The state of US health, 1990-2010: burden of diseases, injuries, and risk factors.
Understanding the major health problems in the United States and how they are changing over time is critical for informing national health policy. To measure the burden of diseases, injuries, and leading risk factors in the United States from 1990 to 2010 and to compare these measurements with those of the 34 countries in the Organisation for Economic Co-operation and Development (OECD) countries. We used the systematic analysis of descriptive epidemiology of 291 diseases and injuries, 1160 sequelae of these diseases and injuries, and 67 risk factors or clusters of risk factors from 1990 to 2010 for 187 countries developed for the Global Burden of Disease 2010 Study to describe the health status of the United States and to compare US health outcomes with those of 34 OECD countries. Years of life lost due to premature mortality (YLLs) were computed by multiplying the number of deaths at each age by a reference life expectancy at that age. Years lived with disability (YLDs) were calculated by multiplying prevalence (based on systematic reviews) by the disability weight (based on population-based surveys) for each sequela; disability in this study refers to any short- or long-term loss of health. Disability-adjusted life-years (DALYs) were estimated as the sum of YLDs and YLLs. Deaths and DALYs related to risk factors were based on systematic reviews and meta-analyses of exposure data and relative risks for risk-outcome pairs. Healthy life expectancy (HALE) was used to summarize overall population health, accounting for both length of life and levels of ill health experienced at different ages. US life expectancy for both sexes combined increased from 75.2 years in 1990 to 78.2 years in 2010; during the same period, HALE increased from 65.8 years to 68.1 years. The diseases and injuries with the largest number of YLLs in 2010 were ischemic heart disease, lung cancer, stroke, chronic obstructive pulmonary disease, and road injury. Age-standardized YLL rates increased for Alzheimer disease, drug use disorders, chronic kidney disease, kidney cancer, and falls. The diseases with the largest number of YLDs in 2010 were low back pain, major depressive disorder, other musculoskeletal disorders, neck pain, and anxiety disorders. As the US population has aged, YLDs have comprised a larger share of DALYs than have YLLs. The leading risk factors related to DALYs were dietary risks, tobacco smoking, high body mass index, high blood pressure, high fasting plasma glucose, physical inactivity, and alcohol use. Among 34 OECD countries between 1990 and 2010, the US rank for the age-standardized death rate changed from 18th to 27th, for the age-standardized YLL rate from 23rd to 28th, for the age-standardized YLD rate from 5th to 6th, for life expectancy at birth from 20th to 27th, and for HALE from 14th to 26th. From 1990 to 2010, the United States made substantial progress in improving health. Life expectancy at birth and HALE increased, all-cause death rates at all ages decreased, and age-specific rates of years lived with disability remained stable. However, morbidity and chronic disability now account for nearly half of the US health burden, and improvements in population health in the United States have not kept pace with advances in population health in other wealthy nations.


Cytoskeletal protein and mRNA accumulation during brush border formation in adult chicken enterocytes.
We have explored the development of the brush border in adult chicken enterocytes by analyzing the cytoskeletal protein and mRNA levels as enterocytes arise from crypt stem cells and differentiate as they move toward the villus. At the base of the crypt, a small population of cells contain a rudimentary terminal web and a few short microvilli with long rootlets. These microvilli appear to arise from bundles of actin filaments which nucleate on the plasma membrane. The microvilli apparently elongate via the addition of membrane supplied by vesicles that fuse with the microvillus and extend the membrane around the actin core. Actin, villin, myosin, tropomyosin and spectrin, but not myosin I (previously called 110 kD; see Mooseker and Coleman, J. Cell Biol. 108, 2395-2400, 1989) are already concentrated in the luminal cytoplasm of crypt cells, as seen by immunofluorescence. Using quantitative densitometry of cDNA-hybridized RNA blots from cells isolated from crypts, villus middle (mid), or villus tip (tip), we found a 2- to 3-fold increase in villin, calmodulin and tropomyosin steady-state mRNA levels; an increase parallel to morphological brush border development. Actin, spectrin and myosin mRNA levels did not change significantly. ELISA of total crypt, mid and tip cell lysates show that there are no significant changes in actin, myosin, spectrin, tropomyosin, myosin I, villin or alpha-actinin protein levels as the brush border develops. The G-/F-actin ratio also did not change with brush border assembly. We conclude that, although the brush border is not fully assembled in immature enterocytes, the major cytoskeletal proteins are present in their full concentration and already localized within the apical cytoplasm. Therefore brush border formation may involve reorganization of a pool of existing cytoskeletal proteins mediated by the expression or regulation of an unidentified key protein(s).


Changes in weight loss, body composition and cardiovascular disease risk after altering macronutrient distributions during a regular exercise program in obese women.
This study's purpose investigated the impact of different macronutrient distributions and varying caloric intakes along with regular exercise for metabolic and physiological changes related to weight loss. One hundred forty-one sedentary, obese women (38.7 ± 8.0 yrs, 163.3 ± 6.9 cm, 93.2 ± 16.5 kg, 35.0 ± 6.2 kg•m(-2), 44.8 ± 4.2% fat) were randomized to either no diet + no exercise control group (CON) a no diet + exercise control (ND), or one of four diet + exercise groups (high-energy diet [HED], very low carbohydrate, high protein diet [VLCHP], low carbohydrate, moderate protein diet [LCMP] and high carbohydrate, low protein [HCLP]) in addition to beginning a 3x•week(-1) supervised resistance training program. After 0, 1, 10 and 14 weeks, all participants completed testing sessions which included anthropometric, body composition, energy expenditure, fasting blood samples, aerobic and muscular fitness assessments. Data were analyzed using repeated measures ANOVA with an alpha of 0.05 with LSD post-hoc analysis when appropriate. All dieting groups exhibited adequate compliance to their prescribed diet regimen as energy and macronutrient amounts and distributions were close to prescribed amounts. Those groups that followed a diet and exercise program reported significantly greater anthropometric (waist circumference and body mass) and body composition via DXA (fat mass and % fat) changes. Caloric restriction initially reduced energy expenditure, but successfully returned to baseline values after 10 weeks of dieting and exercising. Significant fitness improvements (aerobic capacity and maximal strength) occurred in all exercising groups. No significant changes occurred in lipid panel constituents, but serum insulin and HOMA-IR values decreased in the VLCHP group. Significant reductions in serum leptin occurred in all caloric restriction + exercise groups after 14 weeks, which were unchanged in other non-diet/non-exercise groups. Overall and over the entire test period, all diet groups which restricted their caloric intake and exercised experienced similar responses to each other. Regular exercise and modest caloric restriction successfully promoted anthropometric and body composition improvements along with various markers of muscular fitness. Significant increases in relative energy expenditure and reductions in circulating leptin were found in response to all exercise and diet groups. Macronutrient distribution may impact circulating levels of insulin and overall ability to improve strength levels in obese women who follow regular exercise.


Bacterial Associates Modify Growth Dynamics of the Dinoflagellate Gymnodinium catenatum.
Marine phytoplankton cells grow in close association with a complex microbial associate community known to affect the growth, behavior, and physiology of the algal host. The relative scale and importance these effects compared to other major factors governing algal cell growth remain unclear. Using algal-bacteria co-culture models based on the toxic dinoflagellate Gymnodinium catenatum, we tested the hypothesis that associate bacteria exert an independent effect on host algal cell growth. Batch co-cultures of G. catenatum were grown under identical environmental conditions with simplified bacterial communities composed of one-, two-, or three-bacterial associates. Modification of the associate community membership and complexity induced up to four-fold changes in dinoflagellate growth rate, equivalent to the effect of a 5°C change in temperature or an almost six-fold change in light intensity (20-115 moles photons PAR m-2 s-1). Almost three-fold changes in both stationary phase cell concentration and death rate were also observed. Co-culture with Roseobacter sp. DG874 reduced dinoflagellate exponential growth rate and led to a more rapid death rate compared with mixed associate community controls or co-culture with either Marinobacter sp. DG879, Alcanivorax sp. DG881. In contrast, associate bacteria concentration was positively correlated with dinoflagellate cell concentration during the exponential growth phase, indicating growth was limited by supply of dinoflagellate-derived carbon. Bacterial growth increased rapidly at the onset of declining and stationary phases due to either increasing availability of algal-derived carbon induced by nutrient stress and autolysis, or at mid-log phase in Roseobacter co-cultures potentially due to the onset of bacterial-mediated cell lysis. Co-cultures with the three bacterial associates resulted in dinoflagellate and bacterial growth dynamics very similar to more complex mixed bacterial community controls, suggesting that three-way co-cultures are sufficient to model interaction and growth dynamics of more complex communities. This study demonstrates that algal associate bacteria independently modify the growth of the host cell under non-limiting growth conditions and supports the concept that algal-bacterial interactions are an important structuring mechanism in phytoplankton communities.


CD157 enhances malignant pleural mesothelioma aggressiveness and predicts poor clinical outcome.
Malignant mesothelioma is a deadly tumor whose diagnosis and treatment remain very challenging. There is an urgent need to advance our understanding of mesothelioma biology and to identify new molecular markers for improving management of patients. CD157 is a membrane glycoprotein linked to ovarian cancer progression and mesenchymal differentiation. The common embryonic origin of ovarian epithelial cells and mesothelial cells and the evident similarities between ovarian and mesothelial cancer prompted us to investigate the biological role and clinical significance of CD157 in malignant pleural mesothelioma (MPM). CD157 mRNA and protein were detected in four of nine MPM cell lines of diverse histotype and in 85.2% of MPM surgical tissue samples (32/37 epithelioid; 37/44 biphasic). CD157 expression correlated with clinical aggressiveness in biphasic MPM. Indeed, high CD157 was a negative prognostic factor and an independent predictor of poor survival for patients with biphasic MPM by multivariate survival analysis (HR = 2.433, 95% CI 1.120-5.284; p = 0.025). In mesothelioma cell lines, CD157 gain (in CD157-negative cells) or knockdown (in CD157-positive cells) affected cell growth, migration, invasion and tumorigenicity, most notably in biphasic MPM cell lines. In these cells, CD157 expression was associated with increased activation of the mTOR signaling pathway, resulting in decreased platinum sensitivity. Moreover, a trend towards reduced survival was observed in patients with biphasic MPM receiving postoperative platinum-based chemotherapy. These findings indicate that CD157 is implicated in multiple aspects of MPM progression and suggest that CD157 expression could be used to stratify patients into different prognostic groups or to select patients that might benefit from particular chemotherapeutic approach.


A framework for production of systematic review based briefings to support evidence-informed decision-making.
We have developed a framework for translating existing sources of synthesized and quality-assessed evidence, primarily systematic reviews, into actionable messages in the form of short accessible briefings. The service aims to address real-life problems in response to requests from decision-makers.Development of the framework was based on a scoping review of existing resources and our initial experience with two briefing topics, including models of service provision for young people with eating disorders. We also drew on previous experience in dissemination research and practice. Where appropriate, we made use of the SUPporting POlicy relevant Reviews and Trials (SUPPORT) tools for evidence-informed policymaking. To produce a product that it is fit for this purpose it has been necessary to go beyond a traditional summary of the available evidence relating to effectiveness. Briefings have, therefore, included consideration of cost effectiveness, local applicability, implications relating to local service delivery, budgets, implementation and equity. Our first evidence briefings produced under this framework cover diagnostic endoscopy by specialist nurses and integrated care pathways in mental healthcare settings. The framework will enable researchers to present and contextualize evidence from systematic reviews and other sources of synthesized and quality-assessed evidence. The approach is designed to address the wide range of questions of interest to decision-makers, especially those commissioning services or managing service delivery and organization in primary or secondary care. Evaluation of the use and usefulness of the evidence briefings we produce is an integral part of the framework and will help to fill a gap in the literature.


Fusion of the envelope of mucous droplets with the luminal plasma membrane in acinar cells of the cat submandibular gland.
The release of mucus from acinar cells of the cat submandibular gland was examined by electron microscopy. The limiting membrane of mucous droplets fuses with the luminal plasma membrane to form a five-layered contact. This is converted to a three-layered membrane (unit membrane) by avulsion of the plasmalemma. Attenuation and rupture of this membranous barrier permits the contents of the mucous droplets to flow into the lumen.


Emerging MEK inhibitors.
The Ras/Raf/MEK/ERK pathway is often activated by genetic alterations in upstream signaling molecules. Integral components of this pathway such as Ras and B-Raf are also activated by mutation. The Ras/Raf/MEK/ERK pathway has profound effects on proliferative, apoptotic and differentiation pathways. This pathway can often be effectively silenced by MEK inhibitors. AREAS COVERED BY THIS REVIEW: This review will discuss targeting of MEK which could lead to novel methods to control abnormal proliferation which arises in cancer and other proliferative diseases. This review will cover the scientific literature from 1980 to present and is a follow on from a review which focused on Emerging Raf Inhibitors published in this same review series. By reading this review the reader will understand the important roles that genetics play in the response of patients to MEK inhibitors, the potential of combining MEK inhibitors with other types of therapy, the prevention of cellular aging and the development of cancer stem cells. Targeting MEK has been shown to be effective in suppressing many important pathways involved in cell growth and the prevention of apoptosis. MEK inhibitors have many potential therapeutic uses in the suppression of cancer, proliferative diseases and aging.


I'll be gone, you'll be gone: why American employers underinvest in health.
It has become increasingly common to hear a business case for wellness that emphasizes the benefits of having a healthy workforce. This is essentially the same as the case for employers to train their workers; training a worker and investing in the health of the worker both represent a productivity-enhancing investment in the worker by the firm. The problem is that the employer frequently fails to capture the returns on the investment. A healthier or better-skilled worker can command a higher wage and threaten to leave the firm making the investment. This risk of failing to capture the gains from investment produces underinvestment in skills and, by the same mechanism, should produce underinvestment in workforce wellness. We further divide wellness into positive and negative policies: Positive wellness is an investment, expenditure on the workforce in expectation of future increased returns, or perhaps better recruitment and retention. Negative wellness is an effort to reduce the wage bills associated with ill health with, for example, co-pays. Most stable and meaningful employer wellness programs are likely to be negative wellness programs that reduce the effective wages of the sick.


An explicit transition density expansion for a multi-allelic Wright-Fisher diffusion with general diploid selection.
Characterizing time-evolution of allele frequencies in a population is a fundamental problem in population genetics. In the Wright-Fisher diffusion, such dynamics is captured by the transition density function, which satisfies well-known partial differential equations. For a multi-allelic model with general diploid selection, various theoretical results exist on representations of the transition density, but finding an explicit formula has remained a difficult problem. In this paper, a technique recently developed for a diallelic model is extended to find an explicit transition density for an arbitrary number of alleles, under a general diploid selection model with recurrent parent-independent mutation. Specifically, the method finds the eigenvalues and eigenfunctions of the generator associated with the multi-allelic diffusion, thus yielding an accurate spectral representation of the transition density. Furthermore, this approach allows for efficient, accurate computation of various other quantities of interest, including the normalizing constant of the stationary distribution and the rate of convergence to this distribution.


Maximum use of the anterior maxillary buttress in severe maxillary atrophy with tilted, palatally positioned implants: a preliminary study.
To evaluate an alternative treatment for rehabilitation of the atrophic maxilla with palatal and tilted implants and to assess patient satisfaction with the results. A retrospective case study was made of completely edentulous subjects with tilted, palatally positioned implants in the anterior maxillary buttress placed and loaded between January 2005 and January 2007. Patients with severely resorbed edentulous maxillae (Class V according to Cawood and Howell) who requested overdentures and were followed for 12 months after implant loading were included. Mesial and distal implant bone loss was measured on panoramic radiographs. Subjects indicated satisfaction with the new prosthesis after 12 months on a visual analog scale. Twelve patients treated with tilted and palatal implants in the anterior maxillary buttress were included in the study; 48 implants were placed (4 implants in each patient) to support 12 overdentures with bars. One implant failed, resulting in a survival rate of 97.9%. The mean peri-implant bone loss of implants with palatal anchorage after 1 year of loading was 0.78 ± 0.5 mm. All patients had stable prostheses at the end of the observation period. Patients were satisfied with comfort and stability, ability to speak, ease of cleaning, esthetics, and function of the prosthesis. Placement of implants slightly to the palatal and tilted in the anterior maxillary buttress to support an overdenture with bars may be a viable treatment alternative for the rehabilitation of the atrophic maxilla, providing a high level of satisfaction with the prosthesis and reducing patient morbidity and costs.


Synthesis of novel 3-halo-3-nitroflavanones and their activities as DNA methyltransferase inhibitors in cancer cells.
The implication of DNA methylation in cancer is today clearly established. Despite that nucleoside analogues are currently used for leukaemia treatment, their low stability in physiological conditions and their lack of selectivity arise the need for the identification of non-nucleoside DNA methyltransferase inhibitors. Here, we describe the synthesis and pharmacological characterisation of a novel class of DNA methyltransferase inhibitors: the 3-halo-3-nitroflavanones. We showed that 3-bromo-3-nitroflavanones 3b and 4a have a micromolar DNMT inhibition and an increased potency in a cell reporter model. Interestingly they are significantly more stable than the reference compounds and induce a low cytotoxicity, supporting them as new candidates for the development of non-cytotoxic cell-reprogramming epi-drugs for anticancer treatment.


Magnetic resonance imaging-guided laser interstitial thermal therapy for previously treated hypothalamic hamartomas.
OBJECTIVE Hypothalamic hamartomas (HHs) are associated with gelastic seizures and the development of medically refractory epilepsy. Magnetic resonance imaging-guided laser interstitial thermal therapy (MRg-LITT) is a minimally invasive ablative treatment that may have applicability for these deep-seated lesions. Here, the authors describe 3 patients with refractory HHs who they treated with MRg-LITT. METHODS An institutional review board-approved prospective database of patients undergoing Visualase MRg-LITT was retrospectively reviewed. Demographic and historical medical data, including seizure and medication histories, previous surgeries, procedural details, and surgical complications, along with radiological interpretation of the HHs, were recorded. The primary outcome was seizure freedom, and secondary outcomes included medication reduction, seizure frequency, operative morbidity, and clinical outcome at the latest follow-up. RESULTS All 3 patients in the multi-institutional database had developed gelastic seizures related to HH at the ages of 7, 7, and 9 years. They presented for further treatment at 25, 28, and 48 years of age, after previous treatments with stereotactic radiosurgery in all cases and partial hamartoma resection in one case. One ablation was complicated by a small tract hemorrhage, which was stable on postoperative imaging. One patient developed hyponatremia and experienced weight gain, which were respectively managed with fluid restriction and counseling. At the most recent follow-up at a mean of 21 months (range 1-32 months), one patient was seizure free while another had meaningful seizure reduction. Medication was reduced in one case. CONCLUSIONS Adults with gelastic seizures despite previous treatments can undergo MRg-LITT with reasonable safety and efficacy. This novel therapy may provide a minimally invasive alternative for primary and recurrent HH as the technique is refined.


Amiloride inhibition of gamma-aminobutyric acid(A) receptors depends upon the alpha subunit subtype.
gamma-Aminobutyric acid(A) (GABA(A)) receptors (GABARs) are responsible for most fast inhibitory neurotransmission in the mammalian brain. The GABARs contain several allosteric modulatory sites, many of which are useful clinically. The activity of most of these modulators depends upon the subunit composition of the receptor. The diuretic amiloride was previously reported to inhibit GABARs in frog sensory neurons. We measured its effects on recombinant GABARs to determine its mechanism of action at mammalian receptors and to examine the effect of subunit composition. Amiloride acted primarily as a competitive antagonist, reducing the sensitivity of the receptor to GABA without affecting the maximal current amplitude. Receptors containing an alpha6 subunit were about 10-fold more sensitive to amiloride than those containing other alpha subunits. In contrast, the identity of the beta or gamma subtype had little effect on amiloride sensitivity. Although several other modulators have specific effects at alpha6-containing receptors, amiloride is the first inhibitor to be reported with no additional dependence on the identity of the beta or gamma subunit. Therefore, it probably represents a unique modulatory site on the GABAR, which could be useful for developing drugs targeting these receptors. The selective activity of amiloride could also be helpful for isolating the contribution of receptors composed of alpha6 subtypes in heterogeneous native GABAR populations.


Sir Henry Solomon Wellcome and Dr Andrew Balfour: an enterprise on the Nile and the early foundation of public health and medical research in the Sudan (1899-1935).
In Sudan, modern medical practice and medical research began soon after the creation of Anglo-Egyptian Sudan at the turn of the 20th century. The benevolent involvement of Sir Henry Solomon Wellcome, and the ingenious feat of his protégé Sir Andrew Balfour, was crucial to the strong foundation of that establishment. Sir Henry Wellcome provided the financial sponsorship plus influential, logistical and moral support. Dr Balfour put great energy into making the enterprise one of the most amazing medical achievements in colonial medicine. Improvement in the public health of the capital Khartoum was emulated by other doctors working in this vast country. Research was not restricted to tropical medicine; it also encompassed agricultural and chemical research. This helped with the establishment of the first modern medical school in the country in 1924 and resulted in the medical service in Sudan being described as one of the best in the world. Many British doctors flocked to Sudan to make a fortune and to set a path for their career back in Britain.


High prevalence of structural heart disease in children with cblC-type methylmalonic aciduria and homocystinuria.
To characterize the frequency and nature of cardiovascular defects in patients with CblC-type methylmalonic aciduria and homocystinuria (cblC), an inborn error of cobalamin (vitamin B12) metabolism resulting in accumulation of methylmalonic acid and homocysteine. A retrospective observational study was conducted investigating 10 patients with cblC ranging in age from 2 weeks to 24 years (mean 4.4 years +/- 7.5 years, median 0.6 years). All patients underwent a complete 2-D echocardiogram including quantitative assessment of left ventricular systolic function. Structural heart defects were detected in 50% of patients with cblC. Heart defects included left ventricular (LV) non-compaction (3), secundum atrial septal defect (2), muscular ventricular septal defect (1), dysplastic pulmonary valve without pulmonary stenosis (1) and mitral valve prolapse with mild mitral regurgitation (1). One patient had resolved cor pulmonale and right heart failure secondary to pulmonary embolism. All patients had quantitatively normal LV systolic function. Diverse and clinically significant structural heart defects appear to be highly prevalent in cblC, perhaps due to abnormal DNA and histone methylation during embryogenesis. The specific cardiac defects detected in our cohort were variable, and studies with a larger number of patients are needed to establish which forms are most common. Routine and periodic cardiovascular evaluation may be indicated in patients with cblC.


Statistical modeling of single target cell encapsulation.
High throughput drop-on-demand systems for separation and encapsulation of individual target cells from heterogeneous mixtures of multiple cell types is an emerging method in biotechnology that has broad applications in tissue engineering and regenerative medicine, genomics, and cryobiology. However, cell encapsulation in droplets is a random process that is hard to control. Statistical models can provide an understanding of the underlying processes and estimation of the relevant parameters, and enable reliable and repeatable control over the encapsulation of cells in droplets during the isolation process with high confidence level. We have modeled and experimentally verified a microdroplet-based cell encapsulation process for various combinations of cell loading and target cell concentrations. Here, we explain theoretically and validate experimentally a model to isolate and pattern single target cells from heterogeneous mixtures without using complex peripheral systems.


Anticipatory synergy adjustments in preparation to self-triggered perturbations in elderly individuals.
We tested the ability of healthy elderly persons to use anticipatory synergy adjustments (ASAs) prior to a self-triggered perturbation of one of the fingers during a multifinger force production task. An index of a force-stabilizing synergy was computed reflecting covariation of commands to fingers. The subjects produced constant force by pressing with the four fingers of the dominant hand on force sensors against constant upwardly directed forces. The middle finger could be unloaded either by the subject pressing the trigger or unexpectedly by the experimenter. In the former condition, the synergy index showed a drop (interpreted as ASA) prior to the time of unloading. This drop started later and was smaller in magnitude as compared with ASAs reported in an earlier study of younger subjects. At the new steady state, a new sharing pattern of the force was reached. We conclude that aging is associated with a preserved ability to explore the flexibility of the mechanically redundant multifinger system but a decreased ability to use feedforward adjustments to self-triggered perturbations. These changes may contribute to the documented drop in manual dexterity with age.


Systematic comparison of peptidic proteasome inhibitors highlights the α-ketoamide electrophile as an auspicious reversible lead motif.
The ubiquitin-proteasome system (UPS) has been successfully targeted by both academia and the pharmaceutical industry for oncological and immunological applications. Typical proteasome inhibitors are based on a peptidic backbone endowed with an electrophilic C-terminus by which they react with the active proteolytic sites. Although the peptide moiety has attracted much attention in terms of subunit selectivity, the target specificity and biological stability of the compounds are largely determined by the reactive warheads. In this study, we have carried out a systematic investigation of described electrophiles by a combination of in vitro, in vivo, and structural methods in order to disclose the implications of altered functionality and chemical reactivity. Thereby, we were able to introduce and characterize the class of α-ketoamides as the most potent reversible inhibitors with possible applications for the therapy of solid tumors as well as autoimmune disorders.


Nonalcoholic Fatty Liver Disease in Adults: Current Concepts in Etiology, Outcomes, and Management.
Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disease, extending from simple steatosis to inflammation and fibrosis with a significant risk for the development of cirrhosis. It is highly prevalent and is associated with significant adverse outcomes both through liver-specific morbidity and mortality but, perhaps more important, through adverse cardiovascular and metabolic outcomes. It is closely associated with type 2 diabetes and obesity, and both of these conditions drive progressive disease toward the more advanced stages. The mechanisms that govern hepatic lipid accumulation and the predisposition to inflammation and fibrosis are still not fully understood but reflect a complex interplay between metabolic target tissues including adipose and skeletal muscle, and immune and inflammatory cells. The ability to make an accurate assessment of disease stage (that relates to clinical outcome) can also be challenging. While liver biopsy is still regarded as the gold-standard investigative tool, there is an extensive literature on the search for novel noninvasive biomarkers and imaging modalities that aim to accurately reflect the stage of underlying disease. Finally, although no therapies are currently licensed for the treatment of NAFLD, there are interventions that appear to have proven efficacy in randomized controlled trials as well as an extensive emerging therapeutic landscape of new agents that target many of the fundamental pathophysiological processes that drive NAFLD. It is highly likely that over the next few years, new treatments with a specific license for the treatment of NAFLD will become available.


Oscheius microvilli n. sp. (Nematoda: Rhabditidae): A Facultatively Pathogenic Nematode from Chongming Island, China.
A new species, Oscheius microvilli n. sp., was found on Chongming Island (Shanghai, China). The new species is morphologically similar to the type strain of Oscheius myriophilus, but can be distinguished from it and other species of Oscheius on the basis of unique morphological characteristics of the bursa as well as male papillae. In this new species, the male bursal papillar formula is 2, 1, 3, 3 with everted tips in the first, fifth, and seventh pairs. The bursal rim is jagged, joins together anterior to the spicules, and is partially extended and decorated with microvilli. The spicules are incompletely separated, and the tail does not extend beyond the bursa. Phylogenetic trees of 18S rDNA and internal transcribed spacer indicate that the new species belongs to the insectivora group of the genus Oscheius; it is most closely related to O. myriophilus, and the two species can be distinguished on the basis of their different body length, morphological features of the bursa, and molecular data. The new species is facultatively associated with a bacterial strain of Serratia. The LC50 of this novel nematode against Galleria mellonella was 69.1 dauer juveniles per milliliter after 48 hr of infection.


Isolation and characterization of mesenchymal stem cells from chicken bone marrow.
The bone marrow mesenchymal stem cells (BMSCs) are multipotent stem cells, which can differentiate in vitro into many cell types. However, the vast majority of experimental materials were obtained from human, mouse, rabbit and other mammals, but rarely in poultry. So, in this study, Thirty- to sixty-day old chicken was chosen as experimental animal, to isolate and characterize BMSCs from them. To investigate the biological characteristics of chicken BMSCs, immunofluorescence and RT-PCR were used to detect the characteristic surface markers of BMSCs. Growth curves were drawn in accordance with cell numbers. To assess the differentiation capacity of the BMSCs, cells were induced to differentiate into osteoblasts, adipocytes, and endothelial cells. The surface markers of BMSCs, CD29, CD44, CD31, CD34, CD71 and CD73, were detected by immunofluorescence and RT-PCR assays. The growth curves of different passages were all typically sigmoidal. Karyotype analysis showed that these in vitro cultured cells were genetically stable. In addition, BMSCs were successfully induced to differentiate into osteoblasts, adipocytes, and endothelial cells. The results suggest that the BMSCs isolated from chicken possess similar biological characteristics with those separated from other species, and their multi-lineage differentiation potentiality herald a probable application for cellular transplant therapy in tissue engineering.


A microbiological evaluation of level of disinfection for flexible cystoscopes protected by disposable endosheaths.
Flexible cystoscopy is used in urological outpatient departments for diagnostic cystoscopy of bladder cancer and requires a high-level disinfection between each patient. The purpose of this study was to make a microbiological post disinfection efficacy assessment of flexible cystoscopes (FC) using disposable sterile endosheaths. One hundred endosheaths underwent a leak-test for barrier integrity after cystoscopy. Microbiological samples from these cystoscopies were obtained; after removal of the endosheath, and after cleaning the scope with a detergent cloth, rinsing with tap water followed by 70% ethanol disinfection and subsequent drying. The number of colony forming units (cfu) from the samples was counted after 72 hours and then divided in three categories, Clean FC (<5 cfu/sample), Critical FC (5-50 cfu/sample) and High-risk FC (>50 cfu/sample). The result was compared with data of 10 years continuous control sampling recorded in the Copenhagen Clean-Endoscope Quality Control Database (CCQCD) and analyzed with a Chi-square test for homogeneity. All 100 endosheaths passed the leak-test. All samples showed a Clean FC and low means of cfu. A query to the CCQCD, showed that 99.8% (1264/1267) of all FC with a built-in work-channel reprocessed in a WD were clean before use. The reprocessing of FC using endosheaths, as preformed in this study, provides a patient-ready procedure. The results display a reprocessing procedure with low risk of pathogen transmission, high patient safety and a valid alternative to the recommended high-level disinfection procedure of FC. However, the general impression was that sheaths slightly reduced vision and resulted in some patient discomfort.


Phosphorylation of the C-Raf N Region Promotes Raf Dimerization.
The activation of Raf kinases by the small GTPase Ras requires two major sets of phosphorylations. One set lies within the activation loop, and the other lies within the N-terminal acidic region (N region). In the most abundant isoform of Raf, C-Raf, N-region phosphorylations occur on serine 338 (S338) and tyrosine 341 (Y341) and are thought to provide allosteric activation of the Raf dimer. We show that the phosphorylations of these N-region sites does not require C-Raf dimerization, but rather, they precede dimerization. One of these phosphorylations (phospho-Y341) is required for C-Raf dimerization, and this action can be replicated by phosphomimetic mutants both in vivo and in vitro The role of the phosphorylation of Y341 in promoting Raf dimerization is distinct from its well-known function in facilitating S338 phosphorylation. In Ras mutant pancreatic cancer cell lines, the phosphorylation and dimerization of C-Raf are basally elevated. Dimerization is thought to contribute to their elevated growth rate through their activation of the mitogen-activated protein (MAP) kinase (extracellular signal-regulated kinase [ERK]) signaling cascade. Blocking the tyrosine phosphorylation of C-Raf with Src family inhibitors blocks growth, basal dimerization, and ERK activation in these cells. We suggest that the kinases mediating C-Raf Y341 phosphorylation are potential candidate drug targets in selected Ras-dependent cancers.


Use of medicines by adults in Germany.
The use of medicines is an essential aspect of treating disease. In this field, surveys that map the population's use of medicines are of particular interest. The GEDA 2014/2015-EHIS study collected data on the use of medically prescribed and self-medicated drugs during the two weeks that preceded the survey. 58.9% of women and 52.0% of men reported that they had taken medically prescribed drugs during this period. 48.5% of women and 35.4% of men stated they had taken medication during this period that had not been prescribed by a doctor. The prevalence of the use of medically prescribed drugs and self-medication was higher among women than among men. Finally, the prevalence of the use of medically prescribed drugs increased significantly with age, whereas the prevalence of self-medication decreased with age.


Comparison of the clinical efficacy and safety of the on-demand use of paroxetine, dapoxetine, sildenafil and combined dapoxetine with sildenafil in treatment of patients with premature ejaculation: A randomised placebo-controlled clinical trial.
The aim of the study was to compare the clinical efficacy and safety of the on-demand use of paroxetine, dapoxetine, sildenafil and combined dapoxetine with sildenafil in treatment of patients with premature ejaculation (PE). In a single-blind placebo-controlled clinical study, 150 PE patients without erectile dysfunction (ED) were included during the period of March 2015 to May 2016. Patients were randomly divided into five groups (30 patients each). On demand placebo, paroxetine (30 mg), dapoxetine (30 mg), sildenafil citrate (50 mg) and combined dapoxetine (30 mg) with sildenafil citrate (50 mg) were given for patients for 6 weeks in each group respectively. All patients were instructed to record intravaginal ejaculatory latency time (IELT) and evaluated with Premature Ejaculation Diagnostic Tool (PEDT) and the patient satisfaction score before and after treatment. The mean of IELT, satisfaction score and PEDT in all groups was significantly improved after treatment (p value = .001). Combined dapoxetine with sildenafil group had the best values of IELT, satisfaction scores and PEDT in comparison with other treatment groups (p value <.001). The combined dapoxetine with sildenafil therapy could significantly improve PE patients without ED as compared to paroxetine alone or dapoxetine alone or sildenafil alone with tolerated adverse effects.


An in vivo test of the biologically relevant roles of carotenoids as antioxidants in animals.
Carotenoids are well known for their contribution to the vibrant coloration of many animals and have been hypothesized to be important antioxidants. Surprisingly few examples of carotenoids acting as biologically relevant antioxidants in vivo exist, in part because experimental designs often employ carotenoid doses at levels that are rarely observed in nature. Here, we used an approach that reduces carotenoid content from wild-type levels to test for the effect of carotenoids as protectants against an oxidative challenge. We used the marine copepod Tigriopus californicus reared on a carotenoid-free or a carotenoid-restored diet of nutritional yeast and then exposed them to a pro-oxidant. We found that carotenoid-deficient copepods not only accumulated more damage but also were more likely to die during an oxidative challenge than carotenoid-restored copepods. We suggest that carotenoid reduction, and not supplementation, better tests the proposed roles of carotenoids in other physiological functions in animals.


Sequence capture and next-generation resequencing of multiple tagged nucleic acid samples for mutation screening of urea cycle disorders.
Molecular genetic testing is commonly used to confirm clinical diagnoses of inherited urea cycle disorders (UCDs); however, conventional mutation screenings encompassing only the coding regions of genes may not detect disease-causing mutations occurring in regulatory elements and introns. Microarray-based target enrichment and next-generation sequencing now allow more-comprehensive genetic screening. We applied this approach to UCDs and combined it with the use of DNA bar codes for more cost-effective, parallel analyses of multiple samples. We used sectored 2240-feature medium-density oligonucleotide arrays to capture and enrich a 199-kb genomic target encompassing the complete genomic regions of 3 urea cycle genes, OTC (ornithine carbamoyltransferase), CPS1 (carbamoyl-phosphate synthetase 1, mitochondrial), and NAGS (N-acetylglutamate synthase). We used the Genome Sequencer FLX System (454 Life Sciences) to jointly analyze 4 samples individually tagged with a 6-bp DNA bar code and compared the results with those for an individually sequenced sample. Using a low tiling density of only 1 probe per 91 bp, we obtained strong enrichment of the targeted loci to achieve ≥90% coverage with up to 64% of the sequences covered at a sequencing depth ≥10-fold. We observed a very homogeneous sequence representation of the bar-coded samples, which yielded a >30% increase in the sequence data generated per sample, compared with an individually processed sample. Heterozygous and homozygous disease-associated mutations were correctly detected in all samples. The use of DNA bar codes and the use of sectored oligonucleotide arrays for target enrichment enable parallel, large-scale analysis of complete genomic regions for multiple genes of a disease pathway and for multiple samples simultaneously. This approach thus may provide an efficient tool for comprehensive diagnostic screening of mutations.


RNA sequencing of synaptic and cytoplasmic Upf1-bound transcripts supports contribution of nonsense-mediated decay to epileptogenesis.
The nonsense mediated decay (NMD) pathway is a critical surveillance mechanism for identifying aberrant mRNA transcripts. It is unknown, however, whether the NMD system is affected by seizures in vivo and whether changes confer beneficial or maladaptive responses that influence long-term outcomes such the network alterations that produce spontaneous recurrent seizures. Here we explored the responses of the NMD pathway to prolonged seizures (status epilepticus) and investigated the effects of NMD inhibition on epilepsy in mice. Status epilepticus led to increased protein levels of Up-frameshift suppressor 1 homolog (Upf1) within the mouse hippocampus. Upf1 protein levels were also higher in resected hippocampus from patients with intractable temporal lobe epilepsy. Immunoprecipitation of Upf1-bound RNA from the cytoplasmic and synaptosomal compartments followed by RNA sequencing identified unique populations of NMD-associated transcripts and altered levels after status epilepticus, including known substrates such as Arc as well as novel targets including Inhba and Npas4. Finally, long-term video-EEG recordings determined that pharmacologic interference in the NMD pathway after status epilepticus reduced the later occurrence of spontaneous seizures in mice. These findings suggest compartment-specific recruitment and differential loading of transcripts by NMD pathway components may contribute to the process of epileptogenesis.


Women's health status and gender inequality in China.
This paper examines the health status of women in China by reviewing levels and trends of female mortality at several phases of a woman's life cycle focusing on infancy girlhood, childbearing and old age. The mortality rates of Chinese women and men are compared for the period 1950-1990 as are comparisons with women in selected countries. The cause-specific death rate, expressed as a percentage of all deaths, and the burden of disease, measured in terms of the disability-adjusted life years (DALYs), are used to reflect the changing patterns of female diseases and causes of deaths. Significant improvement in the health status of Chinese women since 1950 is widely acknowledged as a major achievement for a developing country with the largest population in the world, but the differentials in women's health by region and urban/rural areas are considerable. The Physical Quality of Life Index (PQLI) indicates that the overall level of physical well-being of Chinese women has increased in recent decades, but disparity in health between men and women still exists. The Gender-Related Development Index (GDI) further reveals that China has achieved significant progress in women's health during the past four decades, but far less has been achieved with respect to gender equality overall. The final sections of the paper focus on the discussion of some health problems faced by the female population during the process of economic reform since the 1980 s. In order to promote gender equality between women and men, concerns on women's health care needs are highlighted.


Floral markers of cornflower (Centaurea cyanus) honey and its peroxide antibacterial activity for an alternative treatment of digital dermatitis.
Cornflower (Centaurea cyanus) honey can be characterized by a greenish yellow color and an intense flavor with a bitter aftertaste. Because cornflower honey contains only a limited amount of pollen for the verification of its floral origin, one objective was the characterization of its polyphenol and norisoprenoid contents to assign floral markers. Here, lumichrome (18.8-43.5 mg/kg), 7-carboxylumichrome, (Z/E)-3-oxo-retro-α-ionol, and 3-oxo-α-ionol appeared to be quite suitable for distinguishing cornflower honey from other unifloral honeys. Additionally, due to its comparably high hydrogen peroxide content (0.5-0.9 mM/h) and the associated antibacterial activity, cornflower honey was used as an alternative treatment of digital dermatitis on an organic dairy farm. Cows affected by this hoof disease often show severe lameness and a subsequent decline in milk yield and loss of body condition. The cows' hooves treated with cornflower honey showed significantly faster healing than the control group without any treatment.


Immune response to chemically modified flagellin. I. Induction of antibody tolerance to flagellin by acetoacetylated derivatives of the protein.
Flagellin (mol. wt. 40,000) from S. adelaide organisms was acetoacetylated to varying extents with diketene (acetoacetic anhydride). Chemical studies demonstrated that the amino groups of flagellin were more readily acetoacetylated than the hydroxyl groups. Several antigenic tests revealed that as flagellin was acetoacetylated to increasing extents there was a steady decline in the affinity of the molecule for anti-flagellin antibodies. Loss in antigenic activity following acetoacetylation was not related to the number of acetoacetyl groups attached but was determined by the type of residue substituted. Reactive lysine residues were much less important anti-genically than easily substituted hydroxyl groups. Acetoacetylation very readily destroyed the antibody-forming capacity of flagellin in rats. This fall in immunogenicity was related to the antigenic activity of the preparations. In fact, only a 40% reduction in the antigenic activity of flagellin produced a 90-95% reduction in primary antibody formation. The more heavily acetoacetylated flagellins produced no detectable antibody and, in fact, rendered adult rats tolerant (in terms of antibody formation) to a subsequent challenge of flagellin. Tolerance was induced by acetoacetylated flagellins which had drastically reduced affinities for anti-flagellin antibodies. These results were interpreted as indicating that the affinity of antigen for receptors on cells appears to be of crucial importance in determining whether antibody formation or immunological tolerance (antibody suppression) occurs.


Perisaccadic mislocalization as optimal percept.
The spatially uniform mislocalization of stimuli flashed around the onset of fast eye-movements (perisaccadic shift) has previously been explained by an inaccurate internal representation of current eye position. However, this hypothesis does not account for the observation that continuously presented stimuli are correctly localized during saccades. Here we show that the two findings are not mutually exclusive. The novelty of our approach lies in our interpretation of the extraretinal signal which, in contrast to other models, is not considered an (erroneous) estimate of current eye-position. Based on the reafference principle, our model assumes that the extraretinal signal is optimal in that it accurately predicts the neural representation of the retinal position of a continuously present stimulus. Perisaccadic shift arises as a consequence of maintaining stable perisaccadic position estimates for continuously present stimuli under the physiologically plausible assumption of temporal low-pass filtering in the afferent visual pathway. Consequently, our model reconciles the reafference principle with the finding of perisaccadic shift.


Bioinformatics Approaches to Profile the Tumor Microenvironment for Immunotherapeutic Discovery.
In the microenvironment of a malignancy, tumor cells do not exist in isolation, but rather in a diverse ecosystem consisting not only of heterogeneous tumor-cell clones, but also normal cell types such as fibroblasts, vasculature, and an extensive pool of immune cells at numerous possible stages of activation and differentiation. This results in a complex interplay of diverse cellular signaling systems, where the immune cell component is now established to influence cancer progression and therapeutic response. It is experimentally difficult and laborious to comprehensively and systematically profile these distinct cell types from heterogeneous tumor samples in order to capitalize on potential therapeutic and biomarker discoveries. One emerging solution to address this challenge is to computationally extract cell-type specific information directly from bulk tumors. Such in silico approaches are advantageous because they can capture both the cell-type specific profiles and the tissue systems level of cell-cell interactions. Accurately and comprehensively predicting these patterns in tumors is an important challenge to overcome, not least given the success of immunotherapeutic drug treatment of several human cancers. This is especially challenging for subsets of closely related immune cell phenotypes with relatively small gene expression differences, which have critical functional distinctions. Here, we outline the existing and emerging novel bioinformatics strategies that can be used to profile the tumor immune landscape.


A simple method for confidence rating of eutrophication status classifications.
We report the development of a methodology for assessing confidence in ecological status classifications. The method presented here can be considered as a secondary assessment, supporting the primary assessment of eutrophication or ecological status. The confidence assessment is based on scoring the quality of the indicators on which the primary assessment is made. This represents a first step towards linking status classification with information regarding their accuracy and precision. Applied to an existing data set used for assessment of eutrophication status of the Baltic Sea (including the Kattegat and Danish Straits) we demonstrate that confidence in the assessment is Good or High in 149 out of 189 areas assessed (79%). Contrary to our expectations, assessments of the open parts of the Baltic Sea have a higher confidence than assessments of coastal waters. We also find that in open waters of the Baltic Sea, some biological indicators have a higher confidence than indicators representing physical-chemical conditions. In coastal waters, phytoplankton, submerged aquatic vegetation and indicators of physical-chemical conditions have a higher confidence than indicators of the quality of benthic invertebrate communities. Our analyses also show that the perceived weaknesses of eutrophication assessments are due more to Low confidence in reference conditions and acceptable deviations, rather than in the monitoring data.


The Family Needs Questionnaire-Revised: a Rasch analysis of measurement properties in the chronic phase after traumatic brain injury.
The main aim was to evaluate the measurement properties of the Family Needs Questionnaire-Revised (FNQ-R) in family members of individuals living with severe traumatic brain injury (TBI). A total of 309 family members of individuals with severe TBI from Colombia, Denmark, Mexico, Norway and Spain participated. Rasch analysis of the FNQ-R and its 6 subscales was conducted. The Rasch analysis indicated a lack of fit of the 37-item FNQ-R to one single underlying construct of needs, and less than half of the items were invariant across the countries. Misfit of single items was revealed in the Need for Health Information, Need for Emotional Support, Need for Instrumental Support, Need for Professional Support and Need for Community Support Network subscales. Fit to the Rasch model was obtained after removal of misfitting items. The Involvement in Care subscale had too few items to be adequately assessed by the Rasch approach. The FNQ-R is a well-targeted instrument for assessing the unmet needs of caregivers regarding the need for health information, emotional support, professional support and a community support network after some scoring adjustment and the removal of misfitting items. Caution should be taken when comparing responses across countries.


Electrochemical detection of bovine immunoglobulins G to determine passive transfer of antibodies to calves.
Bovine antibodies, such as immunoglobulin G (IgG), cannot pass the placental barrier and as such are not transferred from the mother to the foetus, in utero. Instead a calf must absorb antibodies following ingestion of colostrum postpartum. Failure of Passive Transfer (FPT) is a condition that predisposes calves to development of disease and increases the risk of mortality. Thus, continuous early monitoring of IgG absorption in a calf, within the first 6 to 12 hours of life, is imperative to allow faster treatment and prevent FPT. In this paper, we present the development of a label-free impedimetric immunosensor device for bovine IgG in serum and demonstrate its suitability to determine early FPT in new-born calves. The developed sensors were challenged to discriminate between new born calf sera, both pre- and post-colostrum feeding, and demonstrated efficient detection of IgG in under 15 minutes. Such a device could enable rapid determination of FPT, thereby improving calves' vitality and survival rate.


WIP remodeling actin behind the scenes: how WIP reshapes immune and other functions.
Actin polymerization is a fundamental cellular process regulating immune cell functions and the immune response. The Wiskott-Aldrich syndrome protein (WASp) is an actin nucleation promoting factor, which is exclusively expressed in hematopoietic cells, where it plays a key regulatory role in cytoskeletal dynamics. WASp interacting protein (WIP) was first discovered as the binding partner of WASp, through the use of the yeast two hybrid system. WIP was later identified as a chaperone of WASp, necessary for its stability. Mutations occurring at the WASp homology 1 domain (WH1), which serves as the WIP binding site, were found to cause the Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT). WAS manifests as an immune deficiency characterized by eczema, thrombocytopenia, recurrent infections, and hematopoietic malignancies, demonstrating the importance of WIP for WASp complex formation and for a proper immune response. WIP deficiency was found to lead to different abnormalities in the activity of various lymphocytes, suggesting differential cell-dependent roles for WIP. Additionally, WIP deficiency causes cellular abnormalities not found in WASp-deficient cells, indicating that WIP fulfills roles beyond stabilizing WASp. Indeed, WIP was shown to interact with various binding partners, including the signaling proteins Nck, CrkL and cortactin. Recent studies have demonstrated that WIP also takes part in non immune cellular processes such as cancer invasion and metastasis, in addition to cell subversion by intracellular pathogens. Understanding of numerous functions of WIP can enhance our current understanding of activation and function of immune and other cell types.


Effects of adiposity and 30 days of caloric restriction upon protein metabolism in moderately vs. severely obese women.
Protein metabolism adapts during caloric restriction (CR) to minimize protein loss, and it is unclear whether greater fat stores favorably affect this response. We sought to determine whether protein metabolism is related to degree of obesity and whether the response to CR is impacted by pre-CR adiposity level. Whole body protein metabolism was studied in 12 obese women over a wide range of BMI (30-53 kg/m(2)) as inpatients using [1-(13)C]leucine as a tracer following 5 days of a weight-maintaining diet and then after 30 days of CR (1,400 kcal deficit with maintained protein intake). When expressed as total rates, per body weight (BW) or per fat-free mass (FFM), leucine rate of appearance (Ra), and nonoxidative leucine disposal (NOLD) were significantly higher in the individuals with a greater degree of obesity (P < 0.05). Leucine oxidation (Rox) was also higher in more highly obese women when expressed as a total rate (P < 0.05) but not if expressed per BW or FFM. CR reduced BW, FFM, and fat mass (P < 0.001), and declines were relatively similar between individuals. CR reduced Ra (P < 0.001), NOLD (P < 0.01), and Rox (P < 0.05), and the relative decline was not affected by differences in fat mass. CR-induced declines were significant even when Ra and NOLD were normalized to BW or FFM. We conclude that fat mass, like FFM, is a key determinant of protein turnover. However, during CR, higher fat mass does not favorably alter the response of protein metabolism and does not mitigate the loss of FFM.


Identifying children with excess malaria episodes after adjusting for variation in exposure: identification from a longitudinal study using statistical count models.
The distribution of Plasmodium falciparum clinical malaria episodes is over-dispersed among children in endemic areas, with more children experiencing multiple clinical episodes than would be expected based on a Poisson distribution. There is consistent evidence for micro-epidemiological variation in exposure to P. falciparum. The aim of the current study was to identify children with excess malaria episodes after controlling for malaria exposure. We selected the model that best fit the data out of the models examined and included the following covariates: age, a weighted local prevalence of infection as an index of exposure, and calendar time to predict episodes of malaria on active surveillance malaria data from 2,463 children of under 15 years of age followed for between 5 and 15 years each. Using parameters from the zero-inflated negative binomial model which best fitted our data, we ran 100 simulations of the model based on our population to determine the variation that might be seen due to chance. We identified 212 out of 2,463 children who had a number of clinical episodes above the 95(th) percentile of the simulations run from the model, hereafter referred to as "excess malaria (EM)". We then identified exposure-matched controls with "average numbers of malaria" episodes, and found that the EM group had higher parasite densities when asymptomatically infected or during clinical malaria, and were less likely to be of haemoglobin AS genotype. Of the models tested, the negative zero-inflated negative binomial distribution with exposure, calendar year, and age acting as independent predictors, fitted the distribution of clinical malaria the best. Despite accounting for these factors, a group of children suffer excess malaria episodes beyond those predicted by the model. An epidemiological framework for identifying these children will allow us to study factors that may explain excess malaria episodes.


Nutritional status of a group of alcoholics before and after admission to an alcoholism treatment unit.
The nutritional status of the alcoholic has been presumed to be less than adequate because of the large quantity of alcohol ingested. Most reports have focused on the derelict alcoholic. In contrast, the patients in this investigation are more representative of the usual alcoholic population. The pretreatment dietary histories of 58 alcoholics were compared with their actual dietary intake while they were hospitalized for the treatment of alcoholism. Comparisons were also made between dietary intake by history and Recommended Dietary Allowances. The mean calorie, protein, fat, and carbohydrate intake of the patients was adequate and was well within the Recommended Dietary Allowances ranges. After the patients stopped drinking, they increased their intake of all major nutrients, especially carbohydrates. A subgroup of 11 patients whose recent dietary intake by history was corroborated by their urinary nitrogen excretion had no change in total caloric intake after they stopped drinking.


How reliable are light traps in estimating biting rates of adult Anopheles gambiae s.l. (Diptera: Culicidae) in the presence of treated bed nets?
The sampling efficiency of light trap catches relative to human bait catches in estimating biting rates of the mosquito Anopheles gambiae Giles was investigated in two types of community in southern Sierra Leone: (i) where most of the inhabitants slept under treated bed nets; and (ii) where most of the inhabitants slept without bed nets. The number of female A. gambiae mosquitoes caught in these communities by light trap was strongly correlated (r > or = 0.72) with those from corresponding human biting catches performed either on the same or adjacent nights. It was found that the relative sampling efficiency of light traps varied slightly but significantly with mosquito abundance in villages with treated bed nets, but not in those without them. Nevertheless, the relationship between relative sampling efficiency and mosquito abundance did not differ significantly between the two types of village. Overall, there was insufficient evidence to show that the presence of treated nets altered the relative efficiency of light traps and any bias was only slight, and unlikely to be of any practical importance. Hence, it was concluded that light traps can be used as a surrogate for human bait catches in estimating biting rates of A. gambiae mosquitoes in the two communities.


Mice producing reduced levels of insulin-like growth factor type 1 display an increase in maximum, but not mean, life span.
Reduced signaling through the IGF type 1 (IGF-1) receptor increases life span in multiple invertebrate organisms. Studies on mammalian longevity suggest that reducing levels of IGF-1 may also increase life span. However, the data are conflicting and complicated by the physiology of the mammalian neuroendocrine system. We have performed life-span analysis on mice homozygous for an insertion in the Igf1 gene. These mice produce reduced levels of IGF-1 and display a phenotype consistent with a significant decrease in IGF-1. Life-span analysis was carried out at three independent locations. Although the life-span data varied between sites, the maximum life span of the IGF-1-deficient mice was significantly increased and age-specific mortality rates were reduced in the IGF-1-deficient mice; however, mean life span did not differ except at one site, where mean life span was increased in female IGF-1-deficient animals. Early life mortality was noted in one cohort of IGF-1-deficient mice. The results are consistent with a significant role for IGF-1 in the modulation of life span but contrast with the published life-span data for the hypopituitary Ames and Snell dwarf mice and growth hormone receptor null mice, indicating that a reduction in IGF-1 alone is insufficient to increase both mean and maximal life span in mice.


Complete Genome Sequence of Paenibacillus sp. CAA11: A Promising Microbial Host for Lignocellulosic Biorefinery with Consolidated Processing.
Several bioprocessing technologies, such as separate hydrolysis and fermentation (SHF), simultaneous saccharification and fermentation (SSF), and consolidated bioprocessing (CBP), have been highlighted to produce bio-based fuels and chemicals from lignocellulosic biomass. Successful CBP, an efficient and economical lignocellulosic biorefinery process compared with other processes, requires microorganisms with sufficient cellulolytic activity and biofuel/chemical-producing ability. Here, we report the complete genome of Paenibacillus sp. CAA11, a newly isolated promising microbial host for CBP-producing ethanol and organic acids from cellulose. The genome of Paenibacillus sp. CAA11 comprises one 4,888,410 bp chromosome with a G + C content of 48.68% containing 4418 protein-coding genes, 102 tRNA genes, and 39 rRNA genes. The functionally active cellulase, encoded by CAA_GH5 was identified to belong to glycosyl hydrolase family 5 (GH5) and consisted of a catalytic domain and a cellulose-binding domain 3 (CBM3). When cellulolytic activity of CAA_GH5 was assayed through Congo red method by measuring the size of halo zone, the recombinant Bacillus subtilis RIK1285 expressing CAA_GH5 showed a comparable cellulolytic activity to B. subtilis RIK1285 expressing Cel5, a previously verified powerful bacterial cellulase. This study demonstrates the potential of Paenibacillus sp. CAA11 as a CBP-enabling microbe for cost-effective biofuels/chemicals production from lignocellulosic biomass.


Thrombopoiesis-stimulating agents and myelodysplastic syndromes.
Thrombocytopenia in patients with myelodysplastic syndromes (MDS) is a frequent cause of haemorrhage-related morbidity and mortality, and is associated with increased risk of leukaemic transformation and reduced overall survival. In addition, thrombocytopenia in MDS limits the tolerability and therapeutic efficacy of disease-modifying therapies, such as azacitidine or lenalidomide. The recombinant human erythropoietin (rHuEPO) erythropoiesis-stimulating agents, epoetin and darbepoetin, are an established component of anaemia management in lower-risk MDS. Their success has, in turn, driven the development of haematopoietic growth factors targeting thrombocytopenia. While recombinant thrombopoietin (THPO) proved too immunogenic for clinical use, novel thrombopoiesis-stimulating agents (TSAs) have the potential to reduce bleeding events, decrease dependency on platelet transfusions and extend exposure to disease-modifying therapies. Two TSAs, eltrombopag and romiplostim, have demonstrated benefit in chronic immune thrombocytopenia purpura (ITP) and safety and efficacy data for use of these agents in MDS is growing. However, important safety concerns remain, such as the potential for stimulation of neoplastic myeloid clones by THPO agonists. In this narrative review, we discuss the rationale and biological mechanism for TSAs in MDS, describe the agents currently available and their mechanism of action, and present current clinical data relating to TSA safety and efficacy in the context of MDS.


Character displacement from the receiver's perspective: species and mate recognition despite convergent signals in suboscine birds.
Many social animals use long-distance signals to attract mates and defend territories. They face the twin challenges of discriminating between species to identify conspecific mates, and between individuals to recognize collaborators and competitors. It is therefore often assumed that long-distance signals are under strong selection for species-specificity and individual distinctiveness, and that this will drive character displacement when closely related species meet, particularly in noisy environments. However, the occurrence of signal stereotypy and convergence in rainforest species seems to contradict these ideas, and raises the question of whether receivers in these systems can recognize species or individuals by long-distance signals alone. Here, we test for acoustically mediated recognition in two sympatric antbird species that are known to have convergent songs. We show that male songs are stereotyped yet individually distinctive, and we use playback experiments to demonstrate that females can discriminate not only between conspecific and heterospecific males, but between mates and strangers. These findings provide clear evidence that stereotypy and convergence in male signals can be accommodated by fine tuning of perceptual abilities in female receivers, suggesting that the evolutionary forces driving divergent character displacement in animal signals are weaker than is typically assumed.


Diabetes care and outcomes for American Indians and Alaska natives in commercial integrated delivery systems: a SUrveillance, PREvention, and ManagEment of Diabetes Mellitus (SUPREME-DM) Study.
To compare cardiovascular disease risk factor testing rates and intermediate outcomes of care between American Indian/Alaska Native (AI/AN) patients with diabetes and non-Hispanic Caucasians enrolled in nine commercial integrated delivery systems in the USA. We used modified Poisson regression models to compare the annual testing rates and risk factor control levels for glycated haemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-C), and systolic blood pressure (SBP); number of unique diabetes drug classes; insulin use; and oral diabetes drug medication adherence between insured AI/AN and non-Hispanic white adults with diabetes aged ≥18 in 2011. 5831 AI/AN patients (1.8% of the cohort) met inclusion criteria. After adjusting for age, gender, comorbidities, insulin use, and geocoded socioeconomic status, AI/AN patients had similar rates of annual HbA1c, LDL-C, and SBP testing, and LDL-C and SBP control, compared with non-Hispanic Caucasians. However, AI/AN patients were significantly more likely to have HbA1c >9% (>74.9 mmol/mol; RR=1.47, 95% CI 1.38 to 1.58), and significantly less likely to adhere to their oral diabetes medications (RR=0.90, 95% CI 0.88 to 0.93) compared with non-Hispanic Caucasians. AI/AN patients in commercial integrated delivery systems have similar blood pressure and cholesterol testing and control, but significantly lower rates of HbA1c control and diabetes medication adherence, compared with non-Hispanic Caucasians. As more AI/ANs move to urban and suburban settings, clinicians and health plans should focus on addressing disparities in diabetes care and outcomes in this population.


Eluana Englaro, chronicle of a death foretold: ethical considerations on the recent right-to-die case in Italy.
In 1992, Eluana Englaro was involved in a car accident in Italy that eventually left her in a permanent vegetative state requiring artificial nutrition and hydration. This paper, after briefly reviewing Eluana's case, gives a chronicle of Eluana last months until her death on 9 February 2009, and discusses the right-to-die controversy in Italy. For many years, Mr Englaro, Eluana's father, would litigate to enforce what he considered to be his daughter's wish to discontinue life-prolonging treatment. In July 2008, the Court of Appeal of Milan has given its authorization for artificial life support to be withdrawn. This ruling sparked a crusade, led by the government and the Vatican, against the court and Eluana's father, which included insinuations that the latter was murdering his daughter. Public opinion has overwhelmingly been sympathetic to the father's difficult decision, in stark contrast to the reactionary stance taken by the government. With the notable advances of medicine, doctors are increasingly faced with ethical issues. The vegetative state is just one of the many clinical conditions that obligate health professionals to reflect on ethical matters. The withdrawal of life-supporting care, and of artificial nutrition and hydration in particular in permanent vegetative state patients remains a measure which violates a tradition and a consolidated practice. It was thus inevitable that it would create great controversy. We should work towards making a decision process that ensures that continuation or suspension of artificial nutrition and hydration follows an explicit procedure, promoting the sharing and respect of the diverse moral responsibility of family members, nursing and medical staff.


The lipoprotein lipase Gly188----Glu mutation in South Africans of Indian descent: evidence suggesting common origins and an increased frequency.
Lipoprotein lipase (LPL) plays a crucial role in the hydrolysis of the triglyceride core of circulating chylomicrons and very low density lipoproteins (VLDL) and also has a major effect on the levels and lipid composition of high density lipoproteins (HDL). LPL deficiency is inherited as an autosomal recessive trait and most commonly presents with chylomicronaemia, abdominal pain, and eruptive xanthomata. We have previously described a mutation in exon 5 of the LPL gene which results in a substitution of glutamic acid for glycine at amino acid 188. We have now assessed 16 South African LPL deficient patients from nine separate kindreds for this mutation. Nine of these probands were homozygous for the mutation and were from four families, all of Indian descent. The ancestors of these probands have their origins in villages close to Bombay, India, which suggests a common ancestral mutation for the four Indian kindreds, particularly as the mutant allele in each family carried the identical restriction fragment length polymorphism (RFLP) haplotype. The presence of at least nine affected subjects in this small community around Cape Town is evidence for a higher than expected gene frequency for LPL deficiency in this population.


Neutralizing antibodies and pathogenesis of hepatitis C virus infection.
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide. The interplay between the virus and host innate and adaptive immune responses determines the outcome of infection. There is increasing evidence that host neutralizing responses play a relevant role in the resulting pathogenesis. Furthermore, viral evasion from host neutralizing antibodies has been revealed to be an important contributor in leading both to viral persistence in acute liver graft infection following liver transplantation, and to chronic viral infection. The development of novel model systems to study HCV entry and neutralization has allowed a detailed understanding of the molecular mechanisms of virus-host interactions during antibody-mediated neutralization. The understanding of these mechanisms will ultimately contribute to the development of novel antiviral preventive strategies for liver graft infection and an urgently needed vaccine. This review summarizes recent concepts of the role of neutralizing antibodies in viral clearance and protection, and highlights consequences of viral escape from neutralizing antibodies in the pathogenesis of HCV infection.


Lactobacillus paracasei K5 displays adhesion, anti-proliferative activity and apoptotic effects in human colon cancer cells.
Lactobacillus paracasei K5 is a lactic acid bacteria (LAB) strain, isolated recently from feta-type cheese. Its probiotic potential has been demonstrated in a series of established in vitro tests. Moreover, incorporation of L. paracasei K5 as starter culture offered organoleptic and technological advantages to novel fermented food products. In the present study, further investigation of the potential probiotic activity of L. paracasei K5 was performed and its mechanisms of action were investigated. Employing quantitative analysis and confocal, fluorescent microscopy the adhesion properties of the above strain were studied. L. paracasei K5 displayed efficient adherence capacity to Caco-2 colon cancer cells, similarly to the reference strains Lactobacillus casei ATCC 393 and Lactobacillus rhamnosus GG. Moreover, treatment of Caco-2 cells with L. paracasei K5 inhibited cell proliferation in a time-and dose-dependent manner. The anti-proliferative effects appear to be mediated through induction of apoptosis via modulation of expression of specific Bcl-2 family proteins. These results elucidate the mechanisms of action of L. paracasei K5 and enhance its potential probiotic activity.


Velocity-based Adaptive Registration and Fusion for Fractionated Stereotactic Radiosurgery Using the Small Animal Radiation Research Platform.
To implement Velocity-based image fusion and adaptive deformable registration to enable treatment planning for preclinical murine models of fractionated stereotactic radiosurgery (fSRS) using the small animal radiation research platform (SARRP). C57BL6 mice underwent 3 unique cone beam computed tomography (CBCT) scans: 2 in the prone position and a third supine. A single T1-weighted post-contrast magnetic resonance imaging (MRI) series of a murine metastatic brain tumor model was selected for MRI-to-CBCT registration and gross tumor volume (GTV) identification. Two arms were compared: Arm 1, where we performed 3 individual MRI-to-CBCT fusions using rigid registration, contouring GTVs on each, and Arm 2, where the authors performed MRI-to-CBCT fusion and contoured GTV on the first CBCT followed by Velocity-based adaptive registration. The first CBCT and associated GTV were exported from MuriPlan (Xstrahl Life Sciences) into Velocity (Varian Medical Systems, Inc, Palo Alto, CA). In Arm 1, the second and third CBCTs were exported similarly along with associated GTVs (Arm 1), while in Arm 2, the first (prone) CBCT was fused separately to the second (prone) and third (supine) CBCTs, performing deformable registrations on initial CBCTs and applying resulting matrices to the contoured GTV. Resulting GTVs were compared between Arms 1 and 2. Comparing GTV overlays using repeated MRI fusion and GTV delineation (Arm 1) versus those of Velocity-based CBCT and GTV adaptive fusion (Arm 2), mean deviations ± standard deviation in the axial, sagittal, and coronal planes were 0.46 ± 0.16, 0.46 ± 0.22, and 0.37 ± 0.22 mm for prone-to-prone and 0.52 ± 0.27, 0.52 ± 0.36, and 0.68 ± 0.31 mm for prone-to-supine adaptive fusions, respectively. Velocity-based adaptive fusion of CBCTs and contoured volumes allows for efficient fSRS planning using a single MRI-to-CBCT fusion. This technique is immediately implementable on current SARRP systems, facilitating advanced preclinical treatment paradigms using existing clinical treatment planning software.


Randomized trial of sumatriptan and naproxen sodium combination in adolescent migraine.
Treatment of adolescent migraine remains a significant unmet medical need. We compared the efficacy and safety of 3 doses of sumatriptan and naproxen sodium (suma/nap) combination tablets to placebo in the acute treatment of adolescent migraine. This randomized, parallel group study in 12 to 17 year olds required 2 to 8 migraines per month (typically lasting >3 hours untreated) for ≥ 6 months. Subjects entered a 12-week run-in phase, treating 1 moderate-to-severe migraine (attack 1) with single-blind placebo. Subjects reporting headache pain 2 hours after dosing were randomly assigned into a 12-week double-blind phase, treating 1 moderate-to-severe migraine (attack 2) with placebo (n = 145), suma/nap 10/60 mg (n = 96), 30/180 mg (n = 97), or 85/500 mg (n = 152). The primary end point was the percentage of subjects pain-free at 2 hours. The attack 2 adjusted (age; baseline pain severity) 2-hour pain-free rates were higher with suma/nap 10/60 mg (29%; adjusted P = .003), 30/180 mg (27%; adjusted P = .003), and 85/500 mg (24%; adjusted P = .003) versus placebo (10%). Posthoc primary end-point analyses did not demonstrate differences among the 3 doses or an age-by-treatment interaction. Statistically significant differences were found for 85/500 mg versus placebo for sustained pain-free 2 to 24 hours (23% vs 9%; adjusted P = .008), 2-hour photophobia-free (59% vs 41%; adjusted P = .008), and 2-hour phonophobia-free (60% vs 42%; adjusted P = .008). Analyses of other pain, associated symptoms, rescue medication use, and health outcome end points supported higher efficacy for active doses versus placebo. All active doses were well tolerated. All doses of suma/nap were well tolerated, providing similarly effective acute treatment of adolescent migraine pain and associated symptoms, as compared with placebo.


Biodiversity baselines, thresholds and resilience: testing predictions and assumptions using palaeoecological data.
Fossil records are replete with examples of long-term biotic responses to past climate change. One particularly useful set of records are those preserved in lake and marine sediments, recording both climate changes and corresponding biotic responses. Recently there has been increasing focus on the need for conservation of ecological and evolutionary processes in the face of climate change. We review key areas where palaeoecological archives contribute to this conservation goal, namely: (i) determination of rates and nature of biodiversity response to climate change; (ii) climate processes responsible for ecological thresholds; (iii) identification of ecological resilience to climate change; and (iv) management of novel ecosystems. We stress the importance of long-term palaeoecological data in fully understanding contemporary and future biotic responses.


Evaluating DNA Mixtures with Contributors from Different Populations Using Probabilistic Genotyping.
It is common practice to evaluate DNA profiling evidence with likelihood ratios using allele frequency estimates from a relevant population. When multiple populations may be relevant, a choice has to be made. For two-person mixtures without dropout, it has been reported that conservative estimates can be obtained by using the Person of Interest's population with a θ value of 3%. More accurate estimates can be obtained by explicitly modelling different populations. One option is to present a minimum likelihood ratio across populations; another is to present a stratified likelihood ratio that incorporates a weighted average of likelihoods across multiple populations. For high template single source profiles, any difference between the methods is immaterial as far as conclusions are concerned. We revisit this issue in the context of potentially low-level and mixed samples where the contributors may originate from different populations and study likelihood ratio behaviour. We first present a method for evaluating DNA profiling evidence using probabilistic genotyping when the contributors may originate from different ethnic groups. In this method, likelihoods are weighted across a prior distribution that assigns sample donors to ethnic groups. The prior distribution can be constrained such that all sample donors are from the same ethnic group, or all permutations can be considered. A simulation study is used to determine the effect of either assumption on the likelihood ratio. The likelihood ratios are also compared to the minimum likelihood ratio across populations. We demonstrate that the common practise of taking a minimum likelihood ratio across populations is not always conservative when FST=0. Population stratification methods may also be non-conservative in some cases. When FST>0 is used in the likelihood ratio calculations, as is recommended, all compared approaches become conservative on average to varying degrees.


The effect of STW defects on the mechanical properties and fracture toughness of pristine and hydrogenated graphene.
Graphene is emerging as a versatile material with a diverse field of applications. Synthesis techniques for graphene introduce several topological defects such as vacancies, dislocations and Stone-Thrower-Wales (STW) defects. Among them STW defects are generated without deleting any atom from the lattice position, but are introduced by rotating single C-C bonds. In this article, molecular dynamics based simulations have been performed to study the effect of STW defects on the fracture toughness of pristine graphene as well as graphene with crack edges passivated with hydrogen atoms. STW defects help in generating out of plane displacement in conjunction with redistribution of stress around the crack edges that can be used to improve the fracture toughness of brittle graphene. An overall improvement in the fracture toughness of pristine graphene as well as graphene containing hydrogen at the crack edges was predicted in this work.


How information about other people's personal experiences can help with healthcare decision-making: a qualitative study.
To investigate people's views of using 'general facts' and information about other people's 'personal experiences' for health-related decision-making. Sixty-two people, who between them had experience of five different focal health issues, participated in 12 focus groups and 9 interviews. Exploration of uses of the two types of information was supported by discussion of illustrative excerpts. There was less discussion of 'general facts'; participants thought it obvious that good decisions required these. Participants reported having used 'personal experiences' information to: recognise decisions that needed consideration; identify options; appraise options and make selections (including by developing and reflecting on their reasoning about possible choices); and support coping strategies. Their inclination to use 'personal experiences' information was apparently moderated by assessments of personal relevance, the motives of information providers and the 'balance' of experiences presented. People can use 'personal experiences' information in various ways to support their decision-making, and exercise some discrimination as they do. 'Personal experiences' information may help people in a number of ways in relation to decision-making. However, 'personal experiences' information does not replace the need for 'general facts' and care should be taken when it is used in resources for patients.


Risedronate did not block the maximal anabolic effect of PTH in aged rats.
The study was designed to investigate if pre-treating rats with a therapeutic equivalent dose of risedronate blunted the anabolic effects of PTH, and whether a withdrawal period prior to PTH treatment would alter any effect of risedronate on PTH treatment. Skeletally mature rats were treated for 18 weeks with vehicle, risedronate, or risedronate for 8 weeks followed by vehicle for 10 weeks (withdrawal period). At the end of this period, animals were treated for a further 12 weeks with PTH or PTH vehicle. Trabecular and cortical bone mass were monitored by serial pQCT, or by DXA and microCT. Bone histomorphometry was performed on the proximal tibiae and tibial shafts for bone turnover parameters at week 40. Risedronate alone moderately increased while PTH alone markedly increased trabecular bone mass at the proximal tibial (35% and 200%, respectively) and lumbar vertebral body (14% and 36%, respectively). The maximum bone gains were similar with and without pretreatment with risedronate as compared to the PTH alone. Continuous administration of risedronate for 18 weeks prior to PTH treatment had lower percentage increases in proximal tibial BMD during the first 8 weeks of PTH treatments, and had lower active bone forming surface and bone formation rates after being treated with PTH 12 weeks as compared to the PTH alone group. However, with the 10-week withdrawal period, risedronate did not blunt the stimulatory effect of PTH on osteoblast activity as shown by similar bone formation rates as with PTH alone. Our findings suggest that while risedronate pretreatment may slow the bone anabolic response to PTH, a withdrawal period prior to PTH treatment allows osteoblastic activity to respond normally to PTH stimulation.


Physical activity long-term after liver transplantation yields better quality of life.
Transplantation is the only effective method of treatment for end-stage and acute liver failure. Increased average survival time has been observed, and results from improved surgical technique and amended immunosuppression protocols. However, longer survival of patients after orthotopic liver transplantation (OLT) results in higher rate of various complications and ailments (eg, chronic fatigue, anxiousness, social isolation). Hence, gradual deterioration of health-related quality of life (HRQoL) is likely. The goal of this study was to examine the relation between physical activity and quality of life in patients 5 years after OLT. Twenty-six randomly selected patients who survived more than 5 years after orthotopic liver transplantation were included into the study. An SF-36 questionnaire was used for assessment of quality of life. Physical activity was measured subjectively by characterizing its type, duration and frequency per week during the previous 12 months. Patients were divided into 2 groups according to the results of physical activity assessment. Group A consisted of patients who had indicated they had a sedentary life style, and group B of those regularly engaging in physical exercise. Results of the SF-36 questionnaire in 10 categories were compared between the 2 groups. The majority of aspects of health-related quality of life (physical function, body problems, general health, social function, and emotional reaction) were significantly improved in patients who indicated they regularly engaged in physical exercise. Better quality of life was observed in patients who were physically active after OLT. Improving life quality with regular physical activity could be a valuable supplementation of complex management of OLT recipients.


Combination of Circulating Type I Collagen-Related Biomarkers Is Associated With Atrial Fibrillation.
A combination of circulating biomarkers associated with excessive myocardial collagen type-I cross-linking or CCL+ (i.e., decreased carboxy-terminal telopeptide of collagen type-I to matrix metalloproteinase-1 ratio) and with excessive myocardial collagen type-I deposition or CD+ (i.e., increased carboxy-terminal propeptide of procollagen type-I) has been described in heart failure (HF) patients and associates with poor outcomes. The purpose of this study was to investigate whether the CCL+CD+ combination of biomarkers associates with atrial fibrillation (AF). Biomarkers were analyzed in serum samples from 242 HF patients (study 1) and 150 patients referred for AF ablation (study 2). Patients were classified into 3 groups (CCL-CD-, CCL+CD- or CCL-CD+, and CCL+CD+) in accordance to biomarker threshold values. Left atrial electroanatomic high-density mapping was performed in 71 patients from study 2. In study 1, 53.7% patients had AF at baseline and 19.6% developed AF (median follow-up 5.5 years). Adjusted odds and hazard ratios associated with baseline and new-onset AF, respectively, were both ≥3.3 (p ≤ 0.050) in CCL+CD+ patients compared with CCL-CD- patients, with nonsignificant changes in the other group. In study 2, 29.3% patients had AF recurrence during 1-year post-ablation. The adjusted hazard ratio for AF recurrence was 3.4 (p = 0.008) in CCL+CD+ patients compared with CCL-CD- patients, with nonsignificant changes in the other group. The CCL+CD+ combination added incremental predictive value over relevant covariables. CCL+CD+ patients exhibited lower left atrial voltage than the remaining patients (p = 0.005). A combination of circulating biomarkers reflecting excessive myocardial collagen type-I cross-linking and deposition is associated with higher AF prevalence, incidence, and recurrence after ablation.


Paired immunoglobulin-like receptor B regulates platelet activation.
Murine paired immunoglobulin-like receptors B (PIRB), as the ortholog of human leukocyte immunoglobulin-like receptor B2 (LILRB2), is involved in a variety of biological functions. Here, we found that PIRB and LILRB2 were expressed in mouse and human platelets, respectively. PIRB intracellular domain deletion (PIRB-TM) mice had thrombocythemia and significantly higher proportions of megakaryocytes in bone marrow. Agonist-induced aggregation and spreading on immobilized fibrinogen were facilitated in PIRB-TM platelets. The rate of clot retraction in platelet-rich plasma containing PIRB-TM platelets was also increased. Characterization of signaling confirmed that PIRB associated with phosphatases Shp1/2 in platelets. The phosphorylation of Shp1/2 was significantly downregulated in PIRB-TM platelets stimulated with collagen-related peptide (CRP) or on spreading. The results further revealed that the phosphorylation levels of the linker for activation of T cells, SH2 domain-containing leukocyte protein of 76kDa, and phospholipase C were enhanced in PIRB-TM platelets stimulated with CRP. The phosphorylation levels of FAK Y397 and integrin β3 Y759 were also enhanced in PIRB-TM platelet spread on fibrinogen. The PIRB/LILRB2 ligand angiopoietin-like-protein 2 (ANGPTL2) was expressed and stored in platelet α-granules. ANGPTL2 inhibited agonist-induced platelet aggregation and spreading on fibrinogen. The data presented here reveal that PIRB and its ligand ANGPTL2 possess an antithrombotic function by suppressing collagen receptor glycoprotein VI and integrin αIIbβ3-mediated signaling.


End-of-life measures in Huntington disease: HDQLIFE Meaning and Purpose, Concern with Death and Dying, and End of Life Planning.
Huntington disease (HD) is a progressive neurodegenerative disorder. There are no HD-specific measures to assess for end-of-life (EOL) preferences that have been validated for clinical use. The purpose of this study is to demonstrate reliability and validity of three HD-specific EOL measures for use in and clinical research settings. We examined internal reliability, test-retest reliability, floor and ceiling effects, convergent and discriminant validity, known groups' validity, measurement error, and change over time to systematically examine reliability and validity of the HDQLIFE EOL measures. Internal consistency and test-retest reliability were > 0.70. The measures were generally free of floor and ceiling effects and measurement error was minimal. Convergent and discriminant validity were consistent with well-known constructs in the field. Hypotheses for known groups validity were partially supported (there were generally group differences for the EOL planning measures, but not for meaning and purpose or concern with death and dying). Measurement error was acceptable and there were minimal changes over time across the EOL measures. Results support the clinical utility of the HDQLIFE EOL measures in persons with HD.