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Overlap myositis is a distinct subgroup of idiopathic inflammatory myositis (IIM) with various clinical phenotypes. The aim of this study was to determine the clinical, serological, and genetic features of systemic sclerosis (SSc)-IIM overlap patients. It was a retrospective study using clinical database of 39 patients, fulfilling both the criteria of SSc and IIM. 56.4% of the patients had limited cutaneous, 43.6% had diffuse cutaneous SSc, whereas 7.7% of the patients had dermatomyositis and 92.3% polymyositis. The two diseases occurred simultaneously in 58.97%, while 10.26% in myositis and 30.77% in scleroderma were initially diagnosed. The frequencies of organ involvement were interstitial lung disease 71.8%, dysphagia 66.7%, cardiac involvement 41%, pulmonary arterial hypertension (PAH) 30.8%, and renal involvement 12.8%, respectively. The presence of human leukocyte antigen (HLA) - DRB1∗03 and DQA1∗051∗01 alleles were significantly higher in the overlap patients than in healthy controls (82.35% vs. 27.54%

MicroRNA (miRNA) research has intensively developed over the past decade. Characterization of dysregulated miRNA expression profiles could give a better understanding of the development of pathological conditions and clinical disorders, such as autoimmune diseases with polygenic etiology, including idiopathic inflammatory myopathies (IIMs). IIMs are a group of rare autoimmune disorders characterized by skeletal weakness and inflammation. Polymyositis (PM) is one of the conditions of autoimmune myopathies with proximal skeletal muscle weakness. A novel group of miRNAs, known as myomiRs are described as striated muscle-specific or muscle-enriched miRNAs. They are involved in myoblast proliferation/differentiation as well as muscle regeneration. To determine the role of myomiRs in the development and progression of PM, we performed an initial skeletal muscle miRNA profiling using microarray technique at diagnosis. The aim of the study was to examine myomiRs expression profile in patients with PM in order to remark the association between the dysregulated myomiRs’ expression and the development of the disease. As a results of microarray investigation, most of the myomiRs showed altered expression patterns in the muscle samples of PM patients compared to controls. These results suggest that myomiRs, especially miR-1, miR-133a, miR-208b, miR-486, and miR-499 function in a network, and are associated with the development of PM.

Diffuse large B-cell lymphoma (DLBCL) accounts for 30% of all non-Hodgkin lymphomas (NHL) and 80% of agressive lymphomas. Besides the traditional International Prognostic Index (IPI), some other factors may also influence the prognosis of DLBCL patients.To study how the genetic polymorphisms in the metabolic pathway influence the event-free and overall survivals and therapeutic responses in DLBCL.The study was comprised of 51 patients (32 men, 19 women). The average age was 53.1 years. DLBCL was diagnosed between 2011 and 2016 and the average follow-up time was 3.78 years. These patients received 1-8 cycles (an average of 6.2 cycles) of rituximab, cyclophosphamide, doxorubicin, vincristin, prednisolon (R-CHOP) immunochemotherapy. Real-time polymerase chain reaction was used to determine the genetic polymorphisms of CYP2E1, GSTP1, NAT1, and NAT2 genes.Our results showed that the polymorphisms of CYP2E1, GSTP1, and NAT1 genes did not influence the prognosis of DLBCL patients significantly. In terms of the NAT2 gene, GG homozygous patients showed slightly better therapeutic response and survival results compared to those bearing an A allele; however, the differences were not statistically significant.Our results could not confirm that genetic polymorphism in metabolic pathways has any predictive role in DLBCL.

Aim We described earlier a simultaneously increased that the increased expression of miRNA-146a/b was accompanied by an increase in the expression of and TRAF6 and a decrease in the expression of IRAK1 genes in the peripheral mononuclear cells (PBMCs) of patients with primary Sjogren's syndrome (pSS) patients. Recently, the expression of EBV encoded. RNA (EBER) was published in the B cells of salivary glands of in pSS. In the present study, we applied an EBV-EBER1 specific synthetic single stranded complementary DNA molecule (EBV-EBER1-cDNA) to test whether any EBER1 related effect exists also in PBMCs of pSS patients. Methods In the PBMCs of pSS patients and healthy controls, we investigated in vitro the effects of a synthetic single stranded EBV-EBER1-cDNA molecule, synthetic double-stranded (ds)RNA polyinosinic-polycytidylic acid [poly (I:C)] and polyadenylic acid potassium salt poly-adenylic acid [poly-(A)] on the expression of TRAF6 gene tested by qRTPCR. The release of interferon -α was detected by ELISA. Results EBV-EBER1-cDNA resulted in a significant reduction in the expression of TRAF6 in the cells of patients, but in the healthy controls not, whereas the treatments with poly (I:C) and poly-(A) could not reduce the TRAF6 over-expression. No release of EBER1 could be observed in the culture supernatants of patients with pSS. Only the treatment with poly (I:C) resulted in a significant increase of interferon -α release, and only in the heathy controls. No release of EBER1 molecules took place during the culturing of cells. EBV-EBER- cDNA acted functionally on the cells of patients only. Conclusion These findings give a further evidence of the linkage between EBV and pSS, furthermore, they show the possible role of EBV-EBER1 in the induction of increased TRAF6 expression in the peripheral B cells of Sjogren's patients.

Cell division is controlled by a complex network involving regulated transcription of genes and postranslational modification of proteins. The aim of this study is to demonstrate that the Mediator complex, a general regulator of transcription, is involved in the regulation of the second phase (cell separation) of cell division of the fission yeast Schizosaccharomyces pombe. In previous studies we have found that the fission yeast cell separation genes sep10 ( + ) and sep15 ( + ) code for proteins (Med31 and Med8) associated with the Mediator complex. Here, we show by genome-wide gene expression profiling of mutants defective in these genes that both Med8 and Med31 control large, partially overlapping sets of genes scattered over the entire genome and involved in diverse biological functions. Six cell separation genes controlled by the transcription factors Sep1 and Ace2 are among the target genes. Since neither sep1 ( + ) nor ace2 ( + ) is affected in the mutant cells, we propose that the Med8 and Med31 proteins act as coactivators of the Sep1-Ace2-dependent cell separation genes. The results also indicate that the subunits of Mediator may contribute to the coordination of cellular processes by fine-tuning of the expression of larger sets of genes.

Previous studies in isolated perfused heart and in atrial preparations have demonstrated significant reductions in beating rate in STZ-induced diabetic rats, which suggests that sinus arrhythmias in diabetes mellitus may be partly caused by intrinsic alteration of sino-atrial node (SAN) function. The effects of diabetes on electrical activity and expression levels of mRNA for gap junction proteins in the SAN have been investigated. Diabetes was induced by a single intraperitoneal injection of STZ (60 mg/kg) administered to young male Wistar rats (200-250 g). Experiments were performed 8-10 weeks after treatment. Conduction time and pacemaker cycle length were measured in sino-atrial node preparations with extracellular electrodes. Expression levels of mRNA for Gja5 (Cx40), Gja1 (Cx43) and Gja7 (Cx45) were measured in SAN and compared with right atrium and right ventricle with real-time quantitative reverse transcription-polymerase chain reaction. Diabetes was confirmed by a significant elevation of blood glucose (356+/-21 mg/dl) compared to age-matched controls (66+/-2 mg/dl). Pacemaker cycle length was significantly prolonged in diabetic heart (415+/-43 ms, n=6) compared to controls (255+/-7 ms, n=6). Sino-atrial conduction time was also significantly prolonged in diabetic hearts (12+/-2 ms) compared to controls (7+/-1 ms). Expression levels of mRNA for Gja5 (Cx40) and Gja1 (Cx43) were moderately increased and for Gja7 (Cx45) was significantly increased in SAN from diabetic heart compared to controls. Expression levels for gap junction connexin proteins were not significantly altered in right atrium or right ventricle from diabetic heart compared to controls. Structural remodelling of gap junction connexin proteins may partly underlie electrophysiological defects in STZ-induced diabetic rat SAN.

Aim The microRNA-155 (miR-155) is regarded as a central modulator of T-cell responses and could be a potential therapeutic target for certain inflammatory diseases. In our present study we analyzed the expression rate of miR-155 and its functionally linked gene, the suppressor gene of cytokine signaling 1 (SOCS1) in primary Sjogren's syndrome (pSS). Method We enrolled 23 pSS patients and 10 healthy individuals in the study. The expression of miR-155 and SOCS1 gene were measured by real-time polymerase chain reaction. Results We observed the over-expression of miR-155 in the peripheral mononuclear cells of patients with pSS. Surprisingly, SOCS1 gene was also over-expressed in pSS patients. Conclusion This unanticipated phenomenon might be a laboratory characteristic of Sjogren's syndrome, and presumably a consequence of the noteworthy difference in the pSS immune system reacting with Epstein–Barr virus.

The Middle East is a culturally and politically diverse region at the gateway between Europe, Africa and Asia. Spatial dynamics of the fatal zoonotic disease rabies among countries of the Middle East and surrounding regions is poorly understood. An improved understanding of virus distribution is necessary to direct control methods. Previous studies have suggested regular trans-boundary movement, but have been unable to infer direction. Here we address these issues, by investigating the evolution of 183 rabies virus isolates collected from over 20 countries between 1972 and 2014. We have undertaken a discrete phylogeographic analysis on a subset of 139 samples to infer where and when movements of rabies have occurred. We provide evidence for four genetically distinct clades with separate origins currently circulating in the Middle East and surrounding countries. Introductions of these viruses have been followed by regular and multidirectional trans-boundary movements in some parts of the region, but relative isolation in others. There is evidence for minimal regular incursion of rabies from Central and Eastern Asia. These data support current initiatives for regional collaboration that are essential for rabies elimination., Author Summary Despite being one of the oldest recognised infectious diseases, rabies continues to cause thousands of preventable human deaths per year. As a zoonotic disease, control of infection in the reservoir has been proven the most efficient route to reduction of human cases. In some regions, the epidemiology is well understood, with either dogs or wildlife known to be the primary reservoir and with little or no movement from, or into other regions. This is not the case in the Middle East, where rabies is underreported in animals and humans, there is little laboratory confirmation of infection, and the extent of rabies spread from country to country is not known. Previous studies have demonstrated trans-boundary movement of rabies but have been limited by a low number of available samples from some countries, and the direction of spread has been difficult to estimate. Here we use rabies virus partial genome sequences of 183 viruses from over 20 countries, combined with geographical and temporal information, to reconstruct the evolution of rabies viruses circulating in the Middle East. The results reveal an apparent barrier to spread between some regions but regular movement between others. These analyses will support policy on rabies control by indicating the relative importance of local control and animal movement restrictions when allocating resources.

Idiopathic inflammatory myopathies are autoimmune diseases characterized by symmetrical proximal muscle weakness. Our aim was to identify a correlation between VDR polymorphisms or haplotypes and myositis. We studiedVDR-BsmI,VDR-ApaI,VDR-TaqI, andVDR-FokIpolymorphisms and haplotypes in 89 Hungarian poly-/dermatomyositis patients (69 females) and 93 controls (52 females). We did not obtain any significant differences forVDR-FokI,BsmI,ApaI, andTaqIgenotypes and allele frequencies between patients with myositis and healthy individuals. There was no association of VDR polymorphisms with clinical manifestations and laboratory profiles in myositis patients. Men with myositis had a significantly different distribution ofBB,Bb, andbbgenotypes than female patients, control male individuals, and the entire control group. Distribution ofTT,Tt, andttgenotypes was significantly different in males than in females in patient group. According to four-marker haplotype prevalence, frequencies of sixteen possible haplotypes showed significant differences between patient and control groups. The three most frequent haplotypes in patients were thefbAt,FBaT, andfbAT. Our findings may reveal that there is a significant association:BbandTtgenotypes can be associated with myositis in the Hungarian population we studied. We underline the importance of our result in the estimated prevalence of four-marker haplotypes.

Resume Nous rapportons le cas d’une patiente ayant presente une polymyosite avec presence d’anticorps anti-Jo1 associee a un adenocarcinome pulmonaire. Le diagnostic de polymyosite a repose sur les symptomes, les resultats electromyographiques et l’elevation des enzymes musculaires dont la creatine kinase et la lactate dehydrogenase. La positivite des anticorps anti-Jo1, l’hyperleucocytose et l’elevation des marqueurs tumoraux CA 15-3 et CA 72-4 ont egalement permis le diagnostic positif. Le caractere malin de la tumeur a ete confirme par la biopsie transthoracique a l’aiguille, realisee deux ans apres l’apparition des premiers signes cliniques de polymyosite. Apres l’exerese tumorale, la polymyosite etait en remission. Etant donnes les symptomes et la survenue concomitante de la tumeur et de la polymyosite, une origine paraneoplasique a ete suspectee.

Incretins, such as glucagon-like peptide-1 (GLP)-1, have been shown to elevate plasma insulin concentration. The purpose of this study is to investigate the cellular and molecular basis of the beneficial effects of GLP-1. Normal and diabetic male Wistar rats were treated with GLP-1 (50 ng/kg body weight) for 10 weeks. At the end of the experiment, pancreatic tissues were taken for immunohistochemistry, immunoelectron microscopy and real-time polymerase chain reaction studies. Samples of blood were retrieved from the animals for the measurement of enzymes and insulin. The results show that treatment of diabetic rats with GLP-1 caused significant (P

The establishment of growth polarity in Schizosaccharomyces pombe cells is a combined function of the cytoplasmic cytoskeleton and the shape of the cell wall inherited from the mother cell. The septum that divides the cylindrical cell into two siblings is formed midway between the growing poles and perpendicularly to the axis that connects them. Since the daughter cells also extend at their ends and form their septa at right angles to the longitudinal axis, their septal (division) planes lie parallel to those of the mother cell. To gain a better understanding of how this regularity is ensured, we investigated septation in spherical cells that do not inherit morphologically predetermined cell ends to establish poles for growth. We studied four mutants (defining four novel genes), over 95% of whose cells displayed a completely spherical morphology and a deficiency in mating and showed a random distribution of cytoplasmic microtubules, Tea1p, and F-actin, indicating that the cytoplasmic cytoskeleton was poorly polarized or apolar. Septum positioning was examined by visualizing septa and division scars by calcofluor staining and by the analysis of electron microscopic images. Freeze-substitution, freeze-etching, and scanning electron microscopy were used. We found that the elongated bipolar shape is not essential for the determination of a division plane that can separate the postmitotic nuclei. However, it seems to be necessary for the maintenance of the parallel orientation of septa over the generations. In the spherical cells, the division scars and septa usually lie at angles to each other on the cell surface. We hypothesize that the shape of the cell indirectly affects the positioning of the septum by directing the extension of the spindle.

Genetic analysis of 20 sterile mutants prone to form hyphae revealed 11 novel ste genes (sep6 to sep16) of Schizosaccharomyces pombe. None of the mutants was completely mycelial. Most mutants formed branching hyphae and showed normal septation. Aberrant septal structures and actin distribution were seen only at 36°C. sep9-307, sep14-576 and sep15-598 showed genetic interactions with sep1-1, a mutation in a forkhead transcription factor homologue. Additional genetic interactions were detected between sep6-194, sep15-598 and cdc16-116, a mutant allele of an anaphase modulator of p34cdc2. sep9-307 and sep15-598 caused dikaryosis in wee1− background. In mating and sporulation tests, sep6−, sep7−, sep9−, sep10−, sep11− and sep15− proved to be defective in conjugation only, whereas sep8−, sep13− and sep16− were also defective in meiosis-sporulation. sep12− and sep14− were only partially sterile. All mutants could produce M-factor but sep8−, sep11−, sep15− and sep16− were defective in P-factor production. The mutations in sep8, sep11 and sep16 suppressed the pat1-114-driven meiosis. All mutants were sensitive to the presence of higher concentrations of chloride in the medium and to short heat shocks. The diversity of the mutant phenotypes and the pleiotropic effects of the mutations suggest that these sep genes might act in, or interact with, a multiple overlapping network of regulatory modules. Copyright © 1999 John Wiley & Sons, Ltd.

Glucagon-like peptide 1 (GLP1) agonists are promising therapeutic agents in the treatment of diabetes mellitus. This study examines the mechanism of the protective effects of exenatide in experimental diabetes, employing four groups of ten rats each, in which two groups were streptozotocin-induced diabetic and two were control groups. One control and one diabetic group were treated with exenatide (1 μg/kg body weight (BW)) for 10 weeks. Blood plasma was taken for biochemical analyses while pancreatic tissue was taken for immunofluorescence and immunoelectron microscopy studies and real-time PCR to examine the expression of genes. The results show that exenatide improved BW gain and reduced blood glucose in diabetic rats compared with controls. Similarly, exenatide enhanced insulin release from the pancreatic fragments and improved liver and kidney functions and lipid profile in diabetic rats compared with controls. Exenatide not only induced significant increases in serum insulin level but also elevated the number of insulin-, GLP1- and exenatide-positive cells compared with untreated controls. Exenatide also elevated the number of catalase- and glutathione reductase-positive cells in diabetic rat pancreas compared with controls. Exenatide caused significant elevation in the expressions of pancreatic duodenal homeobox-1, heat shock protein-70, glutathione peroxidase, insulin receptor and GLP1 receptor genes in the pancreas of both control and diabetic rats compared with untreated animals. The results have demonstrated that exenatide can exert its beneficial and protective effects by elevating the levels of endogenous antioxidants and genes responsible for the survival, regeneration and proliferation of pancreatic β-cell.

Objectives HLA-DRB1*03 is strongly associated with anti-Jo-1-positive idiopathic infl ammatory myopathies (IIM) and there is now increasing evidence that Jo-1 antigen is preferentially expressed in lung tissue. This study examined whether smoking was associated with the development of anti-Jo-1 antibodies in HLA-DRB1*03-positive IIM. Methods IIM cases were selected with concurrent information regarding HLA-DRB1 status, smoking history and anti-Jo-1 antibody status. DNA was genotyped at DRB1 using a commercial sequence-specifi c oligonucleotide kit. Anti-Jo-1 antibody status was established using a line blot assay or immunoprecipitation. Results 557 Caucasian IIM patients were recruited from Hungary (181), UK (99), Sweden (94) and Czech Republic (183). Smoking frequency was increased in anti-Jo-1positive IIM cases, and reached statistical signifi cance in Hungarian IIM (45% Jo-1-positive vs 17% Jo-1-negative, OR 3.94, 95% CI 1.53 to 9.89, p

MicroRNA-146a (miR-146a) is a microRNA supposed to regulate innate immune, inflammatory response and antiviral pathway negatively. Recently, its potential use as a biomarker for disease diagnosis, prevention and treatment has become widely investigated. In the current study, we measured the expression of miR-146a/b, and their target genes, IRAK1, IRAK4, TRAF6 in the peripheral mononuclear cells of patients with Sjogren's syndrome (n=21) and healthy controls (n=10) by quantitative reverse transcription polymerase chain reaction. We found that both miR-146a and miR-146b, furthermore, the gene of TRAF6 were significantly overexpressed in the Sjogren's patients, whereas the expression of IRAK1 gene was significantly decreased. The expression of IRAK4 did not differ significantly. These results suggest that in the peripheral mononuclear cells of Sjogren's patients, the transcriptional repression of IRAK1 is taking place, whereas the other NF-κB pathway regulating gene, TRAF6 is overexpressed. As IRAK1 has been regarded a crucial gene in the pathogenesis of systemic lupus erythematosus, TRAF6 can be a Sjogren's syndrome specific biomarker, confirming and partly explaining the existance of different pathogenic pathways in the two diseases. These observations, however, need still wider confirmations.

The addition of rituximab to conventional chemotherapy has significantly improved the treatment outcome in diffuse large B-cell lymphoma. However, differences in treatment response and survival data can be observed independently from the International Prognostic Index scores. The current study evaluated the impact of Fc-gamma-receptor IIIa polymorphism and gene expression profile on the response of DLBCL patients to R-CHOP therapy as well as on their survival results. Fifty-one patients were involved, thirty-two females, nineteen males, their median age was 53.1 years. The FCGR3A polymorphism at the 158. amino acid position determined with PCR method showed the following results: VV: 12 cases (23.5%), VF: 29 cases (56.8%) and FF: 10 cases (19.6%), respectively. There was no significant difference between the treatment responses of the three groups. The event-free survival data were less favorable in the F-allele carriers than in V/V homozygous patients, but without any significancy, and the overall survival curves were almost the same. As for the gene expression profile, 20 patients’ biopsy specimens showed germinal center and 31 showed non-germinal center characteristics. Treatment results did not differ from each other in the two groups. Both the event-free and the overall survival data were more favorable in the GC group, however the differences were not significant. Our results contest the predictive value of Fc-gamma-receptor IIIa polymorphism and gene expression profile in diffuse large B-cell lymphoma.

Ventricular electrical conduction has been investigated in the streptozotocin (STZ)-induced diabetic rat. Diabetes was induced with a single injection of STZ (60 mg/kg bodyweight, ip). The ECG was measured continuously, in vivo, using a biotelemetry system. Left ventricular action potentials were recorded with an extracellular suction electrode. Expression of mRNA transcripts for selected ion transport proteins was measured in left ventricle with real-time RT-PCR. At 10 weeks after STZ treatment, in vivo heart rate (HR) was reduced (267 ± 3 vs. 329 ± 5 BPM), QRS complex duration and QT interval were prolonged in diabetic rats compared to controls. In vitro spontaneous HR was reduced and paced heart action potential repolarization was prolonged in diabetic rats compared to controls. The mRNA expression for Kcnd2 (I to channel) and Kcne2 (I kr channel) was significantly reduced in diabetic rats compared to controls. Altered gene expression and, in particular, genes that encode K+ channel proteins may underlie delayed propagation of electrical activity in the ventricular myocardium of STZ-induced diabetic rat.

Genetic alterations of the proto-oncogene human epidermal growth factor receptor (HER-2/neu) have been shown to induce malignant transformation and metastasis. Genotyping studies have addressed the association of codon 655 isoleucine to valine polymorphism located in the transmembrane coding region and the risk of breast cancer, but the results are inconsistent. In this study, we investigated the association of HER-2/neu Ile655Val polymorphism and the risk of breast cancer in a Sudanese population. In addition, the joint effects of HER-2/neu variants and our previously reported ESR1C325G polymorphism were tested for their association with breast cancer risk. Candidate single nucleotide polymorphism (SNP) in HER-2/neu Ile655Val [db SNP rs1136200] was genotyped in breast cancer patients and in healthy controls that were randomly selected from the same age group as the patients. Genotyping was performed using a high-throughput allelic discrimination method using real-time PCR, and data on clinical features and demographic details were collected. Associations between genotype and breast cancer were assessed by means of logistic regression. The prevalence of Val/Val genotype was similar in patients of breast cancer and control subjects. In comparison with the Ile/Ile genotype, the Ile/Val had a borderline significantly (P= 0.06) higher risk of breast cancer (OR = 2.95, 95% CI: 0.97-8.96). Regarding the genotypic and allelic frequencies stratified by age and menopausal status, there were no significant associations. A significantly higher risk of breast cancer was observed among homozygous carriers of ESR1325 CC genotype and heterozygous carriers of HER-2/neu655 Ile/Val genotype (P= 0.05; adjusted OR = 4.9, 95% CI: 1.0-24). The association of HER-2/neu Ile655Val polymorphism and the risk of breast cancer was borderline significant with the heterozygous carrier being at higher risk. However, the frequency of different polymorphic variants varies with ethnicity. The results of this study suggest that a significant gene-gene interaction between ESR1325C (previously reported) and HER-2/neu Ile655Val variants may jointly contribute to a higher risk of breast cancer.

Objective. To determine the genetic, clinical and serological characteristics of systemic sclerosis (SSc)-rheumatoid arthritis (RA) overlap syndrome. Methods. Clinical manifestations and immunolaboratory features of 22 SSc-RA patients were assessed. The HLA-DR genotype of the 22 SSc-RA patients determined by SSP-PCR was compared with that of 38 SSc patients, 100 RA patients and 50 healthy controls. Results. All overlap patients fulfilled the American College of Rheumatology (ACR) criteria for SSc and RA. Five of the 22 patients (23%) had diffuse cutaneous SSc (dcSSc) and 17 patients (77%) had limited cutaneous SSc (lcSSc). Antinuclear antibody, anti-Scl70, IgM rheumatoid factor and anti-CCP antibody positivity were detected in 22 (100%), 5 (23%), 16 (73%) and 18 patients (82%), respectively. Seventeen patients (77%) had pulmonary fibrosis, 12 (55%) had oesophageal dismotility, 11 (50%) had cardiac and five (23%) had renal involvement. Hand joint destruction was observed in 18 patients (82%). Significantly increased frequencies of HLA-DR3 (36% vs 5%), HLA-DR7 (9% vs 4%), HLA-DR11 (36% vs 7%) and HLA-DRw53 (23% vs 5%) were observed in SSc-RA compared with RA patients (P

Oxytocin (OT) and vasopressin (VP) are neurohypophyseal hormones with potent stimulatory actions on the uterus. In order to determine whether these hormones may have a paracrine action on the uterus, OT and VP gene expression was studied in myometrium from pregnant rats at gestational ages of 14 and 20 days, and from ovariectomized animals treated with oestradiol and progesterone. OTand VP mRNA concentrations were measured using real-time quantitative reverse transcription-PCR, and OT- and VP-like immunoreactivities were determined using RIA. OT mRNA was detected in the uterus from pregnant rats, but did not differ between the groups of different gestational ages. Oestradiol significantly (POT gene expression in ovariectomized rats. Progesterone alone was without effect on OT mRNA concentrations, but significantly (POT gene in the rat uterus and processing of uterine preprooxytocin to the mature nonapeptide. The data support the theory that this peptide may act in a paracrine pathway. No evidence was found for the presence of VP in the uterus so that, if the hormone is involved in a stimulatory action on this tissue, it probably acts via an endocrine mechanism.

Background The most frequent myositis specific antibody (MSA) in the serum of patients with idiopathic inflammatory myopathies is anti-Jo-1. The presence of anti-Jo-1 define a distinct clinical phenotype, antisynthetase syndrome (ASS), which is characterized by poor prognosis and multiple organ involvement, such as myositis, interstitial lung disease (ILD), non-erosive arthritis, Raynaud9s phenomen, mechanic9s hand, skin rashes, and fever. Objectives The aim of this study was to determine the clinical, serological, laboratory and genetic features of anti-Jo1 positive patients followed by our department. Methods Retrospective analysis of medical records of 49 patients (42 female, 7 male) were reviewed. Anti-Jo-1 titer was detected with enzyme-linked immunosorbent assay. HLA DRB1, DQA1 and DQB1 genotype was determined using commercial sequence-specific oligonucleotide kit. Statistical analysis was performed using Pearson Chi 2 , Fisher exact test, or Spearman correlation. Results The median age at diagnosis was 43±13,28 years (range: 18-70), 48 patients exhibited myositis (98%), 35 ILD (73%), 43 arthritis (88%), 32 Raynaud9s phenomen (65%), 21 fever (43%), 16 mechanic9s hand (33%), 27 skin rash (55%) and 6 dysphagia (12%). We could detect significant correlation between the initial anti-Jo-1 titer and the first CK (R=0,328; p=0,003) and CRP (R=0,374; p=0,016) level. Furthermore anti-Jo1 levels during disease course had significant correlation to the corresponding CK (R=0,497; p Conclusions Our results confirm previously reported data from other centers considering the clinical features of anti-Jo1 positive patients. HLA DRB1*03 positivity was associated with lower CK level but has no influence on clinical or serological features. It seems that anti-Jo1 level might reflect disease activity; ESR, CRP levels, associated fever and anti-SSA positivity at the diagnosis could be considered as prognostic markers. Disclosure of Interest None declared

We describe a unique family where each of the 5 siblings in the second generation has rheumatoid arthritis (RA). Two other members of the family have RA and systemic lupus erythematosus (SLE), respectively. No members of previous generations in the family had documented inflammatory arthritis. Due to the suspected genetic predisposition, HLA-DR genotypes were determined in the affected siblings and their parents, children, and grandchildren. We investigated the possible role of various HLA-DR alleles in the evolution of RA in this multicase family.HLA-DRB1* alleles were determined by polymerase chain reaction using the sequence-specific primer-Olerup method.The most common alleles in the 6 persons with RA were HLA-DRB1*07 and DRB1*15, which are known to be protective and neutral in RA. No patient or family member carried any HLA-DR4 alleles.HLA-DRB1*07 and DRB1*15 alleles are thought to be protective or neutral in RA. However, the majority of RA patients in the family and nearly half of all family members carried these alleles, suggesting a role of these genotypes in susceptibility to RA. No RA patient in this family carried HLA-DR4 alleles. Thus, in our rare family with 6 RA cases, an unexpected genetic background may be involved in the increased susceptibility to inflammatory arthritis.

Susceptibility to and outcome for rheumatoid arthritis (RA) have been associated with particular HLA-DR alleles, but these alleles vary among ethnic groups and geographic areas. The frequency of HLA-DR1 (HLA-DRB1*0101, DRB1*0102) and HLA-DR4 (DRB1*0401, DRB1*0404) alleles is elevated among Caucasian patients with RA. We studied a northeastern Hungarian population of RA patients to determine the frequency of HLA-DR1 and HLA-DR4 phenotypes in this population and to compare it with healthy control subjects, as well as to investigate whether the presence of these alleles could be a marker for RA. We performed HLA-DRB1 genotyping (DRB1*01-DRB1*16) in 83 RA patients and 55 healthy controls using polymerase chain reaction with sequence-specific primers (PCR-SSP). In the case of HLA-DR1- or HLA-DR4-positive patients, the DR1 and DR4 subtypes were also determined. The frequency of HLA-DR4 alleles was significantly higher in RA patients than in controls (31.3 vs. 10.9%; P < .05). HLA-DR1, in particular, tended to be more frequent in patients than in controls (32.5 vs. 18.1%). Among the HLA-DR4 subtypes, DRB1*0401 and DRB1*0404 were the most common alleles found in both groups. However, no significant differences were seen in the frequency of HLA-DRB1*0401 and HLA-DRB1*0404 between RA patients and controls. In contrast, HLA-DRB1*0405 and HLA-DRB1*0408 were significantly more common in RA patients than in control subjects. Among HLA-DR1 subtypes, the DRB1*0101 allele was most commonly detected, but HLA-DRB1*0101 as well as DRB1*0102 and DRB1*0105 were similarly frequent in RA patients and controls. HLA-DR12 was more common among controls than in RA patients (18.1 vs. 0%; P < .05). Our results generally agree with the findings in other Caucasian populations. Nonetheless, we found differences in the frequency of HLA-DR1 and HLA-DR4 subtypes among Hungarian patients compared with reports from other geographic regions (e.g., Finland and Asia). Our data suggest that in northeastern Hungary, HLA-DR4 as well as its subtypes DRB1*0405 and DRB1*0408 may be involved in susceptibility to RA, but HLA-DR1 may not. In addition, the presence of HLA-DR12, at least in Hungary, may protect from this disease.

Rheumatoid arthritis (RA) is commonly associated with decreased bone mineral density (BMD) due to numerous factors. BsmI polymorphism of the vitamin D receptor (VDR) gene has been implicated in the pathogenesis of osteoporosis. Vitamin D has several immunomodulatory effects and thus may play a role in the course of arthritis. However, little data is available on the possible relationship between RA and VDR gene polymorphisms. In this study, the frequency of BsmI polymorphism genotypes were compared with that found in other countries. In this study, 64 RA patients and 40 healthy controls were tested for VDR gene BsmI polymorphism genotypes. Frequencies of B and b alleles were associated with markers of bone metabolism and RA. Among control subjects, the frequency of the BB genotype is relatively high (27.5%). In RA with secondary osteopenia/osteoporosis the BB genotype was more rare, the bb was more common than in control subjects. Markers of bone metabolism were associated with the B allele. RA patients carrying the B allele had lower BMD and increased bone loss over 1 year. The B allele was also correlated with increased osteoclast and osteoblast function, as determined by the assessment of biochemical markers of bone metabolism. Rheumatoid factor titer, which is an independent marker for disease progression in RA, was higher in bb patients. Our data suggest, that the imbalance in B and b allele expression may be involved in the pathogenesis of RA-associated osteoporosis. The possible involvement of vitamin D and VDR gene polymorphisms in the development and progression of RA needs further elucidation.

The genes for the human ATP-binding cassette (ABC) transporter ABCA7 and the minor histocompatibility antigen HA-1 are juxtaposed in close proximity on chromosome 19p13.3. The multispan transmembrane protein ABCA7 contains an extracellular domain that is recognized by antisera from patients with Sjogren's syndrome (“Sjogren-epitope”). Recent work from our laboratory demonstrating the involvement of ABCA7 in cellular ceramide and phosphatidylserine export suggests a role for this transporter in programmed cell death. In HA-1, a protein of unknown function, a His/Arg polymorphism (His168Arg), which constitutes the immunologic target for HA-1-specific cytotoxic T cells, has been causatively linked to graft-versus-host disease after allogeneic stem cell transplantation. Because these findings suggest a potential implication of ABCA7 and HA-1 in immune processes, we tested the hypothesis that allelic variants in both genes are associated with autoimmune disorders. We identified a total of 31 exonic single-nucleotide polymorphisms (SNP) in the ABCA7/HA-1 gene complex, nine of which represent non-synonymous nucleotide alterations. Genotypes of ABCA7 and HA-1 SNP were determined in three distinct Caucasian populations of patients with primary Sjogren's syndrome and ethnically matched controls. Comparison of allele frequencies between these groups revealed that the incidence of the HA-1 168His allele is significantly lower in Sjogren's syndrome patients than in controls (p

Two peptides with antimicrobial and cytolytic properties were purified from an extract of the skin of Tago's brown frog Rana tagoi. The primary structure of one peptide (FLPILGKLLS(10)GIL.NH(2)) identifies it as a member of the temporin family, whereas the second peptide (AIGSILGALA(10)KGLPTLISWI(20)KNR.NH(2)) displays 78% sequence identity to melittin from the venom of the honeybee Apis florea. Compared with melittin, the melittin-related peptide (MRP) was equipotent in inhibiting the growth of the Gram-positive bacterium Staphylococcus aureus, 5-fold less potent against the Gram-negative bacterium Escherichia coli and against the fungal pathogen, Candida albicans. MRP was 13-fold less hemolytic than melittin against human erythrocytes and 4- and 5-fold less cytolytic against mouse EL4 T-lymphoma-derived cells and L929 fibroblasts, respectively. However, at non-cytotoxic concentrations (or=8 microM), MRP did not protect HeLa cells from cell death produced by human rhinovirus type 2 infection.

The proper division of cells is essential for the production of viable daughter cells. In plants and fungi, the dividing cell produces a cross-wall or septum that bisects the cytoplasm. For separation of the daughter cells, the septum has to be cleaved. To study the regulation of this process, we isolated mutants defective in septum cleavage. The mutants showed highly pleiotropic phenotypes and defined 17 novel genes. The deduced amino acid sequences of the products of the cloned genes exhibited homologies to various transcription regulators of other organisms. The homologies and the pleiotropic effects of the mutations on sexual development, stress response, mitotic stability, septum initiation and septum placement indicated that these genes affect cell separation indirectly, through multifunctional regulatory modules.

We previously described the isolation of mutants defective in cell separation and the identification of 16 sep genes with complex functions. Here we report on the cloning and analysis of sep15+. The deduced amino acid sequence of the Sep15 protein shows significant homology to Med8, a component of the Saccharomyces cerevisiae transcription mediator complex. The mutation sep15-598 confers hyphal morphology and causes temperature-sensitive lethality. Disruption of sep15+ is lethal, indicating that Sep15 exerts an essential function and its role in cell separation is indirect.

The orderSchizosaccharomycetalescontains a dimorphic and two yeast species.Sch. japonicuscan form both yeast cells and mycelium, depending on the substrate and the culturing conditions.Sch. pombeis a strictly unicellular organism, but it can be forced to form mycelial cell chains by inactivating members of thesepgene family. The mutations in most of thesepgenes confer pleitropic phenotypes indicating functional involvement in MAP-kinase-mediated signalling pathways. Two of them were found to encode transcription factor homologues of other eukaryotes.

The Schizosaccharomyces pombe sep1 gene encodes a putative transcription factor that is required for cell separation. Among the genes required for septum formation and cytokinesis in fission yeast examined to date, the only one whose mRNA fluctuates significantly during the cell cycle is cdc15. In this study we have examined cdc15 mRNA levels in sep1 mutant and null backgrounds and have found that sep1p function is required for periodic accumulation of cdc15 mRNA. We have also localised sep1p and find that it is a nuclear protein, consistent with its proposed role as a transcription factor.