Redox Activated MAP Kinase Death Signaling Cascade Initiated by ASK1 is not Activated in Female Mice Following MPTP: Novel Mechanism of Neuroprotection

Incidence of Parkinson’s disease (PD) is lower in women compared to men (1:1.46), which is reflected in animal models. However, precise mechanisms are unclear. Administration of MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) to female mice does not lead to mitochondrial complex I inhibition as seen in males and the progressive dopaminergic cell loss in substantia nigra (SNpc) is significantly attenuated. Redox driven apoptotic signaling pathways regulated by thiol disulfide oxidoreductase(s) have been implicated in the neurodegeneration seen in PD. Oxidation of thioredoxin leads to activation of apoptosis signal regulating kinase 1 (ASK1; MAPKKK) initiating cell death cascade through MAP kinase(s). Higher constitutive expression of enzymes involved in cellular redox maintenance, such as glutathione reductase, thioredoxin, and thioredoxin reductase is observed in female brain. Exposure to MPTP activates ASK1 in male but not in female mice. Higher expression of Trx in females potentially prevents ASK1 activation. Downstream of ASK1, phosphorylation of p38 MAP kinase is seen in male but not female mice. Expression of DJ-1, the redox sensing protein is higher in females and the loss of nuclear DJ-1, followed by translocation of Daxx (death associated protein) from the nucleus to the cytosol, which promotes ASK1 mediated death cascade is not seen in females. The enzymes involved in redox maintenance potentially could play a crucial role in preventing the activation of redox driven death signaling cascade and offer neuroprotection. Theraupeutic strategies that help maintain redox homeostasis may help prevent the progressive neurodegeneration seen in PD.     

The impact of periodontitis on oral health‐related quality of life: a review of the evidence from observational studies

Modern population based oral health management requires a complete understanding of the impact of disease in order to provide efficient and effective oral health care and guidance. Periodontitis is an important cause of tooth loss and has been shown to be associated with a number of systemic conditions. The impact of oral conditions and disorders on quality of life has been extensively studied. However, the impact of periodontitis on quality of life has received less attention. This review summarizes the literature on the impact of periodontitis on oral health‐related quality of life (OHRQoL). Relevant publications were identified after searching the MEDLINE and EMBASE electronic databases. Screening of titles and abstracts and data extraction was conducted. Only observational studies were included in this review. Most of the reviewed studies reported a negative impact of periodontitis on OHRQoL. However, the reporting standards varied across studies. Moreover, most of the studies were conducted in developed countries.     

Characterization of non-human primate antisera to acute lymphoblastic leukemia (ALL): evidence for unique antigen(s) on childhood ALL of "T" phenotype

A non-human primate antiserum was prepared to acute lymphoblastic leukemia of T-cell phenotype (T-ALL) and, after absorptions with normal blood elements, reacted by immunofluorescence and microcytotoxicity to all the T-ALL tested. In addition, the antiserum reacted with cells from about 70% of the common ALL studied and immunoprecipitated the common ALL antigen of 100,000 daltons. However, when the anti-T-ALL serum was absorbed with with lymphoblasts from common ALL, it failed to react with common ALL lymphoblasts, yet reacted significantly with cells from patients with T-ALL phenotype and defined a 100,000-dalton membrane component not found on common ALL lymphoblasts. In addition, sequential immunoprecipitation of 125I-labeled T-ALL membranes by anti- common-ALL serum followed by anti-T-ALL serum detected the T-ALL membrane component of 100,000 daltons that was not found on common ALL. Thus, our results demonstrate the presence of of a unique human T-ALL antigen present on all T-ALL distinct from the common ALL antigen.     

Synergistic cytotoxic effect of azidothymidine and recombinant interferon alpha on normal human bone marrow progenitor cells

Azidothymidine (AZT) and interferon alpha (IFN-alpha) are among the drugs showing strong in vitro activity against the human immunodeficiency virus type-1 (HIV-1). Each drug, however, has significant toxicity against normal marrow progenitor cells that frequently proves dose-limiting in patients. In this study, AZT and recombinant IFN-alpha 2a (rIFN-alpha 2a) were tested as single agents and in combination against normal myeloid (CFU-GM) and erythroid (BFU- E) colony forming cells in a standard methylcellulose culture assay. The data were analyzed using a quantitative computerized analysis based on the median-effect principle and the isobologram equation as described by Chou and Talalay (Adv Enz Regul 22:27, 1984). The ED90 for BFU-E and CFU-GM inhibition was then compared with previously measured in vivo plasma levels of each drug and the ED90 for the anti-HIV-1 effect in vitro. We demonstrate that (a) the drugs are strongly synergistic in inhibiting marrow progenitor cell growth and that this synergism occurs at drug levels that are within the range of measured plasma levels in phase I clinical trials, (b) BFU-E are more sensitive than CFU-GM to the inhibiting effects of AZT, rIFN-alpha 2a or both drugs in combination, (c) the drug concentrations in combination that synergistically inhibit bone marrow progenitors are much higher than those required to inhibit HIV-1 replication in vitro, and (d) the anti- HIV-1 effect for the combination of AZT and rIFN-alpha 2a was clearly superior to the effect of AZT or rIFN-alpha 2a alone as indicated by the combination index and the dose-reduction index. These data suggest that substantially lower doses of AZT and rIFN-alpha than those currently being tested in clinical trials might not only maintain a strong synergistic anti-HIV-1 effect but might also avoid significant hematologic toxicity.     

The effects of whole‐body vibration training and vitamin D supplementation on muscle strength,muscle mass,and bone density in institutionalized elderly women: A 6‐month randomized,controlled trial

Sarcopenia and osteoporosis represent a growing public health problem. We studied the potential benefit of whole‐body vibration (WBV) training given a conventional or a high dose of daily vitamin D supplementation in improving strength, muscle mass, and bone density in postmenopausal women. In a 2 × 2 factorial‐design trial, 113 institutionalized elderly females aged over 70 years (mean age 79.6 years) were randomly assigned either to a WBV or a no‐training group, receiving either a conventional dose (880 IU/day) or a high dose (1600 IU/day) of vitamin D₃. The primary aim was to determine the effects of 6 months of WBV and/or vitamin D supplementation on isometric and dynamic strength, leg muscle mass, and hip bone mineral density (BMD). Additionally, the increase in 25‐hydroxyvitamin D [25(OH)D] levels between conventional and high‐dose supplementation was compared. After 6 months of treatment, dynamic muscle strength, hip BMD, and vitamin D serum levels improved significantly in all groups, whereas isometric strength and muscle mass did not change. When compared with no training, the WBV program did not result in additional improvements. When compared with 880 IU, a high dose of 1600 IU of vitamin D did result in higher serum vitamin D levels but did not result in additional improvements. In institutionalized women older than 70 years, the WBV training protocol tested is not more efficient in enhancing muscle mass, strength, and hip BMD compared with vitamin D supplementation. A higher dose of 1600 IU of vitamin D does not provide additional musculoskeletal benefit in this population compared with conventional doses. © 2011 American Society for Bone and Mineral Research.     

冠状动脉粥样硬化ADAMTS7新位点的发现和冠状动脉粥样硬化中ABO位点与心肌梗死的相关性:两项全基因组关联研究

<正>背景:该研究旨在评价在现有的冠状动脉粥样硬化的病变中,遗传因素对粥样硬化斑块进展及特异性心肌梗死是否存在显著作用。方法:对欧洲后裔参与者冠状动脉造影表型进行了两项全基因组关联研究(GWAS),为寻找冠状动脉疾病(CAD)易感性基因位点,研究比较了有异常(n=12393)和无异常的(对照组n=7383)个体;为寻找心肌梗死易感性基因位点,也同时比较了造影证实存在CAD并且有心肌梗死的个体(n=5783)与虽有CAD但无心肌梗死的个体(n=3644)。