Changes in CVD risk factors in the activity counseling trial

Primary care facilities may be a natural setting for delivering interventions that focus on behaviors that improve cardiovascular disease (CVD) risk factors. The purpose of this study was to examine the 24-month effects of the Activity Counseling Trial (ACT) on CVD risk factors, to examine whether changes in CVD risk factors differed according to baseline risk factor status, and to examine whether changes in fitness were associated with changes in CVD risk factors. ACT was a 24-month multicenter randomized controlled trial to increase physical activity. Participants were 874 inactive men and women aged 35–74 years. Participants were randomly assigned to one of three arms that varied by level of counseling, intensity, and resource requirements. Because there were no significant differences in change over time between arms on any of the CVD risk factors examined, all arms were combined, and the effects of time, independent of arm, were examined separately for men and women. Time × Baseline risk factor status interactions examined whether changes in CVD risk factors differed according to baseline risk factor status. Significant improvements in total cholesterol, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol, the ratio of total cholesterol to HDL-C, and triglycerides were seen in both men and women who had high (or low for HDL-C) baseline levels of risk factors, whereas significant improvements in diastolic blood pressure were seen only in those men with high baseline levels. There were no improvements in any risk factors among participants with normal baseline levels. Changes in fitness were associated with changes in a number of CVD risk factors. However, most relationships disappeared after controlling for changes in body weight. Improvements in lipids from the ACT interventions could reduce the risk of coronary heart disease in people with already high levels of lipids by 16%–26% in men and 11%–16% in women. Interventions that can be implemented in health care settings nationwide and result in meaningful population-wide changes in CVD risk factors are needed. The ACT physical activity interventions produced substantial improvements among men and women with elevated CVD risk factors

The efficacy of vigorous-intensity exercise as an aid to smoking cessation in adults with elevated anxiety sensitivity: study protocol for a randomized controlled trial

Background: Although cigarette smoking is a leading cause of death and disability in the United States (US), over 40 million adults in the US currently smoke. Quitting smoking is particularly difficult for smokers with certain types of psychological vulnerability. Researchers have frequently called attention to the relation between smoking and anxiety-related states and disorders, and evidence suggests that panic and related anxiety vulnerability factors, specifically anxiety sensitivity (AS or fear of somatic arousal), negatively impact cessation. Accordingly, there is merit to targeting AS among smokers to improve cessation outcome. Aerobic exercise has emerged as a promising aid for smoking cessation for this high-risk (for relapse) group because exercise can effectively reduce AS and other factors predicting smoking relapse (for example, withdrawal, depressed mood, anxiety), and it has shown initial efficacy for smoking cessation. The current manuscript presents the rationale, study design and procedures, and design considerations of the Smoking Termination Enhancement Project (STEP). Methods: STEP is a randomized clinical trial that compares a vigorous-intensity exercise intervention to a health and wellness education intervention as an aid for smoking cessation in adults with elevated AS. One hundred and fifty eligible participants will receive standard treatment (ST) for smoking cessation that includes cognitive behavioral therapy (CBT) and nicotine replacement therapy (NRT). In addition, participants will be randomly assigned to either an exercise intervention (ST+EX) or a health and wellness education intervention (ST+CTRL). Participants in both arms will meet 3 times a week for 15 weeks, receiving CBT once a week for the first 7 weeks, and 3 supervised exercise or health and wellness education sessions (depending on randomization) per week for the full 15-week intervention. Participants will be asked to set a quit date for 6 weeks after the baseline visit, and smoking cessation outcomes as well as putative mediator variables will be measured up to 6 months following the quit date. Discussion: The primary objective of STEP is to evaluate whether vigorous-intensity exercise can aid smoking cessation in anxiety vulnerable adults. If effective, the use of vigorous-intensity exercise as a component of smoking cessation interventions would have a significant public health impact. Specifically, in addition to improving smoking cessation treatment outcome, exercise is expected to offer benefits to overall health, which may be particularly important for smokers. The study is also designed to test putative mediators of the intervention effects and therefore has the potential to advance the understanding of exercise-anxiety-smoking relations and guide future research on this topic

Characterization of HCV Interactions with Toll-Like Receptors and RIG-I in Liver Cells

The aim of this study was to examine the mechanisms of IFN induction and viral escape. In order to accomplish the goal we compared our new hepatoma cell line LH86, which has intact TLR3 and RIG-I expression and responds to HCV by inducing IFN, with Huh7.5 cells which lack those features.The initial interaction of LH86 cells, Huh7.5 cells or their transfected counter parts (LH86 siRIG-I, siTLR3 or siTLR7 and Huh7.5 RIG-I, TLR3 or TLR7) after infection with HCV (strain JFH-1) was studied by measuring the expression levels of IFNβ, TRAIL, DR4, DR5 and their correlation to viral replication.HCV replicating RNA induces IFN in LH86 cells. The IFN induction system is functional in LH86, and the expression of the RIG-I and TLR3 in LH86 is comparable to the primary hepatocytes. Both proteins appear to play important roles in suppression of viral replication. We found that innate immunity against HCV is associated with the induction of apoptosis by RIG-I through the TRAIL pathway and the establishment of an antiviral state by TLR3. HCV envelope proteins interfere with the expression of TLR3 and RIG-I.These findings correlate with the lower expression level of PRRs in HCV chronic patients and highlight the importance of the PRRs in the initial interaction of the virus and its host cells. This work represents a novel mechanism of viral pathogenesis for HCV and demonstrates the role of PRRs in viral infection

Choosing between measures: comparison of EQ-5D, HUI2 and HUI3 in persons with hearing complaints

OBJECTIVES: To generate insight into the differences between utility measures EuroQol 5D (EQ-5D), Health Utilities Index Mark II (HUI2) and Mark III (HUI3) and their impact on the incremental cost-effectiveness ratio (ICER) for hearing aid fitting METHODS: Persons with hearing complaints completed EQ-5D, HUI2 and HUI3 at baseline and, when applicable, after hearing aid fitting. Practicality, construct validity, agreement, responsiveness and impact on the ICER were examined. RESULTS: All measures had high completion rates. HUI3 was capable of discriminating between clinically distinctive groups. Utility scores (n = 315) for EQ-5D UK and Dutch tariff (0.83; 0.86), HUI2 (0.77) and HUI3 (0.61) were significantly different, agreement was low to moderate. Change after hearing aid fitting (n = 70) for HUI2 (0.07) and HUI3 (0.12) was statistically significant, unlike the EQ-5D UK (0.01) and Dutch (0.00) tariff. ICERs varied from 647,209 euros/QALY for the EQ-5D Dutch tariff to 15,811 euros/QALY for HUI3. CONCLUSION: Utility scores, utility gain and ICERs heavily depend on the measure that is used to elicit them. This study indicates HUI3 as the instrument of first choice when measuring utility in a population with hearing complaints, but emphasizes the importance of a clear notion of what constitutes utility with regard to economic analyse

Molecular Architectures of Trimeric SIV and HIV-1 Envelope Glycoproteins on Intact Viruses: Strain-Dependent Variation in Quaternary Structure

The initial step in target cell infection by human, and the closely related simian immunodeficiency viruses (HIV and SIV, respectively) occurs with the binding of trimeric envelope glycoproteins (Env), composed of heterodimers of the viral transmembrane glycoprotein (gp41) and surface glycoprotein (gp120) to target T-cells. Knowledge of the molecular structure of trimeric Env on intact viruses is important both for understanding the molecular mechanisms underlying virus-cell interactions and for the design of effective immunogen-based vaccines to combat HIV/AIDS. Previous analyses of intact HIV-1 BaL virions have already resulted in structures of trimeric Env in unliganded and CD4-liganded states at ∼20 Å resolution. Here, we show that the molecular architectures of trimeric Env from SIVmneE11S, SIVmac239 and HIV-1 R3A strains are closely comparable to that previously determined for HIV-1 BaL, with the V1 and V2 variable loops located at the apex of the spike, close to the contact zone between virus and cell. The location of the V1/V2 loops in trimeric Env was definitively confirmed by structural analysis of HIV-1 R3A virions engineered to express Env with deletion of these loops. Strikingly, in SIV CP-MAC, a CD4-independent strain, trimeric Env is in a constitutively “open” conformation with gp120 trimers splayed out in a conformation similar to that seen for HIV-1 BaL Env when it is complexed with sCD4 and the CD4i antibody 17b. Our findings suggest a structural explanation for the molecular mechanism of CD4-independent viral entry and further establish that cryo-electron tomography can be used to discover distinct, functionally relevant quaternary structures of Env displayed on intact viruses

Impact of Diabetes on Postinfarction Heart Failure and Left Ventricular Remodeling

Diabetes mellitus, the metabolic syndrome, and the underlying insulin resistance are increasingly associated with diastolic dysfunction and reduced stress tolerance. The poor prognosis associated with heart failure in patients with diabetes after myocardial infarction is likely attributable to many factors, important among which is the metabolic impact from insulin resistance and hyperglycemia on the regulation of microvascular perfusion and energy generation in the cardiac myocyte. This review summarizes epidemiologic, pathophysiologic, diagnostic, and therapeutic data related to diabetes and heart failure in acute myocardial infarction and discusses novel perceptions and strategies that hold promise for the future and deserve further investigation

Spiral ligament fibrocyte-derived MCP-1/CCL2 contributes to inner ear inflammation secondary to nontypeable H. influenzae-induced otitis media

<p>Abstract</p> <p>Background</p> <p>Otitis media (OM), one of the most common pediatric infectious diseases, causes inner ear inflammation resulting in vertigo and sensorineural hearing loss. Previously, we showed that spiral ligament fibrocytes (SLFs) recognize OM pathogens and up-regulate chemokines. Here, we aim to determine a key molecule derived from SLFs, contributing to OM-induced inner ear inflammation.</p> <p>Methods</p> <p>Live NTHI was injected into the murine middle ear through the tympanic membrane, and histological analysis was performed after harvesting the temporal bones. Migration assays were conducted using the conditioned medium of NTHI-exposed SLFs with and without inhibition of MCP-1/CCL2 and CCR2. qRT-PCR analysis was performed to demonstrate a compensatory up-regulation of alternative genes induced by the targeting of MCP-1/CCL2 or CCR2.</p> <p>Results</p> <p>Transtympanic inoculation of live NTHI developed serous and purulent labyrinthitis after clearance of OM. THP-1 cells actively migrated and invaded the extracellular matrix in response to the conditioned medium of NTHI-exposed SLFs. This migratory activity was markedly inhibited by the viral CC chemokine inhibitor and the deficiency of MCP-1/CCL2, indicating that MCP-1/CCL2 is a main attractant of THP-1 cells among the SLF-derived molecules. We further demonstrated that CCR2 deficiency inhibits migration of monocyte-like cells in response to NTHI-induced SLF-derived molecules. Immunolabeling showed an increase in MCP-1/CCL2 expression in the cochlear lateral wall of the NTHI-inoculated group. Contrary to the <it>in vitro </it>data, deficiency of MCP-1/CCL2 or CCR2 did not inhibit OM-induced inner ear inflammation <it>in vivo</it>. We demonstrated that targeting MCP-1/CCL2 enhances NTHI-induced up-regulation of MCP-2/CCL8 in SLFs and up-regulates the basal expression of CCR2 in the splenocytes. We also found that targeting CCR2 enhances NTHI-induced up-regulation of MCP-1/CCL2 in SLFs.</p> <p>Conclusions</p> <p>Taken together, we suggest that NTHI-induced SLF-derived MCP-1/CCL2 is a key molecule contributing to inner ear inflammation through CCR2-mediated recruitment of monocytes. However, deficiency of MCP-1/CCL2 or CCR2 alone was limited to inhibit OM-induced inner ear inflammation due to compensation of alternative genes.</p

Current clinical applications of spectral tissue Doppler echocardiography (E/E' ratio) as a noninvasive surrogate for left ventricular diastolic pressures in the diagnosis of heart failure with preserved left ventricular systolic function

Congestive heart failure with preserved left ventricular systolic function has emerged as a growing epidemic medical syndrome in developed countries, which is characterized by high morbidity and mortality rates. Rapid and accurate diagnosis of this condition is essential for optimizing the therapeutic management. The diagnosis of congestive heart failure is challenging in patients presenting without obvious left ventricular systolic dysfunction and additional diagnostic information is most commonly required in this setting. Comprehensive Doppler echocardiography is the single most useful diagnostic test recommended by the ESC and ACC/AHA guidelines for assessing left ventricular ejection fraction and cardiac abnormalities in patients with suspected congestive heart failure, and non-invasively determined basal or exercise-induced pulmonary capillary hypertension is likely to become a hallmark of congestive heart failure in symptomatic patients with preserved left ventricular systolic function. The present review will focus on the current clinical applications of spectral tissue Doppler echocardiography used as a reliable noninvasive surrogate for left ventricular diastolic pressures at rest as well as during exercise in the diagnosis of heart failure with preserved left ventricular systolic function. Chronic congestive heart failure, a disease of exercise, and acute heart failure syndromes are characterized by specific pathophysiologic and diagnostic issues, and these two clinical presentations will be discussed separately

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field