An advanced pharmacy practice experience in community engagement

Objective. To implement a 5-week advanced pharmacy practice experience (APPE) in community engagement and assess the impact of the APPE on students’ confidence and ability to provide community-based services.Design. Working with community partners, students provided medication reconciliation, attended interprofessional healthcare meetings, developed health-promotion activities, and conducted medication-therapy reviews.Assessment. Responses to pre- and post-APPE 10-item surveys, preceptor and practice-experience evaluations, and the documented number of pharmacy student recommendations were determined. Conclusion. This APPE provides students opportunities in nontraditional community settings to increase their confidence and enhance their skills in health-promotion activities, medication-therapy management, and interprofessional care of patients, all of which are essential to the practice of pharmacy.     

The role of the circadian clock system in nutrition and metabolism

Mammals have an endogenous timing system in the suprachiasmatic nuclei (SCN) of the hypothalamic region of the brain. This internal clock system is composed of an intracellular feedback loop that drives the expression of molecular components and their constitutive protein products to oscillate over a period of about 24?h (hence the term 'circadian'). These circadian oscillations bring about rhythmic changes in downstream molecular pathways and physiological processes such as those involved in nutrition and metabolism. It is now emerging that the molecular components of the clock system are also found within the cells of peripheral tissues, including the gastrointestinal tract, liver and pancreas. The present review examines their role in regulating nutritional and metabolic processes. In turn, metabolic status and feeding cycles are able to feed back onto the circadian clock in the SCN and in peripheral tissues. This feedback mechanism maintains the integrity and temporal coordination between various components of the circadian clock system. Thus, alterations in environmental cues could disrupt normal clock function, which may have profound effects on the health and well-being of an individual.     

Genomic and proteomic profiling of responses to toxic metals in human lung cells

Examining global effects of toxic metals on gene expression can be useful for elucidating patterns of biological response, discovering underlying mechanisms of toxicity, and identifying candidate metal-specific genetic markers of exposure and response. Using a 1,200 gene nylon array, we examined changes in gene expression following low-dose, acute exposures of cadmium, chromium, arsenic, nickel, or mitomycin C (MMC) in BEAS-2B human bronchial epithelial cells. Total RNA was isolated from cells exposed to 3 M Cd(II) (as cadmium chloride), 10 M Cr(VI) (as sodium dichromate), 3 g/cm2 Ni(II) (as nickel subsulfide), 5 M or 50 M As(III) (as sodium arsenite), or 1 M MMC for 4 hr. Expression changes were verified at the protein level for several genes. Only a small subset of genes was differentially expressed in response to each agent: Cd, Cr, Ni, As (5 M), As (50 M), and MMC each differentially altered the expression of 25, 44, 31, 110, 65, and 16 individual genes, respectively. Few genes were commonly expressed among the various treatments. Only one gene was altered in response to all four metals (hsp90), and no gene overlapped among all five treatments. We also compared low-dose (5 M, noncytotoxic) and high-dose (50 M, cytotoxic) arsenic treatments, which surprisingly, affected expression of almost completely nonoverlapping subsets of genes, suggesting a threshold switch from a survival-based biological response at low doses to a death response at high doses.     

Preventing mental disorders in children: a public health priority

BACKGROUND: Mental disorders affect 14% of children, cause significant long-term disability and are arguably the leading health problems that Canadian children face after infancy. Treatment services alone cannot meet children's mental health needs. In addition to treatment, prevention programs hold potential to reduce the number of children with disorders in the population. Effective programs exist for preventing conduct, anxiety and depressive disorders, three of the most prevalent disorders in children. Therefore, we investigated the state of Canadian programs in comparison with prevention programs described in the literature for these three disorders. METHODS: We identified children's mental health and early child development (ECD) programs across Canada with national or provincial/territorial scope and significance and with potential relevance to mental health. We then interviewed policy-makers to determine which programs included goals related to mental health, and incorporated key features from programs known to be effective for preventing the three disorders of interest. RESULTS: No prevention programs specific to children's mental health were identified. However, 17 ECD programs incorporated generic goals related to mental health and incorporated key features seen in effective prevention programs. Only Ontario's Better Beginnings, Better Futures (BBBF) explicitly included mental health within its major program goals, incorporated multiple features seen in effective (conduct disorder) prevention programs and demonstrated positive child mental health outcomes. DISCUSSION: The lack of Canadian prevention programs specific to children's mental health is concerning. ECD programs have the potential to improve child mental health outcomes within their wider mandates. BBBF is an exemplar for such programs. However, new investments in implementing (and evaluating) programs that specifically aim to prevent mental disorders are required to improve the mental health of children in the population. Preventing children's mental disorders must be a Canadian public health priority.     

Bridging Populations—Sexual Risk Behaviors and HIV Prevalence in Clients and Partners of Female Sex Workers,Bangkok, Thailand 2007

The aim of this study is to estimate HIV prevalence and assess sexual behaviors in a high-risk and difficult-to-reach population of clients of female sex workers (FSWs). A modified variation of respondent-driven sampling was conducted among FSWs in Bangkok, where FSWs recruited 3 FSW peers, 1 client, and 1 nonpaying partner. After informed consent was obtained, participants completed a questionnaire, were HIV-tested, and were asked to return for results. Analyses were weighted to control for the design of the survey. Among 540 FSWs, 188 (35%) recruited 1 client, and 88 (16%) recruited 1 nonpaying partner. Clients’ median age was 38 years. HIV prevalence was 20% and was associated with younger age at first sexual experience [relative risk (RR) = 3.10, 95% confidence interval (CI) 1.16–8.24] and condom use during last sexual encounter with regular partner (RR = 3.97, 95% CI 1.09–14.61). Median age of nonpaying partners was 34 years, and HIV prevalence was 15.1%. There were 56 discordant FSW–client pairs and 14 discordant FSW–nonpaying partner pairs. Condom use was relatively high among discordant FSW–client pairs (90.1%) compared to discordant FSW–nonpaying partner pairs (18.7%). Results suggest that sexual partners of FSWs have a high HIV prevalence and can be a bridge for HIV transmission to other populations. Findings also highlight the importance of initiating surveillance and targeted programs for FSW partners, and demonstrate a recruitment method for hard-to-reach populations.     

Maternal smoking during pregnancy, polymorphic CYP1A1 and GSTM1, and lung-function measures in urban family children

Purpose

Understanding the interplay between genes and in-utero tobacco exposure in affecting child lung development is of great significance. In this study, we tested the hypothesis that tobacco-related lung-function reduction in children differs by maternal polymorphic genes Cytochrome P450 1A1 (CYP1A1) and Glutathione S-transferase Mu 1 (GSTM1).

Materials and methods

Data were collected among 370 children (6–10 years old, 81.6% African-Americans) and their biological mothers visiting a large children’s hospital. Study hypotheses were tested using multiple regression method.

Results

Among the study sample, 143 mothers smoked throughout pregnancy and 72 smoked on a daily basis. Spirometric measures (mean±SD) included were: forced vital capacity (FVC)=1635±431 mL, forced expiratory volume in the first 1 s (FEV₁)=1440 ±360 mL, percent FEV₁/FVC ratio=89±12, and forced expiratory flow between the 25% and 75% of FVC (FEF_25–75)=1745±603 mL. In addition to a tobacco effect on FVC (−131 mL, 95% CI: −245, −17) and FEV₁/FVC ratio (42, 95% CI: 1, 83), regression analysis controlling for covariates indicated that for the subsample of children whose mothers were CYP1A1?2A homozygous, maternal daily smoking was associated with −734 mL (95% CI: −1206, −262) reductions in FEV₁ and −825 mL (95% CI: −909, −795) reductions in FVC; reduced smoking was still associated with −590 mL (95% CI: −629, −551) reductions in FVC. For children of mothers with GSTM1 deletion, persistent daily smoking was associated with −176 mL (95% CI: −305, −47) reductions in FVC.

Discussion and conclusions

Maternal smoking during pregnancy was significantly associated with lung-function reduction in children, particularly for those whose mothers possessed the polymorphic CYP1A1*2A and GSTM1 deletion.     

The female sexual pain disorders: genital pain or sexual dysfunction?

Vaginismus and dyspareunia have been typically classified as sexual dysfunctions. In practice and research, this conceptualization has led to a focus on sexual and interpersonal issues after biological causes were excluded. Although this approach has been very useful, it has not led to significant theoretical or therapeutic progress in the last 20 years. We propose a reconceptualization of vaginismus and dyspareunia as pain disorders that interfere with sexuality rather than as sexual disorders characterized by pain. This reconceptualization focuses the clinician and researcher on the central phenomenon—pain. It also suggests new approaches to research and treatment. Data from diagnostic, etiologic, and therapeutic studies will be presented to illustrate these points.     

Discovery and Evaluation of BMS-708163, a Potent,Selective and Orally Bioavailable γ-Secretase Inhibitor

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HDAC inhibitors restore BRAF‐inhibitor sensitivity by altering PI3K and survival signalling in a subset of melanoma

Mutations in BRAF activate oncogenic MAPK signalling in almost half of cutaneous melanomas. Inhibitors of BRAF (BRAFi) and its target MEK are widely used to treat melanoma patients with BRAF mutations but unfortunately acquired resistance occurs in the majority of patients. Resistance results from mutations or non‐genomic changes that either reactivate MAPK signalling or activate other pathways that provide alternate survival and growth signalling. Here, we show the histone deacetylase inhibitor (HDACi) panobinostat overcomes BRAFi resistance in melanoma, but this is dependent on the resistant cells showing a partial response to BRAFi treatment. Using patient‐ and in vivo‐derived melanoma cell lines with acquired BRAFi resistance, we show that combined treatment with the BRAFi encorafenib and HDACi panobinostat in 2D and 3D culture systems synergistically induced caspase‐dependent apoptotic cell death. Key changes induced by HDAC inhibition included decreased PI3K pathway activity associated with a reduction in the protein level of a number of receptor tyrosine kinases, and cell line dependent upregulation of pro‐apoptotic BIM or NOXA together with reduced expression of anti‐apoptotic proteins. Independent of these changes, panobinostat reduced c‐Myc and pre‐treatment of cells with siRNA against c‐Myc reduced BRAFi/HDACi drug‐induced cell death. These results suggest that a combination of HDAC and MAPK inhibitors may play a role in treatment of melanoma where the resistance mechanisms are due to activation of MAPK‐independent pathways.