Pemphigus Vulgaris Autoantibody Response is Linked to HLA-DQB10503 in Pakistani Patients

ABSTRACT: Pemphigus vulgaris (PV) is an autoimmune disease of the skin and mucous membranes characterized by an autoantibody response against an epidermal cadherin. We performed high resolution HLA class II typing in 19 patients with PV from Rawalpindi, Pakistan and 19 non-Jewish European PV patients from Boston by sequence-specific oligonucleotide probe hybridization. The results were compared with two separate ethnically matched control populations. We found that PV patients from Pakistan had significantly increased frequencies of DRB1*1404 ( p = 0.01), DQA1*0101 ( p = 0.02), and DQB1*0503 ( p = 0.01). Among the patients of non-Jewish European ancestry, DRB1*1401 ( p < 10⁻⁶), DQA1*0101 ( p < 10⁻⁵) and DQB1*0503 ( p < 10⁻⁶), were increased in PV patients. Formal linkage analysis between the major histocompatibility complex and the PV antibody was performed in 67 relatives of the 19 Pakistani patients. The results showed strong evidence for linkage of HLA-DRB1*1404, DQA1*0101, DQB1*0503, with the presence of PV antibody in relatives’ families with a significant logarithm of the odds score of 6.06. Based on the three dimensional structure of class II molecules, we propose that HLA-DQA1*0101 and DQB1*0503, encode a negatively charged P9 peptide binding pocket of the DQ molecule and are significantly associated with susceptibility to PV in non-Jewish populations.     

Effect of mebendazole againstEchinococcus granulosus andTaenia hydatigena cysts in naturally infected sheep and relevance to larval tapeworm infections in man

The ability of three treatment schedules of mebendazole to kill well-established hydatid cysts was studied. Pregnant sheep, naturally infected withEchinococcus granulosus and/orTaenia hydatigena, were treated daily with mebendazole at a dose rate of 50 mg/kg body weight for either five days, one month, or three months.At autopsy, seven months after the commencement of treatment, no evidence was found that the 5-day treatment schedule had any damaging effect onE. granulosus cysts. The effects of the one month treatment were equivocal. There was evidence of a damaging effect from the 3-month treatment schedule and protoscoleces were not infective to dogs. NoT. hydatigena cysts survived the 1- and 3-month treatments, but organisms from the 5-day treatment were infective to dogs.These results forE. granulosus in sheep suggest that long-term treatment with mebendazole may be required in hydatid disease in man. The results obtained forT. hydatigena in sheep are discussed in relation to the treatment of cysticercosis fromT. solium in man. Mebendazole showed no untoward effect on the sheep or their lambs.     

Immune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem inflammatory syndrome in children

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Impaired Microvascular Function in Normal Children: Effects of Adiposity and Poor Glucose Handling

Clustering of cardiovascular risk factors is thought to occur early in life. The endothelium is an important regulator of microvascular function. We investigated the relationship between microvascular function and cardiovascular risk factors in 145 normal, healthy children aged 11-14 years. Skin microvascular responses, measured using laser Doppler imaging, to iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP), were negatively correlated with percentage body fat ( r =−0.20, P < 0.05 and r =−0.18, P < 0.05, respectively). Subjects were stratified into quintiles based on 2-h, post-feeding glucose levels. Subjects in the upper glucose quintile (range 7.4-11.4 mmol l⁻¹) showed significantly lower vasodilatation to both ACh (   P < 0.005  ) and SNP (   P < 0.02  ) than those in the lower quintile (range 3.9-4.9 mmol l⁻¹). Waist-to-hip ratio and the fasting insulin resistance index were significantly greater in subjects in the upper quintile than those in the lower quintile ( P < 0.001 and P < 0.05, respectively). Additionally, in subjects in the upper glucose quintile, fasting triglyceride correlated with fasting insulin ( r = 0.59, P < 0.001) and with the fasting insulin resistance index ( r = 0.49, P < 0.009), and plasma levels of cholesterol and 2-h glucose were also correlated ( r = 0.40, P < 0.05). In a cross-section of normal children, microvascular function was negatively associated with adiposity. Additionally, in a subgroup of subjects, there was a clustering of high post-feeding glucose, impaired microvascular function, increased insulin resistance and higher central fat distribution. These findings suggest that risk factors for adult cardiovascular disease begin to cluster in normal children, which might have important consequences for development of atherosclerosis later in life.     

The non-immunosuppressive immunophilin ligand GPI-1046 potently stimulates regenerating axon growth from adult mouse dorsal root ganglia cultured in Matrigel

We used explant cultures of adult mouse dorsal root ganglia with spinal nerve attached growing in Matrigel to assess the effects of the non-immunosuppressive immunophilin ligand GPI-1046 [Snyder et al. (1998) TIPS 19, 21-26] on the growth rate of regenerating sensory axons and found a potent stimulation of axon growth. In these explant cultures, naked, unfasciculated axons emerge from the cut end of the spinal nerve and continue to grow in the Matrigel for up to eight days [Tonge et al. (1996) Neuroscience 73, 541-551]. Some axons are entirely smooth whilst others show prominent varicosities. Some of the former express the phosphorylated neurofilament epitope recognised by monoclonal antibody RT97, a marker for large calibre, myelinated axons, whilst the latter express calcitonin gene-related peptide, predominantly a marker for unmyelinated, and small diameter myelinated sensory axons. Many of the axons in these cultures also express the low-affinity neurotrophin receptor p75. GPI-1046 has been shown to have striking stimulatory effects on embryonic primary sensory axons growing in vitro and it was therefore of interest to see whether it could also enhance regenerating sensory axon growth from the adult ganglia in our cultures. GPI-1046 potently stimulated axon growth in our cultures in a dose-dependent manner. The stimulatory effect was not dependent on the class of sensory axon. These observations show that GPI-1046 is a potent stimulator of regenerating axons from adult, primary sensory neurones. The cellular site of action of GPI-1046 is unknown. To distinguish between a direct effect of the drug on neurones and an indirect effect we compared the effects of GPI-1046 on explant and dissociated cultures. In confirmation of previous results, we found that GPI-1046 potently stimulated axon outgrowth from explants of embryonic chick dorsal root ganglia. However, the drug was without effect on dissociated embryonic dorsal root ganglion neurones, suggesting that non-neuronal cells are important for axon growth stimulation.     

Calcium and the biological activities of two Streptomyces species isolated from the rhizosphere of soybean plants

Careful examination of the characteristics of both organisms revealed that we are dealing with Streptomyces violaceochromogenes and Streptomyces glaucescens. Calcium chloride decreased the permeability of both organisms as indicated by the low total nitrogen content of their media compared to the controls. Small doses of calcium nitrate suppressed the permeability of S. violaceochromogenes and increased that of S. glaucescens whereas the larger doses were stimulatory for both organisms. Calcium nitrate had similar effects on S. violaceochromogenes only without affecting S. glaucescens. The stimulatory effects of calcium gradually faded with increased concentration. Calcium chloride increased the proteolytic activity in S. violaceochromogenes media; a phenomenon that was apparent in S. glaucescens media only in the case of the larger doses. Calcium nitrate suppressed the proteolytic activity in S. glaucescens media. The cellulolytic activity of both organisms was suppressed by calcium but amylases were initiated in S. glaucescens media. Those of S. violaceochromogenes were arrested with the lower levels of calcium but the larger doses restored or stimulated their activity.     

Epstein–Barr virus in Reed–Sternberg G-like cells in non Hodgkin's lymphomas

In the course of our study on Hodgkin's disease (HD), ten cases of non-Hodgkin's lymphomas (NHL) containing Hodgkin and Reed-Sternberg-like (MRS) cells were encountered. Many of these cases had initially been diagnosed as HD, but on careful review of the histology, with the aid of immunophenotyping studies, they were reclassified as NHL. The presence of Epstein–Barr virus (EBV) in these HRS-like cells was investigated using a combination of EBER in situ hybridization (ISH) and immunostaining for the detection of EBV-encoded latent membrane protein (LMP). HRS-like cells in four cases (two lymphoplasmacytoid lymphomas, one Richter's transformation of lymphoplasmacytoid lymphoma, and one immunoblastic lymphoma of T-cell type) were found to be EBV-positive. In two of these cases, a second biopsy taken up to 10 years later also contained EBV in the HRS-like cells. In three of the four cases, HRS-like cells expressed the activation antigen CD30, but the expression of B- or T-cell antigens was variable. All cases of T-cell-rich B-cell lymphomas were negative for EBV. In conclusion, EBV may play a role in the development of HRS-like cells i some cases of NHL. The relationship of HRS-like cells to HRS cells of HD is discussed.     

Cervical specimen order and performance measures of Chlamydia trachomatis diagnostic testing

The orders of three endocervical specimens of 3,561 women for Chlamydia trachomatis testing were randomized to determine whether test performance measures of two nucleic acid amplification tests and a DNA probe were affected by swab order. Specimen collection order did not appear to affect the diagnostic accuracy of these tests.     

Development of a single-tube, cell lysis-based, genus-specific PCR method for rapid identification of mycobacteria: optimization of cell lysis, PCR primers and conditions, and restriction pattern analysis

A single-tube PCR method was developed for efficient identification of nontuberculous mycobacteria (NTM) and their environmental isolates in about 3 h without conventional DNA isolation. The following three steps were optimized or developed: (i). a simple, 6-min direct cell lysis protocol as a PCR prestep for generation of DNA-template, (ii). an improved Mycobacterium-specific PCR amplification protocol with a broader species specificity using newly designed primers targeting a 228-bp region of the 65-kDa heat shock protein (hsp) gene and optimal PCR amplification conditions, and (iii). a genus-specific restriction analysis of the PCR product for conclusive identification of the unknown NTM isolates.