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The Medical-Surgical Journal, Vol. 118, No. 3/2014 Download contents from here (/uploads/1/5/7/2/15722076/0_2_contents.pdf). Click on the paper title for full text.

EDITORIAL E. Târcoveanu, Valentina Dorobăţ, D. Dorobăţ, A. Vasilescu: Iaşi School of Medicine  is 135 years old (/uploads/1/5/7/2/15722076/0_3_editorial.pdf) [Page: 585]   

INTERNAL MEDICINE ­ PEDIATRICS UPDATES 1. Sînziana Preda, Anca Trifan, Irina Gîrleanu, C. Stanciu, Camelia Cojocariu: Infectious complications in patients with liver cirrhosis (/uploads/1/5/7/2/15722076/1__preda_sinziana_mip_act.pdf) [Page: 590] 2. I. Sporea, Alina Popescu: No colorectal cancer screening program in Romania! Thus, start with opportunistic screening (/uploads/1/5/7/2/15722076/2__sporea_i_mip_act.pdf) [Page: 598] 3. Raluca Haliga, Ancuta Didita, Carmen Anton, L. Sorodoc: Up dates in the pathogenesis and diagnosis of hepatic encephalopathy (/uploads/1/5/7/2/15722076/3_haliga_r_mip_act.pdf) [Page: 601] 4. Roxana­Maria Nemes, Paraschiva Postolache, Doina­Clementina Cojocaru,  Mimi­Floarea Nitu: Tracheomalacia in children and adults ­ not so rare as expected (/uploads/1/5/7/2/15722076/4_nemes_roxana_mip_act.pdf)   [Page: 608] ORIGINAL PAPERS 5. Oana Teslariu, M. Nechifor, P. Plămădeală, Ingrith Crenguţa Miron: Influence of Montelukast on cisplatin­induced experi­ mental acute renal failure (/uploads/1/5/7/2/15722076/5_teslariu_oana_mip_ao.pdf) [Page: 612] 6. A. O. Petris, D. Iliescu, D. M. Alexandrescu, Irina­Iuliana Costache: Ischemic mitral regurgitation in patients with acute myocardial infarction (/uploads/1/5/7/2/15722076/6__petris_ao_mip_ao.pdf) [Page: 618] 7. O. Mitu, F. Mitu, S. Constantin, Elena Cojocaru, Maria­Magdalena Leon: Therapeutical considerations in associated atrial fibrillation and heart failure (/uploads/1/5/7/2/15722076/7__mitu_o_mip_ao.pdf) [Page: 624] 8. F. Mitu, Elena Rezuş, Claudia Banu, Cristina Jufă, O. Mitu, Corina Dima­Cozma: Inflammatory markers in hypertensive patients and influence of some associated metabolic risk factor (/uploads/1/5/7/2/15722076/8__mitu_f_mip_ao_637.pdf) [Page: 631] CASE REPORTS 9. Corina Dima­Cozma, F. Mitu1, Luana Macovei, Oana Arhire, Elena Rezuş: Differentiation of rheumatoid arthritis from hepatitis c­related arthropathy: case report (/uploads/1/5/7/2/15722076/9_dima_cozma_c_mip_cc.pdf) [Page: 637] 10. Laura Gheucă Solovăstru, D. Vâţă, Laura Stătescu, Elena Andrese: Pachydermodactyly­ role of local corticotherapy (/uploads/1/5/7/2/15722076/10__solovastru_l_mip_cc.pdf) 

Rev. Med. Chir. Soc. Med. Nat., Iaşi – 2014 – vol. 118, no. 3

BASIC SCIENCES

UPDATES

NUTRITIONAL FACTORS IN TRANSDIFFERENTIATION OF SCHELETAL MUSCLES TO ADIPOCYTES A. Pînzariu 1, Allia Șindilar1, Raluca Haliga1, Liliana Chelaru 2, Veronica Mocanu 1 University of Medicine and Pharmacy “Grigore T. Popa” - Iasi Faculty of Medicine 1. Discipline of Pathophysiology 2. Discipline of Histology NUTRITIONAL FACTORS IN TRANSDIFFERENTIATION OF SCHELETAL MUSCLES INTO ADIPOCYTES (Abstract): A current area of interest is the determination of factors able to promote the transition from muscle to adipose tissue. The current review has highlighted that treatment of myoblasts with fatty acids (especially oleic acid) and thiazolidindiones causes conversion to adipocytes. The molecular mechanisms mediating the adipogenic action of thiazolidinediones and fatty acids in myoblasts could involve peroxisome proliferators-activated receptor-γ (PPAR and CCAAT-enhancer-binding protein C/EBP. The role of 1,25-D3 in adipogenesis is mediated at the molecular level through VDR-dependent inhibition of C/EBP and PPAR expression and a decrease in PPAR transactivation activity. Vitamin D supplementation increases muscle strength and ultimately reduces the incidence of falls. Additional r esearch is needed to fully clarify the role of nutritional factors in adipogenesis. Keywords: TRANSDIFFERENTIATION, MYOGENESIS, ADIPOGENESIS, PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS, FATTY ACIDS, VITAMIN D.

Transdifferentiation is defined as the irreversible switch of one type of differentiated cell to another (1). Transdifferentiation is associated with a discrete change in the program of gene expression and there is a direct ancestor-descendant relationship between the two cell types. At molecular level, the cause of transdifferentiation is presumably a change in the expression of a master switch gene (selector or homeotic gene), whose normal function is to distinguish the two cell types in normal development (1). TRANSDIFFERENTIATION OF SKELETAL MUSCLES TO ADIPOCYTES Determination of the muscle and adipo-

cyte lineages is controlled by a small number of tissue-specific transcription factors. In muscle, proteins MyoD and myf-5 play an important role in lineage determination, while the related factors myogenin and MRF4 function to execute the differentiation program (2). In adipocytes, differentiation appears to be controlled by two major factors or groups of factors: PPARs and the C/EBPs. However, a number of diverse lipids and lipid-like compounds can activate the PPARs, including fatty acids and synthetic arachidonate leukotrienes as well as drugs known to induce peroxisome proliferation. Several pathologies of adult skeletal muscle are associated with increased in-

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tramuscular adipose tissue. In the muscles of frail elderly people, muscle loss occurs and quality declines, with the accumulation of intramuscular fat and fibrosis impairing both contractile and metabolic function. Furthermore, there are also numerous diseases such as obesity and type 2 diabetes, as well as a range of muscular diseases where fibro-fatty accumulation occurs. The essential role of satellite cells in muscle regeneration is well known, but it has been suggested that satellite cells, which are adult skeletal muscle stem cells can be diverted from the myogenic lineage and transformed into adipogenic cells under appropriate culture conditions in vitro and also in vivo (3). Recently, a population of undifferentiated ‘fibro-adipogenic’ precursors (FAPs) isolated from mouse skeletal muscle was reported to differentiate into fibroblasts or adipocytes (4). Fatty acids (FAs) and adipocyte-inducing medium (AIM) treatment of human muscle fibroblasts induced a strong upregulation of PPAR and C/EBP expression, and an extensive accumulation of lipid droplets (3). By contrast, when myogenic cells were exposed to AIM they failed to upregulate expression of either PPAR or C/EBP, and did not accumulate lipid droplets. In another experiment, the human muscle-derived stem cells exposed to FAs and AIM accumulated some lipid, but showed no evidence of adipogenic differentiation (3). BIOLOGIC IMPLICATION OF TRANSDIFFERENTIATION OF SCHELETAL MUSCLES TO ADIPOCYTES The formation of muscle, bone, and adipose tissue are complex processes involving the determination of common precursor cells towards specific differentiation pathways. A

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current area of interest is the determination of factors that are able to promote the transition from one differentiated lineage to another, in particular, the transdifferentiation of muscle to adipose tissue. The imbalance between adipose and muscle mass is a hallmark of many disorders, including type 2 diabetes, obesity, and sarcopenia. Skeletal muscle and adipose tissue are key players in the development of insulin resistance, manifested by decreased insulin-stimulated glucose transport and metabolism in these tissues. It is known that myogenic cell lines and muscle satellite cells are capable of transdifferentiating to adipocytes, among other cell types (2). Thus, the study of transdifferentiation of muscle tissue to fat is highly applicable to the study of disorders where muscle atrophy and increase in adipose tissue mass are correlated. Increased amounts of intramuscular adipose tissue are desirable in meat animals and are of interest to meat scientists. Raising lipid synthesis through feed is not economical (5). Therefore, assuming that myoblasts and adipoblasts have similar germinal origins (6), the possibility of transdifferentiation was hypothesized and tested to generate marbling or intramuscular adipogenesis. PATHWAYS OF TRANSDIFFERENTATION OF MYOBLST TO ADIPOCYTE The development of skeletal muscle is controlled by the muscle regulatory factors, such as myf-5, myogenin, and MyoD (7). Fusion of myocytes into multinucleated myotubes is the end step of muscle differentiation. In vitro, the major steps in muscle differentiation can be reproduced with myoblastic cell lines, such as C2C12 murine myoblast cells (8). Differentiation of

Nutritional factors in transdifferentiation of scheletal muscles to adipocytes

adipocytes appears to be controlled PPARγ and the C/EBP families of transcription factors (9). PPARγ, a nuclear hormone receptor, is expressed primarily in adipose tissue, and is induced early in the process of adipose differentiation. Fatty acids, natural and synthetic agonists of PPARγ, and vitamin D deficiency are known to promote

adipogenesis (Fig. 1). These factors activate PPARγ resulting in the upregulation of adipocyte-specific genes, such as adipocyte lipid-binding protein 2 (aP2), Glut4, and fatty acid transporter. The mitogenactivated protein (MAP) kinase signaling pathways are crucial for the processes of myogenesis and adipogenesis (7).

Fig. 1. This diagram summarizes the nutritional factors involved in transdifferentiation of myoblast to adipocyte [adapted from (7)] Myoblasts and adipocytes arise from the same germ layer of the embryo, the mesoderm. Therefore, Li and collaborators hypothesized that it is possible to induce a direct conversion of myoblasts to adipocytes (6). Using a tissue model of myogenesis (G8 myoblasts), they demonstrated that these cells can differentiate spontaneously to myotubes when cultured in medium containing fetal calf serum. Subsequently, studies revealed that the expression of transcription factors such C/EBPα and PPARγ during the differentiation of G8 myoblasts can suppress the muscle- specific transcription factors (2). In addition, upregulation of PPARγ and subsequent activation of C/EBPα, β, and γ can stimulate adipogenesis in fibroblasts in the presence of PPARγ ligand (10). Thiazolidinediones (TZD), synthetic activators of PPARγ, are considered potent stimulators of adipogenesis and are presently used to reduce hyperglycemia

in type 2 diabetes. FACTORS IN TRANSDIFFERENTIATION OF SKELETAL MUSCLES TO ADIPOCYTES Fatty acids. Inclusion of food rich in saturated fats or linoleic acid (LA) and n−6 polyunsaturated fatty acids (n−6 PUFAs) in the daily diet leads to insulin resistance (11). Many studies have also demonstrated that cis-unsaturated, nonesterified fatty acids, such as oleic acid (OA) and LA, exert a proliferative effect in cultured vascular smooth muscle (12, 13). OA induces proliferation of rat aortic smooth muscle cells by activating protein kinase C (13). These findings imply that fatty acids may play an important role in regulating skeletal muscle growth. Hurley et al. have reported the prodifferentiation effects of fatty acids on

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skeletal cell differentiation in vitro (14). On myoblast cell lines (rat cell line L6), the fatty acids showed different effects on muscle differentiation. The experiments indicated that inhibition of differentiation by the trans10, cis12 (t10, c12) isomer of conjugated LA (CLA) was dose-dependent (up to 200 mM) and may be via increased cell proliferation. LA and c9, t11 CLA stimulated differentiation at low concentrations (up to 50 mM), but inhibited differentiation at high concentrations (200 mM). In contrast, OA stimulated differentiation at all concentrations, whereas the saturated fatty acid, palmitic acid, had no effect. The mechanism appeared not to involve either PPAR  or γ. The data suggest that only unsaturated fatty acids have an effect and the presence or absence of a cis-9 double bond may be important. Natural agonist of PPAR and thiazolidinediones. PPARs are members of the nuclear receptor superfamily that regulate the gene expression of proteins involved in energy, glucose and lipid metabolism, adipocyte proliferation and differentiation, and insulin sensitivity (15). PPAR regulates fatty acid storage and glucose metabolism. The genes activated by PPAR stimulate lipid uptake and adipogenesis by fat cells. The study of the natural agonist of PPAR is in its infancy. The potential natural ligands of PPAR are several unsaturated fatty acids, such as 15-hydroxiecosateraenoic acid, 9- and 13-hydroxy-octadecadienoic acid , 15-deoxy delta 12,14 prostaglandin J2, and PGJ2 (16). Thiazolidinediones (TZDs) are an important class of synthetic agonists of PPARγ. TZDs are antidiabetic agents that target adipose tissue and improve insulin sensitivity, and they are currently used in

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the treatment of type 2 diabetes. TZDs promote the transition from myogenic lineage to adipogenic lineage. The transition of porcine satellite cells from myogenic lineage to adipogenic lineage under the influence of ciglitizone or pioglitazone (TZDs), the adipogenic mixture, or both was observed (17). Similarly, the transition of C2C12 myoblasts to adipoblasts upon rosiglitazone (TZD) treatment (7) has also been reported. TZDs have been reported to have physio-logically relevant effects on semi-tendinosus muscle of postnatal pigs in potentiating marbling or intramuscular adipogenesis (18). 1,25 dihydroxy vitamin D 3. 1,25Dihydroxyvitamin D (1,25-D3 ), the active form of vitamin D, is widely recognized for its regulation of calcium and phosphate homeostasis in relation to bone development and maintenance and for its calcemic effects on target organs, such as intestine, kidney, and parathyroid glands. Emerging evidence has shown that vitamin D administration improves muscle performance and reduces falls in vitamin D-deficient older adults. However, little is known of the underlying mechanism or the role 1,25-D3 plays in promoting myogenic differentiation at the cellular and/or molecular level. Vitamin D, a fat-soluble secosteroid prohormone, is obtained from sun exposure or from dietary sources. 25-Hydroxivitamin D3 is biologically inactive and is converted primarily in the kidney by the 25hydroxyvitamin D-1-hydroxylase to its biologically active form 1,25-D3 or calcitriol. Activation then enables 1,25-D3 to bind to the vitamin D receptor (VDR), a type of nuclear receptor, and thereby regulates transcription of a number of vitamin D target genes, which is thought to be the

Nutritional factors in transdifferentiation of scheletal muscles to adipocytes

main mechanism of action of vitamin D. VDR is expressed in human muscle tissue, which provides a rationale for a direct role of vitamin D in muscle function. Muscle biopsies in adults with severe vitamin D deficiency showed predominantly type II (fast-twitch) muscle, which may help explain the falling tendency of vitamin Ddeficient elderly individuals (19). It has been reported that 1,25-D3 induces genomic effects, leading to the synthesis of new proteins that affect muscle cell contractility, proliferation, and differentiation (20). Furthermore, mice lacking VDR show a skeletal muscle phenotype with smaller and variable muscle fibers and persistence of immature muscle gene expression during adult life, suggesting a role of vitamin D in muscle development (21). Recent findings suggest that low (deficient) levels of 1,25-D3 (i.e. 10 -13 M) may actually enhance adipogenic trans differentiation (on murine C2C12 muscle cell line), whereas high (sufficient) levels (i.e. 10 -9 M) inhibit adipogenesis, thereby potentially impacting on fat infiltration and muscle function (22). This increased accumulation of fat with low physiological concentrations (10-13 and 10-11 M) was associated with a sequential up(Pparg) and Fabp4 mRNA, indicating formation of adipocytes, whereas higher concentrations (≥10 -9 M) reduced all these effects. The nanomolar concentrations of 1,25D3 could inhibit adipogenesis and reduce the accumulation of triacylglycerol by 50% compared to fully differentiated control cells (23). In addition, treatment of preadipocytes with other vitamin metabolites, such as 24,25-dihydroxyvitamin D, could also inhibit preadipocyte differentiation, but at higher concentrations than 1,25-D3 that paralleled their reduced affinity for the vitamin D re-

ceptor. This finding is consistent with the idea that any influence of vitamin D on adipogenesis would likely be exerted early in the preadipocyte to adipocyte transition when more VDR was available. Recent studies, predominantly using the mouse 3T3-L 1preadipocyte cell culture model, have shown that the role of vitamin D in inhibiting adipogenesis is mediated at the molecular level through a VDRdependent inhibition of C/EBP and PPAR expression and a decrease in PPAR transactivating activity in the preadipocyte (24). Also, in the presence of 1,25-D3, VDR blocks adipogenesis by down-regulating both C/EBP mRNA expression and C/EBP nuclear protein levels at a critical stage of differentiation. In contrast, in the absence of 1,25-D3 , the unliganded VDR appears necessary for lipid accumulation, since knock-down of the VDR using siRNA both delays and prevents this process (25). CONCLUSIONS A current area of interest is the determination of factors that are able to promote the transition from muscle to adipose tissue. The change of skeletal muscle to adipocyte could be associated with certain diseases and may also be useful in the early diagnosis (e.g., diagnosis of insulin resistance), in the treatment of the disease itself (reversing the transformation of muscle to adipocyte in the development of sarcopenia), or in improving the meat quality by generating marbling or intramuscular adipogenesis in cattle and pigs. Nutritional factors, such as fatty acids or vitamin D deficiency, could modulate the expression of the genes involved in adipogenesis. ACKNOWLEDGEMENTS This work received financial support

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through the project “Program of excellence in doctoral and postdoctoral research multidisciplinary chronic diseases”, contract no. HRD / 159 / 1.5 / S / 133377,

financed from the European Social Fund through the Sectoral Operational Programme Human Resources Development 2007-2013.

REFERENCES 1. Shen CN, Burke ZD, Tosh D. Transdifferentiation, metaplasia and tissue regeneration. Organogenesis 2004; 1: 36-44. 2. Hu E, Tontonoz P, Spiegelman BM. Transdifferentiation of myoblasts by the adipogenic transcription factors PPAR gamma and C/EBP alpha. Proc Natl Acad Sci U S A 1995; 92: 9856-9860. 3. Agley CC, Rowlerson AM, Velloso CP, Lazarus NR, Harridge SD. Human skeletal muscle fibroblasts, but not myogenic cells, readily undergo adipogenic differentiation. J Cell Sci 2013; 126: 56105625. 4. Joe AW, Yi L, Natarajan A, Le Grand F, So L, Wang J, et al. Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis. Nat Cell Biol 2010; 12: 153-163. 5. Novakofski J. Adipogenesis: usefulness of in vitro and in vivo experimental models. J Anim Sci 2004;82:905-915. 6. Li WC, Yu WY, Quinlan JM, Burke ZD, Tosh D. The molecular basis of transdifferentiation. J Cell Mol Med 2005;9:569-582. 7. Yeow K, Phillips B, Dani C, Cabane C, Amri EZ, Derijard B. Inhibition of myogenesis enables adipogenic trans-differentiation in the C2C12 myogenic cell line. FEBS Lett 2001; 506: 157-162. 8. Yaffe D, Saxel O. Serial passaging and differentiation of myogenic cells isolated from dystrophic mouse muscle. Nature 1977; 270: 725-727. 9. Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell 1994; 79: 1147-1156. 10. Wu Z, Xie Y, Bucher NL, Farmer SR. Conditional ectopic expression of C/EBP beta in NIH-3T3 cells induces PPAR gamma and stimulates adipogenesis. Genes Dev 1995; 9: 2350-2363. 11. Storlien LH, James DE, Burleigh KM, Chisholm DJ, Kraegen EW. Fat feeding causes widespread in vivo insulin resistance, decreased energy expenditure, and obesity in rats. Am J Physiol 1986; 251: E576-583. 12. Rao GN, Alexander RW, Runge MS. Linoleic acid and its metabolites, hydroperoxyoctadecadienoic acids, stimulate c-Fos, c-Jun, and c-Myc mRNA expression, mitogen-activated protein kinase activation, and growth in rat aortic smooth muscle cells. J Clin Invest 1995; 96: 842-847. 13. Lu G, Morinelli TA, Meier KE, Rosenzweig SA, Egan BM. Oleic acid-induced mitogenic signaling in vascular smooth muscle cells. A role for protein kinase C. Circ Res 1996; 79: 611-618. 14. Hurley MS, Flux C, Salter AM, Brameld JM. Effects of fatty acids on skeletal muscle cell differentiation in vitro. Br J Nutr 2006; 95: 623-630. 15. Francis GA, Annicotte JS, Auwerx J. PPAR-alpha effects on the heart and other vascular tissues. Am J Physiol Heart Circ Physiol 2003; 285: H1-9. 16. Grygiel-Gorniak B. Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications--a review. Nutr J 2014; 13: 17. 17. Teboul L, Gaillard D, Staccini L, Inadera H, Amri EZ, Grimaldi PA. Thiazolidinediones and fatty acids convert myogenic cells into adipose-like cells. J Biol Chem 1995; 270: 28183-28187. 18. Hausman GJ, Poulos SP, Pringle TD, Azain MJ. The influence of thiazolidinediones on adipogenesis in vitro and in vivo: potential modifiers of intramuscular adipose tissue deposition in meat animals. J Anim Sci 2008; 86: E236-243.

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19. Snijder MB, van Schoor NM, Pluijm SM, van Dam RM, Visser M, Lips P. Vitamin D status in relation to one-year risk of recurrent falling in older men and women. J Clin Endocrinol Metab 2006; 91: 2980-2985. 20. Ceglia L. Vitamin D and skeletal muscle tissue and function. Mol Aspects Med 2008; 29: 407-414. 21. Bouillon R, Bischoff-Ferrari H, Willett W. Vitamin D and health: perspectives from mice and man. J Bone Miner Res 2008; 23: 974-979. 22. Ryan KJ, Daniel ZC, Craggs LJ, Parr T, Brameld JM. Dose-dependent effects of vitamin D on transdifferentiation of skeletal muscle cells to adipose cells. J Endocrinol 2013; 217: 45-58. 23. Ishida Y, Taniguchi H, Baba S. Possible involvement of 1 alpha,25-dihydroxyvitamin D3 in proliferation and differentiation of 3T3-L1 cells. Biochem Biophys Res Commun 1988; 151: 1122-1127. 24. Wood RJ. Vitamin D and adipogenesis: new molecular insights. Nutr Rev 2008; 66: 40-46. 25. Blumberg JM, Tzameli I, Astapova I, Lam FS, Flier JS, Hollenberg AN. Complex role of the vitamin D receptor and its ligand in adipogenesis in 3T3-L1 cells. J Biol Chem 2006; 281: 11205-11213.

NEWS CLINICAL EFFICACY OF POLYSPECIFIC INTRAVENOUS IMMUNOGLOBULIN THERAPY IN PATIENS WITH STREPTOCOCCAL TOXIC SHOCK SYNDROME Streptococcal toxic shock syndrome (STSS) and necrotizing fasciitis are the 2 most severe invasive manifestations caused by group A Streptococcus (GAS). Intravenous immunoglobulin (IVIG) therapy has been suggested as adjunctive treatment with a beneficial effect on mortality. A study made by Linner et al aimed to document the clinical efficacy of admi nistered IVIG therapy in a comparative observational study of well-defined patients with STSS. The study involved patients with STSS prospectively identified in a nationwide Swedish surveillance study conducted between April 2002 and December 2004. Detailed data on symptoms, severity of disease, treatment, and outcome were obtained from 67 patients. Twenty-three patients received IVIG therapy compared with 44 who did not. No significant difference in comorbidities, severity of disease, organ failures, or sex was seen, but the IVIG group was slightly younger and had a higher degree of necrotizing fasciitis (56% vs 14%). The primary endpoint was 28-day survival. Adjusted analysis revealed that factors influencing survival in STSS were Simplified Acute Physiology Score II (odds ratio [OR], 1.1; P = .007), clindamycin (OR, 8.6; P = .007), and IVIG (OR, 5.6; P = .030). This comparative observational study of prospectively identified STSS patients demonstrates that both IVIG and clindamycin therapy contribute to a significantly improved survival in STSS. (Linnér A, DarenbergJ, Jan SjölinJ, Normark BH et al.Clinical efficacy of polyspecific intravenous i mmunoglobulin therapy in patients with streptococcal toxic shock syndrome: A comparative observational study. Clin Infect Dis. (2014) 59 (6):851-857). Ecaterina Enache

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[Page: 643] 11. Paraschiva Postolache, Roxana­Maria Nemeş, Doina­Clementina Cojocaru: Progressive dyspnea – comprehensive evaluation of a common symptom (/uploads/1/5/7/2/15722076/11__postolache_p_mip_cc.pdf) [Page: 649] 12. Amalia Orac, Anca Artenie, Mihaela Paula Toader, Raluca Harnagea, Diana Dinu­Mitrofan, Mirela Grigorovici, G. Ungureanu: Sneddon syndrome: rare disease or under diagnosed clinical entity? Review of the literature related to a clinical case (/uploads/1/5/7/2/15722076/12_orac_amalia_mip_cc.pdf)  [Page: 654]  

SURGERY ORIGINAL PAPERS 13. O.B. Bodnar, L. I. Vatamanesku, B. M. Bodnar, R. I. Sydorchuk: Surgical treatment of chronic colostasis in children: a ten­ year experience (/uploads/1/5/7/2/15722076/13_bodnar_o_ch_ao.pdf) [Page: 661] 14. Nicoleta Anton Apreutesei, D. Chiselita, O. I. Motas: Glaucoma evolution in patients with diabetes (/uploads/1/5/7/2/15722076/14_apreutesei_n_ch_ao.pdf) [Page: 667] 15. Lidia Ionescu, R. Dănilă, D. Timofte, Doina Butcovan, Cipriana Stefanescu: Multidisciplinary treated thymomas with fatal outcome. a retrospective study (/uploads/1/5/7/2/15722076/15_ionescu_l_ch_ao.pdf) [Page: 675] CASE REPORTS 16. Saima Anwar, S. Mehmood, F. Siddiqui, N. Khurshaidi: Management dilemmas of retroperitoneal paraganglioma: report of a case (/uploads/1/5/7/2/15722076/16_anwar_saima_ch_cc.pdf) [Page: 679] 17. M. G. Dabija, B. F. Iliescu, D. Andronic, C. Popescu, N. Ianovici: Rare complication of the cervical spine trauma – traumatic esophageal fistula: case report and review of the literature (/uploads/1/5/7/2/15722076/17_dabija_marius_ch_cc.pdf) [Page: 683]  

BASIC SCIENCES UPDATES 18. Ioana Cristina Amihăesei, Elena Cojocaru: Main neuroendocrine features, diagnosis and therapeutic possibilities in the chronic fatigue syndrome, an underdiagnosed entity (/uploads/1/5/7/2/15722076/18_amihaesei_ioana_stf_act.pdf) [Page: 688] 19. Andreea Silvana Szalontay: Physiopathological and therapeutical correlations in alcohol dependence (/uploads/1/5/7/2/15722076/19_szalontay_a_stf_act.pdf) [Page: 692] 20. A. Pînzariu, Allia Șindilar, Raluca Haliga, Liliana Chelaru, Veronica Mocanu: Nutritional factors in transdifferentiation of scheletal muscles to adipocytes (/uploads/1/5/7/2/15722076/20_panzaru_stf_act.pdf) [Page: 699] ORIGINAL PAPERS 21. Iuliana Zavadovschi: Pain as a late emotional reaction. clinical research evaluating the psychosocial expression of pain disorder in preoperative and postoperative period (/uploads/1/5/7/2/15722076/21_zavadovschi_iuliana_stf_ao.pdf) [Page: 706] 22. Diana Ciubotariu, M. Nechifor: Sertraline influence on morphine­induced conditioned place preference in rats (/uploads/1/5/7/2/15722076/22_ciubotaru_diana_stf_ao.pdf) [Page: 712]   

PREVENTIVE MEDICINE ­ LABORATORY UPDATES 23. S.D. Miron, V. Astărăstoae: Long term biological effects induced by ionizing radiation – implications for dose mediated risk (/uploads/1/5/7/2/15722076/23_miron_sd_mpl_act.pdf) [Page: 717] 24. Viviana Aursulesei, Iulia Cristina Roca: Long term biological effects induced by ionizing radiation – implications for dose mediated risk (/uploads/1/5/7/2/15722076/24_aursulesei_v_mpl_act.pdf) [Page: 724] ORIGINAL PAPERS 25. Maria Alexandra Largu, Carmen Mihaela Dorobăţ, L. Prisacariu, Cristina Nicolau, V. Astărăstoae, Carmen Manciuc: The psycho­emotional profile of the hiv­positive naïve patient (/uploads/1/5/7/2/15722076/25_largu_maria_mpl_ao.pdf) [Page: 733] 26. Carmen Manciuc, Carmen Mihaela Dorobăţ, F.Roşu, V. Astărăstoae, Maria Alexandra Largu: The HIV­positive patient in intensive care – psychological profile (/uploads/1/5/7/2/15722076/26_manciuc_carmen_mpl_ao.pdf) [Page: 738] 27. Olga­Odetta Duma, Solange Tamara Roşu, M. Manole, F.D. Petrariu, Brânduşa Constantin: Disparities in the access to primary healthcare in rural areas from the county of Iasi ­ Romania (/uploads/1/5/7/2/15722076/27_duma_odetta_mpl_ao.pdf) [Page: 743]

28. Carmen Mihaela Dorobăţ, Ana Maria Haliciu, Codrina Bejan: Interdisciplinary correlations regarding the clinical and paraclinical evaluations in HIV­positive pregnant women (/uploads/1/5/7/2/15722076/28_dorobat_carmen_mpl_ao.pdf) [Page: 749] 29. M. D. Ciobotaru, Mariana Luca, Roxana Gabriela Cobzaru: Surgical management of pulmonary hydatidosis in children (/uploads/1/5/7/2/15722076/29_ciobotaru_m_mpl_ao.pdf) (/uploads/1/5/7/2/15722076/29_ciobotaru_m_mpl_ao.pdf)[Page: 753] 30. Codrina Bejan, Simona Constantinescu, G. Dorobăţ, Carmen Dorobăţ: Hepatorenal dysfunction in sepsis: epidemiological, clinical and laboratory aspects (/uploads/1/5/7/2/15722076/30_bejan_c_mpl_ao.pdf) [Page: 759] 31. Livia Genoveva Baroi, J. Verbist, P. Peeters, R. F. Popa: Clinical and epidemiological assessment concerning hybrid revascularization techniques in the treatment of multilevel arterial occlusive disease (/uploads/1/5/7/2/15722076/31_baroi_l_mpl_ao.pdf) [Page: 764] 32. Alamir Diaa, Elena Popa, Agnes Bacusca, Maria Gabriela Traian, Rodica Petrovanu, Adorata Elena Coman: Epidemiological study of metabolic syndrome and risk of diabetes mellitus in a rural family medicine practice in Bacau county (/uploads/1/5/7/2/15722076/32_alamir_d_mpl_ao.pdf) [Page: 772] 33. D. Tucaliuc, O. Alexa, Cristina Gabriela Tuchiluş, Ramona Gabriela Ursu, Elena Simona Tucaliuc, Luminiţa Smaranda Iancu: Analysis of antibiotic resistance pattern of S.aureus strains isolated from the orthopedics–traumatology section of  (/uploads/1/5/7/2/15722076/33_tucaliuc_d_mpl_ao.pdf) “Sf. Spiridon” Clinical Emergency Hospital, Iaşi (/uploads/1/5/7/2/15722076/33_tucaliuc_d_mpl_ao.pdf) [Page: 780] 34. Mihaela Mihai, Alina­Mihaela Manole, M. Manole, Elena Duca, F.D. Petrariu, D. Moraru: Epidemiological assessments on incidence of acute gastroenteritis in 0­14 aged children, in the Iasi county, Romania, between 2009­2012 (/uploads/1/5/7/2/15722076/34_mihai_mihaela_mpl_ao.pdf) [Page: 788] 35. Elenis Gabriela Manafu, Raluca Mihaela Filimon , Irina Jari, F.D. Petrariu, Alina Manole: Clinical epidemiological study on the incidence of Escherichia coli infections in the cancer patients admitted to Surgery Department II of the Iasi Regional Oncology Institute in 2013 (/uploads/1/5/7/2/15722076/35__manafu_elenis_mpl_ao.pdf) [Page: 796] 36. Beatrice Ioan, M. Neagu, Irina Manoilescu, Teodora Plăieşu, Simona Damian: Utility of autopsy in medical education ­ students’ opinions and attitudes (/uploads/1/5/7/2/15722076/36_ioan_beatrice_mpl_ao.pdf) [Page: 801] 37. Ionela Cristina Deliu, E.F. Georgescu, Maria Cristina Bezna: Analysis of prognostic factors in colorectal carcinoma (/uploads/1/5/7/2/15722076/37_deliu_ic_mpl_ao.pdf)  [Page: 808] 38. Daciana Elena Brănişteanu, Gabriela Stoleriu, A. Oanţă, Carmen Mihaela Dorobăţ, F.D. Petrariu, Daniela Mihaela Anchidin, Florina Mihaela Filip Ciubotaru, D.C. Brănişteanu: Clinical­epidemiological trends of herpes zoster: a 5­year study (/uploads/1/5/7/2/15722076/38_branisteanu_mpl_ao.pdf) [Page: 817]  

DENTAL MEDICINE UPDATES 39. I.C. Lupu, Norina Consuela Forna: Malpraxis risk management in implantology (/uploads/1/5/7/2/15722076/39_lupu_ic_md_act.pdf) [Page: 823] ORIGINAL PAPERS 40. Diana Nica, Emilia Ianes, S.Brad: CBCT fine preoperrative evaluation of inflammatory radicular cysts and postoperative local integration appreciation of alloplastic grafts materials (/uploads/1/5/7/2/15722076/40_nica_a_md_ao.pdf) [Page: 828] 41. Ana Petcu, Adriana Bălan, Laura Maria Vasilca Gavrilă, Carmen Savin: Assessment of the consequences in premature loss of the temporary lower molar (/uploads/1/5/7/2/15722076/41_petcu_a_md_ao.pdf) [Page: 833] 42. Yllka Deçolli, A. Nemţoi, Sidonia Susanu, Danisia Haba, Ana Petcu: A software tool used in 3D evaluation of the alveolar bone defect in bilateral cleft lip and palate patients (/uploads/1/5/7/2/15722076/42_yllka_d_haba_d_md_ao.pdf) [Page: 841]  

PHARMACY ORIGINAL PAPERS 43. Mihaela Boancă, Eliza Graţiela Popa, R.V. Lupuşoru, V. Poroch, Liliana Mititelu­Tarţău, Cătălina Elena Lupuşoru: The effects of magnesium nanovesicle formulations on spatial memory performance in mice (/uploads/1/5/7/2/15722076/43_boanca_farma_ao.pdf) [Page: 847] 44. Gabriela Rusu, F. Mitu, Cătălina Elena Lupuşoru, M. Nechifor, R.V. Lupuşoru, Liliana Mititelu­Tarţău: Effects of two serotoninergic agents on the behavioral manifestations in rats (/uploads/1/5/7/2/15722076/44_rusu_g_farma_ao.pdf) [Page: 854] 45. B. Sevastre, M. Taulescu, I. Marcus, Daniela Benedec, A. Mocanu, Daniela Hanganu: Protective effect of grape seed extract in experi­mental menopausal syndrome (/uploads/1/5/7/2/15722076/45_sevastre_b_farm_ao.pdf) [Page: 860] 46. Al. Vasincu, Anca Miron, Veronica Bild: Preliminary research concerning antinociceptive and antiinflammatory effects of two extracts from Glinus oppositifolius (L.) Aug. DC.   (/uploads/1/5/7/2/15722076/46_vasincu_a_farma_ao.pdf)[Page: 866]

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