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Objectives: Publication bias has the potential to adversely impact clinical decision making and patient health if alternative decisions would have been made had there been complete publication of evidence. Methods: The objective of our analysis was to determine if earlier publication of the complete evidence on rosiglitazone's risk of myocardial infarction (MI) would have changed clinical decision making at an earlier point in time. We tested several methods for adjustment of publication bias to assess the impact of potential time delays to identifying the MI effect. We then performed a cumulative meta-analysis (CMA) for both published studies (published-only data set) and all studies performed (comprehensive data set). We then created an adjusted data set using existing methods of adjustment for publication bias (Harbord regression, Peter's regression, and the nonparametric trim and fill method) applied to the limited data set. Finally, we compared the time to the decision threshold for each data set using CMA. Results: Although published-only and comprehensive data sets did not provide notably different final summary estimates [OR = 1.4 (95 percent confidence interval [CI]:.95–2.05) and 1.42 (95 percent CI: 1.03–1.97)], the comprehensive data set reached the decision threshold 36 months earlier than the published-only data set. All three adjustment methods tested did not show a differential time to decision threshold versus the published-only data set. Conclusions: Complete access to studies capturing MI risk for rosiglitazone would have led to the evidence reaching a clinically meaningful decision threshold 3 years earlier. [ABSTRACT FROM AUTHOR]

Objectives: Publication bias has the potential to adversely impact clinical decision making and patient health if alternative decisions would have been made had there been complete publication of evidence. Methods: The objective of our analysis was to determine if earlier publication of the complete evidence on rosiglitazone's risk of myocardial infarction (MI) would have changed clinical decision making at an earlier point in time. We tested several methods for adjustment of publication bias to assess the impact of potential time delays to identifying the MI effect. We then performed a cumulative meta-analysis (CMA) for both published studies (published-only data set) and all studies performed (comprehensive data set). We then created an adjusted data set using existing methods of adjustment for publication bias (Harbord regression, Peter's regression, and the nonparametric trim and fill method) applied to the limited data set. Finally, we compared the time to the decision threshold for each data set using CMA. Results: Although published-only and comprehensive data sets did not provide notably different final summary estimates [OR = 1.4 (95 percent confidence interval [CI]:.95–2.05) and 1.42 (95 percent CI: 1.03–1.97)], the comprehensive data set reached the decision threshold 36 months earlier than the published-only data set. All three adjustment methods tested did not show a differential time to decision threshold versus the published-only data set. Conclusions: Complete access to studies capturing MI risk for rosiglitazone would have led to the evidence reaching a clinically meaningful decision threshold 3 years earlier. [ABSTRACT FROM AUTHOR]

Transfer cells (TCs) facilitate high rates of nutrient transport into, and within, the plant body. Their transport function is conferred by polarized wall ingrowth papillae, deposited upon a specialized uniform wall layer, that form a scaffold supporting an amplified area of plasma membrane enriched in nutrient transporters. We explored the question of whether lipid-enriched domains of the TC plasma membrane could serve as organizational platforms for proteins regulating the construction of the intricate TC wall labyrinth using developing Vicia faba cotyledons. When these cotyledons are placed in culture, their adaxial epidermal cells trans -differentiate to a TC phenotype regulated by auxin, ethylene, extracellular hydrogen peroxide (apoH2O2), and cytosolic Ca2+ ([Ca2+]cyt) arranged in series. Staining cultured cotyledons with the sterol-specific dye, Filipin III, detected a polarized sterol-enriched domain in the plasma membrane of their trans- differentiating epidermal transfer cells (ETCs). Ethylene activated sterol biosynthesis while extracellular apoH2O2 directed sterol-enriched vesicles to fuse with the outer periclinal region of the ETC plasma membrane. The sterol-enriched domain was essential for generating the [Ca2+]cyt signal and orchestrating construction of both the uniform wall layer and wall ingrowth papillae. A model is presented outlining how the sterol-enriched plasma membrane domain forms and functions to regulate wall labyrinth assembly. [ABSTRACT FROM AUTHOR]

This article describes the development of the Claudication Symptom Instrument (CSI) and its measurement properties for evaluating the symptom experience of patients diagnosed with intermittent claudication (IC). We conducted semistructured qualitative interviews with IC patients for item development and cognitive interviews in which patient comprehension of items was tested. We evaluated measurement properties using data collected and analyzed in the context of an observational comparative effectiveness study of IC treatments. Items measuring five symptom important to patients were developed and cognitively tested: Pain, Numbness, Heaviness, Cramping, and Tingling. Item means (higher means worse) ranged from 1.1 (Tingling) to 2.3 (Pain) (range: 0 'none' to 4 'extreme'). Rasch analysis yielded support for an overall score (χ²=26.5, df=20, p=0.15). The total CSI score differed by clinician-rated severity of mild versus moderate (p<0.05), but not moderate versus severe. Re-administration of the CSI 5-10 days after baseline yielded an intra-class correlation coefficient of 0.86. Changes in CSI total score and VASCUQOL total score between baseline and 6 months post-treatment were correlated at -0.52 (p<0.05). The CSI preliminarily meets accepted measurement standards for content validity, internal consistency and test-retest reliability, construct validity, and sensitivity for detecting change. Because of its high test-retest reliability, it may also be useful in clinical care with individual patients. It takes approximately 3 minutes to complete. [ABSTRACT FROM AUTHOR]

We explored perceived and reported sex (male and female) differences in heterosexual, cisgender undergraduate sexual engagement across 10 common behaviors. Results from 1,007 students suggest that males are perceived to be more sexually engaged than women despite generally no sex differences in reported behavior. Across behaviors, perception versus report comparisons largely demonstrated significant dif fer ences. While no sex-related patterns emerged among differences, patterns regarding behavior type did. More standard, objectively defined behaviors (intercourse) demonstrated greater reported engagement than perceived, whereas more promiscuous behaviors (one night stand) demonstrated greater perceived engage ment than reported. [ABSTRACT FROM AUTHOR]

Background: Increases in prescriptions of opioid medications for chronic pain have been accompanied by increases in opioid overdoses, abuse, and other harms and uncertainty about long-term effectiveness. Purpose: To evaluate evidence on the effectiveness and harms of long-term (>3 months) opioid therapy for chronic pain in adults. Data Sources: MEDLINE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, PsycINFO, and CINAHL (January 2008 through August 2014); relevant studies from a prior review; reference lists; and ClinicalTrials.gov. Study Selection: Randomized trials and observational studies that involved adults with chronic pain who were prescribed long-term opioid therapy and that evaluated opioid therapy versus placebo, no opioid, or nonopioid therapy; different opioid dosing strategies; or risk mitigation strategies. Data Extraction: Dual extraction and quality assessment. Data Synthesis: No study of opioid therapy versus no opioid therapy evaluated long-term (>1 year) outcomes related to pain, function, quality of life, opioid abuse, or addiction. Good- and fair-quality observational studies suggest that opioid therapy for chronic pain is associated with increased risk for overdose, opioid abuse, fractures, myocardial infarction, and markers of sexual dysfunction, although there are few studies for each of these outcomes; for some harms, higher doses are associated with increased risk. Evidence on the effectiveness and harms of different opioid dosing and risk mitigation strategies is limited. Limitations: Non-English-language articles were excluded, meta-analysis could not be done, and publication bias could not be assessed. No placebo-controlled trials met inclusion criteria, evidence was lacking for many comparisons and outcomes, and observational studies were limited in their ability to address potential confounding. Conclusion: Evidence is insufficient to determine the effectiveness of long-term opioid therapy for improving chronic pain and function. Evidence supports a dose-dependent risk for serious harms. Primary Funding Source: Agency for Healthcare Research and Quality. [ABSTRACT FROM AUTHOR]

Objective: To describe headache-related health resource usage in chronic and episodic migraine across six countries. Methods: A web-based questionnaire eliciting data on several topics, including health resource usage, was administered to panellists with migraine from the USA, Canada, UK, Germany, France and Australia. Respondents were grouped into episodic and chronic migraine, based on reported headache phenotype and headache-day frequency. ORs were calculated, comparing usage in each country to that in the US, controlling for chronic versus episodic migraine and other factors. Results: Relative to the USA, the odds of visiting a provider for headache during the preceding 3 months were significantly higher in all countries, except Germany. Respondents in France were more likely to report having a provider they typically visited for headache-related care. The odds of visiting the emergency department for headache were significantly lower in France, the UK and Germany, and hospitalisation for headache was significantly more frequent in Canada and Australia. Respondents from all countries, except Canada, were more likely to report currently using a prescription-acute treatment, and those from France were more likely to report trying more than three acute treatments. Preventive treatment use did not differ significantly. Conclusions: Headache-related resource usage differed significantly between the USA and other countries. US respondents were generally less likely to report recent provider visits and use of prescription-acute treatments. They were more likely to report emergency department visits than in European countries, but less likely to report hospitalisation than in Canada and Australia. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Patients with type 2 diabetes mellitus (T2DM) are at increased risk of developing cardiovascular disease, largely as a result of defective production of cardioprotective nitric oxide and a concomitant rise in oxidative stress. Dietary interventions that could reverse this trend would be extremely beneficial. Here we investigated whether dietary n-3 polyunsaturated fatty acid (n-3 PUFA) supplementation positively affected platelet nitroso-redox imbalance. RESEARCH DESIGN AND METHODS--We randomized hypertensive T2DM patients (T2DM HT; = 22) and age-and-sex matched hypertensive study participants without diabetes (HT alone; = 23) in a double-blind, crossover fashion to receive 8 weeks of n-3 PUFAs (1.8 g eicosapentaenoic acid and 1.5 g docosahexaenoic acid) or identical olive oil capsules (placebo), with an intervening 8-week washout period. Platelet nitrite and superoxide were measured and compared before and after treatment; 8-isoprostane was determined by ELISA and subcellular compartmentalization of the NAD(P)H oxidase subunit p47-phox examined by Western blotting. RESULTS--The n-3 PUFA supplementation reduced 8-isoprostane and superoxide levels in platelets from T2DM HT, but not HT alone, participants, without effect on nitrite production. This coincided with a significant decrease in p47-phox membrane localization and a similar reduction in superoxide to that achieved with apocynin. At baseline, a subcohort of T2DM HT and HT alone participants showed evidence of nitric oxide synthase (NOS)--derived superoxide production, indicating defective enzymatic activity. This was reversed significantly in T2DM HT participants after treatment, demonstrating improved NOS function. CONCLUSIONS--Our finding that n-3 PUFAs diminish platelet superoxide production in T2DM HT patients in vivo suggests a therapeutic role for these agents in reducing the vascular-derived oxidative stress associated with diabetes. [ABSTRACT FROM AUTHOR]

Background: Current guidelines encourage the use of statins to reduce the risk of cardiovascular disease in diabetic patients; however the impact of these drugs on diabetic retinopathy is not well defined. Moreover, pleiotropic effects of statins on the highly specialised retinal microvascular endothelium remain largely unknown. The objective of this study was to investigate the effects of clinically relevant concentrations of simvastatin on retinal endothelium in vitro and in vivo. Methods and Findings: Retinal microvascular endothelial cells (RMECs) were treated with 0.01-10 μM simvastatin and a biphasic dose-related response was observed. Low concentrations enhanced microvascular repair with 0.1 mM simvastatin significantly increasing proliferation (p<0.05), and 0.01 mM simvastatin significantly promoting migration (p,0.05), sprouting (p<0.001), and tubulogenesis (p<0.001). High concentration of simvastatin (10 mM) had the opposite effect, significantly inhibiting proliferation (p<0.01), migration (p<0.01), sprouting (p<0.001), and tubulogenesis (p,0.05). Furthermore, simvastatin concentrations higher than 1 μM induced cell death. The mouse model of oxygen-induced retinopathy was used to investigate the possible effects of simvastatin treatment on ischaemic retinopathy. Low dose simvastatin(0.2 mg/Kg) promoted retinal microvascular repair in response to ischaemia by promoting intra-retinal revascularisation (p<0.01). By contrast, high dose simvastatin(20 mg/Kg) significantly prevented re-vascularisation (p<0.01) and concomitantly increased pathological neovascularisation (p<0.01). We also demonstrated that the pro-vascular repair mechanism of simvastatin involves VEGF stimulation, Akt phosphorylation, and nitric oxide production; and the antivascular repair mechanism is driven by marked intracellular cholesterol depletion and related disorganisation of key intracellular structures. Conclusions: A beneficial effect of low-dose simvastatin on ischaemic retinopathy is linked to angiogenic repair reducing ischaemia, thereby preventing pathological neovascularisation. High-dose simvastatin may be harmful by inhibiting reparative processes and inducing premature death of retinal microvascular endothelium which increases ischaemiainduced neovascular pathology. Statin dosage should be judiciously monitored in patients who are diabetic or are at risk of developing other forms of proliferative retinopathy. [ABSTRACT FROM AUTHOR]

Background /aims: Chronic inhibition of nitric oxide (NO) synthesis is associated with hypertension, myocardial ischemia, oxidative stress and hypertrophy; expression of adrenomedullin (AM) and intermedin (IMD) and their receptor activity modifying proteins (RAMPs 1-3) is augmented in cardiomyocytes, indicating that the myocardial AM/ IMD system may be activated in response to pressure loading and ischemic insult. The aim was to examine effects on (i) parameters of cardiomyocyte hypertrophy and on (ii) expression of AM and IMD and their receptor components in NO-deficient cardiomyocytes of an intervention chosen specifically for ability to alleviate pressure loading and ischemic injury concurrently. Methods: The NO synthesis inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 35mg.kg–1.day–1) was given to rats for 8 weeks, with/ without concurrent administration of β-adrenoceptor antagonist, atenolol (25mg.kg–1.day–1) / calcium channel blocker, nifedipine (20mg.kg–1.day–1). Results: In L-NAME treated rats, atenolol / nifedipine abolished increases in systolic blood pressure and plasma AM and IMD levels and in left ventricular cardiomyocytes: (i) normalized increased cell width and mRNA expression of hypertrophic (sk-α-actin) and cardio-endocrine (ANP, BNP, ET) genes; (ii) normalized augmented membrane protein oxidation; (iii) normalized mRNA expression of AM, IMD, RAMP1, RAMP2 and RAMP3. Conclusions: normalization of blood pressure and membrane oxidant status together with prevention of hypertrophy and normalization of the augmented expression of AM, IMD and their receptor components in NO-deficient cardiomyocytes by atenolol / nifedipine supports involvement of both pressure loading and ischemic insult in stimulating cardiomyocyte hypertrophy and induction of these counter-regulatory peptides and their receptor components. Attenuation of augmented expression of IMD in this model cannot however be explained simply by prevention of cardiomyocyte hypertrophy. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

AbstractBackground: Chronic inhibition of nitric oxide (NO) synthesis is associated with hypertension, myocardial oxidative stress and hypertrophic remodeling. Up-regulation of the cardiomyocyte adrenomedullin (AM) / intermedin (IMD) receptor signaling cascade is also apparent in NO-deficient cardiomyocytes: augmented expression of AM and receptor activity modifying proteins RAMP2 and RAMP3 is prevented by blood pressure normalization while that of RAMP1 and intermedin (IMD) is not, indicating that the latter is regulated by a pressure-independent mechanism. Aims: to verify the ability of an anti-oxidant intervention to normalize cardiomyocyte oxidant status and to investigate the influence of such an intervention on expression of AM, IMD and their receptor components in NO-deficient cardiomyocytes. Methods: NO synthesis inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 35mg/kg/day) was given to rats for 8 weeks, with/without con-current administration of antioxidants (Vitamin C (25mg/kg/day) and Tempol (25mg/kg/day)). Results: In left ventricular cardiomyocytes isolated from L-NAME treated rats, increased oxidative stress was indicated by augmented (3.6 fold) membrane protein oxidation, enhanced expression of catalytic and regulatory subunits of pro-oxidant NADPH oxidases (NOX1, NOX2) and compensatory increases in expression of anti-oxidant glutathione peroxidase and Cu/Zn superoxide dismutases (SOD1, SOD3). Vitamin C plus Tempol did not reduce systolic blood pressure but normalized augmented plasma levels of IMD, but not of AM, and in cardiomyocytes: (i) abolished increased membrane protein oxidation; (ii) normalized augmented expression of prepro-IMD and RAMP1, but not prepro-AM, RAMP2 and RAMP3; (iii) attenuated (by 42%) increased width and normalized expression of hypertrophic markers, skeletal-α-actin and prepro-endothelin-1 similarly to blood pressure normalization but in contrast to blood pressure normalization did not attenuate augmented brain natriuretic peptide (BNP) expression. Conclusion: normalization specifically of augmented IMD/RAMP1 expression in NO-deficient cardiomyocytes by antioxidant intervention in the absence of blood pressure reduction indicates that these genes are likely to be induced directly by myocardial oxidative stress. Although oxidative stress contributed to cardiomyocyte hypertrophy, induction of IMD and RAMP1 is unlikely to be secondary to cardiomyocyte hypertrophy. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Presents a medical case of a Jack Russell crossbred with left ventricular flow propagation using color M-mode echocardiocraphy in the diagnosis of effusive-constructive pericardial disease. Condition of the mucuos membranes after a physical examination; Findings of a serum biochemical analysis; Clinical findings associated with constrictive pericarditis.

OBJECTIVE: To determine the contribution of fast and slow inward channels to the electrocardiogram (ECG) of ventricular fibrillation. METHODS: Ventricular fibrillation was induced by endocardial electrical stimulation in pigs anaesthetised with pentobarbitone sodium (30 mg/kg intravenously). ECGs simultaneously recorded from the body surface (lead II) and from the endocardium were studied by power spectrum analysis (0-40 Hz). RESULTS: The mean (SEM) dominant frequency of fibrillation (9.0 (1.1) Hz in lead II at 0-40 s) did not change significantly with time in pigs given intravenous saline. However, the dominant frequency was significantly reduced by intravenous pretreatment with the class I antiarrhythmic drugs, lignocaine (3 mg/kg, 6.5 (0.5) Hz; 10 mg/kg, 4.2 (0.6) Hz), mexiletine (3 mg/kg, 6.2 (0.4) Hz; 10 mg/kg, 5.5 (0.4) Hz), and disopyramide (2.5 mg/kg, 5.4 (0.6) Hz). After flecainide (3 mg/kg, 6.9 (0.5) Hz) the reduction in frequency was not significant. Similar data were obtained with endocardial recordings. In contrast pre-treatment with verapamil (0.2 mg/kg, 11.7 (0.8) Hz; and 1.0 mg/kg, 12.9 (1.6) Hz) produced a significantly higher dominant frequency of fibrillation than saline and widened the bandwidth of frequencies around the dominant frequency. CONCLUSIONS: These results indicate that voltage-dependent sodium channel currents contribute to the rapid frequencies of ventricular fibrillation. Blockade of L-type inward calcium channel activity increases the fibrillation frequency and fractionates the frequencies of the fibrillation wavefronts. [ABSTRACT FROM PUBLISHER]