Enhanced sensitivity of hippocampal pyramidal neurons from mdx mice to hypoxia-induced loss of synaptic transmission.

The gene at the Duchenne/Becker muscular dystrophy locus encodes dystrophin, a member of a protein superfamily that links the actin cytoskeleton to transmembrane plasmalemmal proteins. In mature skeletal myocytes, the absence of dystrophin is associated with decreased membrane stability, altered kinetics of several calcium channels, and increased intracellular calcium concentration. In the central nervous system, dystrophin is restricted to specific neuronal populations that show heightened susceptibility to excitotoxic damage and is localized in proximal dendrites and the neuronal somata. We report that CA1 pyramidal neurons in a hippocampal slice preparation from a dystrophin-deficient mouse genetic model of Duchenne muscular dystrophy (the mdx mouse) exhibit significant increased susceptibility to hypoxia-induced damage to synaptic transmission. This selective vulnerability was substantially ameliorated by pretreatment with diphenylhydantoin, an anticonvulsant that blocks both sodium-dependent action potentials and low-threshold transient calcium conductances. These findings suggest that dystrophin deficiency could predispose susceptible neuronal populations to cumulative hypoxic insults that may contribute to the development of cognitive deficits in Duchenne/Becker muscular dystrophy patients and that the effects of such periods of hypoxia may be pharmacologically remediable.     

The many weak instruments problem and Mendelian randomization

Instrumental variable estimates of causal effects can be biased when using many instruments that are only weakly associated with the exposure. We describe several techniques to reduce this bias and estimate corrected standard errors. We present our findings using a simulation study and an empirical application. For the latter, we estimate the effect of height on lung function, using genetic variants as instruments for height. Our simulation study demonstrates that, using many weak individual variants, two‐stage least squares (2SLS) is biased, whereas the limited information maximum likelihood (LIML) and the continuously updating estimator (CUE) are unbiased and have accurate rejection frequencies when standard errors are corrected for the presence of many weak instruments. Our illustrative empirical example uses data on 3631 children from England. We used 180 genetic variants as instruments and compared conventional ordinary least squares estimates with results for the 2SLS, LIML, and CUE instrumental variable estimators using the individual height variants. We further compare these with instrumental variable estimates using an unweighted or weighted allele score as single instruments. In conclusion, the allele scores and CUE gave consistent estimates of the causal effect. In our empirical example, estimates using the allele score were more efficient. CUE with corrected standard errors, however, provides a useful additional statistical tool in applications with many weak instruments. The CUE may be preferred over an allele score if the population weights for the allele score are unknown or when the causal effects of multiple risk factors are estimated jointly. © 2014 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.     

Psoriatic arthritis and physical activity: a systematic review

Clinical Rheumatology - The positive effects of physical activity in both rheumatoid arthritis and ankylosing spondylitis have been proven, but no clear data is yet published regarding psoriatic...     

New products for managing inhibitors to coagulation factors: a focus on recombinant factor VIIa concentrate

The treatment of alloantibody and autoantibody inhibitors directed against the factor VIII coagulant protein is one of the most challenging and expensive problems in hematology. Because the currently available plasma replacement products used in this context do not control the bleeding complications in all patients, and because of the usual emergent quality of the bleeding complications, there has been a definite need to have a uniformly reliable product for instant use, which possesses a high degree of hemostatic reliability and safety. The recent introduction of recombinant factor VIIa (rFVIIa) has been a welcome addition to the pharmacologic armamentarium for the treatment of neutralizing antibodies against coagulation factors. The mechanisms of action of rFVIIa have also been interesting and have provided insight into how the coagulation pathway accomplishes adequate hemostasis. This review will discuss this new medication and place into the context of coagulation inhibitor therapy.     

Marital quality and psychological adjustment to widowhood among older adults: a longitudinal analysis

OBJECTIVES: This study examined whether psychological adjustment to widowhood is affected by three aspects of marital quality--warmth, conflict, and instrumental dependence-assessed prior to the loss. METHODS: The Changing Lives of Older Couples (CLOC) is a prospective study of a two-stage area probability sample of 1,532 married individuals aged 65 and older. The CLOC includes baseline data on marital quality and mental health and data on grief, anxiety, and depression collected 6, 18, and 48 months after spousal loss. RESULTS: Widowhood was associated with elevated anxiety among those who were highly dependent on their spouses and lower levels of anxiety among those who were not dependent on their spouses. Levels of yearning were lower for widowed persons whose relationships were conflicted at baseline and higher for those reporting high levels of marital closeness and dependence on their spouses. Women who relied on their husbands for instrumental support had significantly higher levels of yearning than men who depended on their wives. DISCUSSION: The findings contradict the widespread belief that grief is more severe if the marriage was conflicted and suggest a more complex relationship between bereavement and characteristics of the marriage.     

Agranulocytosis associated with "Mexican aspirin" (dipyrone): evidence for an autoimmune mechanism affecting multipotential hematopoietic progenitors

A case of acute, transient agranulocytosis and thrombocytopenia associated with ingestion of dipyrone is reported. This once widely used analgesic, which is now banned in the United States, was obtained by the patient as "aspirin" while traveling in Mexico. Studies of the effects of this patient's serum on purified CD34+ marrow cells, which were highly enriched for hematopoietic progenitors, showed not only a drug-dependent suppression of the in vitro growth of myeloid progenitors, as has been reported previously, but also a drug-dependent suppression of primitive multipotential progenitors (CFU-Mix) and erythroid progenitors (BFU-E). These findings indicate that autoimmune, antibody-hapten interactions which have been reported to occur in dipyrone- and aminopyrine-induced agranulocytosis are not restricted to the neutrophil lineage.     

Increased efficiency of retroviral-mediated gene transfer and expression in primate bone marrow progenitors after 5-fluorouracil-induced hematopoietic suppression and recovery.

To define conditions for improved efficiency of retroviral-mediated gene transfer and expression in primate progenitor cells, four rhesus monkeys were treated with a 200 mg/kg intravenous bolus of 5-fluorouracil (5-FU). The kinetics of hematopoietic suppression and recovery were assessed in peripheral blood, bone marrow mononuclear cells, and bone marrow cells fractionated in an albumin density gradient. Bone marrow mononuclear cells were transduced with N2, a retroviral vector carrying the bacterial neomycin phosphotransferase gene (NPT), which confers resistance to the otherwise toxic neomycin analogue, G418. Circulating colony-forming units-granulocyte-macrophage (CFU-GM) disappeared at 2 days. CFU-GM, transducible CFU-GM, CD34+ cells, and the percent of cells in cycle decreased at 3 days in unfractionated bone marrow cells and in a light density population known to be enriched for these progenitors and for stem cells. NPT activity in the light-density fraction, marginally detectable before treatment, disappeared at 3 days as well. At day 7 the CFU-GM plating efficiency, the CD34+ cell content, and the percentage of cells in cell cycle began to increase in the light-density fraction. The NPT assay became faintly positive again but the CFU-GM were not yet transducible, implying that it was an earlier progenitor population that was dividing and differentiating. By day 15, there was a marked rebound in all of the progenitors measured, and transduction efficiency assessed by G418R CFU-GM and NPT assay rebounded to several times pretreatment levels. The data suggest that CFU-GM are optimally transduced at 15 days but that earlier progenitors are more likely cycling and transducible before 5 days, a time when a gene transfer experiment would probably have the best chance to succeed.     

Mental health services use by elderly adults in a primary care setting

This study examined the use of general health, mental health, and other medical specialty services by elderly persons 65 and older with mental disorders and compares them with adults 45 to 64 and 18 to 44. Data were collected at the Bunker Hill Health Center (BHHC), a Boston neighborhood health center providing a broad range of ambulatory medical and specialty mental health services. Results show that the 5-year rate of mental disorder diagnoses for elderly individuals is not significantly different from persons 45 to 64, although it is higher than the rate for young adults 18 to 44. Not only were elderly adults less likely to see a mental health specialist, but when they did, their use of mental health specialty services was usually lower.