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Determining Menstrual Phase in Human Biobehavioral Research: A Review With Recommendations. - Experimental and clinical psychopharmacology
Given the volume and importance of research focusing on menstrual phase, a review of the strategies being used to identify menstrual phase and recommendations that will promote methodological uniformity in the field is needed. We conducted a literature review via Ovid Medline and PsycINFO. Our goal was to review methods used to identify menstrual phase and subphases in biobehavioral research studies with women who had physiologically natural menstrual cycles. Therefore, we excluded articles that focused on any of the following: use of exogenous hormones, the postpartum period, menstrual-related problems (e.g., polycystic ovarian syndrome, endometriosis), and infertility/anovulation. We also excluded articles on either younger (<18 years old) or older (>45 years old) study samples. We initially identified a total of 1,809 articles. After our exclusionary criteria were applied, 146 articles remained, within which our review identified 6 different methods used to identify menstrual phase and subphases. The most common method used was self-report of onset of menses (145/146 articles) followed by urine luteinizing hormone testing (50/146 articles) and measurement of hormones (estradiol and/or progesterone) in blood samples (49/146 articles). Overall, we found a lack of consistency in the methodology used to determine menstrual phase and subphases. We provide several options to improve accuracy of phase identification, as well as to minimize costs and burden. Adoption of these recommendations will decrease misclassification within individual studies, facilitate cross-study comparisons, and enhance the reproducibility of results. (PsycINFO Database Record(c) 2015 APA, all rights reserved).
Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. - Lancet (London, England)
The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the first of a series of annual updates of the GBD. Risk factor quantification, particularly of modifiable risk factors, can help to identify emerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution.Attributable deaths, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs) have been estimated for 79 risks or clusters of risks using the GBD 2010 methods. Risk-outcome pairs meeting explicit evidence criteria were assessed for 188 countries for the period 1990-2013 by age and sex using three inputs: risk exposure, relative risks, and the theoretical minimum risk exposure level (TMREL). Risks are organised into a hierarchy with blocks of behavioural, environmental and occupational, and metabolic risks at the first level of the hierarchy. The next level in the hierarchy includes nine clusters of related risks and two individual risks, with more detail provided at levels 3 and 4 of the hierarchy. Compared with GBD 2010, six new risk factors have been added: handwashing practices, occupational exposure to trichloroethylene, childhood wasting, childhood stunting, unsafe sex, and low glomerular filtration rate. For most risks, data for exposure were synthesised with a Bayesian meta-regression method, DisMod-MR 2.0, or spatial-temporal Gaussian process regression. Relative risks were based on meta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all risks combined took into account evidence on the mediation of some risks such as high body-mass index (BMI) through other risks such as high systolic blood pressure and high cholesterol.All risks combined account for 57Â·2% (95% uncertainty interval [UI] 55Â·8-58Â·5) of deaths and 41Â·6% (40Â·1-43Â·0) of DALYs. Risks quantified account for 87Â·9% (86Â·5-89Â·3) of cardiovascular disease DALYs, ranging to a low of 0% for neonatal disorders and neglected tropical diseases and malaria. In terms of global DALYs in 2013, six risks or clusters of risks each caused more than 5% of DALYs: dietary risks accounting for 11Â·3 million deaths and 241Â·4 million DALYs, high systolic blood pressure for 10Â·4 million deaths and 208Â·1 million DALYs, child and maternal malnutrition for 1Â·7 million deaths and 176Â·9 million DALYs, tobacco smoke for 6Â·1 million deaths and 143Â·5 million DALYs, air pollution for 5Â·5 million deaths and 141Â·5 million DALYs, and high BMI for 4Â·4 million deaths and 134Â·0 million DALYs. Risk factor patterns vary across regions and countries and with time. In sub-Saharan Africa, the leading risk factors are child and maternal malnutrition, unsafe sex, and unsafe water, sanitation, and handwashing. In women, in nearly all countries in the Americas, north Africa, and the Middle East, and in many other high-income countries, high BMI is the leading risk factor, with high systolic blood pressure as the leading risk in most of Central and Eastern Europe and south and east Asia. For men, high systolic blood pressure or tobacco use are the leading risks in nearly all high-income countries, in north Africa and the Middle East, Europe, and Asia. For men and women, unsafe sex is the leading risk in a corridor from Kenya to South Africa.Behavioural, environmental and occupational, and metabolic risks can explain half of global mortality and more than one-third of global DALYs providing many opportunities for prevention. Of the larger risks, the attributable burden of high BMI has increased in the past 23 years. In view of the prominence of behavioural risk factors, behavioural and social science research on interventions for these risks should be strengthened. Many prevention and primary care policy options are available now to act on key risks.Bill & Melinda Gates Foundation.Copyright Â© 2015 Elsevier Ltd. All rights reserved.
Systematic and meta-analytic review of research examining the impact of menstrual cycle phase and ovarian hormones on smoking and cessation. - Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco
To determine the effect of ovarian hormones on smoking, we conducted a systematic review of menstrual cycle effects on smoking (i.e., ad lib smoking, smoking topography, and subjective effects) and cessation-related behaviors (i.e., cessation, withdrawal, tonic craving, and cue-induced craving).Thirty-six papers were identified on MEDLINE that included a menstrual-related search term (e.g., menstrual cycle, ovarian hormones), a smoking-related search term (e.g., smoking, nicotine), and met all inclusion criteria. Thirty-two studies examined menstrual phase, 1 study measured hormone levels, and 3 studies administered progesterone.Sufficient data were available to conduct meta-analyses for only 2 of the 7 variables: withdrawal and tonic craving. Women reported greater withdrawal during the luteal phase than during the follicular phase, and there was a nonsignificant trend for greater tonic craving in the luteal phase. Progesterone administration was associated with decreased positive and increased negative subjective effects of nicotine. Studies of menstrual phase effects on the other outcome variables were either small in number or yielded mixed outcomes.The impact of menstrual cycle phase on smoking behavior and cessation is complicated, and insufficient research is available upon which to conduct meta-analyses on most smoking outcomes. Future progress will require collecting ovarian hormone levels to more precisely quantify the impact of dynamic changes in hormone levels through the cycle on smoking behavior. Clarifying the relationship between hormones and smoking-particularly related to quitting, relapse, and medication response-could determine the best type and timing of interventions to improve quit rates for women.Â© The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: firstname.lastname@example.org.
Protease nexin 1 induces apoptosis of prostate tumor cells through inhibition of X-chromosome-linked inhibitor of apoptosis protein. - Oncotarget
Protease nexin 1 (PN1) is an endogenous serine protease inhibitor (SERPIN), expressed at high levels in the prostate, and capable of inhibiting the proliferation of prostate cancer cells. We previously showed that PN1-uPA complexes inhibited Sonic Hedgehog (SHH) signalling through engagement of the LRP receptor. Here, we describe an alternative anti-proliferative mechanism through which PN1 expression leads to apoptosis. In prostate cancer cells, increased expression of PN1 led to substantial reduction of XIAP levels and apoptosis mediated through the uPAR, but not the LRP receptor. The alterations in XIAP were effected in two ways 1) via alteration in the NF-ÎºB pathway, a pathway known to signal XIAP transcription and 2) by promoting XIAP instability. The AKT pathway is known to phosphorylate XIAP at serine 87 leading to protein stability and PN1 expression is shown to interfere with this process. As a result of both mechanisms, programmed cell death is substantially increased. Consistent with these observations, reduced PN1 protein correlated with elevated p65/XIAP expression and with higher Gleason scores in human prostate tissue arrays. Thus, PN1 expression appears to differentially down-regulate distinct oncogenic pathways depending upon the cell surface receptor engaged by its complexes and demonstrates a novel molecular mechanism by which the protein can promote tumor cell apoptosis.
Protease nexin 1 inhibits hedgehog signaling in prostate adenocarcinoma. - The Journal of clinical investigation
Prostate adenocarcinoma (CaP) patients are classified into low-, intermediate-, and high-risk groups that reflect relative survival categories. While there are accepted treatment regimens for low- and high-risk patients, intermediate-risk patients pose a clinical dilemma, as treatment outcomes are highly variable for these individuals. A better understanding of the factors that regulate the progression of CaP is required to delineate risk. For example, aberrant activation of the Hedgehog (Hh) pathway is implicated in CaP progression. Here, we identify the serine protease inhibitor protease nexin 1 (PN1) as a negative regulator of Hh signaling in prostate. Using human CaP cell lines and a mouse xenograft model of CaP, we demonstrate that PN1 regulates Hh signaling by decreasing protein levels of the Hh ligand Sonic (SHH) and its downstream effectors. Furthermore, we show that SHH expression enhanced tumor growth while overexpression of PN1 inhibited tumor growth and angiogenesis in mice. Finally, using comparative genome hybridization, we found that genetic alterations in Hh pathway genes correlated with worse clinical outcomes in intermediate-risk CaP patients, indicating the importance of this pathway in CaP.
Novel late-onset Alzheimer disease loci variants associate with brain gene expression. - Neurology
Recent genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) identified 9 novel risk loci. Discovery of functional variants within genes at these loci is required to confirm their role in Alzheimer disease (AD). Single nucleotide polymorphisms that influence gene expression (eSNPs) constitute an important class of functional variants. We therefore investigated the influence of the novel LOAD risk loci on human brain gene expression.We measured gene expression levels in the cerebellum and temporal cortex of autopsied AD subjects and those with other brain pathologies (âˆ¼400 total subjects). To determine whether any of the novel LOAD risk variants are eSNPs, we tested their cis-association with expression of 6 nearby LOAD candidate genes detectable in human brain (ABCA7, BIN1, CLU, MS4A4A, MS4A6A, PICALM) and an additional 13 genes Â±100 kb of these SNPs. To identify additional eSNPs that influence brain gene expression levels of the novel candidate LOAD genes, we identified SNPs Â±100 kb of their location and tested for cis-associations.CLU rs11136000 (p = 7.81 Ã— 10(-4)) and MS4A4A rs2304933/rs2304935 (p = 1.48 Ã— 10(-4)-1.86 Ã— 10(-4)) significantly influence temporal cortex expression levels of these genes. The LOAD-protective CLU and risky MS4A4A locus alleles associate with higher brain levels of these genes. There are other cis-variants that significantly influence brain expression of CLU and ABCA7 (p = 4.01 Ã— 10(-5)-9.09 Ã— 10(-9)), some of which also associate with AD risk (p = 2.64 Ã— 10(-2)-6.25 Ã— 10(-5)).CLU and MS4A4A eSNPs may at least partly explain the LOAD risk association at these loci. CLU and ABCA7 may harbor additional strong eSNPs. These results have implications in the search for functional variants at the novel LOAD risk loci.
Brain expression genome-wide association study (eGWAS) identifies human disease-associated variants. - PLoS genetics
Genetic variants that modify brain gene expression may also influence risk for human diseases. We measured expression levels of 24,526 transcripts in brain samples from the cerebellum and temporal cortex of autopsied subjects with Alzheimer's disease (AD, cerebellar n=197, temporal cortex n=202) and with other brain pathologies (non-AD, cerebellar n=177, temporal cortex n=197). We conducted an expression genome-wide association study (eGWAS) using 213,528 cisSNPs within Â± 100 kb of the tested transcripts. We identified 2,980 cerebellar cisSNP/transcript level associations (2,596 unique cisSNPs) significant in both ADs and non-ADs (q<0.05, p=7.70 Ã— 10(-5)-1.67 Ã— 10(-82)). Of these, 2,089 were also significant in the temporal cortex (p=1.85 Ã— 10(-5)-1.70 Ã— 10(-141)). The top cerebellar cisSNPs had 2.4-fold enrichment for human disease-associated variants (p<10(-6)). We identified novel cisSNP/transcript associations for human disease-associated variants, including progressive supranuclear palsy SLCO1A2/rs11568563, Parkinson's disease (PD) MMRN1/rs6532197, Paget's disease OPTN/rs1561570; and we confirmed others, including PD MAPT/rs242557, systemic lupus erythematosus and ulcerative colitis IRF5/rs4728142, and type 1 diabetes mellitus RPS26/rs1701704. In our eGWAS, there was 2.9-3.3 fold enrichment (p<10(-6)) of significant cisSNPs with suggestive AD-risk association (p<10(-3)) in the Alzheimer's Disease Genetics Consortium GWAS. These results demonstrate the significant contributions of genetic factors to human brain gene expression, which are reliably detected across different brain regions and pathologies. The significant enrichment of brain cisSNPs among disease-associated variants advocates gene expression changes as a mechanism for many central nervous system (CNS) and non-CNS diseases. Combined assessment of expression and disease GWAS may provide complementary information in discovery of human disease variants with functional implications. Our findings have implications for the design and interpretation of eGWAS in general and the use of brain expression quantitative trait loci in the study of human disease genetics.
Is main operating room sterility really necessary in carpal tunnel surgery? A multicenter prospective study of minor procedure room field sterility surgery. - Hand (New York, N.Y.)
Over 70% of Canadian carpal tunnel syndrome (CTS) operations are performed outside of the main operating room (OR) with field sterility and surgeon-administered pure local anesthesia [LeBlanc et al., Hand 2(4):173-8, 14]. Is main OR sterility necessary to avoid infection for this operation? This study evaluates the infection rate in carpal tunnel release (CTR) using minor procedure room field sterility.This is a multicenter prospective study reporting the rate of infection in CTR performed in minor procedure room setting using field sterility. Field sterility means prepping of the hand with iodine or chlorhexidine, equivalent of a single drape, and a sterile tray with modest instruments. Sterile gloves and masks are used, but surgeons are not gowned. No prophylactic antibiotics are given.One thousand five hundred four consecutive CTS cases were collected from January 2008 to January 2010. Six superficial infections were reported and four of those patients received oral antibiotics. No deep postoperative wound infection was encountered, and no patient required admission to hospital, incision and drainage, or intravenous antibiotics.A superficial infection rate of 0.4% and a deep infection rate of 0% following CTR using field sterility confirm the low incidence of postoperative wound infection using field sterility. This supports the safety and low incidence of postoperative wound infection in CTR using minor procedure field sterility without prophylactic antibiotics. The higher monetary and environmental costs of main OR sterility are not justified on the basis of infection for CTR cases.
The efficacy of a brief intervention in reducing hazardous drinking in working age men in Russia: the HIM (Health for Izhevsk men) individually randomised parallel group exploratory trial. - Trials
Russia has particularly low life expectancy for an industrialised country, with mortality at working ages having fluctuated dramatically over the past few decades, particularly among men. Alcohol has been identified as the most likely cause of these temporal variations. One approach to reducing the alcohol problem in Russia is 'brief interventions' which seek to change views of the personal acceptability of excessive drinking and to encourage self-directed behaviour change. Very few studies to evaluate the efficacy of brief interventions in Russia have been conducted. Motivational Interviewing (MI) is a person-centred counselling style which can be adapted to brief interventions in which help is offered in thinking through behaviour in the context of values and goals, to decide whether change is needed, and if so, how it may best be achieved.This paper reports on an individually randomised two-armed parallel group exploratory trial. The primary hypothesis is that a brief adaptation of MI will be effective in reducing self-reported hazardous and harmful drinking at 3 months. Participants were drawn from the Izhevsk Family Study II, with eligibility determined based on proxy reports of hazardous and harmful drinking in the past year. All participants underwent a health check, with MI subsequently delivered to those in the intervention arm. Signed consent was obtained from those in the intervention arm only at this point. Both groups were then invited for 3 and 12 month follow ups. The control group did not receive any additional intervention.441 men were randomised. Of these 61 did not have a health check leaving 190 in each trial arm. Follow up at 3 months was high (97% of those having a health check), and very similar in the two trial arms (183 in the intervention and 187 in the control). No significant differences were detected between the randomised groups in either the primary or the secondary outcomes at three months in the intention to treat analyses. The unadjusted odds ratio (95% CI) for the effect of MI on hazardous and harmful drinking was 0.77 (0.51, 1.16). An adjusted odds ratio of 0.52 (0.28, 0.94) was obtained in the pre-specified per protocol analysis.This trial demonstrates that it is possible to engage Russian men who drink hazardously in a brief intervention aimed at reducing alcohol related harm. However the results with respect to the efficacy are equivocal and further, larger-scale trials are warranted.ISRCTN: ISRCTN82405938.
Seasonal reproduction in wild and captive male koala (Phascolarctos cinereus) populations in south-east Queensland. - Reproduction, fertility, and development
The effects of breeding season (late spring to early autumn) on south-east Queensland male koala fertility were examined to improve the efficacy of the AI procedure and to determine the practicality of using free-range animals as semen donors for a genome resource bank. Seasonal changes in male koala reproductive function were assessed in a wild free-range population (n = 14; obtained every 6 weeks from January to November 2005), a necropsied healthy wild population (n = 84; obtained monthly from September 2004 to August 2005) and a captive population (n = 7; obtained monthly from October 2005 to October 2006). Reproductive parameters investigated included bodyweight, coat score, sternal gland area and activity, testosterone secretion, reproductive anatomy volume and semen quality (before and after cryopreservation). Collectively, these findings show that reproduction in male koalas from south-east Queensland changes seasonally and that winter appears to be the optimal season in which to collect semen samples by electroejaculation. While it was possible to repeatedly collect semen from free-range koalas for future genetic management via potential storage in a genome resource bank, the survival of these spermatozoa after cryopreservation was poor and will require further improvement.
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