Bile salt-induced apoptosis involves NADPH oxidase isoform activation

BACKGROUND & AIMS: Hydrophobic bile salts trigger a rapid oxidative stress response as an upstream event of CD95 activation and hepatocyte apoptosis. METHODS: The underlying mechanisms were studied by Western blot, immunocytochemistry, protein knockdown, and fluorescence resonance energy transfer microscopy in rat hepatocytes and human hepatoma cell line 7 (Huh7). RESULTS: The rapid oxidative stress formation in response to taurolithocholate-3-sulfate (TLCS) was inhibited by diphenyleneiodonium, apocynin, and neopterin, suggestive for the involvement of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases. TLCS induced a rapid serine phosphorylation of the regulatory subunit p47phox, which was sensitive to inhibition of sphingomyelinase and protein kinase Czeta (PKCzeta). Inhibitors of p47phox phosphorylation and p47phox protein knockdown abolished the TLCS-induced oxidative stress response and blunted subsequent CD95 activation. Consequences of TLCS-induced oxidative stress were c-Jun-N-terminal kinase activation and Yes-dependent activation of the epidermal growth factor receptor (EGFR), followed by EGFR-catalyzed CD95 tyrosine phosphorylation, formation of the death-inducing signaling complex, and execution of apoptosis. As shown by fluorescence resonance energy transfer experiments in Huh7 cells, TLCS induced a c-Jun-N-terminal kinase-dependent EGFR/CD95 association in the cytosol and trafficking of this protein complex to the plasma membrane. Inhibition of EGFR tyrosine kinase activity by AG1478 allowed for cytosolic EGFR/CD95 association, but prevented targeting of the EGFR/CD95 complex to the plasma membrane. Both processes, and TLCS-induced Yes and EGFR activation, were sensitive to inhibition of sphingomyelinase, PKCzeta, or NADPH oxidases. CONCLUSIONS: The data suggest that hydrophobic bile salts activate NADPH oxidase isoforms with the resulting oxidative stress response triggering activation of the CD95 system and apoptosis.     

Longitudinal association between ideal cardiovascular health status and muscular fitness in adolescents: The LabMed Physical Activity Study

Background and aims

Muscular fitness is an emerging predictor for cardiovascular disease mortality. The ideal cardiovascular health metrics has been inversely related to a subsequent cardiometabolic health in adulthood. However, evidence regarding muscular fitness and ideal cardiovascular health in adolescents is scarce. This study aimed to examine the longitudinal association between ideal cardiovascular health index and muscular fitness.

The review process used by U.S. health care plans to evaluate new medical technology for coverage

OBJECTIVE: To examine the process and information used by medical directors (MDs) of private health plans to make medical coverage determinations for new medical technologies, and to assess the influence of plan characteristics on the process. DESIGN: Cross-sectional national survey. PARTICIPANTS: Two hundred thirty-one MDs at private health plans representing 66% and 72% of the U.S. population covered by HMOs and indemnity plans, respectively. MEASUREMENTS: Actual and optimal review process, final decision authority, sources, and evidence used for technology coverage decisions. RESULTS: In 96% of plans, MDs take part in the medical policy review process for new technology. However, MDs have final authority over coverage decisions in only 27% of plans. Indemnity plans are more likely to assert that MDs should be responsible for final decisions, odds ratio (OR)=3.3 (95% confidence interval [95% CI] 1.4, 10). Optimal sources of information on new technology were journals, medical society statements or practice guidelines, and opinions of national experts. Actual sources of information used differed from optimal ones; local experts were used more often than is considered optimal (p<.001). For-profit plans were more likely than nonprofit plans to use national experts, OR 2.5 (95% CI 1.3, 5.0), and practice guidelines, OR 5.0 (95% CI 2.5, 10). Randomized trials (94% of MDs) meta-analyses (61%), and reviews (42%) were considered the best evidence for making coverage decisions. Barriers to making optimal decisions were lack of timely evidence on effectiveness and cost-effectiveness, not legal or regulatory issues; HMO, small, and nonprofit plans were two to three times more likely to list lack of cost-effectiveness data than their counterparts (p<.05). CONCLUSIONS: Although MDs are nearly always involved in the technology evaluation process, a minority of MDs retain final authority over coverage decisions. Evidence from strong scientific research designs is the most frequently cited basis for decisions, but there is need for more timely, rigorous scientific evidence on medical interventions. How a health plan evaluates a new medical technology for coverage varies with identifiable plan characteristics. Presented in part at the 18th annual meeting of the Society of General Internal Medicine and the American Federation for Clinical Research national meeting, San Diego, Calif., May 1995. Supported in part by the Office of Technology Assessment, U.S. Congress, Washington, DC, and computational assistance from General Clinical Research Center grants 5M01RR00722 and RR0035 from the National Center for Research Resources, Bethesda, Md. This paper does not represent policy of either the Agency for Health Care Policy and Research or the U.S. Department of Health and Human Services (DHHS). The views expressed herein are those of the authors and no official endorsement by AHCPR or DHHS is intended or should be inferred.     

Discrete TrkB-expressing neurons of the dorsomedial hypothalamus regulate feeding and thermogenesis

Mutations in the TrkB neurotrophin receptor lead to profound obesity in humans, and expression of TrkB in the dorsomedial hypothalamus (DMH) is critical for maintaining energy homeostasis. However, the functional implications of TrkB-fexpressing neurons in the DMH (DMH^TrkB) on energy expenditure are unclear. Additionally, the neurocircuitry underlying the effect of DMH^TrkB neurons on energy homeostasis has not been explored. In this study, we show that activation of DMH^TrkB neurons leads to a robust increase in adaptive thermogenesis and energy expenditure without altering heart rate or blood pressure, while silencing DMH^TrkB neurons impairs thermogenesis. Furthermore, we reveal neuroanatomically and functionally distinct populations of DMH^TrkB neurons that regulate food intake or thermogenesis. Activation of DMH^TrkB neurons projecting to the raphe pallidus (RPa) stimulates thermogenesis and increased energy expenditure, whereas DMH^TrkB neurons that send collaterals to the paraventricular hypothalamus (PVH) and preoptic area (POA) inhibit feeding. Together, our findings provide evidence that DMH^TrkB neuronal activity plays an important role in regulating energy expenditure and delineate distinct neurocircuits that underly the separate effects of DMH^TrkB neuronal activity on food intake and thermogenesis.

Impairments in energy homeostasis resulting from the compound effects of overeating and sedentary lifestyles have led to a profound increase in the rate of obesity around the world (1). Therapeutic strategies aimed at combating obesity by increasing energy expenditure or decreasing appetite have commonly failed due to counterregulatory mechanisms (2) and adverse side effects on cardiovascular physiology (3–5). To achieve safe and sustained weight loss, it will be essential to understand the mechanisms that govern and coordinate discrete physiological processes that contribute to energy homeostasis.Adaptive thermogenesis is the process by which energy is converted into heat and occurs primarily in brown adipose tissue (BAT) in response to environmental cues (6). BAT has a particularly high capacity for dissipating energy from fat and thus represents an important component of energy homeostasis. The dorsomedial hypothalamus (DMH) in the brain is centrally positioned in an established thermoregulatory neurocircuit, receiving inputs from the preoptic area (POA) (7–9) and sending excitatory projections to preautonomic neurons in the raphe pallidus (RPa) (10–13) that promote sympathetic activity in BAT, leading to increased thermogenesis. Direct chemical stimulation of the DMH (14) or activation of select populations of thermogenic DMH neurons (9, 11, 12, 15) leads to increased body temperature and energy expenditure but also significantly increases heart rate and blood pressure (12, 13, 15, 16). An inability to target increased sympathetic tone specifically in BAT without affecting other target tissues has greatly hampered strategies to treat obesity by targeting thermogenesis (4, 5).In addition to its influence on energy expenditure, the DMH also represents an important brain region in the regulation of feeding (17–19). Lesioning studies support an orexigenic role for the DMH (17), which can promote food intake through inhibitory projections to either the paraventricular hypothalamus (PVH) (18) or the arcuate nucleus (ARC) (20). Despite these early findings, evidence has also emerged that demonstrates the importance of anorexigenic populations of DMH neurons (19, 21, 22). We previously established that the activity of DMH neurons expressing the neurotrophin receptor TrkB (DMH^TrkB) is important for regulating feeding, showing that activation of DMH^TrkB neurons suppresses feeding and that deletion of the TrkB-encoding Ntrk2 gene in the DMH results in hyperphagia and obesity (21). Furthermore, humans with mutations in the TrkB-encoding NTRK2 gene exhibit severe obesity and impaired thermoregulation (23). However, it is unclear whether activation of DMH^TrkB neurons has a direct influence on adaptive thermogenesis. Additionally, the neurocircuitry through which DMH^TrkB neurons govern feeding or energy expenditure is unknown.Here, we demonstrate that DMH^TrkB neuronal activity potently promotes energy expenditure by elevating thermogenesis and physical activity with a notable lack of influence on heart rate and blood pressure. We further reveal that DMH^TrkB neurons send diverging projections to the RPa or the POA and PVH to differentially regulate energy expenditure and food intake, respectively.     

Circulating IL-18 concentration is associated with insulin sensitivity and glucose tolerance through increased fat-free mass

Aims/hypothesis Knowledge of the factors which simultaneously contribute to insulin-resistance-related inflammation may contribute to early therapeutic targeting. IL-18 has recently been described as one of the factors which, in addition to insulin resistance, may also contribute to atherosclerosis. However, the source of IL-18 is not well characterised.Materials and methods We aimed to study body composition (bioelectric impedance), glucose tolerance (OGTT) and insulin sensitivity (minimal model method) in relation to serum IL-18 (ELISA) concentration in 144 otherwise healthy men aged 51.9±12.5 years.Results In contrast to previous observations in women, circulating IL-18 was not significantly associated with BMI (r=0.12, p=0.1) or WHR (r=0.08, p=0.3). IL-18 was also not associated with absolute or percent fat mass (bioelectric impedance, p>0.20) but, interestingly, it was significantly linked to fat-free mass (p=0.03). Serum IL-18 increased with each quartile of fat-free mass, corresponding to values of 64.2; >64.2 to 71.6; >71.6 to 80.9; and 80.9 kg (ANOVA, p<0.0001). IL-18 was more closely associated with postload glucose during an OGTT (p=0.04) rather than with fasting glucose (p=0.1). HbA₁c (p=0.03), HDL-cholesterol (p=0.04) and serum triglycerides (p=0.03) and parameters of systemic inflammation (C-reactive protein, p=0.02) were also significantly associated with circulating IL-18. Insulin sensitivity (minimal model analysis) was linked to circulating IL-18 (p=0.01). In a multiple linear regression analysis this relationship remained significant after controlling for BMI, age and glucose tolerance status. In another model, both fat-free mass and insulin sensitivity contributed to 10% of IL-18 variance.Conclusions/interpretation Fat mass does not seem to influence circulating IL-18, as initially proposed. In contrast, the fat-free mass compartment (a well-known confounder in the evaluation of insulin sensitivity) may significantly contribute to the relationship between IL-18 and insulin action.     

It's LiFe! Mobile and Web-Based Monitoring and Feedback Tool Embedded in Primary Care Increases Physical Activity: A Cluster Randomized Controlled Trial

BackgroundPhysical inactivity is a major public health problem. The It’s LiFe! monitoring and feedback tool embedded in the Self-Management Support Program (SSP) is an attempt to stimulate physical activity in people with chronic obstructive pulmonary disease or type 2 diabetes treated in primary care.ObjectiveOur aim was to evaluate whether the SSP combined with the use of the monitoring and feedback tool leads to more physical activity compared to usual care and to evaluate the additional effect of using this tool on top of the SSP.MethodsThis was a three-armed cluster randomised controlled trial. Twenty four family practices were randomly assigned to one of three groups in which participants received the tool + SSP (group 1), the SSP (group 2), or care as usual (group 3). The primary outcome measure was minutes of physical activity per day. The secondary outcomes were general and exercise self-efficacy and quality of life. Outcomes were measured at baseline after the intervention (4-6 months), and 3 months thereafter.ResultsThe group that received the entire intervention (tool + SSP) showed more physical activity directly after the intervention than Group 3 (mean difference 11.73, 95% CI 6.21-17.25; P<.001), and Group 2 (mean difference 7.86, 95% CI 2.18-13.54; P=.003). Three months after the intervention, this effect was still present and significant (compared to Group 3: mean difference 10.59, 95% CI 4.94-16.25; P<.001; compared to Group 2: mean difference 9.41, 95% CI 3.70-15.11; P<.001). There was no significant difference in effect between Groups 2 and 3 on both time points. There was no interaction effect for disease type.ConclusionsThe combination of counseling with the tool proved an effective way to stimulate physical activity. Counseling without the tool was not effective. Future research about the cost-effectiveness and application under more tailored conditions and in other target groups is recommended.

Trial Registration

ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT01867970","term_id":"NCT01867970"}}NCT01867970, https://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT01867970","term_id":"NCT01867970"}}NCT01867970 (archived by WebCite at http://www.webcitation.org/6a2qR5BSr).     

Patient and Provider Attitudes Toward the Use of Patient Portals for the Management of Chronic Disease: A Systematic Review

Background

Patient portals provide patients with the tools to better manage and understand their health status. However, widespread adoption of patient portals faces resistance from patients and providers for a number of reasons, and there is limited evidence evaluating the characteristics of patient portals that received positive remarks from patients and providers.

Objective

The objectives of this systematic review are to identify the shared characteristics of portals that receive favorable responses from patients and providers and to identify the elements that patients and providers believe need improvement.

Methods

The authors conducted a systematic search of the CINAHL and PubMed databases to gather data about the use of patient portals in the management of chronic disease. Two reviewers analyzed the articles collected in the search process in order remove irrelevant articles. The authors selected 27 articles to use in the literature review.

Results

Results of this systematic review conclude that patient portals show significant improvements in patient self-management of chronic disease and improve the quality of care provided by providers. The most prevalent positive attribute was patient-provider communication, which appeared in 10 of 27 articles (37%). This was noted by both patients and providers. The most prevalent negative perceptions are security (concerns) and user-friendliness, both of which occurred in 11 of 27 articles (41%). The user-friendliness quality was a concern for patients and providers who are not familiar with advanced technology and therefore find it difficult to navigate the patient portal. The high cost of installation and maintenance of a portal system, not surprisingly, deters some providers from implementing such technology into their practice, but this was only mentioned in 3 of the 27 articles (11%). It is possible that the incentives for meaningful use assuage the barrier of cost.

Conclusions

This systematic review revealed mixed attitudes from patients and their providers regarding the use of patient portals to manage their chronic disease. The authors suggest that a standard patient portal design providing patients with the resources to understand and manage their chronic conditions will promote the adoption of patient portals in health care organizations.     

3D技术打印椎体在全脊椎整块切除术中应用的初步探索

目的初步探索3D技术打印椎体在全脊椎整块切除术(Total en bloc spondylectomy,TES)中应用的可行性。方法选取广东紫金蓝塘土猪3只,T12、L1椎体进行后路全椎体切除术,置入3D打印假体,于T11、L2进行双侧椎弓根螺钉固定。观察术后土猪活动度、脊柱影像、双后腿痛觉和肌力。术后4月时处死,观察实体标本情况。结果手术成功,术后猪双后腿活动、痛觉良好。正侧位X片及CT三维重建,实物脊柱3D打印椎体-脊柱复合体观察,提示假体位置、椎间高度、脊椎序列完好。结论 3D技术打印椎体在临床脊柱全椎体切除术中的应用具有可行性,但需充分做好术前准备,如抗感染、补充血容量、假体型号合适、手术器械齐全等,才能保证手术的顺利完成。     

基于课堂视频分析的信息技术与音乐深层整合的研究

信息技术以其突出的优势对中小学音乐教学产生了很大的影响,而在其与音乐课程整合的过程中,所暴露的不足也不容忽视。文章以基于设计的研究为研究范式,建构出深度交融的教学内容,以进行创新教学形式的探索。经过 ITIAS 课堂互动系统的综合分析表明：信息技术和音乐课程的整合教学,不仅营造了信息化的教学环境,更构建了主导—主体相结合的教学结构,也切实提高了学生学习两课程的兴趣。     

教育技术:一种制造“人-机”系统的技术

在教育技术的研究和发展中,系统科学理论及其方法论一直起到非常重要的作用,有着极其深远的意义。文章以系统科学为基础,从教育技术"94定义"与钱学森技术系统定义对比和一些学者的看法这两个方面,指出可把教育技术看作制造教育技术系统的系统方法,然后从教育技术"人-机"系统概念界定、多数教育技术系统是教育技术"人-机"系统、学习者与学习环境整合为一个系统较合理以及教育技术重新解读四方面展开论述,得出教育技术不仅是制造教育技术系统的技术,而且绝大多数的教育技术系统主要是教育技术"人-机"系统,并进而对教育技术的内涵给予了新的解读,以期对教育技术研究及学科发展有所促进。