A systematic review of pharmacist-led medicines review services in New Zealand – is there equity for Māori older adults?

BackgroundPharmacist involvement in medicines reviews for older adults can improve prescribing and reduce adverse drug reactions. Māori experience poorer health outcomes than non-Māori resulting, in part, from inequitable access to and quality of medicine-related care. Despite international data showing benefit, it is unclear whether pharmacist-led medicines review services can improve outcomes for Māori older adults.ObjectiveThis systematic review aims to describe pharmacist-led medicines review services for community-dwelling adults in New Zealand, assess effectiveness of these interventions and identify their effect on health equity for Māori and older adults.MethodsThe review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses – Equity (PRISMA-E 2012). Observational studies were included. The intervention in included studies had to involve a pharmacist, occur in the outpatient setting in New Zealand, and involve review of all medicines for an individual patient. At least one patient-related outcome had to be reported.ResultsThe search identified seven observational studies with 542 total participants. Study interventions included adherence-based reviews in community pharmacies and multi-step comprehensive clinical reviews in outpatient haemodialysis units. Medicines reviews identified up to a median of 3 drug-related problems per review. The effect of interventions on medicines adherence and knowledge was not clear. Māori may have been less likely than non-Māori to benefit from improved medicines knowledge as a result of interventions. None of the studies incorporated aspects in study design or delivery to address inequities for Māori.ConclusionFurther investigation is needed to understand whether the development of culturally safe pharmacist-led medicines review services, responsive to community identified needs, can help to achieve equity in health outcomes for Māori older adults.     

Effect of Moringa oleifera lectins on survival and enzyme activities of Aedes aegypti larvae susceptible and resistant to organophosphate

The indiscriminate use of synthetic insecticides to control Aedes aegypti has led to emergence of resistant populations. Moringa oleifera seeds contain the lectins WSMoL and cMoL. WSMoL has larvicidal activity on fourth-stage of A. aegypti organophosphate-susceptible larvae (Rockefeller L₄). This study reports on the effects of cMoL on the survival of Rockefeller L₄ as well as of WSMoL and cMoL on L₄ from an organophosphate-resistant population (Rec-R). The effects of lectins on digestive (amylase, trypsin, and protease) and detoxifying (superoxide dismutase (SOD), α- and β-esterases) enzymes from larvae were also determined. cMoL (0.1–0.8 mg/ml) did not kill Rockefeller L₄ as well as WSMoL and cMoL (0.1–0.8 mg/ml) were not larvicidal for Rec-R L₄. WSMoL stimulated protease, trypsin-like, and α-amylase from Rockefeller L₄ while cMoL inhibited these enzymes. WSMoL had no effect on trypsin-like activity from Rec-R L₄ but inhibited protease and α-amylase. Among digestive enzymes of Rec-R L₄, cMoL inhibited only trypsin-like activity. cMoL inhibited SOD activities from Rockefeller and Rec-R L₄ in a higher level than WSMoL while β-esterase from Rockefeller L₄ was more inhibited by WSMoL. The lectins promoted low stimulation or inhibition of α-esterase activities from both populations. In conclusion, Rockefeller and Rec-R larvae were distinctly affected by M. oleifera lectins, and larvicidal mechanism of WSMoL on Rockefeller L₄ may involve deregulation of digestive enzymes. cMoL interfered mainly on SOD activity and thus it can be investigated as a synergistic agent for controlling populations whose resistance is linked to an increased detoxifying process mediated by this enzyme.     

Predicting type 2 diabetes mellitus using haemoglobin A1c: A community-based historic cohort study

Background: The ADA 2010 guidelines added HbA1c ≥ 6.5% as a criterion for diagnosing diabetes mellitus type 2.

Objective: To evaluate the HbA1c test in predicting type 2 diabetes in a high risk population.

Methods: A community-based historic cohort study was conducted including 10 201 patients, who had not been diagnosed with diabetes, and who underwent HbA1c test during the years 2002–2005. Data was retrieved on diabetes risk factors and the onset of diabetes (according to the ADA 2003 criteria), during a follow-up period of five-to-eight years.

Results: Mean age was 58.25 ± 15.58 years; mean HbA1c level was 5.59 ± 0.55% and 76.8% had a BMI > 25 kg/m² (mean: 30.74 ± 8.30). In a Cox proportional hazards regression model, the risk of developing type 2 diabetes was 2.49 (95% CI: 1.29–3.71) for 5.5% ≤ HbA1c < 6% at baseline, 4.82 (95% CI: 2.83–8.20) for 6% ≤ HbA1c < 6.5% at baseline and 7.57 (95% CI: 4.43–12.93) for 6.5% ≤ HbA1c < 7% at baseline, compared to HbA1c < 4.5%. The risk of developing diabetes was 1.14 (95% CI: 1.05–1.25) for male gender, 1.16 (95% CI: 1.04–1.28) for cardiovascular diseases and 2.06 (95% CI: 1.80–2.35) for overweight (BMI > 25 kg/m²) at baseline. Neither age nor low socio-economic status was associated with increased risk of diabetes.

Conclusion: Levels of HbA1c ≥ 5.5% were associated with increased risk of type 2 diabetes during a five-to-eight-year follow-up period. Findings support the use of HbA1c testing as a screening tool in populations at risk of developing diabetes.     

A novel valproic acid prodrug as an anticancer agent that enhances doxorubicin anticancer activity and protects normal cells against its toxicity in vitro and in vivo

The poor survival of patients with malignant gliomas, underscores the need to develop effective treatment modalities for this devastating disease. Epigenetic agents used in combination with chemotherapy provide a promising approach to evoke synergistic cytotoxicity in glioblastomas. Previously we have described the cytotoxic synergy between a butyric acid prodrug and radiation in glioblastoma cell lines and the potentiation of radiation efficacy in glioma xenografts. Herein, we describe and compare the activities of AN446 (valproyl ester-valpramide of acyclovir) a novel histone deacetylase inhibitor (HDACI) to the previously described AN7 a HDACI prodrug of butyric acid. In various cancer cell lines, AN446 was a ∼2–5-fold more potent anticancer agent HDACI than AN7. While AN446 augmented the anticancer efficacy of doxorubicin (Dox) it also reduced the Dox toxicity in non-cancerous cells. The interaction between AN446 and Dox in U251 and in 4T1 cell lines was synergistic in inducing cytotoxicity. We examined the concomitant physical and molecular changes in the tumor and heart of glioblastoma xenografts treated with AN446, AN7, Dox and the combination of the prodrugs with Dox. A weekly dose of 4 mg/kg Dox, caused toxicity in mice whereas AN446 (25 mg/kg) or AN7 (50 mg/kg) administered thrice weekly, did not. When Dox was administered with AN446 or AN7, the prodrugs ameliorated the decline in body weight, prolonged the time to failure and increased anticancer efficacy. Thus, the combination of Dox with AN446 or AN7 could add safety and efficacy to future treatment protocols for treating glioblastoma and other cancers.     

Glioblastoma cellular architectures are predicted through the characterization of two-cell interactions

To understand how pairwise cellular interactions influence cellular architectures, we measured the levels of functional proteins associated with EGF receptor (EGFR) signaling in pairs of U87EGFR variant III oncogene receptor cells (U87EGFRvIII) at varying cell separations. Using a thermodynamics-derived approach we analyzed the cell-separation dependence of the signaling stability, and identified that the stable steady state of EGFR signaling exists when two U87EGFRvIII cells are separated by 80–100 μm. This distance range was verified as the characteristic intercellular separation within bulk cell cultures. EGFR protein network signaling coordination for the U87EGFRvIII system was lowest at the stable state and most similar to isolated cell signaling. Measurements of cultures of less tumorigenic U87PTEN cells were then used to correctly predict that stable EGFR signaling occurs for those cells at smaller cell–cell separations. The intimate relationship between functional protein levels and cellular architectures explains the scattered nature of U87EGFRvIII cells relative to U87PTEN cells in glioblastoma multiforme tumors.Pathological analysis of tumor tissues is typically led by the analyses of cellular architectures within those tumors. Relationships between those architectures and molecular biomarkers of disease are often poorly understood. We seek to establish such a relationship, starting from physical principles. We take as an example glioblastoma multiforme (GBM) cancer cells that express the EGF receptor (EGFR) variant III oncogene receptor (EGFRvIII). Although these cells enhance tumorigenicity, invasion, and other hallmarks of cancer (1, 2), they comprise only a subpopulation of the cancer cells within an EGFRvIII+ tumor, and their distribution is diffuse (1, 3, 4). To help understand this diffuse cellular architecture, we developed an experimental–theoretical methodology based on analysis of EGFR signaling in two interacting cells. In many physical systems—from planets to atomic solids—the interactions of an element of that system with its surroundings can be understood within the context of two-body interactions. This broad observation inspired our experimental approach, which was to measure EGFR-associated signaling activity in statistically significant numbers of two EGFRvIII+ GBM cells, as a function of intercellular separation. Our theoretical approach was similarly inspired: it assumed that the resultant two-cell data sets could be interpreted using thermodynamic-like considerations.Our approach allows a determination of the stability of a phosphoprotein signaling network in two interacting cells, and demonstrates how that stability dictates the cell–cell distance distribution in a bulk culture. Using this concept we determined the most probable intercellular separation distance range within cell populations, and the deviations thereof. The available literature suggests our conclusions can be extended to bulk tumors (1).EGFR signaling plays an important role in motility and promoting tumor growth within EGFRvIII+ GBM tumors (2, 5–8). We thus hypothesized that a detailed examination of the EGFR signaling pathway, within two GBM cells at different separations, would allow a determination of a distance range that exhibited the most stable EGFR signaling. This approach assumes that cell–cell separations with the most stable EGFR signaling will appear with a higher frequency within a bulk population.Our experimental/theoretical analysis combines measurements of functional proteins, such as phosphorylated kinases, within the EGFR signaling pathway in isolated pairs of GBM cells, at varying cell separations, with surprisal analysis (9–11). Here we use surprisal analysis to determine the most balanced state of the two cells at different distance ranges. We thereby identified a steady-state separation distance between two U87EGFRvIII cells of 80–100 μm. The steady-state separation of two cells was found to correspond to the most probable distance range determined through microscopy measurements of the radial distribution function (RDF) of those same cells in bulk culture. The RDF represents the measured distributions of cell locations with respect to each other. We then turned this approach around, and used measurements of the RDF from a bulk culture of the less tumorigenic U87PTEN cells [model GBM cells expressing wild-type EGFR and the tumor suppressor phosphatase and tensin homolog (PTEN)] to identify the most probable cell–cell separation distance. Thereby we predict that the most stable cell–cell pairwise signaling in U87PTEN cells occurs at smaller cell–cell separations. Those predictions were then shown to be consistent with two-cell, functional proteomics assays.Our results may help explain the scattered distribution of EGFRvIII cells and less infiltrative nature of U87PTEN cells; furthermore, they point to an intimate relationship between cellular signaling activity, distance dependent cell–cell interactions, and cell culture architectures. The methodology demonstrated here shows how a thermodynamic-like approach, coupled with quantitative functional protein measurements, can provide information about the stability of a cellular system. This approach should be broadly applicable.     

Sexually Assaulted Males: 115 Men Consulting a Counseling Service

The nature of sexual assault on men and their help seeking following the assault was investigated. All men were seen at least once for face-to-face counseling at SURVIVORS, a counseling service for male victims. Data on 115 men were analyzed: 69 were assaulted while under age 16. Mean time from assault to contact with SURVIVORS was 16.4 years. 51 men (44%) were assaulted more than once. The assailant was known to the victim in all but 16 cases. 100 men (87%) were assaulted by at least one man, 7 (6%) by a man and a woman, and 8 (7%) by women. Forced anal penetration took place in 88. 27 men (23%) feared for their lives during the assault. 88 men (79%) sought no help and only 17 men (15%) reported to police. For victims assaulted under the age of 16, the assault was more likely to be their first sexual experience and they were more likely to delay contact with SURVIVORS for more than 17 years. They were also less likely to report to police. Victims assaulted by more than one person were more likely to have been assaulted by strangers, by women, and to have suffered physical harm. They were less likely to have experienced the assault as their first sexual experience.     

幽门螺杆菌感染与非溃疡性消化不良儿童出现的特定症状无关

背景与目的：肠腔内胆汁酸（BA）浓度对胆固醇的吸收有重要作用。该研究旨在探讨先天性BA合成障碍患儿肠腔内BA明显减少对胆固醇吸收的影响，以及在人肠内容物作用的动物模型中胆固醇增溶作用对其吸收的影响。方法：选取了5例受试，其中3β-羟-C27皮质激素脱氢酶异构酶缺乏（3-HSD）2例、△^4—3-酮固醇-5β还原酶缺乏2例、2-甲基酯酰CoA总状分支缺乏1例，观察受试在BA补充治疗及治疗停止3周后的情况。治疗期间进流食。采集十二指肠标本，分析计算胆固醇吸收及胆固醇成分的合成率。将人肠内容物注入胆汁转流大鼠的淋巴瘘模型中以评价胆固醇的微胞与囊泡吸收效果。结果：未补充BA肠内BA浓度低于必要微胞浓度（CMC），而补充BA后，所有受试肠内BA均高于CMC。未治疗组肠腔内胆固醇主要以囊泡形式转运，而治疗组则由微胞和囊泡两种形式转运。与未治疗组相比，治疗组胆固醇的吸收约增加55％（P=0．041），而其合成率则下降70％（P=0．029）。在大鼠淋巴瘘模型中，最小囊泡胆固醇被吸收，囊泡和微胞脂肪酸及磷脂也被同等吸收。     

Sexual dysfunction risk and associated factors in young Peruvian university women

IntroductionInformation regarding sexual dysfunction risk among young Latin American women is limited.AimAssess female sexual dysfunction (FSD) risk and associated factors in young Peruvian university women.MethodsThis was a nested case-control study, using the Female Sexual Function Index (FSFI). Cases were defined as women with total FSFI scores at or below 26.55 (increased FSD risk). Demographic characteristics, gynecologic aspects, body mass index, mood disorders, substance abuse, and issues related to the couple, were also evaluated.Main Outcome MeasuresPrimary end point was assessment of FSD risk and associated factors.ResultsA total of 625 women were surveyed of which 409 (65.4%) were sexually active. The average total FSFI score was 27.2 ± 4.3. Overall, 39.9% were at higher risk for FSD. Multivariate analysis using a binary logistic regression model found that male premature ejaculation (odds ratios [OR] = 2.47, 95% confidence interval [CI]: 1.27–4.77), oral emergency contraception use (OR = 1.87, 95% CI: 1.04–3.38), good partner relationship (OR = 0.24, 95% CI: 0.12–0.49), and length of relationship (≥3 years; OR = 0.025, 95% CI: 0.013–0.05) were factors independently associated to a higher FSD risk (goodness of fit P = 0.39).ConclusionIn this young university female population, FSD risk was high and associated to male and female factors. Escajadillo-Vargas N, Mezones-Holguín E, Castro-Castro J, Córdova-Marcelo W, Blümel JE, Pérez-López FR, and Chedraui P. Sexual dysfunction risk and associated factors in young Peruvian university women.     

Review: Transport of maternal cholesterol to the fetal circulation

Data obtained from recent studies in humans, rodents, and cell culture demonstrate that circulating maternal cholesterol can be transported to the fetus. The two major cell types responsible for the transport are trophoblasts and endothelial cells of the fetoplacental vasculature. Maternal lipoprotein-cholesterol is initially taken up by trophoblasts via receptor-mediated and receptor-independent processes, is transported by any number of the sterol transport proteins expressed by cells, and is effluxed or secreted out of the basal side via protein-mediated processes or by aqueous diffusion. This cholesterol is then taken up by the endothelium and effluxed to acceptors within the fetal circulation. The ability to manipulate the mass of maternal cholesterol that is taken up by the placenta and crosses to the fetus could positively impact development of fetuses affected with the Smith-Lemli-Opitz Syndrome (SLOS) that have reduced ability to synthesize cholesterol and possibly impact growth of fetuses unaffected by SLOS but with low birthweights.