Circulating MicroRNA Levels Indicate Platelet and Leukocyte Activation in Endotoxemia Despite Platelet P2Y12 Inhibition

There is evidence for the effects of platelet inhibition on innate immune activation. Circulating microRNAs (miRNAs) have been implicated as markers of platelet and leukocyte activation. In the present study, we assessed the effects of P2Y12 inhibitors on platelet and leukocyte miRNAs during endotoxemia. Healthy volunteers were randomly assigned to receive oral ticagrelor (n = 10), clopidogrel (n = 8) or no drug (n = 8) for one week, followed by an intravenous bolus of 2 ng/kg endotoxin. Serum was collected at baseline, after one week of antiplatelet treatment and 6 and 24 h after endotoxin administration. MiRNAs were screened using LNA-based qPCR, followed by TaqMan-qPCR validation of candidates. Clinical validation was performed in 41 sepsis patients. Platelet-enriched miR-197, miR-223 and miR-223* were decreased in volunteers following antiplatelet therapy. Endotoxin increased platelet miRNAs, whilst the opposite effect was seen for leukocyte-enriched miR-150. Neither of these endotoxin-mediated effects were altered by P2Y12 inhibitors. Sepsis patients with fatal outcomes (n = 12) had reduced miR-150 levels compared with survivors (n = 29). In conclusion, we show that miR-150 is downregulated in experimental endotoxemia and can predict survival in sepsis but is unaffected by P2Y12 inhibition. While P2Y12 inhibition reduces platelet-associated miRNAs in healthy volunteers, it fails to attenuate the response of platelet miRNAs to endotoxemia

Pharmacodynamic Effects of a 6-Hour Regimen of Enoxaparin in Patients Undergoing Primary Percutaneous Coronary Intervention (PENNY PCI Study)

Delayed onset of action of oral P2Y₁₂ inhibitors in ST-elevation myocardial infarction (STEMI) patients may increase the risk of acute stent thrombosis. Available parenteral anti-thrombotic strategies, to deal with this issue, are limited by added cost and increased risk of bleeding. We investigated the pharmacodynamic effects of a novel regimen of enoxaparin in STEMI patients undergoing primary percutaneous coronary intervention (PPCI). Twenty patients were recruited to receive 0.75 mg/kg bolus of enoxaparin (pre-PPCI) followed by infusion of enoxaparin 0.75 mg/kg/6 h. At four time points (pre-anti-coagulation, end of PPCI, 2–3 hours into infusion and at the end of infusion), anti-Xa levels were determined using chromogenic assays, fibrin clots were assessed by turbidimetric analysis and platelet P2Y₁₂ inhibition was determined by VerifyNow P2Y₁₂ assay. Clinical outcomes were determined 14 hours after enoxaparin initiation. Nineteen of 20 patients completed the enoxaparin regimen; one patient, who developed no-reflow phenomenon, was switched to tirofiban after the enoxaparin bolus. All received ticagrelor 180 mg before angiography. Mean (± standard error of the mean) anti-Xa levels were sustained during enoxaparin infusion (1.17 ± 0.06 IU/mL at the end of PPCI and 1.003 ± 0.06 IU/mL at 6 hours), resulting in prolonged fibrin clot lag time and increased lysis potential. Onset of platelet P2Y₁₂ inhibition was delayed in opiate-treated patients. No patients had thrombotic or bleeding complications. In conclusion, enoxaparin 0.75 mg/kg bolus followed by 0.75 mg/kg/6 h provides sustained anti-Xa levels in PPCI patients. This may protect from acute stent thrombosis in opiate-treated PPCI patients who frequently have delayed onset of oral P2Y₁₂ inhibition

Longevity in mice: is stress resistance a common factor?

A positive relationship between stress resistance and longevity has been reported in a multitude of studies in organisms ranging from yeast to mice. Several mouse lines have been discovered or developed that exhibit extended longevities when compared with normal, wild-type mice of the same genetic background. These long-living lines include the Ames dwarf, Snell dwarf, growth hormone receptor knockout (Laron dwarf), IGF-1 receptor heterozygote, Little, α-MUPA knockout, p66shc knockout, FIRKO, mClk-1 heterozygote, thioredoxin transgenic, and most recently the Klotho transgenic mouse. These mice are described in terms of the reported extended lifespans and studies involving resistance to stress. In addition, caloric restriction (CR) and stress resistance are briefly addressed for comparison with genetically altered mice. Although many of the long-living mice have GH/IGF-1/insulin signaling-related alterations and enhanced stress resistance, there are some that exhibit life extension without an obvious link to this hormone pathway. Resistance to oxidative stress is by far the most common system studied in long-living mice, but there is evidence of enhancement of resistance in other systems as well. The differences in stress resistance between long-living mutant and normal mice result from complex interrelationships among pathways that appear to coordinate signals of growth and metabolism, and subsequently result in differences in lifespan

An instrument to measure job satisfaction of nursing home administrators

BACKGROUND: The psychometric properties of the nursing home administrator job satisfaction questionnaire (NHA-JSQ) are presented, and the steps used to develop this instrument. METHODS: The NHA-JSQ subscales were developed from pilot survey activities with 93 administrators, content analysis, and a research panel. The resulting survey was sent to 1,000 nursing home administrators. Factor analyses were used to determine the psychometric properties of the instrument. RESULTS: Of the 1,000 surveys mailed, 721 usable surveys were returned (72 percent response rate). The factor analyses show that the items were representative of six underlying factors (i.e., coworkers, work demands, work content, work load, work skills, and rewards). CONCLUSION: The NHA-JSQ represents a short, psychometrically sound job satisfaction instrument for use in nursing homes

Association between the metabolic syndrome and its components and gait speed among U.S. adults aged 50 years and older: a cross-sectional analysis

BACKGROUND: To examine the relationship between the metabolic syndrome and its components and gait speed among older U.S. men and women. Whether these associations are independent of physical activity was also explored. METHODS: Eight hundred and thirty-five men and 850 women aged ≥50 years from the continuous National Health and Nutrition Examination Survey 1999–2002 were examined. We used the definition of the metabolic syndrome developed by the U.S. National Cholesterol Education Program Adult Treatment Panel III. Gait speed was measured with a 6.10-meter timed walk examination. RESULTS: The prevalence of the metabolic syndrome was 40.2% in men and 45.6% in women (P = .127). The prevalence of gait speed impairment was 29.3% in men and 12.5% in women (P < .001). No association was found between the metabolic syndrome and gait speed impairment. After including the individual components of the metabolic syndrome in a logistic model adjusted for age and leisure-time physical activity, abdominal obesity, low HDL cholesterol, and high fasting glucose were significantly associated with gait speed impairment among women (adjusted odds ratio [AOR] = 0.48, 95% confidence interval [CI] = 0.26 to 0.89; AOR = 2.26, 95% CI = 1.08 to 4.75; and AOR = 2.05, 95% CI = 1.12 to 3.74, respectively). Further adjustment for race/ethnicity, education, smoking status, alcohol consumption, arthritis status, and use of an assistive device attenuated these associations; among women, abdominal obesity and low HDL cholesterol remained significantly associated with gait speed impairment (AOR = 0.37, 95% CI = 0.18 to 0.76 and AOR = 2.45, 95% CI = 1.07 to 5.63, respectively) while the association between hyperglycemia and impaired gait speed attenuated to nonsignificance. CONCLUSION: Among women, gait speed impairment is associated with low HDL cholesterol and inversely with abdominal obesity. These associations may be sex-dependent and warrant further research

An Assessment of the Impact of Hafting on Paleoindian Point Variability

It has long been argued that the form of North American Paleoindian points was affected by hafting. According to this hypothesis, hafting constrained point bases such that they are less variable than point blades. The results of several studies have been claimed to be consistent with this hypothesis. However, there are reasons to be skeptical of these results. None of the studies employed statistical tests, and all of them focused on points recovered from kill and camp sites, which makes it difficult to be certain that the differences in variability are the result of hafting rather than a consequence of resharpening. Here, we report a study in which we tested the predictions of the hafting hypothesis by statistically comparing the variability of different parts of Clovis points. We controlled for the potentially confounding effects of resharpening by analyzing largely unused points from caches as well as points from kill and camp sites. The results of our analyses were not consistent with the predictions of the hypothesis. We found that several blade characters and point thickness were no more variable than the base characters. Our results indicate that the hafting hypothesis does not hold for Clovis points and indicate that there is a need to test its applicability in relation to post-Clovis Paleoindian points

Describing the impact of health research: a Research Impact Framework

BACKGROUND: Researchers are increasingly required to describe the impact of their work, e.g. in grant proposals, project reports, press releases and research assessment exercises. Specialised impact assessment studies can be difficult to replicate and may require resources and skills not available to individual researchers. Researchers are often hard-pressed to identify and describe research impacts and ad hoc accounts do not facilitate comparison across time or projects. METHODS: The Research Impact Framework was developed by identifying potential areas of health research impact from the research impact assessment literature and based on research assessment criteria, for example, as set out by the UK Research Assessment Exercise panels. A prototype of the framework was used to guide an analysis of the impact of selected research projects at the London School of Hygiene and Tropical Medicine. Additional areas of impact were identified in the process and researchers also provided feedback on which descriptive categories they thought were useful and valid vis-à-vis the nature and impact of their work. RESULTS: We identified four broad areas of impact: I. Research-related impacts; II. Policy impacts; III. Service impacts: health and intersectoral and IV. Societal impacts. Within each of these areas, further descriptive categories were identified. For example, the nature of research impact on policy can be described using the following categorisation, put forward by Weiss: Instrumental use where research findings drive policy-making; Mobilisation of support where research provides support for policy proposals; Conceptual use where research influences the concepts and language of policy deliberations and Redefining/wider influence where research leads to rethinking and changing established practices and beliefs. CONCLUSION: Researchers, while initially sceptical, found that the Research Impact Framework provided prompts and descriptive categories that helped them systematically identify a range of specific and verifiable impacts related to their work (compared to ad hoc approaches they had previously used). The framework could also help researchers think through implementation strategies and identify unintended or harmful effects. The standardised structure of the framework facilitates comparison of research impacts across projects and time, which is useful from analytical, management and assessment perspectives

Neuronal Nitric Oxide Synthase-Rescue of Dystrophin/Utrophin Double Knockout Mice does not Require nNOS Localization to the Cell Membrane

Survival of dystrophin/utrophin double-knockout (dko) mice was increased by muscle-specific expression of a neuronal nitric oxide synthase (nNOS) transgene. Dko mice expressing the transgene (nNOS TG+/dko) experienced delayed onset of mortality and increased life-span. The nNOS TG+/dko mice demonstrated a significant decrease in the concentration of CD163+, M2c macrophages that can express arginase and promote fibrosis. The decrease in M2c macrophages was associated with a significant reduction in fibrosis of heart, diaphragm and hindlimb muscles of nNOS TG+/dko mice. The nNOS transgene had no effect on the concentration of cytolytic, CD68+, M1 macrophages. Accordingly, we did not observe any change in the extent of muscle fiber lysis in the nNOS TG+/dko mice. These findings show that nNOS/NO (nitric oxide)-mediated decreases in M2c macrophages lead to a reduction in the muscle fibrosis that is associated with increased mortality in mice lacking dystrophin and utrophin. Interestingly, the dramatic and beneficial effects of the nNOS transgene were not attributable to localization of nNOS protein at the cell membrane. We did not detect any nNOS protein at the sarcolemma in nNOS TG+/dko muscles. This important observation shows that sarcolemmal localization is not necessary for nNOS to have beneficial effects in dystrophic tissue and the presence of nNOS in the cytosol of dystrophic muscle fibers can ameliorate the pathology and most importantly, significantly increase life-span