Tapasin gene polymorphism in systemic onset juvenile rheumatoid arthritis: a family-based case-control study

Juvenile rheumatoid arthritis (JRA) comprises a group of chronic systemic inflammatory disorders that primarily affect joints and can cause long-term disability. JRA is likely to be a complex genetic trait, or a series of such traits, with both genetic and environmental factors contributing to the risk for developing the disease and to its progression. The HLA region on the short arm of chromosome 6 has been intensively evaluated for genetic contributors to JRA, and multiple associations, and more recently linkage, has been detected. Other genes involved in innate and acquired immunity also map to near the HLA cluster on 6p, and it is possible that variation within these genes also confers risk for developing JRA. We examined the TPSN gene, which encodes tapasin, an endoplasmic reticulum chaperone that is involved in antigen processing, to elucidate its involvement, if any, in JRA. We employed both a case-control approach and the transmission disequilibrium test, and found linkage and association between the TPSN allele (Arg260) and the systemic onset subtype of JRA. Two independent JRA cohorts were used, one recruited from the Rheumatology Clinic at Cincinnati Children's Hospital Medical Center (82 simplex families) and one collected by the British Paediatric Rheumatology Group in London, England (74 simplex families). The transmission disequilibrium test for these cohorts combined was statistically significant (chi(2) = 4.2, one degree of freedom; P = 0.04). Linkage disequilibrium testing between the HLA alleles that are known to be associated with systemic onset JRA did not reveal linkage disequilibrium with the Arg260 allele, either in the Cincinnati systemic onset JRA cohort or in 113 Caucasian healthy individuals. These results suggest that there is a weak association between systemic onset JRA and the TPSN polymorphism, possibly due to linkage disequilibrium with an as yet unknown susceptibility allele in the centromeric part of chromosome 6

Hip joint replacement surgery for idiopathic osteoarthritis aggregates in families

In order to determine whether there is a genetic component to hip or knee joint failure due to idiopathic osteoarthritis (OA), we invited patients (probands) undergoing hip or knee arthroplasty for management of idiopathic OA to provide detailed family histories regarding the prevalence of idiopathic OA requiring joint replacement in their siblings. We also invited their spouses to provide detailed family histories about their siblings to serve as a control group. In the probands, we confirmed the diagnosis of idiopathic OA using American College of Rheumatology criteria. The cohorts included the siblings of 635 probands undergoing total hip replacement, the siblings of 486 probands undergoing total knee replacement, and the siblings of 787 spouses. We compared the prevalence of arthroplasty for idiopathic OA among the siblings of the probands with that among the siblings of the spouses, and we used logistic regression to identify independent risk factors for hip and knee arthroplasty in the siblings. Familial aggregation for hip arthroplasty, but not for knee arthroplasty, was observed after controlling for age and sex, suggesting a genetic contribution to end-stage hip OA but not to end-stage knee OA. We conclude that attempts to identify genes that predispose to idiopathic OA resulting in joint failure are more likely to be successful in patients with hip OA than in those with knee OA

A Prospective Evaluation of the Effect of Salpingectomy on Endometrial Receptivity in Cases of Women with Communicating Hydrosalpinges

BACKGROUND: We aimed to assess whether salpingectomy in women with communicating hydrosalpinges influenced endometrial receptivity. METHODS: The inclusion criteria were: women with communicating hydrosalpinges, absence of other confounding infertility factors and aged < 40 years. Patients were scheduled for laparoscopy during the putative window of implantation (cycle days 19-21). In patients in whom salpingectomy was decided upon due to the severity of tubal disease (it = 10), an intra-operative endometrial biopsy was performed. Post-treatment endometrial sampling was done between day 19-21 of the fourth consecutive cycle. Pre-treatment and post-treatment samples were assessed by both conventional histologic criteria and alphav beta (3) integrin immunostaining, where histological score (HSCORE) was used for quantification. RESULTS: Despite normal histological maturation assessed by conventional criteria, 8/10 hydrosalpinx cases yielded an epithelial HSCORE of <0.7, which was below the accepted threshold. Following salpingectomy, luminal endometrial epithelium demonstrated a significantly increased alphav beta (3) integrin expression (Wilcoxon's signed rank test, P = 0.017). Although the mean HSCORE for glandular epithelia improved, it failed to reach statistical significance. Ultrasound visible hydrosalpinges (n = 5) and non-visible cases (it = 5) were also compared. However, neither the pre-treatment integrin expression, nor the postoperative improvement were significantly different between these groups. CONCLUSIONS: We conclude that the surgical treatment of communicating hydrosalpinges may improve endometrial receptivity as assessed by alphav beta (3) integrin expression. Women with hydrosalpinges may undergo endometrial evaluation by the molecular markers of implantation, such as alphav beta (3) integrin. This evaluation may be decisive in determining the optimal management of cases, and may also be used to assess the efficacy of the treatment. The expression of the implantation markers should be correlated with implantation and clinical pregnancy rates in IVF-embryo transfer programs.WoSScopu

Pleural effusion: A rare complication of hepatitis A

Hepatitis A (HAV) infection, which is the most common form of hepatitis in the paediatric age group and which sometimes has a fulminant course, is endemic in Turkey, constituting one of the country′s important health problems. Pleural effusion also represents a rare benign complication of acute HAV infections. We describe here a case of Hepatitis A who developed pleural effusion

Co-Administration Of Metformin During Rfsh Treatment In Patients With Clomiphene Citrate-Resistant Polycystic Ovarian Syndrome: A Prospective Randomized Trial

BACKGROUND: This study aims to evaluate the impact of metformin on ovarian response when co-administered during recombinant (r)FSH using the low-dose step-up protocol in clomiphene citrate-resistant polycystic ovarian syndrome (PCOS) patients with normal glucose tolerance. METHODS AND RESULTS: Thirty-two patients were randomized to metformin (n = 16) and placebo (n = 16) groups. Hormonal assessment, a 75 g oral glucose tolerance test (OGTT) and a frequently sampled i.v. glucose tolerance test (FSIGTT) were performed before and after oral administration of metformin (850 mg twice daily) or placebo for 6 weeks. Recombinant FSH treatment was undertaken, thereafter, in women who did not ovulate on metformin (n = 10) or placebo (n = 15). There was no significant change in all insulin sensitivity indices in both groups. The only change noted was a decline in mean serum free testosterone concentration in the metformin group (P = 0.049). One patient on placebo and six patients on metformin ovulated spontaneously (P 0.05). The respective figures for pregnancy were 6.3 and 31.3% (P > 0.05). CONCLUSIONS: Metformin may restore ovulation with no improvement on insulin resistance in clomiphene citrate-resistant PCOS patients with normal glucose tolerance, but has no significant effect on ovarian response during rFSH treatment.Wo

Removal of Hydrosalpinges Increases Endometrial Leukaemia Inhibitory Factor (Lif) Expression At The Time of The Implantation Window

BACKGROUND: The presence of hydrosalpinges is associated with lower implantation and pregnancy rates in women undergoing IVF-embryo transfer, while salpingectomy improves these parameters. Although the mechanism by which hydrosalpinges affects fertility is not entirely understood, an adverse effect on endometrial receptivity has been postulated. In this study, we hypothesized that the adverse effects of hydrosalpinges on fertility may be in part mediated by inappropriate endometrial expression of leukaemia inhibitory factor (LIF), a cytokine implicated in implantation. METHODS: In order to test our hypothesis, we prospectively examined the expression of LIF during the window of implantation in the endometrium of infertile women (n = 10) with hydrosalpinges prior to and following salpingectomy and of fertile controls (n = 10) by Western blotting and immunohistochemistry. RESULTS: LIF expression was significantly lower in infertile women with hydrosalpinges compared with fertile controls (P < 0.05). Salpingectomy resulted in an increase in LIF expression in eight out of 10 women with hydrosalpinges. LIF levels were increased by 231 +/- 49% (mean +/- SEM) following salpingectomy. Immunohistochemical analysis confirmed the Western blot findings. The increased LIF immunoreactivity was predominantly localized to luminal and glandular epithelial cells. CONCLUSIONS: Our findings suggest that observed benefit from salpingectomy in infertile women with hydrosalpinges may be in part mediated by the up-regulation of endometrial LIF expression.WoSScopu

Over Expression of CNP Enhances the Formation of Long Bone Exostoses in Ext1+/- mice

Multiple hereditary exostoses (MHE) is an autosomal dominant skeletal disorder caused by heterozygous loss-of-function mutations in either EXT1 or EXT2. Exostosis in patients with EXT mutations occurs at diverse skeletal sites and can undergo malignant degeneration. The exostosis in EXT1 heterozygous (EXT1+/-) mice predominantly affect the ribs and do not become malignant. In this study EXT1+/- mice were bred to transgenic mice that over-express C-type natriuretic peptide under the control of the type II collagen promoter/enhancer (CNPcol2a1TG). The purpose of this study was to determine whether CNP over expression would enhance the EXT1+/- phenotype. By itself, CNP over-expression causes skeletal overgrowth, but does not produce exostoses. EXT1+/- and CNPcol2a1TG mice were mated and 27 offspring were followed for up to 8 months. Non-rib exostoses were detected clinically and/or radiographically, and they were examined histologically following sacrifice. Eight of the 27 offspring developed non-rib exostoses and these 8 offspring were both EXT1+/- and CNPcol2a1TG positive (EXC). Of the remaining 19 mice in which we did not observe long bone or vertebral exostoses, 9 were CNPcol2a1TG, 4 were EXT1+/-, and 6 were entirely wild-type. The histological appearance of each exostosis was similar to that of human exostotic lesions. Western blots using antibodies towards NPR2 and MMP13 showed an increase in CNPcol2a1TG and EXC mice as compared to their non-transgenic littermates. There was an increase in the phosphorylated form of P38 and JNK in the EXC transgenic mice when compared to EXT and CNP mice. CNP over expression in EXT+/- mice provided the necessary environment for EXT1 haploinsufficiency for exositosis formation. EXT haploinsufficient and CNP over expressing mice provides us a new murine model to study MH