A review and meta-analysis of prostate cancer utilities.

BACKGROUND: Health-related quality of life is a key issue in prostate cancer (PC) management. The authors summarized published utilities for common health-related quality of life outcomes of PC and determined how methodological factors affect them. METHODS: In their systematic review, the authors identified 23 articles in English, providing 173 unique utilities for PC health states, each obtained from 2 to 422 respondents. Data were pooled using linear mixed-effects modeling with utilities clustered within the study, weighted by the number of respondents divided by the variance of each utility. RESULTS: In the base model, the estimated utility of the reference case (scenario of a metastatic PC patient with severe sexual symptoms, rated by non-PC patients using time tradeoff) was 0.76. Disease stage, symptom type and severity, source of utility, and scaling method were associated with utility differences of 0.10 to 0.32 (P < 0.05). Utilities from PC patients rating their own health were 0.14 higher than those from the reference case, but utilities from PC patients rating scenarios were lowest. Time tradeoff yielded the highest utilities. Computer administration yielded lower utilities than personal interview (P = 0.02). Neither the scale's high anchor nor study purpose had significant effects on utilities. CONCLUSIONS: This study provides pooled utility estimates for common PC health states and describes how clinical and methodological factors can significantly affect these values. When possible, utility estimates for a modeling application should be derived similarly. Formal data synthesis methods might be useful to researchers integrating utility data from heterogeneous sources. Further exploration of these methods for this purpose is warranted.     

Dual subcellular roles for LIS1 and dynein in radial neuronal migration in live brain tissue

During brain development, neural precursor cells migrate along radial glial fibers to populate the neocortex. RNA interference (RNAi) of the lissencephaly gene LIS1 (also known as PAFAH1b1) inhibits somal movement but not process extension of neural precursors in live brain slices. Here we report imaging of the subcellular events accompanying neural precursor migration and the effects of LIS1, cytoplasmic dynein and myosin II inhibition. Centrosomes move continuously and often far in advance of nuclei, which show extreme saltatory behavior. LIS1 and dynein RNAi inhibit centrosomal and nuclear movement independently, whereas myosin II inhibition blocks only nuclear translocation. Imaging of the microtubule end-binding protein 3 (EB3) reveals a centrosome-centered array of microtubules in live neural precursors under all conditions examined. Dynein is concentrated both at a swelling in the leading process reported to initiate each migratory cycle and in the soma. Thus, dynein pulls on the microtubule network from the swelling. The nucleus is transported along the trailing microtubules by dynein assisted by myosin II.     

Acceptability of a combination testosterone gel and depomedroxyprogesterone acetate male contraceptive regimen

BACKGROUND: Testosterone (T) gel, administered transdermally in combination with injections of depomedroxyprogesterone acetate (DMPA) every 3 months, results in effective suppression of spermatogenesis in 90% of men. Men's attitudes regarding the daily self-administration of T-gel and the impact of such a regimen on sexual function, however, are unknown. Therefore, we questioned subjects enrolled in a combination T-gel plus DMPA male contraceptive trial regarding the acceptability of T-gel for male contraception and the impact of the T-gel/DMPA regimen on sexual function and satisfaction during treatment. STUDY DESIGN: Thirty-eight healthy men, ages 18-55, were treated with T-gel (100 mg daily) + DMPA (300 mg every 3 months) for 24 weeks. Sexual function was assessed using a validated questionnaire at baseline, after 12 and 24 weeks of treatment and 12 weeks into recovery. The overall acceptability of the method and attitudes regarding the daily self-administration of T-gel were assessed by a questionnaire 12 weeks into recovery. RESULTS: Fifty percent of subjects were either satisfied or very satisfied with the T-gel-based contraceptive regimen, and 45% indicated they would use the regimen if it were commercially available. The T-gel was found to be easy to use by 76% of men, but a third of subjects felt that T-gel administration interfered with their daily routine. Sexual function was largely preserved during treatment; however, slight decreases in sexual function were noted during recovery. CONCLUSIONS: The experimental male hormonal contraceptive regimen of T-gel + DMPA is acceptable to approximately one half of study volunteers, most of whom would use the method if it were commercially available. Given its appeal to a significant proportion of men, additional studies using T-gel and DMPA for male contraception are warranted.     

Tissue-associated self-antigens containing exosomes: Role in allograft rejection

Exosomes are extracellular vesicles that express self-antigens (SAgs) and donor human leukocyte antigens. Tissue-specific exosomes can be detected in the circulation following lung, heart, kidney and islet cell transplantations. We collected serum samples from patients who had undergone lung (n?=?30), heart (n?=?8), or kidney (n?=?15) transplantations to isolate circulating exosomes. Exosome purity was analyzed by Western blot, using CD9 exosome-specific markers. Tissue-associated lung SAgs, collagen V (Col-V) and K-alpha 1 tubulin (Kα1T), heart SAgs, myosin and vimentin, and kidney SAgs, fibronectin and collagen IV (Col-IV), were identified using western blot. Lung transplant recipients diagnosed with bronchiolitis obliterans syndrome had exosomes with higher expression of Col-V (4.2-fold) and Kα1T (37.1-fold) than stable. Exosomes isolated from heart transplant recipients diagnosed with coronary artery vasculopathy had a 3.9-fold increase in myosin and a 4.7-fold increase in vimentin compared with stable. Further, Kidney transplant recipients diagnosed with transplant glomerulopathy had circulating exosomes with a 2-fold increased expression of fibronectin and 2.5-fold increase in Col-IV compared with stable. We conclude that circulating exosomes with tissue associated SAgs have the potential to be a noninvasive biomarker for allograft rejection.     

School and individual‐level characteristics are associated with children's moderate to vigorous‐intensity physical activity during school recess

Objective: The objective of this study was to identify school environmental characteristics associated with moderate to vigorous physical activity during school recess, including morning and lunch breaks. Methods: Accelerometry data, child‐level characteristics and school physical activity, policy and socio‐cultural data were collected from 408 sixth grade children (mean age 11 years) attending 27 metropolitan primary schools in Perth, Western Australia. Hierarchical modelling identified key characteristics associated with children's recess moderate to vigorous physical activity (RMVPA). Results: Nearly 40% of variability in children's RMVPA was explained by school environment and individual characteristics identified in this study. Children's higher daily RMVPA was associated with newer schools, schools with a higher number of grassed surfaces per child and fewer shaded grassed surfaces, and the physical education coordinator meeting Australian physical activity guidelines. Conclusions: Characteristics of the school physical and social environments are strongly correlated with children's MPVA during recess. Implications: The school environment is an ideal target for maximising children's physical activity during recess. Future research could examine the impact of modifying these environmental characteristics on children's school physical activity.     

Regulation of cholesterol synthesis in the hyperlipoproteinaemias. Polymorphonuclear leucocyte abnormality specific to familial type II hypercholesterolaemia.

A simple procedure has been devised to give virtually pure preparations of polymorphonuclear leucocytes. This has permitted study of the regulation of cholesterol biosynthesis at cell level. Freshly isolated cells from donors with various forms of hyperlipoproteinaemia have been shown to have very low levels of cholesterol synthesis, presumably due to high circulating levels of apoprotein-B in donor plasma [1]. The activity of the rate-limiting enzyme for cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A reductase, rapidly increases as the cells are incubated in lipoprotein-deficient medium, until, by 12 h, cells from patients heterozygous for familial type IIa hypercholesterolaemia are clearly distinguished from other hyperlipoproteinaemias. The possible significance of this finding is discussed in relation to the causation and treatment of atherosclerotic disease.     

Relapsing peritonitis in a patient undergoing continuous ambulatory peritoneal dialysis due to Corynebacterium aquaticum

Corynebacterium aquaticum was the cause of peritonitis in a 33-year-old diabetic woman on continuous ambulatory peritoneal dialysis (CAPD). This case represents the first reported instance of CAPD peritonitis due to this organism. Moreover, the organism was recovered from fibrin clots removed from dialysate bags when the patient was on antibiotic therapy. Routine cultural methods failed to reveal the organism at that time. The organism is described and key points differentiating it from similar organisms are emphasised. The world literature on C. aquaticum infections is reviewed.     

Statistical evaluation of coincident prolactin and luteinizing hormone pulses during the normal menstrual cycle

The purpose of this work was 2-fold. First, we sought to develop statistical criteria by which it could be established that the coincident occurrence of pulses of two different hormones exceeds that which would occur by chance alone, thereby suggesting that secretion of the two hormones is either coupled or controlled from a single source generator. Using computer simulations of uncoupled pulse generators operating at different frequencies, we were able to derive the appropriate statistical criteria and to apply them to achieve our second objective, to determine whether the occasional coincidence of plasma LH and serum PRL pulses that occurs throughout the menstrual cycle in normal women exceeds that which would happen by chance. The results of the computer simulations indicated that pulses emanating from two completely independent oscillators will occur coincidently at a predictable rate, despite the fact that the generator sources are not coupled; moreover, the rate of coincidence is increased when the pulse frequency of one of the source generators is increased. Using this knowledge and the statistical criteria we derived, we analyzed the coincidence of LH and PRL pulses in five normal women during their early follicular, late follicular, and midluteal phases and in another five women during their late luteal phase. We found that the number of PRL pulses that occurred coincidently with LH pulses consistently exceeded that which would be predicted if the two pulse generators were operating completely independently of one another; however, only during the late follicular and late luteal phases was the coincidence level between LH and PRL pulses sufficiently high in a sufficient number of women to conclude that there was coupling between the pulse sources. These studies suggest, first, that stringent and rigorous statistical criteria must be applied to the analysis of spontaneously coincident secretory phenomena before it can be deduced that two pulse generators are indeed coupled, and second, that the pulse generators governing the secretion of PRL and LH are probably coupled, at least during certain phases of the menstrual cycle.     

Activation and increased expression of adhesion molecules on peripheral blood lymphocytes is a mechanism for the immediate lymphocytopenia after administration of OKT3

We investigated the mechanism by which antihuman CD3 monoclonal antibodies of the isotypes IgG2a (eg, OKT3) and IgA (eg, IXA) can induce the rapid disappearance of virtually all circulating T lymphocytes. We hypothesize that upregulation of adhesion molecules on the lymphocyte membrane contributes to this effect. However, this hypothesis is difficult to test, because of the inherent lymphocytopenia and/or shifts in lymphocyte populations between intra and extra-vascular compartments. Therefore, studies in vitro were performed, as well. Analysis of peripheral blood lymphocytes isolated at several times after addition of OKT3 or IXA to whole blood of healthy individuals showed an immediate increase in the proportion of T cells expressing NKI-L16, an activation epitope on CD11a/CD18. Likewise, an increase in CD11b/CD18 expression occurred. In parallel experiments, a transiently increased adhesion of T cells to endothelial cell monolayers was observed. This adhesion could be completely blocked by anti-CD18 or anti-CD11a monoclonal antibodies and only partly by an anti-CD11b antibody. Our data indicate that upregulation of activation epitopes of CD11a/CD18, as well as increased expression of CD11b/CD18 on T lymphocytes, may result in increased adhesion of these cells to intercellular adhesion molecule-1 (ICAM-1) and ICAM-2 on vascular endothelium. This phenomenon may, at least, partly explain the rapidly occurring peripheral lymphocytopenia observed in vivo.