro, Equilibriumdependent bisphosphonate interaction with crystalline bone mineral explains anti-resorptive pharmacokinetics and prevalence of osteonecrosis of the jaw in rats, Bone., 53(1):59-68 (2013 Mar) 9. Shinkai, I; Ohta, Y. "New drugs--reports of new drugs recently approved by the FDA. Alendronate". Bioorganic & medicinal chemistry, 4(1): 3–4 (Jan 1996) 10. Michaelson MD, Smith MR., Bisphosphonates for treatment and prevention of bone metastases, J Clin Oncol. 23(32):8219-24 (2005 Nov 10) 11. Hodgesa L.A., Connolly S.M., Winter J., Schmidt T., Stevens H.N.E., Hayward M., Wilson C.G., Modulation of gastric pH by a buffered soluble effervescent formulation: A possible means of improving gastric tolerability of alendronate, International Journal of Pharmaceutics 432: 57– 62 (2012) 12. Emkey Ronald, Delmas Pierre D., Bolognese Michael, Borges Joao Lindolfo C., Cosman Felicia, RagiEis Sergio, Recknor Christopher, Zerbini Cristiano A., Neate Colin, Sedarati Farhad, Epstein Solomon, Efficacy and Tolerability of Once-Monthly Oral Ibandronate (150 mg) and Once-Weekly Oral Alendronate (70 mg): Additional Results From the Monthly Oral Therapy With Ibandronate for Osteoporosis Intervention (MOTION) Study, Clin. Ther. 31(4):751-61 (2009 Apr)

1.

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13. han Kucuk Dervis, Ay Sinan, Kara M. Isa, Avunduk M. Cihat, Gumus Cesur, Comparison of local and systemic alendronate on distraction osteogenesis, Int. J. Oral Maxillofac. Surg., 40: 1395–1400 (2011) 14. Katsumia Hidemasa, Nakatania Maria, Sanoa Jun-ichi, Abea Mari, Kusamoria Kosuke, Kuriharaa Maki, Absorption and safety of alendronate, a nitrogen-containing bisphosphonate, after intrapulmonary administration in rats, International Journal of Pharmaceutics 400 : 124–130 (2010) 15. Torchilin V.P., Recent advances with liposomes as pharmaceutical carriers, Nat. Rev. Drug Discov. 4 (2) (2005) 16. Lupuliasa Dumitru, Hîrjău Victoria, Lipozomi- vectori medicamentosi si cosmetici (Martie 2011) 17. Bangham, A.D. and Horne R.W., Negative staining of phospholipids and their structured modification by surface active agents as observed in the electron microscope, J. Mol. Biol. 8, 660-668 (1964) 18. Budai M., Szogyi M, Liposomes as drug carrier systems. Preparation, classification and therapeutic advantages of liposomes (2001) 19. van Rooijen N, Sanders A. Liposome mediated depletion of macrophages: mechanism of action, preparation of liposomes and applications, J Immunol Methods (1994) 20. van Rooijen N., van Kesteren-Hendrikx E., Clodronate liposomes: perspectives in research and therapeutics, J. Liposome Res. 12 (1–2), 81–94 (2002) 21. Rooijen N. Van, Sanders A., Liposome mediated depletion of macrophages: mechanism of action, preparation of liposomes and applications, J. Immunol. Methods 174(1–2) 83–93 (1994) 22. Szoka Jr.F., Papahadjopoulos D., Comparative properties and methods of preparation of lipid vesicles (liposomes), Ann. Rev. Biophys. Bioeng. 9 (1980) 23. http://avantilipids.com/index.php?option=com_content&view=article&id=1384&Itemid=372 Preparation of Liposomes 24. Lasic, D.D., The mechanism of liposome formation. A review, Biochem. J. 256, 1-11 (1988) 25. Lasic, D.D., Formation of membranes, Nature 351, 163 (1991) 26. Lasic, D.D., Frederik P.M., Stuart M.C.A., Barenholz Y. and McIntosh T.J., Gelation of liposome interior. A novel method for drug encapsulation, FEBS Lett. 312, 255–258 (1992) 27. Helfrich, W., The size of sonicated vesicles, Phys. Lett. 50a, 115-116 (1974). 28. Berne, B.J.; Pecora, R. Dynamic Light Scattering; Wiley: New York, (1976) 29. Koba Marcin, Koba Katarzyna and Przyborowski Lech, Application of UV-derivative spectrophotometry for determination of some bisphosphonates drugs in pharmaceutical formulations, Acta Poloniae Pharmaceutica - Drug Research, Vol. 65 No. 3, 289-294 (2008).

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ATTRACTING EUROPEAN FUNDS – A NEED FOR THE SUSTAINABLE DEVELOPMENT OF HIGHER EDUCATION AND RESEARCH IN HEALTH Cristian Stan, Ludmila Otilia Cinteza*, Ioana Ailiesei, Camelia Petrescu University “Titu Maiorescu”, Medicine Department * University “Titu Maiorescu”, Pharmacy Department Abstract: As a EU member Romania adopted the economical growth principles of the EU member countries, namely intelligent, sustainable and favorable to the social inclusion economical growth. Within the Europe Strategy 2020 the priority for the scientific research, technological development and innovation is announced as one of the seven emblematic resolutions, namely an innovative Europe, that stipulates a coherent action set for the performance increse for CD&I. The new European programme Horizon 2020 integrates all the programmes dedicated to research and innovation with the announced purpose of ensure the continuous financing of the innovative processes based on the scientific research and the technical knowledge defined by the phrase “from idea to market”. Medical and pharmaceutical research has already provided many different medical solutions both for therapeutics and diagnostics. Some novel research area such as nano-delivery of drugs, for example, will provide new products to address unmet medical needs in cancer and other diseases. New solutions in bioimagistic with innovative imaging agents or smart materials will support the implementation of personalised medicine. All these new research domains require substantial financing to obtain valulable results in order to meet the goals of the programme Horizon 2020. INTRODUCTION The research in medicine and pharmacy will actively contribute to the three pillars of the Framework Programme Horizon 2020, which are respectively Industrial Leadership, Excellence in Science and Societal Challenges. This thematic area is a constant in the strategy of development during the last 20 years, and Romania increases its efforts to support the financing in a such demanding domain. One of the important opportunities to ensure the resources to develop material and human resources in the medical research are the Structural Funds, financial instruments through which the European Union acts in order to eliminate the economical and social disparities between the regions, towards achieving an economical and social cohesion. The structural funds are post-adherence funds supplied through the European Union budget whose purpose is to support the member countries. Investments in education, research, agriculture, substructure, SMEs development and measures for the development of the rural areas are supported, with a special attention given to the less developed regions in order to consolidate the economical and social cohesion in the European Union. These structural funds are allowed by reason of the convergence standard, standard that stipulates the elimination of the disparities that exist between the regions of the country, the correspondence with the european standards economically and socially, the improvement of the life and nature quality. The structural funds can be accessed through instruments named operational programmes, that at their turn contain a series of subprogrammes that stipulate a high number of activities that can be financed with grants. At present the scientific research in Romania evolves under the National Research Development and Innovation Strategy 2007-2013 and the new strategy for the next period 2014-2020 is still under debate. In this respect, the scientific community needs to improve the dialog and management of the interactions between different medical academic disciplines, different industries (pharmaceutical, medical devices and diagnostics), clinical organisations to evidence the challenges and opportunities to sustain the medical research. CAPACITY AND PERFORMANCES GROWTH IN MEDICAL CD&I SYSTEM For the period 2014-2020 the foundation of the political decisions for establishing the objectives and for resources assignment will be done according to the recommendations of the National Research Development and Innovation Strategy for the period 2014-2020 and the Sectoral Operational Programme financed from structural funds with the thematic objective “Research, technological development and innovation consolidation” for the period 2014-2020, The National Council of The Scientific Research initiated the elaboration of the Potential of economical growth based on CD&I Analysis – Intelligent specialties identification. At present there are three strategic orientations for the National CD&I System that regards the capacity and performances of the CD&I System, economical competitiveness growth through innovation and international funds absorption. 130

The investments in the CD&I System focused on human resource development resulting in the growth of the quality and number of the researchers and their results, as well as on offering an appropriate environment for supporting their activity by building or updating the research substructure. The national economy competitiveness growth claims mainly two aspects: a number as high as possible of companies capable of penetrating into the international markets and the existence of an inner open market functionally compatible with the EU market. Emphasis of the international dimension of the CD&I policies and programmes for the community funds absorption growth is particularly needed in the medical field, since the research in this area is very expensive and Romanian academic community does not have enough excellence centers and networks in medical and pharmaceutical research. The Romanian research internationalization policy, sustained at this time by several instruments for financing and cooperation at bilateral level with other countries (Bilateral programmes, at multilateral level, through the Main Programme Research Development and Innovation of the European Community, EUROATOM Programme, other pan European programmes and resolutions EUREKA. One of the most important instrument is the IDEAS Programme, with the purpose of the programme is to obtain top scientific and technological results, comparable with the European level ones, reflected by the international visibility and accreditation growth of the Romanian research. Exploratory Research Projects – PCE are the main projects in this programme. The purpose of the projects is the support and promotion of the basic, interdisciplinary and/or exploratory scientific research from Romania. The Ideas programme targets the researchers with proved performances by the quality and by the international recognition of the scientific journals, including those researches that are activating in foreign countries and want to conduct researching projects of higher scientific level in institutions from Romania. Complex Exploratory Research Projects – PCCE is another major component. The purpose of the programme is the support and promotion of the multidisciplinary and interdisciplinary scientific research from Romania. Within this programme several researchers teams from the same institution or from different institutions are contributing at the development of some complex researching tendencies. The programme targets the researchers with experience and special scientific performance, proved by the originality and by the major international impact of their scientific journals and the personalities recognized as leaders in research domain. The programme is also targeting researchers from other countries. Exploratory Workshops deals with the initiation of scientific partnerships between Romanian and foreign researches in order to start and promote some new research lines and to involve students, Ph. D. student and young researchers in present –day scientific activities at international level. Advanced academic courses – SSA aims to goal the approach of exploratory research themes/ explicit defined subjects which are included in one of the priorities sustained by the National Strategy for Research Development and Innovation Strategy for the period 2007-2013 and report of further progresses regarding these themes/subjects, yet unexposed at international course level. CAPACITIES Programme is the main instrument to develop the infrastructure that is more needed in the medical research. The purpose of the programme is the development of the National Research Capacity and the integration of the CDI system in Romania in the international scientific environment. The programme supports projects for the foreground fields stipulated in the CDI National Strategy for the period 2007-2013. THE VISIBILITY

IMPORTANCE

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BILATERAL

COOPERATION

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INTERNATIONAL

The purpose of the programme is to ensure the development of the scientific and technical collaboration between excellence research teams in Romania and the countries with which there exists bilateral cooperation agreements through scientific and technological exchanges. Other opportunities are the funds provided by European Research Council Programme (ERC), which is the support of the Romanian researchers with excellent results in the competitions organized by European Research Council (ERC) for the implementation of the projects in Romania. There are financed two types of projects:  Projects type 1 Grant Support (“Bridge support”) – projects that obtained at least the score of the imposed quality threshold needed for passing into the II stage of evaluation, for the Principal Investigator as well as for the Research Project;  Projects type 2 Excellence Grant – projects that in the II stage of ERC evaluation obtained the excellent score, but due to the ERC budget limit did not receive financing. HUMAN RESOURCES Programme offers the main financial component to develop the human resources. The purpose of the programme is the growth of the researchers number, the improvement of their

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professional performances, attracting foreign researchers in Romania as well as the growth of the attractiveness of a research career. There have been initiated competitions under the scientific coordination of national authorities for the following financing instruments. Prize award for the research results: The purpose of the programme is the growth of the quality, impact and international visibility of the Romanian research through the accreditation and prizing the significant results published in prestige magazines from the main international scientific flow. Postdoctoral research projects – PD: The purpose of the programme is to sustain young researchers and science doctors with exceptional results which want to develop an independent professional research career in research institutions from Romania, in order to encourage scientific excellence in Romanian research. The programme targets too researches that are working in foreign countries and want to conduct research projects. Research projects that encourage the creation of independent young researchers teams –TE: The purpose of the programme is to sustain young researchers and science doctors which are in a period of development or consolidation of a research team, with an independent research programme, in order to obtain relevant results. The programme targets too researches that are working in foreign countries and want to conduct research projects. Under the Programme PARTNERSHIP IN MAIN FIELD, where Health is one of the priorities, the medical and pharmaceutical research could be developed for the main goal of the Horizon 2020 strategy, the conversion of the scientific solution into marketable products and modern therapies in hospitals. The purpose of the programme is to create conditions for a better collaboration between different research development innovation entities, economical agents and/or public administration units in order to solve the identified problems. Collaborative Applied Research Projects – PCCA, the former programme have the purpose to sustain and promote the applied research in main fields inter- and transdisciplinary relevant for the competitiveness growth in CDI at national level and according to the global economy based on knowledge. There are financed experimental research and technological development projects made in partnership and finalized by making innovative products, technologies and services, with the purpose of solving and implementing solutions for complex socio-economical problems of national priority and international actuality. One of the component in the research programme that need special attention for the medical community is INNOVATION Programme The purpose of the programme is the growth of the capacity of innovation technological development and assimilation in manufacture of the research results in order to improve the competitiveness of the national economy and to raise the life quality. There have been initiated competitions under the scientific coordination of CNDI for the following financing instruments:  Products – Systems – Technologies development Purpose: Stimulation of the technological and economical performances of Romanian companies by financing those entities that have history, maturity and the capacity to transform ideas into products and innovative technologies with real market potential.  HIGH – TECH Export Stimulation Purpose: Growth of the competitiveness of the Romanian high-tech products and technologies.  Support Services for Innovation – Innovation Circles Purpose: The insurance of a flexible instrument for sustaining the SMEs from the productive field in order to update the technology and to improve the innovation rate. The SMEs and the authorized natural persons – PFA are encouraged to develop partnerships with research innovation institutions to create innovative products and services based on advanced technologies. All of these programmes targets the economic agents SMEs, Romanian institutions interested to develop projects, namely Romanian economical competitiveness growth, mainly the industry, by obtaining new products, technologies and services. It is an innovative instrument which, by collaboration between economic agents and research institutions for advanced technologies, technological development, technology and innovation transfer, has the purpose to help the member countries of the EU scientific council to obtain and exploit new technologies for the growth of the economy competitiveness and of the improvement of the quality of life. A necessity for the sustainable development of the higher education and research is to attract European funds which develop by the Structural Funds. Unfortunately, under the Operational Programmes that Romania take part: Regional Operational Programme – POR, Economical Competitiveness Growth Sectoral Operational Programme – POS CCE , Human Resources Development Sectoral Operational Programme – POS DRU, Environment Sectoral Operational Programme – POS MEDIU, Transport Sectoral Operational Programme – POST, Administrative Capacity Development Sectoral Operational Programme –PO DCA, Technical Assistance Operational Programme – POAT, Rural Development National Programme – PNDR, Fishing Operational

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Programme – POP and Cross-border, Transnational and Interregional Territorial Cooperation Programme very few thematic refers to health sector.. Under the Economical Competitiveness Growth Sectoral Operational Programme – POS CCE the main objective of the POS CCE is the growth of the productivity of the Romanian companies for the decrease of the disparities to the medium productivity at the Union level. The taken measures will generate by 2015 a medium productivity growth of approximately 5,5% annually and will allow Romania to achieve a level of approximately 55% of the EU average. Specific objectives are  The consolidation and sustainable development of the productive sector;  The building of a favorable environment for the sustainable development of the companies;  The growth of the research development capacity (C&D), the stimulation of the cooperation between research development innovation institutions (CDI) and companies, as well as the growth of the companies access at CDI;  The exploitation of the information and communication technology and its application in the public sector (administration) and the private one (companies, citizens);  The growth of the energetic efficiency and the sustainable development of the energetic system by promoting the renewable energy sources. The scientific community in medical and pharmaceutical research does not exhibit the ability to make strong connections with the companies in the pharmaceutic industry and provate or public hospitals to develop common projects, targeting new drugs, new contrast agents or new medical devices for the development of the productive sector. Human Resources Development Sectoral Operational Programme – POSDRU remain the instrument where the medical research obtain the most valuable results. The main objective of POS DRU is the development of the human resources and the growth of the competitiveness by correlating education and learning during the whole life with the labor market and the insurance of an increased opportunity for a future participation to a modern, flexible and inclusive labor market for 1.650.000 people. Specific objectives:  Promoting of the quality of the education system and initial and continuous professional development system, including the higher education and research;  Promoting of the entrepreneurial culture and improvement of the work quality and productivity;  Facilitating the insertion of the youth and long term unemployed in the labor market;  Development of a modern, flexible and inclusive labor market;  Promoting of the (re)insertion in the labor market of the inactive persons, including the rural areas;  Improvement of the public employment services;  Facilitating of the access to education and to the labor market of the vulnerable groups. Inside the Human Resources Development Sectoral Operational Programme – POSDRU The priority axis 1 named ” Education and professional training to support the economic growth and society development based on knowledge” have the Major intervention domain “Doctoral and postdoctoral programmes to support the research” aims to support the development of a flexible way of learning during all life and to improve the access to education and learning by providing modern and good quality education and training, including the university learning and research. Under this domain the medical high education system in Romania benefits from substantial funds to support the research activity of Ph.D students and postdoctoral students in various medical and pharmaceutical fields. The main results, beyond the scientific work generating publications and conference attendances are the young doctors and pharmacists attract to build a career in scientific research, complementary to clinical activity. Major intervention domain “Quality in university learning” aims to obtain the reorganization and modernization of the university learning as a system and also regarding the universities;  the development and implementation of the National Qualification Frame in University Learning;  the development and implementation of a national system to assurance and management of quality; the development and implementation of the national qualifications system and assurance of the quality in university learning;  the improvement of the university management;  the increasing of the relevance of the university learning for the labour market and for the society based on knowledge, by better university study programmes. For the medical and pharmaceutical high education systems this was the opportunity to ensure the implementation of modern measures for the advanced management of medical education, for a sustainable system of quality and to improve the university programmes. The attraction of European funds, of national dedicated funds CDI and of national programmed inside funds represents a necessity for the sustainable development of the Romanian university learning and research. 133

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