Tumor necrosis factor restricts hematopoietic stem cell activity in mice: involvement of two distinct receptors.

Whereas maintenance of hematopoietic stem cells (HSCs) is a requisite for life, uncontrolled expansion of HSCs might enhance the propensity for leukemic transformation. Accordingly, HSC numbers are tightly regulated. The identification of physical cellular HSC niches has underscored the importance of extrinsic regulators of HSC homeostasis. However, whereas extrinsic positive regulators of HSCs have been identified, opposing extrinsic repressors of HSC expansion in vivo have yet to be described. Like many other acute and chronic inflammatory diseases, bone marrow (BM) failure syndromes are associated with tumor necrosis factor-α (TNF) overexpression. However, the in vivo relevance of TNF in the regulation of HSCs has remained unclear. Of considerable relevance for normal hematopoiesis and in particular BM failure syndromes, we herein demonstrate that TNF is a cell-extrinsic and potent endogenous suppressor of normal HSC activity in vivo in mice. These effects of TNF involve two distinct TNF receptors

The relationship between prevalence and duration of weight loss strategies and weight loss among overweight managed care organization members enrolled in a weight loss trial

BACKGROUND: Many adults in the United States report engaging in weight loss behaviors. The current study examined weight loss strategies among managed care organization members, to determine the prevalence and impact of weight loss behaviors in this population. We hypothesized that greater engagement in weight loss strategies would be associated with greater weight loss success. METHODS: Data were taken from Weigh-to-Be (WTB), a two-year weight loss trial (N = 1801, 72% female, mean age = 50.7 years, mean weight = 95.9 kg, mean BMI = 34.2 kg/m(2)). Every six months, participants completed a questionnaire assessing frequency and duration of weight loss strategies (calorie reduction, fat reduction, increased fruit/vegetable intake, increased exercise, elimination of sweets, consumption of less food). General linear models and structural equation methods were used to examine associations between weight loss strategy use and weight change over time. RESULTS: Weight loss strategy prevalence rates ranged from 68% to 76% over two years. For all dietary strategies, any use of the strategy between baseline and 24 months was associated with weight loss at 24 months; those who did not engage in the strategy showed weight gains during that period. Results of general linear models and structural equation models indicated that increased use of weight loss strategies was significantly associated with greater 24-month weight loss. CONCLUSION: The prevalence of weight loss strategies in this obese adult managed care population was quite high, and use of these strategies was associated in dose-response fashion with better weight loss. Future interventions may benefit from emphasis on persistence of similar strategies to achieve more successful outcomes

Specific food intake, fat and fiber intake, and behavioral correlates of BMI among overweight and obese members of a managed care organization

BACKGROUND: The study examined correlates of body mass index (BMI) in overweight and obese members of a managed care organization seeking treatment for obesity. It assessed intake of specific foods, dietary fat or fiber, and behaviors attempted to control weight. METHODS: Participants were 508 men and 1293 women who were > 18 years and had a self-reported BMI > 27.0. This paper reports analyses of baseline and 24-month follow-up data from a randomized weight-loss trial. Cross-sectional and prospective relationships between BMI and behaviors were examined with regression analyses controlling for age and education. RESULTS: At baseline, hamburger and beef consumption were associated with higher BMI for men; for women, hamburger, fried chicken, hot dog, bacon or sausage, egg, French fry, and overall fat consumption were associated with higher BMI, while eating high fiber cereal, fruit, and overall fiber intake were associated with lower BMI. Virtually all forms of weight control behavior were reported more often in heavier people. Subscribing to exercise magazines, however, was associated with lower BMI. Decreased fat intake and increased fruit/vegetable/fiber intake over the course of the study were associated with reductions in BMI at 24 months. CONCLUSION: The same behaviors that differentiate individuals with different body weight in the general population also differentiate between individuals of different body weights at the high end of the weight distribution. Educational efforts aimed at preventing weight gain and reducing obesity might benefit from focusing on specific foods known to be associated empirically with body weight and weight change over time

Economic evaluation of a weight control program with e-mail and telephone counseling among overweight employees: a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Distance lifestyle counseling for weight control is a promising public health intervention in the work setting. Information about the cost-effectiveness of such interventions is lacking, but necessary to make informed implementation decisions. The purpose of this study was to perform an economic evaluation of a six-month program with lifestyle counseling aimed at weight reduction in an overweight working population with a two-year time horizon from a societal perspective.</p> <p>Methods</p> <p>A randomized controlled trial comparing a program with two modes of intervention delivery against self-help. 1386 Employees from seven companies participated (67% male, mean age 43 (SD 8.6) years, mean BMI 29.6 (SD 3.5) kg/m²). All groups received self-directed lifestyle brochures. The two intervention groups additionally received a workbook-based program with phone counseling (phone; n=462) or a web-based program with e-mail counseling (internet; n=464). Body weight was measured at baseline and 24 months after baseline. Quality of life (EuroQol-5D) was assessed at baseline, 6, 12, 18 and 24 months after baseline. Resource use was measured with six-monthly diaries and valued with Dutch standard costs. Missing data were multiply imputed. Uncertainty around differences in costs and incremental cost-effectiveness ratios was estimated by applying non-parametric bootstrapping techniques and graphically plotting the results in cost-effectiveness planes and cost-effectiveness acceptability curves.</p> <p>Results</p> <p>At two years the incremental cost-effectiveness ratio was €1009/kg weight loss in the phone group and €16/kg weight loss in the internet group. The cost-utility analysis resulted in €245,243/quality adjusted life year (QALY) and €1337/QALY, respectively. The results from a complete-case analysis were slightly more favorable. However, there was considerable uncertainty around all outcomes.</p> <p>Conclusions</p> <p>Neither intervention mode was proven to be cost-effective compared to self-help.</p> <p>Trial registration</p> <p>ISRCTN04265725</p

Tackling Exascale Software Challenges in Molecular Dynamics Simulations with GROMACS

GROMACS is a widely used package for biomolecular simulation, and over the last two decades it has evolved from small-scale efficiency to advanced heterogeneous acceleration and multi-level parallelism targeting some of the largest supercomputers in the world. Here, we describe some of the ways we have been able to realize this through the use of parallelization on all levels, combined with a constant focus on absolute performance. Release 4.6 of GROMACS uses SIMD acceleration on a wide range of architectures, GPU offloading acceleration, and both OpenMP and MPI parallelism within and between nodes, respectively. The recent work on acceleration made it necessary to revisit the fundamental algorithms of molecular simulation, including the concept of neighborsearching, and we discuss the present and future challenges we see for exascale simulation - in particular a very fine-grained task parallelism. We also discuss the software management, code peer review and continuous integration testing required for a project of this complexity.Comment: EASC 2014 conference proceedin

Islands of conformational stability for Filopodia

Filopodia are long, thin protrusions formed when bundles of fibers grow outwardly from a cell surface while remaining closed in a membrane tube. We study the subtle issue of the mechanical stability of such filopodia and how this depends on the deformation of the membrane that arises when the fiber bundle adopts a helical configuration. We calculate the ground state conformation of such filopodia, taking into account the steric interaction between the membrane and the enclosed semiflexible fiber bundle. For typical filopodia we find that a minimum number of fibers is required for filopodium stability. Our calculation elucidates how experimentally observed filopodia can obviate the classical Euler buckling condition and remain stable up to several tens of . We briefly discuss how experimental observation of the results obtained in this work for the helical-like deformations of enclosing membrane tubes in filopodia could possibly be observed in the acrosomal reactions of the sea cucumber Thyone, and the horseshoe crab Limulus. Any realistic future theories for filopodium stability are likely to rely on an accurate treatment of such steric effects, as analysed in this work

Peripheral neuropathy induced by combination chemotherapy of docetaxel and cisplatin.

Docetaxel, a new semisynthetic taxoid that has demonstrated promising activity as an antineoplastic agent, was administered in combination with cisplatin to 63 patients in a dose-escalating study. As both drugs were known to be potentially neurotoxic, peripheral neurotoxicity was prospectively assessed in detail. Neuropathy was evaluated by clinical sum-score for signs and symptoms and by measurement of the vibration perception threshold (VPT). The severity of neuropathy was graded according to the National Cancer Institute's 'Common Toxicity Criteria'. The docetaxel-cisplatin combination chemotherapy induced a predominantly sensory neuropathy in 29 (53%) out of 55 evaluable patients. At cumulative doses of both cisplatin and docetaxel above 200 mg m(-2), 26 (74%) out of 35 patients developed a neuropathy which was mild in 15, moderate in ten and severe in one patient. Significant correlations were present between both the cumulative dose of docetaxel and cisplatin and the post-treatment sum-score of neuropathy (P < 0.01) as well as the post-treatment VPT (P < 0.01). The neurotoxic effects of this combination were more severe than either cisplatin or docetaxel as single agent at similar doses

Associations between daily sitting time and the combinations of lifestyle risk factors in men

Background: Understanding the reciprocal role that multiple problematic behaviours play in men's health is important for intervention delivery and for reducing the healthcare burden. Data regarding the concurrence of problematic health behaviours is currently limited but offers insights into risk profiles, and should now include total time spent sitting/day. Methods: Self-reported data on lifestyle health behaviours was collected from 232 men aged ≥18 years who engaged in a men's health promotion programme delivered by 16 English Premier League Clubs. Results: Men at risk due to high sitting display multiple concurrent lifestyle risk factors, 88.6% displayed at least two ancillary risk factors and were three times more likely to report ≥2 lifestyle risk factors (OR. =3.13, 95% confidence interval (CI). =1.52-6.42) than those with low sitting risk. Significant differences in the mean number of risk factors reported between those participants in the higher risk (2.43. ±. 0.90) and lower risk (2.13. ±. 0.96) sitting categories were also found (P=0.015). Conclusions: Hard-to-reach men displayed multiple problematic concurrent behaviours, strongly linked to total sitting time. © 2012 WPMH GmbH

The Role of Age, Education, and Digital Health Literacy in the Usability of Internet-Based Cognitive Behavioral Therapy for Chronic Pain:Mixed Methods Study

Contains fulltext : 215537.pdf (publisher's version ) (Open Access)BACKGROUND: Internet-based cognitive behavior therapy (iCBT) can be effective in mental and somatic health care. Research on the feasibility of internet interventions in clinical practice is, however, still scarce. Studies with a focus on the patient regarding usability of interventions and digital health literacy skills are especially lacking. OBJECTIVE: The goal of this study was to assess the usability of an iCBT for chronic pain, Master Your Pain, and the relationship between its usability outcomes and the factors age, educational level, and digital health literacy skills. The aims were to determine what changes were needed in the program for sufficient usability and which individual characteristics were related to the usability of the program. METHODS: Patients were recruited from two mental health care practices. A mixed methods approach was used in this study. A qualitative observational study comprising performance tasks in the iCBT program was used to test usability. A quantitative questionnaire was used to measure possible related constructs. Usability was operationalized as the number of tasks that could be completed and the type and number of problems that occurred while doing so. Performance tasks were set up to measure 6 digital skills: (1) operating the computer and internet browser, (2) navigation and orientation, (3) using search strategies, (4) evaluating relevance of content, (5) adding personal content, and (6) protecting and respecting privacy. Participants were asked to think aloud while performing the tasks, and screen activities and webcam recordings were captured. The qualitative observational data was coded using inductive analysis by two independent researchers. Correlational analyses were performed to test how usability relates to sociodemographics and digital health literacy. RESULTS: A total of 32 patients participated, with a mean age of 49.9 years and 84% (27/32) being female. All performance tasks except one (fill in a diary registration) could be completed independently by more than 50% of the participants. On operational, navigation, and search levels, participants struggled most with logging in, logging out, and finding specific parts of the intervention. Half of the sample experienced problems evaluating the relevance and adding content to the program to some extent. Usability correlated moderately negatively with age and moderately positively with digital health literacy skills but not with educational level. CONCLUSIONS: The results provide insight into what is essential for proper usability regarding the design of an iCBT program considering variations in age, educational level, and digital health literacy. Furthermore, the results provide insight into what type of support is needed by patients to properly use the intervention. Tailoring support among the needs of certain age groups or skill levels could be beneficial and could range from no extra support (only online feedback, as intended) to practical support (an additional usability introduction session) to blended care (combined face-to-face sessions throughout the therapy)