Integrin-directed modulation of macrophage responses to biomaterials

Macrophages are the primary mediator of chronic inflammatory responses to implanted biomaterials, in cases when the material is either in particulate or bulk form. Chronic inflammation limits the performance and functional life of numerous implanted medical devices, and modulating macrophage interactions with biomaterials to mitigate this response would be beneficial. The integrin family of cell surface receptors mediates cell adhesion through binding to adhesive proteins nonspecifically adsorbed onto biomaterial surfaces. In this work, the roles of integrin Mac-1 (α_Mβ₂) and RGD-binding integrins were investigated using model systems for both particulate and bulk biomaterials. Specifically, the macrophage functions of phagocytosis and inflammatory cytokine secretion in response to a model particulate material, polystyrene microparticles were investigated. Opsonizing proteins modulated microparticle uptake, and integrin Mac-1 and RGD-binding integrins were found to control microparticle uptake in an opsonin-dependent manner. The presence of adsorbed endotoxin did not affect microparticle uptake levels, but was required for the production of inflammatory cytokines in response to microparticles. Furthermore, it was demonstrated that integrin Mac-1 and RGD-binding integrins influence the in vivo foreign body response to a bulk biomaterial, subcutaneously implanted polyethylene terephthalate. A thinner foreign body capsule was formed when integrin Mac-1 was absent (∼30% thinner) or when RGD-binding integrins were blocked by controlled release of a blocking peptide (∼45% thinner). These findings indicate integrin Mac-1 and RGD-binding integrins are involved and may serve as therapeutic targets to mitigate macrophage inflammatory responses to both particulate and bulk biomaterials.     

Quaternary dynamics and plasticity underlie small heat shock protein chaperone function

Small Heat Shock Proteins (sHSPs) are a diverse family of molecular chaperones that prevent protein aggregation by binding clients destabilized during cellular stress. Here we probe the architecture and dynamics of complexes formed between an oligomeric sHSP and client by employing unique mass spectrometry strategies. We observe over 300 different stoichiometries of interaction, demonstrating that an ensemble of structures underlies the protection these chaperones confer to unfolding clients. This astonishing heterogeneity not only makes the system quite distinct in behavior to ATP-dependent chaperones, but also renders it intractable by conventional structural biology approaches. We find that thermally regulated quaternary dynamics of the sHSP establish and maintain the plasticity of the system. This extends the paradigm that intrinsic dynamics are crucial to protein function to include equilibrium fluctuations in quaternary structure, and suggests they are integral to the sHSPs’ role in the cellular protein homeostasis network.     

Hyperlipidemia and Primary Prevention of Stroke: Does Risk Factor Identification and Reduction Really Work?

Stroke is one of the leading causes of death. Hyperlipidemia is a major risk factor for stroke. The United States Preventive Service Task Force defines lipid screening guidelines. Treatment options of hyperlipidemia include lifestyle modifications and medical management. Statins have been shown to decrease lipids and exert a pleiotropic effect on intracranial vasculature and inflammatory modulators, leading to neuroprotection. Lower low-density lipoprotein and higher high-density lipoprotein levels are associated with decreased risk of stroke. Despite screening guidelines and evidence of the efficacy of statins, there are numerous barriers to maintaining adequate control of lipids.     

Does the Framingham Risk Score Predict Risk in Women as Well as It Does in Men?

The current guidelines for classifying women into high, intermediate and low risk based on the Framingham Risk Score and National Cholesterol Education Program guidelines are biased against women, deprive many women at risk of coronary heart disease of potentially effective lipid-lowering drug therapy, and likely contribute to a very high prevalence of vascular disease, cognitive disorders, disability, and reduced active life expectancy for women. Prevalence of atherosclerosis beginning early in life, use of noninvasive imaging of atherosclerosis, better measurement of lipoprotein levels, awareness of importance of diseases that increase risk of coronary heart disease among women, and earlier and more frequent use of effective therapies to prevent cardiovascular disease are necessary to greatly improve women’s cardiovascular health.     

自发性脑出血治疗指南美国心脏协会/美国卒中协会对医疗卫生专业人员发布的指南

目的 本指南旨在为急性自发性脑出血的诊断和治疗提供最新的综合性推荐意见.方法 通过Medline进行规范的文献检索,利用证据表合并资料.撰写委员会成员通过远程电信会议讨论根据资料得出的推荐意见.采用美国心脏协会卒中委员会的证据分级方案对推荐意见进行分级.由6位同行评议专家以及卒中委员会科学声明监督委员会和卒中委员会领导委员会成员对指南 的草案进行发表前审阅.预期本指南在3年内完全更新.结果 本文为脑出血患者的医疗诊治提供了循证指南.重点包括诊断、止血、血压管理、院内管理和护理、预防内科合并症、外科治疗、转归预测、康复、预防复发以及将来需要考虑的问题.结论 脑出血是一种严重的疾病,早期积极救治可影响其转归.本指南为脑出血患者的目标导向治疗提供了一个框架.     

The concept of caring: Perceptions of radiation therapists

AimsThis study explores radiation therapists’ understanding and interpretations of the concept of caring within their profession.BackgroundHealth professions’ concepts of care have been explored in disciplines such as nursing and medicine. However, there has been little previous attempt to describe what caring means to radiation therapists.MethodsA qualitative phenomenological approach was used and 27 radiation therapists were interviewed in four focus groups. Discussions were transcribed and analysis was performed to identify themes from the data.ResultsThree overarching themes emerged from the data: human connection established between radiation therapists and patients, technical care as the use of technology and procedures in treatment planning and delivery, and the therapist’s unique identity as compared to other professions.ConclusionsThe concept of care was seen by radiation therapists primarily as a supportive relationship with the patient but they were unable to agree if the technical aspects and procedures were considered a part of caring. Further research is needed to further examine the connection between technology and care.     

Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than five years of age for prevention of pneumonia

OBJECTIVE: To determine the effectiveness of the Wyeth heptavalent pneumococcal conjugate vaccine against clinical and radiograph-confirmed pneumonia in children. METHODS: The heptavalent CRM(197) pneumococcal conjugate vaccine (PCV) was given to infants at 2, 4, 6 and 12 to 15 months of age in a randomized, double blind trial. Children were randomized to receive either the CRM(197) PCV (vaccine group) or the meningococcal type C CRM(197) conjugate vaccine (control group). The primary outcome of this trial was invasive pneumococcal disease. In addition children with the clinical diagnosis of pneumonia in the study population were identified through review of automated inpatient, emergency and outpatient databases. The subset of the cohort of these children who had chest radiographs obtained at the time of diagnosis was identified, and the original reading of their radiographs by the radiologist was obtained from automated databases. Rates of clinically diagnosed pneumonia, of pneumonia with a radiograph obtained regardless of result, of pneumonia with positive radiograph (consolidation, empyema or parenchymal infiltrate) and of pneumonia with only perihilar infiltrates were compared between vaccinated and nonvaccinated groups. In addition risk of disease pneumonia was evaluated by race and ethnicity. RESULTS: The incidence of a first pneumonia episode in the control group was 55.9 per 1000 person-years. A radiograph was obtained in 61% of episodes, a positive radiograph in 21% and perihilar findings in an additional 5%. In per protocol follow-up of children given PCV, first episodes of all clinically diagnosed pneumonia were reduced by 4.3% [95% confidence interval (CI), -3.5, 11.5%, = 0.27], episodes with a radiograph were reduced by 9.8% (CI 0.1, 18.5%, < 0.05) and episodes with a positive radiograph were reduced by 20.5% (CI 4.4, 34.0, = 0.02). In the intent to treat analysis including all episodes after randomization, episodes with a positive radiograph were reduced by 17.7%, =.01). The greatest impact was in the first year of life with a 32.2% reduction and a 23.4% reduction in the first 2 years, but only a 9.1% reduction in children >2 years of age. Asians, blacks and Hispanics were at higher risk of pneumonia than were whites, but there was no evidence of ethnic variation in PCV effectiveness. Ten of the 11 cases of pneumococcal pneumonia with a positive blood culture were in the control group. CONCLUSION: The pneumococcal conjugate vaccine tested was effective in reducing the risk of pneumonia in young children.