P66shc regulates endothelial NO production and endothelium-dependent vasorelaxation: implications for age-associated vascular dysfunction

The p66shc adaptor protein mediates age-associated oxidative stress. We examined the role of p66shc in endothelial nitric oxide synthase (eNOS) signaling. Overexpression of p66shc inhibited eNOS-dependent NO production. RNAi-mediated down-regulation of endogenous p66shc led to activation of the proto-oncogene ras, and Akt kinase, with a corresponding increase in phosphorylation of eNOS at S1177 (S1179 on bovine eNOS). In rat aortic rings, down-regulation of p66shc suppressed the vasoconstrictor response to phenyephrine that was abrogated by treatment with the NOS inhibitor l-NAME, and enhanced vasodilation induced by sub-maximal doses of acetylcholine. These findings highlight a pivotal role for p66shc in inhibiting endothelial NO production, and endothelium-dependent vasorelaxation, that may provide important mechanistic information about endothelial dysfunction seen with aging.     

Rapid assessment of glycoprotein IIb/IIIa blockade with the platelet function analyzer (PFA-100) during percutaneous coronary intervention

BACKGROUND: The platelet function analyzer PFA-100 (Dade Behring, Miami, Fla) evaluates platelet function by determining the time to occlusion of an aperture in a membrane coated with collagen and adenosine diphosphate or epinephrine as whole blood flows under shear stress conditions. Platelet aggregation causes aperture occlusion, and results are reported as closure time (CT). Interindividual variability is observed in the level of platelet inhibition achieved with use of the current abciximab dosing regimen (0.25-mg/kg bolus + 10-microg/min infusion for 12 hours). The relationships between specific levels of platelet inhibition and clinical efficacy and safety have not been fully established. METHODS AND RESULTS: We prospectively studied platelet function in 27 patients receiving abciximab during percutaneous coronary intervention. This evaluation included determinations of platelet-rich plasma aggregometry, receptor occupancy studies (D3 assay), and CT measurements at baseline and 10 minutes, 4 hours, 12 hours, and 24 hours after the bolus. All patients received abciximab, aspirin, and heparin; patients undergoing coronary stent implantation received aspirin and ticlopidine after the procedure. CT results were reported within 10 minutes after initiation of testing. For 96% of patients, CT was 300 seconds (maximum CT) immediately after abciximab bolus and remained so throughout the infusion. At 24 hours we observed variable recovery from platelet inhibition and in 72% of patients CT returned to normal (< or =130 seconds). CONCLUSIONS: Findings with the PFA-100 were similar to results observed with platelet aggregometry and receptor occupancy measurements. Most patients treated with abciximab exhibit normalized platelet function at 24 hours despite moderate levels of receptor occupancy, suggesting dissociation between occupancy and function.     

Proteolysis of von Willebrand factor after thrombolytic therapy in patients with acute myocardial infarction.

In 20 patients with acute myocardial infarction (AMI) treated with streptokinase (SK, n = 7), recombinant single-chain tissue plasminogen activator (rt-PA, n = 7) or urokinase (UK, n = 6), the behavior of plasma von Willebrand factor (vWF) was studied before and 1.5, 3, 24, 48, and 72 hours after beginning thrombolytic therapy. vWF antigen (vWF:Ag) was high in plasma, especially after SK. The ristocetin cofactor (RiCof) activity of vWF, high before therapy, tended to decrease soon after therapy. This pattern of vWF changes was paralleled by the early loss of higher molecular weight multimers. By immunoblotting of immunopurified and reduced vWF and monoclonal antibody epitope mapping, we found that vWF was degraded after thrombolysis, especially after SK, as indicated by the higher values of two plasmin-generated fragments of 176 and 145 Kd. There were more plasmin-generated fragments in the five patients who had bleeding complications than in the remaining 15 who did not. In conclusion, quantitative and qualitative changes of vWF compatible with proteolytic degradation of the protein occur during thrombolytic therapy. Such degradation, roughly proportional to the degree of the general lytic state induced by each agent, might be a cofactor of the bleeding complications occurring in treated patients.     

What community-level strategies are needed to secure women's property rights in Western Kenya? Laying the groundwork for a future structural HIV prevention intervention

Despite the recognized need for structural-level HIV prevention interventions that focus on economic empowerment to reduce women's HIV risks, few science-based programs have focused on securing women's land ownership as a primary or secondary HIV risk reduction strategy. The current study focused on a community-led land and property rights model that was implemented in two rural areas of western Kenya where HIV prevalence was high (24–30%) and property rights violations were common. The program was designed to reduce women's HIV risk at the community level by protecting and enhancing women's access to and ownership of land. Through in-depth interviews with 50 program leaders and implementers of this program we sought to identify the strategies that were used to prevent, mediate, and resolve property rights violations. Results included four strategies: (1) rights-based education of both women and men individually and at the community level, (2) funeral committees that intervene to prevent property grabbing and disinheritance, (3) paralegal training of traditional leaders and community members and local adjudication of cases of property rights violations, and (4) referring property rights violations to the formal justice system when these are not resolved at the community level. Study participants underscored that local mediation of cases resulted in a higher success rate than women experienced in the formal court system, underscoring the importance of community-level solutions to property rights violations. The current study assists researchers in understanding the steps needed to prevent and resolve women's property rights violations so as to bolster the literature on potential structural HIV prevention interventions. Future research should rigorously test property rights programs as a structural HIV prevention intervention.     

Associations between model-predicted rivaroxaban exposure and patient characteristics and efficacy and safety outcomes in the treatment of venous thromboembolism

Journal of Thrombosis and Thrombolysis - Traditional statistical models allow population based inferences and comparisons. Machine learning (ML) explores datasets to develop algorithms that do not...     

State Indoor Tanning Laws and Adolescent Indoor Tanning

Objectives. Recently, several state indoor tanning laws, including age restrictions, were promulgated to reduce indoor tanning among minors. We examined the effects of these laws on adolescent indoor tanning.Methods. We used nationally representative data from the 2009 and 2011 national Youth Risk Behavior Surveys (n = 31 835). Using multivariable logistic regression, we examined the association between state indoor tanning laws and indoor tanning among US high school students.Results. Female students in states with indoor tanning laws were less likely to engage in indoor tanning than those in states without any laws. We observed a stronger association among female students in states with systems access, parental permission, and age restriction laws than among those in states without any laws. We found no significant association among female students in states with only systems access and parental permission laws or among male students.Conclusions. Indoor tanning laws, particularly those including age restrictions, may be effective in reducing indoor tanning among female high school students, for whom rates are the highest. Such reductions have the potential to reduce the health and economic burden of skin cancer.Skin cancer is the most common cancer in the United States. Approximately 3.5 million cases of nonmelanoma skin cancers are treated annually, while more than 60 000 melanomas are diagnosed annually.1,2 In addition, skin cancer poses a substantial economic burden, with annual direct medical costs of treatment estimated at $1.7 billion in 2004.3 During the past decade, while most cancers decreased, melanoma increased, especially among young adult women.4 Indoor tanning is thought to be partially responsible for this increase.4–6 Indoor tanning before age 35 years increases the risk of melanoma by 59%,5,7 and indoor tanning before age 25 years increases the risk of basal cell carcinoma by 40% and squamous cell carcinoma by 102%.8 Despite these known health risks, indoor tanning is common among adolescents—6.2% of male high school students and 20.9% of female high school students engaged in indoor tanning in 2011.9In recent years, several states have enacted laws restricting youth access to indoor tanning and laws aimed at reducing consumers’ risk, including facility and operator responsibilities, safety and equipment standards, enforcement authority, and penalties.10 Previous studies that were primarily focused on youth access laws found poor compliance rates among tanning facilities for parental permission laws.11–13 In addition, such laws were ineffective in reducing indoor tanning among adolescents.14,15 Since these earlier studies were conducted, the number of states implementing youth access laws, particularly age restrictions, has increased substantially.16 Although some evidence has suggested that age restrictions may reduce access to indoor tanning among minors,17 no national or international studies have examined the effects these laws have on adolescent indoor tanning behavior. We examined the association between state indoor tanning laws, including age restrictions, and indoor tanning among high school students.     

The Oregon Child Absenteeism Due to Respiratory Disease Study (ORCHARDS): Rationale,objectives, and design

BackgroundInfluenza viruses pose significant disease burdens through seasonal outbreaks and unpredictable pandemics. Existing surveillance programs rely heavily on reporting of medically attended influenza (MAI). Continuously monitoring cause‐specific school absenteeism may identify local acceleration of seasonal influenza activity. The Oregon Child Absenteeism Due to Respiratory Disease Study (ORCHARDS; Oregon, WI) implements daily school‐based monitoring of influenza‐like illness‐specific student absenteeism (a‐ILI) in kindergarten through Grade 12 schools and assesses this approach for early detection of accelerated influenza and other respiratory pathogen transmission in schools and surrounding communities.MethodsStarting in September 2014, ORCHARDS combines automated reporting of daily absenteeism within six schools and home visits to school children with acute respiratory infection (ARI). Demographic, epidemiological, and symptom data are collected along with respiratory specimens. Specimens are tested for influenza and other respiratory viruses. Household members can opt into a supplementary household transmission study. Community comparisons are possible using a pre‐existing and highly effective influenza surveillance program, based on MAI at five family medicine clinics in the same geographical area.ResultsOver the first 5 years, a‐ILI occurred on 6634 (0.20%) of 3,260,461 student school days. Viral pathogens were detected in 64.5% of 1728 children with ARI who received a home visit. Influenza was the most commonly detected virus, noted in 23.3% of ill students.ConclusionORCHARDS uses a community‐based design to detect influenza trends over multiple seasons and to evaluate the utility of absenteeism for early detection of accelerated influenza and other respiratory pathogen transmission in schools and surrounding communities.     

Assessment of retinal manifestations of Parkinson’s disease using spectral domain optical coherence tomography: A study in Indian eyes

Purpose:To assess the retinal manifestations of Parkinson’s disease using optical coherence tomography.Methods:A prospective case-control study comparing 30 eyes from 15 patients with Parkinson’s disease and 22 eyes from 11 healthy age-matched controls. Total macular subfield thickness and the thickness of the ganglion cell layer, nerve fiber layer, and peripapillary retinal nerve fiber layer were measured with spectral-domain optical coherence tomography (SD-OCT).Results:The mean age of PD patients was 68.4 years ± 10.64 (range: 46–82) and in the control group was 66.36 ± 5.22 (range: 64–68). The average disease duration in patients with PD was 6.7 ± 2.8 years (range: 2–10 years). The mean best-corrected visual acuity in PD was 20/26 and 20/20 in controls, with P = 0.0059, which was significant. Significant difference was also found in the contrast sensitivity between both groups. Structural differences in the central macular thickness (P = 0.0001), subfield thicknesses in the superior (P = 0.003), inferior (P = 0.001), nasal (P = 0.004), and temporal subfields (P = 0.017) was seen. Severe thinning of the ganglion cell layer was seen in PD patients (P = 0.000) as well as of the nerve fiber layer (P = 0.004). Peripapillary retinal nerve fiber thickness measured showed significant thinning in superotemporal (P = 0.000), superonasal (P = 0.04), inferonasal (P = 0.000), inferotemporal (P = 0.000), nasal (P = 0.000), and temporal quadrants (P = 0.000).Conclusion:Visual dysfunction was observed in patients with PD along with structural alterations on OCT, which included macular volumes, ganglion cell layer, and peripapillary retinal nerve fiber layer.