Potential of biofluid components to modify silver nanoparticle toxicity

Establishing realistic exposure scenarios is critical for cytotoxic investigation of silver nanoparticles (AgNP) in the gastrointestinal tract. This study investigated the potential interaction with and effect of biofluid components, namely cholic acid, deoxycholic acid and ursodeoxycholic acid, on AgNP toxicity. Two cell lines corresponding to organs related to the biofluid components were employed. These were HepG‐2 a hepatocellular carcinoma derived from liver tissue and Hep2 an epithelial cell line. Physiochemical and cytotoxic screening was performed and the ability of biofluid components to modify AgNP cytotoxicity was explored. No alteration to the physiochemical characteristics of AgNP by biofluid components was demonstrated. However, biofluid component addition resulted in alteration of AgNP toxicity. Greater reactive oxygen species induction was noted in the presence of cholic acid and deoxycholic acid. Ursodeoxycholic acid demonstrated no modification of toxicity in HepG‐2 cells; however, significant modification was noted in Hep2 cells. It is concluded that biofluid components can modify AgNP toxicity but this is dependent on the biofluid component itself and the location where it acts. Copyright © 2015 John Wiley & Sons, Ltd.     

A systematic review and meta-analysis of thiazide-induced hyponatraemia: time to reconsider electrolyte monitoring regimens after thiazide initiation?

AIMS

Hyponatraemia is one of the major adverse effects of thiazide and thiazide-like diuretics and the leading cause of drug-induced hyponatraemia requiring hospital admission. We sought to review and analyze all published cases of this important condition.

METHODS

Ovid Medline, Embase, Web of Science and PubMed electronic databases were searched to identify all relevant articles published before October 2013. A proportions meta-analysis was undertaken.

RESULTS

One hundred and two articles were identified of which 49 were single patient case reports. Meta-analysis showed that mean age was 75 (95% CI 73, 77) years, 79% were women (95% CI 74, 82) and mean body mass index was 25 (95% CI 20, 30) kg m⁻². Presentation with thiazide-induced hyponatraemia occurred a mean of 19 (95% CI 8, 30) days after starting treatment, with mean trough serum sodium concentration of 116 (95% CI 113, 120) mm and serum potassium of 3.3 (95% CI 3.0, 3.5) mm. Mean urinary sodium concentration was 64 mm (95% CI 47, 81). The most frequently reported drugs were hydrochlorothiazide, indapamide and bendroflumethiazide.

CONCLUSIONS

Patients with thiazide-induced hyponatraemia were characterized by advanced age, female gender, inappropriate saliuresis and mild hypokalaemia. Low BMI was not found to be a significant risk factor, despite previous suggestions. The time from thiazide initiation to presentation with hyponatraemia suggests that the recommended practice of performing a single investigation of serum biochemistry 7–14 days after thiazide initiation may be insufficient or suboptimal. Further larger and more systematic studies of thiazide-induced hyponatraemia are required.     

A putative biomarker signature for clinically effective AKT inhibition: correlation of in vitro,in vivo and clinical data identifies the importance of modulation of the mTORC1 pathway

Our identification of dysregulation of the AKT pathway in ovarian cancer as a platinum resistance specific event led to a comprehensive analysis of in vitro, in vivo and clinical behaviour of the AKT inhibitor GSK2141795. Proteomic biomarker signatures correlating with effects of GSK2141795 were developed using in vitro and in vivo models, well characterised for related molecular, phenotypic and imaging endpoints. Signatures were validated in temporally paired biopsies from patients treated with GSK2141795 in a clinical study. GSK2141795 caused growth-arrest as single agent in vitro, enhanced cisplatin-induced apoptosis in vitro and reduced tumour volume in combination with platinum in vivo. GSK2141795 treatment in vitro and in vivo resulted in ~50-90% decrease in phospho-PRAS40 and 20-80% decrease in fluoro-deoxyglucose (FDG) uptake. Proteomic analysis of GSK2141795 in vitro and in vivo identified a signature of pathway inhibition including changes in AKT and p38 phosphorylation and total Bim, IGF1R, AR and YB1 levels. In patient biopsies, prior to treatment with GSK2141795 in a phase 1 clinical trial, this signature was predictive of post-treatment changes in the response marker CA125. Development of this signature represents an opportunity to demonstrate the clinical importance of AKT inhibition for re-sensitisation of platinum resistant ovarian cancer to platinum.     

Rosiglitazone improves insulin sensitivity and lowers blood pressure in hypertensive patients

OBJECTIVE: To examine the effect of rosiglitazone on insulin resistance and blood pressure in patients with essential hypertension, classified based on abnormalities of their renin-angiotensin system. RESEARCH DESIGN AND METHODS: A total of 24 hypertensive nondiabetic patients (age 58 +/- 6 years, BMI 30 +/- 5 kg/m2) were studied before and after rosiglitazone treatment. After 2 weeks off antihypertensive medication, subjects received a euglycemic-hyperinsulinemic clamp (40 mU. m(-2). min(-1)) with 6,6-[2H2]glucose infusion, ambulatory blood pressure monitoring, and blood tests for cardiovascular risk factors. Subjects were then placed on rosiglitazone (4 mg orally b.i.d.) and their usual antihypertensive medications (but not ACE inhibitors) for 16 weeks, and baseline tests were repeated. RESULTS: There was no change in fasting plasma glucose (83 +/- 2 vs. 82 +/- 2 mg/dl, P = 0.60), but fasting insulin decreased (16.1 +/- 1.4 vs. 12.5 +/- 0.9 micro U/ml, P < 0.01). Total glucose disposal during the clamp increased (5.0 +/- 0.4 vs. 5.9 +/- 0.5 mg. kg(-1). min(-1), P < 0.001), with no change in suppression of hepatic glucose output. There were significant decreases in mean 24-h systolic (138 +/- 2 vs. 134 +/- 2 mmHg, P < 0.02) and diastolic (85 +/- 2 vs. 80 +/- 2 mmHg, P < 0.0001) blood pressure, and the decline in systolic blood pressure was correlated with the improvement in insulin sensitivity (r = 0.59, P < 0.005). Triglycerides (135 +/- 16 vs. 89 +/- 8 mg/dl, P < 0.01), LDL cholesterol (129 +/- 6 vs. 122 +/- 8 mg/dl, P = 0.18), and HDL cholesterol (51 +/- 3 vs. 46 +/- 3 mg/dl, P < 0.02) all decreased, with no change in the LDL-to-HDL ratio. Plasminogen activator inhibitor-1 and C-reactive protein also declined significantly. CONCLUSIONS: Rosiglitazone treatment of nondiabetic hypertensive patients improves insulin sensitivity, reduces systolic and diastolic blood pressure, and induces favorable changes in markers of cardiovascular risk. Insulin sensitizers may provide cardiovascular benefits when used in the treatment of patients with hypertension.     

Importance and hurdles to drug discovery for neurological disease

This is a critical time in neurotherapeutics. The prevalence of neurological disease, such as dementia, stroke, and peripheral neuropathy, is large and growing consequent to the aging population. The personal and societal impact of these disorders is enormous, and the number of novel therapies in the pipeline for these disorders has been contracting. Support for the development of neurotherapies must continue from the bench to their ultimate place at the bedside. Academic medicine must continue to play a critical role, in league with industry and government, in the development of novel neurotherapies desperately needed by an ever‐expanding population. Critical steps include the identification and adoption of reliable, valid, and reproducible biomarkers to serve as primary endpoints in clinical trials of neurological disease. Ann Neurol 2013;74:441–446     

Immunological Relationship between Serum Globulins of Man and of Other Primates, Revealed by a Serological Inhibition Test

By a quantitative inhibition technic chimpanzee serum reacted to almost the same titer as human serum with rabbit anti-human immune serum; gorilla serum reacted in considerably lower titer, while serum from gibbons, orangutans and monkeys gave little or no inhibition. Thus, this test for serum gamma globulin indicates that among non-human primates, chimpanzee is most similar to man. Gorilla is next, while sera of other apes and monkeys show little or no crossreactivity.     

Motor learning of a bimanual task in children with unilateral cerebral palsy

Children with unilateral cerebral palsy (CP) have been shown to improve their motor performance with sufficient practice. However, little is known about how they learn goal-oriented tasks. In the current study, 21 children with unilateral CP (age 4–10 years old) and 21 age-matched typically developed children (TDC) practiced a simple bimanual speed stack task over 15 days of practice. Both groups demonstrated their ability to learn the current bimanual task, but their rate of improvement and learning pattern differed. Children with unilateral CP overall were slower and improved ~10% less than TDC. Most of the improvement occurred during the first 3 days for the TDC, whereas performance did not plateau until 6–8 days for the children with unilateral CP. This initial slower learning rate for children with unilateral CP was also confirmed by better fitting of the curve to an exponential function than the power law function (p < 0.05). Therefore, when working with children with unilateral CP, sufficient practice is important (two to three times more than for TDC), and delayed improvement is expected.     

女性护理专业学生心理健康相关因素分析

目的:分析护理专业学生心理健康的影响因素。方法:于2005-12-01/15按整群抽样法抽取西安市高校在读的护理专业学生515名作为被调查对象。症状自评量表总分≥187为高分组,总分≤116为低分组。高分组与低分组配比的条件是均为女性,年龄相差不超过3岁。采用症状自评量表、简易应对方式问卷、自尊量表、护理专业学生相关状况调查表进行问卷调查。对调查变量进行单因素和多因素Logistic回归分析。结果:共发放问卷515份,其中2名学生生病未填写调查表,应答率为99.6%。调查中有效问卷共507份,有效率为98.8%。症状自评量表总分高分组与低分组学生各100名。①护理专业学生心理健康相关个人因素(计量变量)单因素分析结果:高分组积极应对、自尊水平得分明显低于低分组(20.47±5.02,22.15±6.02;25.91±3.60,30.96±3.25),差异有显著性意义(P<0.05,P<0.01)。高分组消极应对得分明显高于低分组(12.57±4.08,8.00±4.12),差异有显著性意义(P<0.01)。②护理专业学生心理健康相关个人因素(二分类变量)单因素分析结果表明,高分组与低分组比较差异有显著性的因素有独生子女、远离家人、孤独、学习压力大、担心拿不到学位、自我实现需要的满足、经常被人误会、受人歧视、失恋、有知心朋友、无处倾诉苦恼、睡眠型态紊乱、近1年来本人健康改变、适应新环境、经常参加体育活动、担心毕业分配、现有最担心的事情。③多因素分析显示,学习压力大(OR=10.017)、近1年来本人健康改变(OR=4.384)为护理专业学生心理健康状况不良的独立危险因素,而自我实现需要的满足(OR=0.037)、高水平自尊(OR=0.357)是保护因素。结论:护理专业学生心理健康状况与教育、成长、社会环境等多方面因素相关,其心理健康干预需考虑学生的个人因素有针对性地进行。