Characterization of peripheral blood acetylcholine receptor-binding B cells in experimental myasthenia gravis

In myasthenia gravis (MG), the neuromuscular transmission is impaired by antibodies (Abs) specific for muscle acetylcholine receptor (AChR). Anti-AChR Abs can be detected in the serum of MG patients, although their levels do not correlate with disease severity. In this study, we developed a flow cytometric assay for the detection of peripheral blood AChR-specific B cells to characterize B cell phenotypes associated with experimental autoimmune myasthenia gravis (EAMG). Alexa-conjugated AChR was used as a probe for AChR-specific B cells (B220+Ig+). Mice with EAMG had significantly elevated frequencies of AChR-specific IgG2+ and IgM+ B cells. While the frequencies of IgG2+ B cells and plasma anti-AChR IgG2 levels significantly correlated with the clinical grades of EAMG, the frequencies of IgM+ B cells and plasma anti-AChR IgM levels did not. These results indicate that the frequency of AChR-specific and IgG1+ (mouse IgG2 equivalent) peripheral blood B cells and anti-AChR IgG1 levels could be potential biomarkers for MG disease severity.     

High annual risk of tuberculosis infection among nursing students in South India: a cohort study

Background

Nurses in developing countries are frequently exposed to infectious tuberculosis (TB) patients, and have a high prevalence of TB infection. To estimate the incidence of new TB infection, we recruited a cohort of young nursing trainees at the Christian Medical College in Southern India. Annual tuberculin skin testing (TST) was conducted to assess the annual risk of TB infection (ARTI) in this cohort.

Methodology/Principal Findings

436 nursing students completed baseline two-step TST testing in 2007 and 217 were TST-negative and therefore eligible for repeat testing in 2008. 181 subjects completed a detailed questionnaire on exposure to tuberculosis from workplace and social contacts. A physician verified the questionnaire and clinical log book and screened the subjects for symptoms of active TB. The majority of nursing students (96.7%) were females, almost 84% were under 22 years of age, and 80% had BCG scars. Among those students who underwent repeat testing in 2008, 14 had TST conversions using the ATS/CDC/IDSA conversion definition of 10 mm or greater increase over baseline. The ARTI was therefore estimated as 7.8% (95%CI: 4.3–12.8%). This was significantly higher than the national average ARTI of 1.5%. Sputum collection and caring for pulmonary TB patients were both high risk activities that were associated with TST conversions in this young nursing cohort.

Conclusions

Our study showed a high ARTI among young nursing trainees, substantially higher than that seen in the general Indian population. Indian healthcare providers and the Indian Revised National TB Control Programme will need to implement internationally recommended TB infection control interventions to protect its health care workforce.     

The effects of oxidative stress on female reproduction: a review

ABSTRACT: Oxidative stress (OS), a state characterized by an imbalance between pro-oxidant molecules including reactive oxygen and nitrogen species, and antioxidant defenses, has been identified to play a key role in the pathogenesis of subfertility in both males and females. The adverse effects of OS on sperm quality and functions have been well documented. In females, on the other hand, the impact of OS on oocytes and reproductive functions remains unclear. This imbalance between pro-oxidants and antioxidants can lead to a number of reproductive diseases such as endometriosis, polycystic ovary syndrome (PCOS), and unexplained infertility. Pregnancy complications such as spontaneous abortion, recurrent pregnancy loss, and preeclampsia, can also develop in response to OS. Studies have shown that extremes of body weight and lifestyle factors such as cigarette smoking, alcohol use, and recreational drug use can promote excess free radical production, which could affect fertility. Exposures to environmental pollutants are of increasing concern, as they too have been found to trigger oxidative states, possibly contributing to female infertility. This article will review the currently available literature on the roles of reactive species and OS in both normal and abnormal reproductive physiological processes. Antioxidant supplementation may be effective in controlling the production of ROS and continues to be explored as a potential strategy to overcome reproductive disorders associated with infertility. However, investigations conducted to date have been through animal or in vitro studies, which have produced largely conflicting results. The impact of OS on assisted reproductive techniques (ART) will be addressed, in addition to the possible benefits of antioxidant supplementation of ART culture media to increase the likelihood for ART success. Future randomized controlled clinical trials on humans are necessary to elucidate the precise mechanisms through which OS affects female reproductive abilities, and will facilitate further explorations of the possible benefits of antioxidants to treat infertility.     

“A Résumé for the Baby”: Biosocial Precarity and Care of Substance-Using,Pregnant Women in San Francisco

Culture, Medicine, and Psychiatry - In the United States, the historical condemnation and punitive legal consequences of substance use during pregnancy—ranging from incarceration to...     

A human lymphoid cell line secreting immunoglobulin G and retaining immunoglobulin M in the plasma membrane

A selected clone, LA 85.2, of a human lymphoid cell line produces μ, γ, and light chains. The cells secrete IgG but not IgM. Assembly of μ chains and light chains produces 8S IgM which is retained in the plasma membrane. IgM is produced at a slow rate and in lesser amounts than IgG. LA 85.2 cells produce a plasma membrane protein which can bind to antibody-antigen precipitates. It is suggested that this protein plays a role in holding the surface IgM in the plasma membrane.     

Comparative structural analyses of the alpha-glucan and glycogen from Mycobacterium bovis

Pathogenic mycobacteria such as Mycobacterium tuberculosis, the causative agent of tuberculosis, are surrounded by a noncovalently bound capsule, whose major carbohydrate constituent is a glycogen-like alpha-glucan. In the present study we compared the structures of the extracellular polysaccharide to that of the ubiquitous intracellular glycogen. The alpha-glucan was isolated from the culture medium of Mycobacterium bovis Bacille Calmette Guérin, the vaccine strain, in which it is released whereas the intracellular glycogen was obtained after the disruption of cells. The two purified polysaccharides were eluted from permeation gel at a similar position but glycogen was less soluble and gave a more opalescent solution in water than alpha-glucan. Combination of gas chromatography-mass spectrometry analysis of partially O-methylated, partially O-acetylated alditols and NMR analysis confirmed that both polysaccharides were composed of -->4-alpha-D-Glcp-1--> core, substituted at some six positions with short chains. Degradation of polysaccharides with pullulanase, followed by mass spectrometry analysis of the resulting products, also showed that the two polysaccharides do not differ in terms of lengths of branching. Interestingly, application of analytical ultracentrifugation and dynamic light scattering to the mycobacterial alpha-glucan and glycogen and their enzymatic degradative products indicated that the alpha-glucan possessed a higher molecular mass and was more compact than the glycogen from the same species, allowing the formulation of working structural models for the two polysaccharides. Consistent with the models, the alpha-glucan was found to be less accessible to pullulanase, a debranching enzyme, than glycogen.     

Synthesis of new coumarin 3-(N-aryl) sulfonamides and their anticancer activity

Synthesis of coumarin 3-(N-aryl) sulfonamides was accomplished either by Knoevenagel condensation of anilinosulfonylacetic acids with suitable salicylaldehydes or by the reaction of methyl anilinosulfonylacetates with substituted salicylaldehydes in presence of a catalytic amount of a base. All the compounds tested for antiproliferative activity in different cancer cell lines have shown GI(50) values less than 100 microM.     

Novel thieno oxazine analogues as antihyperglycemic and lipid modulating agents

A series of phenyl acetic acid and alpha-hydroxy propionic acid derivatives were synthesized. In vivo studies of the compounds indicated compound 2c as the most potent in one of the series, which has both glucose and lipid lowering properties. The syntheses and biological studies have been discussed.     

Germ Line Transmission of the Cdk4R24C Mutation Facilitates Tumorigenesis and Escape from Cellular Senescence

Mutations in CDK4 and its key kinase inhibitor p16(INK4a) have been implicated in the genesis and progression of familial human melanoma. The importance of the CDK4 locus in human cancer first became evident following the identification of a germ line CDK4-Arg24Cys (R24C) mutation, which abolishes the ability of CDK4 to bind to p16(INK4a). To determine the role of the Cdk4(R24C) germ line mutation in the genesis of other cancer types, we introduced the R24C mutation in the Cdk4 locus of mice by using Cre-loxP-mediated "knock-in" technology. Cdk4(R24C/R24C) mouse embryo fibroblasts (MEFs) displayed increased Cdk4 kinase activity resulting in hyperphosphorylation of all three members of the Rb family, pRb, p107, and p130. MEFs derived from Cdk4(R24C/R24C) mice displayed decreased doubling times, escape from replicative senescence, and escape sensitivity to contact-induced growth arrest. These MEFs also exhibited a high degree of susceptibility to oncogene-induced transformation, suggesting that the Cdk4(R24C) mutation can serve as a primary event in the progression towards a fully transformed phenotype. In agreement with the in vitro data, homozygous Cdk4(R24C/R24C) mice developed tumors of various etiology within 8 to 10 months of their life span. The majority of these tumors were found in the pancreas, pituitary, brain, mammary tissue, and skin. In addition, Cdk4(R24C/R24C) mice showed extraordinary susceptibility to carcinogens and developed papillomas within the first 8 to 10 weeks following cutaneous application of the carcinogens 9,10-di-methyl-1,2-benz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). This report formally establishes that the activation of Cdk4 is sufficient to promote cancer in many tissues. The observation that a wide variety of tumors develop in mice harboring the Cdk4(R24C) mutation offers a genetic proof that Cdk4 activation may constitute a central event in the genesis of many types of cancers in addition to melanoma.     

Synthesis and cytotoxic activity of novel quinazolino-beta-carboline-5-one derivatives

A novel series of quinazolino-beta-carbolinone derivatives was synthesized and evaluated for their in vitro and in vivo anticancer activity. Many compounds have shown good in vitro activity in the range 1-8 microM concentration. Three of the compounds were further tested in nude mice bearing HT-29 colon cancer xenografts.