Toxic tau: structural origins of tau aggregation in Alzheimer's disease

Alzheimer’s disease is characterized by the extracellular accumulation of the amyloidβin the form of amyloid plaques and the intracellular deposition of the microtubule-associated protein tau in the form of neurofibrillary tangles.Most of the Alzheimer’s drugs targeting amyloidβhave been failed in clinical trials.Particularly,tau pathology connects greatly in the pathogenesis of Alzheimer’s disease.Tau protein enhances the stabilization of microtubules that leads to the appropriate function of the neuron.Changes in the quantity or the conformation of tau protein could affect its function as a microtubules stabilizer and some of the processes wherein it is involved.The molecular mechanisms leading to the accumulation of tau are principally signified by numerous posttranslational modifications that change its conformation and structural state.Therefore,aberrant phosphorylation,as well as truncation of tau protein,has come into focus as significant mechanisms that make tau protein in a pathological entity.Furthermore,the shape-shifting nature of tau advocates to comprehend the progression of Alzheimer’s disease precisely.In this review,we emphasize the recent studies about the toxic and shape-shifting nature of tau in the pathogenesis of Alzheimer’s disease.     

Assessment of heavy metals by ICP-OES and their impact on insulin stimulating hormone and carbohydrate metabolizing enzymes

Arsenic (As) and cadmium (Cd) have recently emerged as major health concerns owing to their strong association with diabetes mellitus (DM). We aimed to investigate the heavy metals exposure towards incidence of DM at various enzymatic and hormonal levels. Additionally, association of As and Cd with Zinc (Zn, essential metal) was also evaluated. Spot urine samples were collected to assess As, Cd and Zn through ICP-OES. Serum was analyzed by assay method for fasting blood glucose, liver and renal function biomarkers. ELISA was performed to investigate the impact of heavy metals on HbA1c, α-amylase, DPP-IV, IGF-1, leptin, GSH, MDA, SOD, HDL, FFA, TG and interleukin (IL)-6. Association of heavy metals with DM was measured by odds ratio (OR) and level of significance was assessed by Chi-squared test. Unpaired student's t-test was used to compare DM-associated risk factors in heavy metals-exposed and unexposed participants. As and Cd were detectable in 75.4% and 83% participants with mean concentration of 75.5 ppb and 54.5 ppb, respectively. For As exposure, OR in the third quartile was maximum ie 1.34 (95% CI, 0.80 to 2.23), however the result was not statistically significant (P > .05). For Cd exposure, OR in the fourth quartile was considerably high, 1.62 (95% CI, 1.00 to 2.61), with a significant probability value (P < .05). Urinary Cd was negatively associated with Zn. As and Cd exposure increases the incidence of DM in the general population. Impaired hormonal and enzymatic levels in diabetic and non-diabetic exposed participants reflect the multiple organ damage by heavy metal exposure.     

The utilisation of superficial venous surgery for chronic venous insufficiency by the U.K. Asian population.

BACKGROUND: The epidemiology of superficial venous disease is relatively well defined in the U.K. Caucasian population. By contrast, there are currently no data available for Asians, who comprise 3.6% of the U.K., and 14.1% of this institution's catchment population. The aim of this study was to compare surgery for superficial venous disease in Caucasians and Asians in this institution, in the context of our local population. METHODS: A prospectively gathered database of all 2011 superficial venous operations performed between January 1997 and April 2002 was retrospectively analysed with regard to ethnicity. The ethnic, gender and age composition of our catchment area was determined from U.K. census data. The full institutional records of 100 Asian and 100 randomly selected age and sex-matched Caucasian patients were compared in a case control study. RESULTS: After adjusting for age and gender according to census data, Asians were 40% less likely to undergo superficial venous surgery (SVS). Considering the 2011 operated patients as a whole, Asians were significantly younger and more likely to be male. In the case control study, Asians were significantly less likely to be operated for recurrent disease and significantly more likely to be operated for advanced disease. CONCLUSIONS: Although Asians are significantly less likely to undergo SVS; those that do are more likely to be young, male and operated for skin changes and ulcers. This strongly suggests that the under-representation of Asians is due to cultural, genetic or environmental factors and unmet health care need, rather than a lower prevalence of clinically significant venous disease in the Asian population.     

External Iliac Endofibrosis in Endurance Athletes: A Novel Case in an Endurance Runner and a Review of the Literature

BACKGROUND: There is increasing recognition that high-performance athletes can develop symptomatic arterial flow restriction in one or both (15%) legs due to kinking and/or endofibrosis of their iliac arteries. METHODS: Case report and review based on a Medline search of the literature. RESULTS: A 51-year-old female, 24-hour endurance runner presented with a six-month history of rapidly progressing intermittent claudication affecting her right thigh and calf in the absence of classical risk factors for atherosclerosis. On the basis of invasive and non-invasive investigations, a provisional diagnosis of endofibrosis was made and she was treated successfully with angioplasty. CONCLUSIONS: The epidemiology, optimal investigation and treatment of iliac endofibrosis in endurance athletes is poorly described. Each individual unit's experience is likely to be very small. A European register of such cases would increase our understanding of the condition and improve patient outcomes.     

Autologous Blood Stem Cell Transplantation in Hematological Malignancies

Autologous blood stem cell transplants (ABSCT) are increasingly used for the treatment of haematological malignancies. The use of hemopoietic growth factors, in conjunction with stem cell mobilization by chemotherapeutic agents, has permitted successful harvests requir ing only a few leukaphereses; cells mobilized in this manner contain a relatively large number of committed precursors of all lineages, as well as early progenitor cells capable of main taining long-term haemopoiesis. Haematological recovery after ABSCT is rapid, thereby sig nificantly shortening the period of post-chemotherapy neutropenia and thrombocytopenia. Furthermore, blood-derived grafts may contain fewer malignant cells than the bone marrow cells. The preliminary results have been so encouraging that it is envisaged that in myeloma, Hodgkin's disease and non-Hodgkin lymphomas, ABSCT may eventually replace autologous marrow transplantation.     

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.     

Sjögren's syndrome

Sjogren's syndrome (SS) describes xeropthalmia and xerostomia due to lymphocytic infiltrates of lacrimal and salivary glands. SS may occur alone (primary SS) or in association with several other autoimmune diseases (secondary SS). The clinical features involve a wide variety of organs, including skin, eyes, oral cavity and salivary glands, and systems, including nervous, musculoskeletal, genitourinary and vascular. Sicca symptoms can be found in a number of other disorders including rheumatoid arthritis, systemic lupus erythematosus, scleroderma, primary biliary cirrhosis, and other rheumatic disorders.