Safety and Efficacy of Oral Physostigmine in the Treatment of Alzheimer Disease

Results of therapeutic trials with physostigmine in the treatment of Alzheimer disease (AD) have been inconsistent and controversy persists concerning safety and efficacy. In a double-blind, placebo-controlled, crossover study, patients received 6 weeks of oral physostigmine (OP) and placebo in random order. Twenty-nine patients with AD received as much as 16 mg/day of OP and were assessed with neuropsychological and functional measures. No significant cardiac side effects were noted, though other systemic adverse effects were noted, requiring dose reduction in four patients. There was a slight but significant improvement (12%) in performance on the selective reminding test with physostigmine and the memory performance was correlated with dosage. This improvement compares favorably with the 15% decrease in scores seen in an untreated comparison cohort followed for an equivalent time period. There was a trend toward an improvement in communication and a reduction in memory complaint. These results suggest that oral physostigmine is safe and may improve memory in AD

Comparing substance use outcomes by sexual identity among women: Differences using propensity score methods

Background: Differences in alcohol, tobacco, and other drug (ATOD) use by sexual identity vary across samples of women recruited using different sampling methods. We used propensity score (PS) weighting methods to address two methodological questions: (1) Do disparities between sexual minority women (SMW) and heterosexual women persist when differences in risk and protective factors are similarly distributed between groups, and (2) Does accounting for SMW-specific resiliency factors impact differences between non-probability samples of SMW? Methods: Four samples included SMW from a longitudinal study with a nonprobability sample (n = 373), a national general population panel sample (n = 373), and a national LGBTQ-specific panel sample (n = 311), as well as a national probability sample of heterosexual women (n = 446). Between-groups analyses using double-robust PS weighted models estimated differences in ATOD use under hypothetical conditions in which samples have similar risk and protective factors. Results: After PS weighting, imbalance in confounders between SMW and heterosexual samples was substantially reduced, but not eliminated. In double-robust PS weighted models, SMW samples consistently had significantly greater odds of drug use than heterosexuals, with odds from 8.8 to 5.6 times greater for frequent marijuana use and 4.8–3.2 greater for other drug use. Few differences between SMW samples in ATOD outcomes or other variables remained after PS weighting. Conclusion: Relative to heterosexual women, disparities in marijuana and other drug use among SMW are evident regardless of sampling strategy. The results provide some reassurance about the validity of large nonprobability samples, which remain an important recruitment strategy in research with SMW

Development of the research lifecycle model for library services

Can the niche services of individual librarians across multiple libraries be developed into a suite of standard services available to all scientists that support the entire research lifecycle

Examining the differential protective effects of women\u27s spirituality and religiosity on alcohol and marijuana use by sexual identity

The current study explored how religiosity and spirituality may differentially influence substance use by sexual identity based on a sample of adult sexual minority women (SMW; n = 437 lesbian; n = 323 bisexual) relative to a heterosexual comparison sample (n = 636). We examined three questions: (1) whether spirituality was differentially associated with alcohol and marijuana use by sexual identity; (2) whether religiosity was differentially associated with alcohol and marijuana use by sexual identity; (3) whether observed differences between spirituality or religiosity and substance use by sexual identity persisted after adjusting for religious environment. Measures included spirituality (importance of spirituality), religiosity (importance of religion, attending religious services), and past year substance use (alcohol use disorder [AUD], any marijuana use, and regular marijuana use). Higher levels of spirituality were associated with increased odds of AUD among both lesbian and bisexual respondents relative to heterosexuals. Higher levels of religiosity among lesbian participants were associated with increased odds of AUD relative to heterosexuals with higher levels of religiosity. Consistent with theories of minority stress, findings suggest that spirituality and religiosity are less protective for SMW than heterosexual women and, in some cases, may contribute to greater risk of substance use

TaqMan real time RT-PCR assays for detecting ferret innate and adaptive immune responses

AbstractThe ferret is an excellent model for many human infectious diseases including influenza, SARS-CoV, henipavirus and pneumococcal infections. The ferret is also used to study cystic fibrosis and various cancers, as well as reproductive biology and physiology. However, the range of reagents available to measure the ferret immune response is very limited. To address this deficiency, high-throughput real time RT-PCR TaqMan assays were developed to measure the expression of fifteen immune mediators associated with the innate and adaptive immune responses (IFNα, IFNβ, IFNγ, IL1α, IL1β, IL2, IL4, IL6, IL8, IL10, IL12p40, IL17, Granzyme A, MCP1, TNFα), as well as four endogenous housekeeping genes (ATF4, HPRT, GAPDH, L32). These assays have been optimized to maximize reaction efficiency, reduce the amount of sample required (down to 1ng RNA per real time RT-PCR reaction) and to select the most appropriate housekeeping genes. Using these assays, the expression of each of the tested genes could be detected in ferret lymph node cells stimulated with mitogens or infected with influenza virus in vitro. These new tools will allow a more comprehensive analysis of the ferret immune responses following infection or in other disease states

Challenges of Virtual RDS for Recruitment of Sexual Minority Women for a Behavioral Health Study

Respondent-driven sampling (RDS) is an approach commonly used to recruit nonprobability samples of rare and hard-to-find populations. The purpose of this study was to explore the utility of phone- and web-based RDS methodology to sample sexual minority women (SMW) for participation in a telephone survey. Key features included (i) utilizing a national probability survey sample to select seeds; (ii) web-based recruitment with emailed coupons; and (iii) virtual processes for orienting, screening, and scheduling potential participants for computer-assisted telephone interviews. Rather than resulting in a large diverse sample of SMW, only a small group of randomly selected women completed the survey and agreed to recruit their peers, and very few women recruited even one participant. Only seeds from the most recent of two waves of the probability study generated new SMW recruits. Three RDS attempts to recruit SMW over several years and findings from brief qualitative interviews revealed four key challenges to successful phone- and web-based RDS with this population. First, population-based sampling precludes sampling based on participant characteristics that are often used in RDS. Second, methods that distance prospective participants from the research team may impede development of relationships, investment in the study, and motivation to participate. Third, recruitment for telephone surveys may be impeded by multiple burdens on seeds and recruits (e.g., survey length, understanding the study and RDS process). Finally, many seeds from a population-based sample may be needed, which is not generally feasible when working with a limited pool of potential seeds. This method may yield short recruitment chains, which would not meet key RDS assumptions for approximation of a probability sample. In conclusion, potential challenges to using RDS in studies with SMW, particularly those using virtual approaches, should be considered

Three dimensional optic tissue culture and process

A process for artificially producing three-dimensional optic tissue has been developed. The optic cells are cultured in a bioreactor at low shear conditions. The tissue forms normal, functional tissue organization and extracellular matrix

Modelling cross-reactivity and memory in the cellular adaptive immune response to influenza infection in the host

The cellular adaptive immune response plays a key role in resolving influenza infection. Experiments where individuals are successively infected with different strains within a short timeframe provide insight into the underlying viral dynamics and the role of a cross-reactive immune response in resolving an acute infection. We construct a mathematical model of within-host influenza viral dynamics including three possible factors which determine the strength of the cross-reactive cellular adaptive immune response: the initial naive T cell number, the avidity of the interaction between T cells and the epitopes presented by infected cells, and the epitope abundance per infected cell. Our model explains the experimentally observed shortening of a second infection when cross-reactivity is present, and shows that memory in the cellular adaptive immune response is necessary to protect against a second infection.Comment: 35 pages, 12 figure

The nuclear structural protein NuMA is a negative regulator of 53BP1 in DNA double-strand break repair

P53-binding protein 1 (53BP1) mediates DNA repair pathway choice and promotes checkpoint activation. Chromatin marks induced by DNA double-strand breaks and recognized by 53BP1 enable focal accumulation of this multifunctional repair factor at damaged chromatin. Here, we unveil an additional level of regulation of 53BP1 outside repair foci. 53BP1 movements are constrained throughout the nucleoplasm and increase in response to DNA damage. 53BP1 interacts with the structural protein NuMA, which controls 53BP1 diffusion. This interaction, and colocalization between the two proteins in vitro and in breast tissues, is reduced after DNA damage. In cell lines and breast carcinoma NuMA prevents 53BP1 accumulation at DNA breaks, and high NuMA expression predicts better patient outcomes. Manipulating NuMA expression alters PARP inhibitor sensitivity of BRCA1-null cells, end-joining activity, and immunoglobulin class switching that rely on 53BP1. We propose a mechanism involving the sequestration of 53BP1 by NuMA in the absence of DNA damage. Such a mechanism may have evolved to disable repair functions and may be a decisive factor for tumor responses to genotoxic treatments

Aldose Reductase Gene Polymorphisms and Diabetic Retinopathy Susceptibility

OBJECTIVE: Aldose reductase (ALR) is involved in diabetic microvascular damage via the polyol pathway. A recent meta-analysis found genetic variation in the ALR gene (AKR1B1) to be significantly associated with diabetic retinopathy (DR). We investigated the genetic association of AKR1B1 with DR. RESEARCH DESIGN AND METHODS: The study enrolled 909 individuals with diabetes. Participants were genotyped for an AKR1B1 (CA)n microsatellite and 14 tag single nucleotide polymorphisms, and ophthalmological assessment was performed. RESULTS: A total of 514 individuals were found to have DR. rs9640883 was significantly associated with DR (P = 0.0005). However, AKR1B1 variation was not independently associated with DR development after adjusting for relevant clinical parameters. rs9640883 was associated with duration of diabetes (P = 0.002). CONCLUSION: Many previous reports have failed to account for known risk factors for DR. The commonly reported association of AKR1B1 with DR may be due to an association of the gene with younger age at onset of diabetes.Sotoodeh Abhary, Kathryn P. Burdon, Kate J. Laurie, Stacey Thorpe, John Landers, Lucy Goold, Stewart Lake, Nikolai Petrovsky, and Jamie E. Crai