Unintentional Interpersonal Synchronization Represented as a Reciprocal Visuo-Postural Feedback System: A Multivariate Autoregressive Modeling Approach.
People's behaviors synchronize. It is difficult, however, to determine whether synchronized behaviors occur in a mutual direction--two individuals influencing one another--or in one direction--one individual leading the other, and what the underlying mechanism for synchronization is. To answer these questions, we hypothesized a non-leader-follower postural sway synchronization, caused by a reciprocal visuo-postural feedback system operating on pairs of individuals, and tested that hypothesis both experimentally and via simulation. In the behavioral experiment, 22 participant pairs stood face to face either 20 or 70 cm away from each other wearing glasses with or without vision blocking lenses. The existence and direction of visual information exchanged between pairs of participants were systematically manipulated. The time series data for the postural sway of these pairs were recorded and analyzed with cross correlation and causality. Results of cross correlation showed that postural sway of paired participants was synchronized, with a shorter time lag when participant pairs could see one another's head motion than when one of the participants was blindfolded. In addition, there was less of a time lag in the observed synchronization when the distance between participant pairs was smaller. As for the causality analysis, noise contribution ratio (NCR), the measure of influence using a multivariate autoregressive model, was also computed to identify the degree to which one's postural sway is explained by that of the other's and how visual information (sighted vs. blindfolded) interacts with paired participants' postural sway. It was found that for synchronization to take place, it is crucial that paired participants be sighted and exert equal influence on one another by simultaneously exchanging visual information. Furthermore, a simulation for the proposed system with a wider range of visual input showed a pattern of results similar to the behavioral results.


Changes in hypercoagulability by asparaginase: a randomized study between two asparaginases.
Alterations in hemostasis have frequently been observed in children with acute lymphoblastic leukemia. Thrombotic events are well documented in patients receiving L-asparaginase as a single agent or in combination with other chemotherapeutic drugs. The present prospective, randomized study evaluated the effect of two different L-asparaginase preparations, native Escherichia coli L-asparaginase (Crasnitin; Bayer AG, Leverkusen, Germany; n = 10) and L-asparaginase derived from Erwinia chrysanthemi (Erwinase; Porton Pruducts, London, UK; n = 10) on the changes in parameters concerning hypercoagulability. Patients were randomized to receive a total of eight doses of 10,000 IU/m2 L-asparaginase intravenously with intervals of 3 days during induction therapy. Before starting L-asparaginase treatment all patients had already demonstrated an increased thrombin generation shown by the elevated levels of prothrombin fragment 1+2 and thrombin antithrombin III, presumably due to therapy with prednisone, daunorubicin and vincristine. A significant decrease in alpha2-antiplasmin and plasminogen levels was measured in the E. coli L-asparaginase but not in Erwinase-treated patients. Increased thrombin generation combined with a decrease in alpha2-antiplasmin and plasminogen levels may lead to a state of increased risk for thrombosis due to a delay in fibrin elimination in E. coli L-asparaginase-treated patients only.


What do physicians recommend to their overweight and obese patients?
It is recognized that physicians play an important role in responding to the nation's obesity epidemic. Little is known, however, about what physicians say to their obese patients to help them lose weight. This cross-sectional survey examined weight loss recommendations of family physicians and internists. Surveys were mailed to 188 physicians and 54% (n = 101) responded. The survey assessed physicians' weight loss recommendations, the basis for recommendations, and their expected weight loss outcomes for a hypothetical patient. Physicians rated the extent to which they recommended various weight control strategies to their obese patients. They also rated the extent to which clinical experience, personal experience, and the medical literature were important in formulating their recommendations. The most common strategies recommended were increasing physical activity, reducing consumption of fast foods, reducing portion sizes, and reducing soda consumption. Physicians were less likely to recommended regular self-weighing, recording food intake, and decreasing television viewing. Meal replacements and weight loss medications were rarely advised. Physicians reported that they based their weight loss recommendations more on clinical experience than on the medical literature or personal experience; these latter 2 were rated as equally important. Physicians reported that, from their perspective, the equivalent of a 21.5% weight loss would be an "acceptable" outcome for a hypothetical obese patient; a 10.6% weight loss "disappointing." Physicians, like patients, need to be educated about the benefits of modest weight loss and the weight loss strategies empirically proven to be most effective, including self-monitoring. Further research is needed to understand the barriers to recommending and implementing these effective strategies.


Straight sinus stenosis as a proposed cause of perimesencephalic non-aneurysmal haemorrhage.
Perimesencephalic nonaneurysmal haemorrhage (PMNH), a term first coined in 1985, is a diagnosis of exclusion. It is considered a benign form of subarachnoid haemorrhage with a good prognosis and a low risk of rebleeding. Its precise aetiology has not yet been determined. Haemorrhage of venous origin has been proposed as a cause, and has been demonstrated to be associated with venous abnormalities of the basal vein of Rosenthal. We present a patient with PMNH in whom an 80% stenosis at the union of the vein of Galen with the straight sinus is demonstrated. We thus propose hypertensive venous rupture secondary to venous sinus stenosis as an alternative cause for PMNH.


The effect of Sn doping on thermoelectric performance of n-type half-Heusler NbCoSb.
Herein, Sn was successfully doped into the Sb site of n-type NbCoSb half-Heusler compounds to tune the carrier concentration, and a maximum ZT value of ∼0.56 was obtained at 973 K for NbCoSb1-xSnx with x = 0.2, an increase of ∼40% as compared to that of NbCoSb. This enhancement is mainly attributed to the reduced carrier concentration by Sn doping, leading to a doubled Seebeck coefficient at 300 K. More importantly, the total thermal conductivity was reduced with Sn doping, and the reduction was mainly due to the lowered electron thermal conductivity. The decreased electron thermal conductivity resulted from the reduced carrier concentration and the consequent enhanced carrier degeneracy, contributing to a reduced Lorenz constant. A quantitative description of the electron transport characteristics was performed under a single parabolic band model supposing that the acoustic phonon scattering was dominant in the carrier transport. A high density of the state effective mass, m* ≈ 10 me, and relatively high deformation potential Edef = 21 eV were found for the solid solutions.


Habitat continuity and geographic distance predict population genetic differentiation in giant kelp.
Isolation by distance (IBD) models are widely used to predict levels of genetic connectivity as a function of Euclidean distance, and although recent studies have used GIS-landscape ecological approaches to improve the predictability of spatial genetic structure, few if any have addressed the effect of habitat continuity on gene flow. Landscape effects on genetic connectivity are even less understood in marine populations, where habitat mapping is particularly challenging. In this study, we model spatial genetic structure of a habitat-structuring species, the giant kelp Macrocystis pyrifera, using highly variable microsatellite markers. GIS mapping was used to characterize habitat continuity and distance between sampling sites along the mainland coast of the Santa Barbara Channel, and their roles as predictors of genetic differentiation were evaluated. Mean dispersal distance (sigma) and effective population size (Ne) were estimated by comparing our IBD slope with those from simulations incorporating habitat continuity and spore dispersal characteristics of the study area. We found an allelic richness of 7-50 alleles/locus, which to our knowledge is the highest reported for macroalgae. The best regression model relating genetic distance to habitat variables included both geographic distance and habitat continuity, which were respectively, positively and negatively related to genetic distance. Our results provide strong support for a dependence of gene flow on both distance and habitat continuity and elucidate the combination of Ne and a that explained genetic differentiation.


Timebanking and the co-production of preventive social care with adults; what can we learn from the challenges of implementing person-to-person timebanks in England?
This paper explores the potential contribution of timebanking, an innovative volunteering scheme, to the co-production of preventive social care with adults in England. Interest in volunteering in social care has increased as one proposed solution to the international crisis of a rising demand for services in juxtaposition with decreased resources. Volunteering has been particularly promoted in preventive services that prevent or delay care needs arising. Despite sustained interest in volunteering and co-production in social care, little is known about how theory translates into practice. Reporting implementation data from a Realistic Evaluation of six case studies in England, this paper explores one volunteering scheme, timebanking. The research explores how timebanks were working, what contribution they can make to adult social care, and whether they are an example of co-production. Data collected included interviews, focus groups or open question responses on surveys from 84 timebank members, and semi-structured interviews with 13 timebank staff. Each timebank was visited at least twice, and all timebank activity was analysed for a period of 12 months. Data were triangulated to improve reliability. The research found that in practice, timebanks were not working as described in theory, there were small numbers of person-to-person exchanges and some timebanks had abandoned this exchange model. Timebanks faced significant implementation challenges including managing risk and safeguarding and the associated bureaucracy, a paternalistic professional culture and the complexity of the timebank mechanism which required adequate resources. Lessons for timebanks are identified, as well as transferable lessons about co-production and volunteering in social care if such schemes are to be successful in the future.


Imaging of intracellular sulfane sulfur expression changes under hypoxic stress via a selenium-containing near-infrared fluorescent probe.
Hypoxia is a significant global issue affecting the health of organisms. Oxygen homeostasis is critical for mammalian cell survival and cellular activities. Hypoxic stress can lead to cell injury and death, which contributes to many diseases. Sulfane sulfur is involved in crucial roles in physiological processes of maintaining intracellular redox state and ameliorating oxidative damage. Therefore, real-time imaging of changes in sulfane sulfur levels is important for understanding their biofunctions in cells. In this study, we develop a new near-infrared (NIR) fluorescent probe BD-diSeH for imaging of sulfane sulfur changes in cells and in vivo under hypoxic stress. The probe includes two moieties: an NIR azo-BODIPY fluorophore equipped with a strong nucleophilic phenylselenol group (-SeH). The probe is capable of tracing dynamic changes of endogenous sulfane sulfur based on a fast and spontaneous intramolecular cyclization reaction. The probe has been successfully used for imaging sulfane sulfur in 3D-multicellular spheroid and mouse hippocampus under hypoxic stress. The overall levels of sulfane sulfur are affected by the degree and length of hypoxic stress. The results reveal a close relationship between sulfane sulfur and hypoxia in living cells and in vivo, allowing better understanding of physiological and pathological processes involving sulfane sulfur. Moreover, to investigate the effects of environmental hypoxia on aquatic animals, this probe has been applied for sulfane sulfur detection in hypoxic zebrafish.


Mitogen- and stress-activated kinase 1 (MSK1) regulates cigarette smoke-induced histone modifications on NF-κB-dependent genes.
Cigarette smoke (CS) causes sustained lung inflammation, which is an important event in the pathogenesis of chronic obstructive pulmonary disease (COPD). We have previously reported that IKKα (I kappaB kinase alpha) plays a key role in CS-induced pro-inflammatory gene transcription by chromatin modifications; however, the underlying role of downstream signaling kinase is not known. Mitogen- and stress-activated kinase 1 (MSK1) serves as a specific downstream NF-κB RelA/p65 kinase, mediating transcriptional activation of NF-κB-dependent pro-inflammatory genes. The role of MSK1 in nuclear signaling and chromatin modifications is not known, particularly in response to environmental stimuli. We hypothesized that MSK1 regulates chromatin modifications of pro-inflammatory gene promoters in response to CS. Here, we report that CS extract activates MSK1 in human lung epithelial (H292 and BEAS-2B) cell lines, human primary small airway epithelial cells (SAEC), and in mouse lung, resulting in phosphorylation of nuclear MSK1 (Thr581), phospho-acetylation of RelA/p65 at Ser276 and Lys310 respectively. This event was associated with phospho-acetylation of histone H3 (Ser10/Lys9) and acetylation of histone H4 (Lys12). MSK1 N- and C-terminal kinase-dead mutants, MSK1 siRNA-mediated knock-down in transiently transfected H292 cells, and MSK1 stable knock-down mouse embryonic fibroblasts significantly reduced CS extract-induced MSK1, NF-κB RelA/p65 activation, and posttranslational modifications of histones. CS extract/CS promotes the direct interaction of MSK1 with RelA/p65 and p300 in epithelial cells and in mouse lung. Furthermore, CS-mediated recruitment of MSK1 and its substrates to the promoters of NF-κB-dependent pro-inflammatory genes leads to transcriptional activation, as determined by chromatin immunoprecipitation. Thus, MSK1 is an important downstream kinase involved in CS-induced NF-κB activation and chromatin modifications, which have implications in pathogenesis of COPD.


Monte Carlo simulation of fluorescence spectra of normal and dysplastic cervical tissues for optimizing excitation/receiving arrangements.
Recent studies have demonstrated that the autofluorescence technique is a very promising tool for early-stage cancer diagnosis in various tissues. Many researchers have applied the autofluorescence technique through fiber-optic cables to excite tissues and collect the fluorescent emission signal from the tissues for discrimination analysis. In this study, we developed a Monte Carlo-light-induced autofluorescence (MCS LIAF) simulation model to optimize the oblique angle in the excitation optical fiber and the spatial arrangements in the receiving optical fiber. Our aim was to discriminate cervical tissues at different dysplastic stages. The model combined the structure of multi-layered tissues, tissue optical scattering and absorption parameters, tissue fluorophore concentration, the characteristic fluorescent spectrum of fluorophores, and the excitation and receiving arrangement of the optical fibers. The results show that the optimal oblique angle of the excitation optical fiber is between 0 degrees and 45 degrees and that the optimal receiving optical fiber is positioned 200 microm away from the origin. We also observed that changing the excitation angle is very useful in differentiating normal from cervical intraepithelial neoplasia (CIN) I or CIN II tissues. Also, using the fluorescence peak ratio of NADH/collagen can help discriminate CIN III from normal tissues and CIN I/II tissues.


The microRNA-argonaute complex: a platform for mRNA modulation.
With the cloning the lin-4 gene in 1993, the possibility of an approximately 21-nucleotide RNA functioning as a regulatory molecule intrigued a relatively small number of scientists. This idea appeared to be a peculiarity of C. elegans as it was not until seven years later that the second, more conserved small RNA, let-7 was cloned. A spate of papers in 2000 and 2001 revealed that the underlying properties of the lin-4 and let-7 genes were a common facet of animal genomes and the absolute number and potential of this new class of gene products requires us to integrate them with other aspects of gene expression and evolution.(1-3) A wealth of information has accumulated in the intervening years that outline, in general, how these small RNAs are expressed and processed into a functional form. Contemporaneous to these studies, experiments also identified a cadre of evolutionarily conserved proteins, the Argonautes (Agos) that directly associate with and are required for microRNA function. Computational and experimental methods have led the identification of many functional mRNA targets. In the last few years, a significant body of work has focused on resolving two key issues: How do microRNAs function in particular genetic contexts (i.e., as "molecular switches" or "fine-tuners" of gene expression) and secondly, what facet/s of mRNA metabolism do microRNAs modulate in their role(s) as a regulatory molecule? The primary objective here is not to comprehensively compare the competing models of microRNA function (reviewed in refs. 4-6) but to frame a potential solution to these two fundamental questions by suggesting that the core microRNA-Ribonucleic-Protein Complex (microRNP), composed of the microRNA and an Ago protein, functions as a highly modifiable scaffold that associates with specific mRNAs via the bound microRNA and facilitates the localized activity of a variety of accessory proteins. The resulting composite mechanism could account for the apparent complexities of measuring microRNA activity and furthermore, accommodate the broad levels of regulation observed in vivo.


Are women with endocervical adenocarcinoma at risk for lynch syndrome? Evaluation of 101 cases including unusual subtypes and lower uterine segment tumors.
It is well documented that endometrial and ovarian carcinoma are associated with Lynch syndrome (LS), but the association, if any, between endocervical carcinoma and LS has not been fully evaluated. The relationship between endocervical carcinoma and LS is particularly relevant, given the apparent affinity of LS-associated endometrial carcinomas for the lower uterine segment and the attendant difficulties in determining tumor origin at this site. In this study, we examined mismatch repair (MMR) protein expression (MLH1, MSH2, MSH6, and PMS2) in 60 endocervical adenocarcinomas, including variants (minimal deviation adenocarcinoma, mesonephric adenocarcinoma, adenosquamous carcinoma, clear cell carcinoma) and a series of well-characterized lower-uterine segment carcinomas of known endocervical or endometrial origin (n=41). Two of the lower uterine segment tumors occurred in risk-reducing hysterectomy specimens from known LS patients. All endocervical adenocarcinomas including variants and lower uterine segment endocervical tumors (1 from a known LS patient) were proficient in all 4 MMR proteins. In contrast, 2/20 (10%) lower uterine segment endometrial cancers were deficient in at least 1 MMR (1 from a known LS patient). These data provide evidence that, unlike endometrial and ovarian adenocarcinoma, there is no association between LS and endocervical carcinoma. MMR testing is prudent in lower uterine segment tumors in women with possible LS, especially those for which definitive site of origin cannot be determined.


Perceived risk following melanoma genetic testing: a 2-year prospective study distinguishing subjective estimates from recall.
A major goal of predictive genetic testing is to alert people to their risk before illness onset; however, little is known about how risk perceptions change following genetic testing and whether information is recalled accurately over time. In the United States, a CDKN2A/p16 mutation confers 76 % lifetime risk of melanoma. Following genetic counseling and test reporting, subjective risk estimates and recall of counselor-provided risk estimates were assessed 5 times over the next 2 years among 60 adult members of 2 extended CDKN2A/p16 kindreds. No sustained changes from baseline in risk perceptions were reported. Unaffected carriers (n = 15) consistently reported significantly lower subjective risk estimates (46 %) than they were actually given (76 %, p < 0.001) or recalled having been given (60 %, p < 0.001). Noncarriers' (n = 27) risk estimates decreased following results disclosure, but rebounded, with both subjective and recalled estimates subsequently exceeding what they were told by the counselor (both ps < 0.001). Affected carriers' (n = 18) risk estimates for developing a new melanoma corresponded well to counselor-provided information (p = 0.362). For all 3 patient groups, results were consistent across multiple risk measures and remained similar when demographic, phenotypic, and baseline behavioral contributors to melanoma risk were statistically controlled. These findings are consistent with other studies of risk perception, but additional studies of more diverse populations are needed to understand the reasons behind both the persistence of initial risk estimates and their divergence from information provided by the counselor during genetic counseling. Additionally, determining whether holding subjective risk perceptions that differ from counselor-provided information ultimately affects adherence to management recommendations will help guide the presentation of risk information in genetic counseling practice.


Animal models are reliably mimicking human diseases? A morphological study that compares animal with human NAFLD.
Non-alcoholic fatty liver disease (NAFLD) is a clinical-pathological syndrome that includes a wide spectrum of morphological alterations. In research, animal models are crucial in evaluating not only the pathogenesis of NAFLD and its progression, but also the therapeutic effects of various agents. Investigations on the ultrastructural features of NAFLD in humans are not copious, due to the difficulty to obtain human samples and to the long time of NAFLD to evolve. Translational comparative studies on the reliability of animal models in representing the histopathologic picture as seen in humans are missing. To overcome this lack of investigations, we compared the ultrastructural NAFLD features of an animal model versus human. Sprague-Dawley rats were fed with a high fat diet (HFD) for 1-4 weeks, while control rats were fed with a standard diet. Human specimens were collected from patients with diagnosed fatty liver disease, undergoing liver biopsies or surgery. Rat and human samples were examined by light microscopy and by transmission and high resolution scanning electron microscopy. The present work demonstrated that NAFLD in animal model and in human, share overlapping ultrastructural features. In conclusion, animal HFD represent an appropriate tool in studying the pathogenesis of NAFLD.


Carbohydrate feeding during recovery alters the skeletal muscle metabolic response to repeated sessions of high-intensity interval exercise in humans.
Exercise training under conditions of reduced carbohydrate (CHO) availability has been reported to augment gains in skeletal muscle oxidative capacity; however, the underlying mechanisms are unclear. We examined the effect of manipulating CHO intake on the acute metabolic response to high-intensity interval exercise, including signaling cascades linked to mitochondrial biogenesis. Ten men performed two trials in random order separated by >or=1 wk. Each trial consisted of a morning (AM) and afternoon (PM) training session (5 x 4 min cycling at approximately 90-95% of heart rate reserve) separated by 3 h of recovery during which subjects ingested a high-CHO drink (HI-HI) or nonenergetic placebo (HI-LO) before PM exercise. Biopsies (vastus lateralis) revealed that muscle phosphocreatine and ATP content were similar after AM exercise but decreased to a greater extent during PM exercise in HI-LO vs. HI-HI. Phosphorylation of p38 mitogen-activated protein kinase (MAPK) and AMP-activated protein kinase (AMPK) increased approximately 4-fold and 2-fold, respectively, during AM exercise with no difference between conditions. After PM exercise, p38 MAPK phosphorylation was higher in HI-LO vs. HI-HI, whereas AMPK was not different between conditions. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha) gene expression increased approximately 8-fold during recovery from AM exercise and remained elevated during PM exercise with no differences between conditions. Cytochrome oxidase subunit 4 (COXIV) mRNA was also elevated 3 h after AM exercise, with no difference between conditions. These data provide evidence that p38 MAPK is a nutrient-sensitive signaling molecule that could be involved in the altered skeletal muscle adaptive response reported after exercise training under conditions of restricted CHO intake, but further research is required to confirm this hypothesis.


The effect of Lactobacillus acidophilus and Lactobacillus casei on the in vitro bioaccessibility of flaxseed lignans (Linum usitatissimum L.).
Secoisolariciresinol (SECO) is present in flaxseeds as a glucoside, secoisolariciresinol diglucoside (SDG), which can be metabolized to enterodiol (ED) and enterolactone (EL) by the human intestinal microbiota. The aim of this study was to evaluate the effect of Lactobacillus casei and Lactobacillus acidophilus on the bioaccessibility of flaxseed lignans from a complete in vitro digestion of whole flaxseeds (WFs) and flaxseed flour (FF). Lignans are only detected in the large intestine. The bioaccessibility of SDG for FF digestion can be ordered as follows: control (without probiotics) > L. casei > L. acidophilus; and for WF digestion, only in the presence of L. casei SDG was detected. For SECO and EL, the presence of both probiotics had no effect on FF and WF digestion. However, in the digestion of WF both L. casei and L. acidophilus increased ED bioaccessibility in the first 12 h; but both probiotics had no significant effect on FF digestion.


Effect of hepatic and renal dysfunction on disposition of bupropion in rats.
Disposition of bupropion after oral administration was investigated in carbon tetrachloride (CCl4) and gentamicin treated rats. Bupropion exhibits extensive first-pass effect and is mainly cleared by hepatic route. In rats with hepatic damage, maximum plasma concentration (Cmax) was approximately 3 times higher and area under the plasma concentration-time curve up to 6 h (AUC 0-6) and AUC 0-infinity increased on an average 4 and 5 times respectively compared to the control. The half-life was doubled with hepatic dysfunction. These findings suggest that hepatic impairment in rats causes a decrease in first pass effect as well as an increase in the half-life of the drug. Rats with renal impairment, exhibited a significant increase in Cmax, AUC 0-6 and AUC 0-infinity of bupropion approximately 3-fold as compared to the control, no change in half life of the drug was observed. This indicates that rats with renal impairment show less efficient first-pass effect which may lead to increase in systemic bioavailability. The time to peak observed in all treated animals was not significantly different from the control. The percentage of bound bupropion did not differ either in CCl4 or gentamicin treated plasma as compared to the control.


Fundamental constraints on the abundances of chemotaxis proteins.
Flagellated bacteria, such as Escherichia coli, perform directed motion in gradients of concentration of attractants and repellents in a process called chemotaxis. The E. coli chemotaxis signaling pathway is a model for signal transduction, but it has unique features. We demonstrate that the need for fast signaling necessitates high abundances of the proteins involved in this pathway. We show that further constraints on the abundances of chemotaxis proteins arise from the requirements of self-assembly both of flagellar motors and of chemoreceptor arrays. All these constraints are specific to chemotaxis, and published data confirm that chemotaxis proteins tend to be more highly expressed than their homologs in other pathways. Employing a chemotaxis pathway model, we show that the gain of the pathway at the level of the response regulator CheY increases with overall chemotaxis protein abundances. This may explain why, at least in one E. coli strain, the abundance of all chemotaxis proteins is higher in media with lower nutrient content. We also demonstrate that the E. coli chemotaxis pathway is particularly robust to abundance variations of the motor protein FliM.


Rationing scarce organs for transplantation: healthcare provider perspectives on wait-listing and organ allocation.
Ongoing debate about how to maximize the benefit of scarce organs while maintaining equity of access to transplantation exists. This study aims to synthesize healthcare provider perspectives on wait-listing and organ allocation. MEDLINE, Embase, and PsycINFO were searched till February 21, 2011. Quantitative data were extracted, and a qualitative synthesis of the studies was conducted. Twenty studies involving 4254 respondents were included. We identified two goals underpinning healthcare provider preferences for organ allocation: (i) maximize clinical benefit (quality of life gains, patient survival, treatment adherence, and graft survival) and social outcomes (social support, productivity, and valuation); (ii) achieve equity (waiting time, patient preferences, access to live donation, and medical urgency). Maximizing clinical or social outcomes meant organs would be preferentially given to patients expected to achieve good transplant outcomes or wider social gain. Achieving equity meant all patients should have an equal chance of transplant, or patients deemed more urgent receive higher priority. A tension between equity and efficiency is apparent. Balanced against dimensions of efficiency were considerations to instill a degree of perceived fairness in organ allocation. Ongoing engagement with stakeholders is needed to enhance transparency, a reasonable balance between efficiency and equity, and avoid discrimination against specific populations.


Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes.
Over 95% of human multi-exon genes undergo alternative splicing, a process important in normal development and often dysregulated in disease. We sought to analyze the global splicing regulatory network of CELF2 in human T cells, a well-studied splicing regulator critical to T cell development and function. By integrating high-throughput sequencing data for binding and splicing quantification with sequence features and probabilistic splicing code models, we find evidence of splicing antagonism between CELF2 and the RBFOX family of splicing factors. We validate this functional antagonism through knockdown and overexpression experiments in human cells and find CELF2 represses RBFOX2 mRNA and protein levels. Because both families of proteins have been implicated in the development and maintenance of neuronal, muscle, and heart tissues, we analyzed publicly available data in these systems. Our analysis suggests global, antagonistic coregulation of splicing by the CELF and RBFOX proteins in mouse muscle and heart in several physiologically relevant targets, including proteins involved in calcium signaling and members of the MEF2 family of transcription factors. Importantly, a number of these coregulated events are aberrantly spliced in mouse models and human patients with diseases that affect these tissues, including heart failure, diabetes, or myotonic dystrophy. Finally, analysis of exons regulated by ancient CELF family homologs in chicken, Drosophila, and Caenorhabditis elegans suggests this antagonism is conserved throughout evolution.


Oral appliances for obstructive sleep apnea: an evidence-based analysis.
The objective of this review was to determine the clinical effectiveness of oral appliances compared to 'no treatment', continuous positive airway pressure (CPAP), or surgery for the management of obstructive sleep apnea (OSA). CONDITION AND TARGET POPULATION OSA is characterized by repeated occurrences of upper airway collapse and obstruction during sleep. The condition leads to excessive daytime sleepiness, diminished quality of life, and increased risks of accidents, cardiovascular disease and death. In the general population, the prevalence of OSA is estimated to be 4% in men and 2% in women. Risk factors for OSA include obesity, male gender, increasing age, alcohol use, sedative use, and a family history of OSA. DESCRIPTION OF ORAL APPLIANCES: ORAL APPLIANCES FOR OSA FALL INTO TWO BROAD CATEGORIES: mandibular advancement splints (MAS), also known as mandibular repositioning devices, and tongue repositioning or retaining devices. The aim of MAS devices is to advance the mandible forward slightly to enlarge the upper airway and prevent it from collapsing. Similarly, tongue repositioning devices suction the tongue forward to prevent it from falling back and obstructing the airway during sleep. The alternatives to oral appliances include continuous positive airway pressure (CPAP) devices, surgery, drug therapy, positional devices, and lifestyle modification. CPAP is the gold standard of treatment, but despite its effectiveness, compliance rates for CPAP have declined because required systems are noisy and because wearing the mask can be uncomfortable, causing claustrophobia in some users. Are oral appliances effective in improving sleep-disordered breathing in patients with OSA compared to alternative treatments?Are there safety concerns with oral appliances?What is the evidence regarding patient preference, quality of life, and compliance for oral appliances?If effective, are oral appliances cost effective? A literature search was conducted up to February 2009. Systematic reviews, meta-analyses and randomized controlled trials (RCTs) with more than 20 adults with OSA were eligible for inclusion. The primary outcomes of interest were the Apnea Hypopnea Index (AHI), measures of daytime sleepiness, patient preference, compliance, and adverse events. Five systematic reviews and 16 RCTs that met the inclusion criteria were identified. The systematic reviews consistently concluded that CPAP was more effective than oral appliances at improving sleep disordered breathing, although there may be a niche area for the latter, especially among those with mild OSA as CPAP is difficult to tolerate by some users. Based on the results of the RCTs analyzed for this review, MAS devices are less effective than CPAP when AHI is used as the outcome of interest. MAS devices were shown to decrease AHI levels, but whether this reduction is clinically meaningful is uncertain. The Epworth Sleepiness Scale (ESS) was not able to achieve statistical significance in comparisons of MAS versus CPAP and MAS versus placebo. Nonetheless, after treatment with either MAS or CPAP, patients seem to be able to achieve normal ESS levels. The ESS has substantial limitations including its subjective nature and low construct validity (i.e. it is unclear if the scale is an accurate measure of sleepiness). Adverse events among patients with MAS devices in the RCTs were common, but mostly mild and transient. Jaw discomfort was the most commonly reported adverse event. Based on the results of the RCTs, compliance does not seem to be better or worse with MAS or CPAP. Similarly, there is no clear patient preference for MAS or CPAP among the studies reporting preference and satisfaction. Obstructive sleep apnea, oral appliances, mandibular advancement splints, tongue repositioning devices.


Functional studies of threonine 310 mutations in Glut1: T310I is pathogenic, causing Glut1 deficiency.
We have previously reported on a patient with the Glut1 deficiency syndrome (Online Mendelian Inheritance in Man number 606777) carrying a heterozygous T310I missense mutation in the GLUT1 gene (Klepper, J., Wang, D., Fischbarg, J., Vera, J. C., Jarjour, I. T., O'Driscoll, K. R., and De Vivo, D. C. (1999) Neurochem. Res. 24, 587-594). To investigate the molecular basis for the associated functional deficit, we constructed T310A, T310S, and T310I human GLUT1 mutants for expression in Xenopus laevis oocytes via cRNA injection. For all mutants, glucose transport was decreased, and osmotic water permeability (Pf) was increased. Km values for 3-O-methylglucose (3-OMG) uptake under zero-trans influx and equilibrium exchange influx conditions were, respectively, 13 +/- 1 and 68 +/- 5 mm for wild-type Glut1, 5 +/- 1 and 25 +/- 6 mm for T310A, 6 +/- 3 and 30 +/- 6 mm for T310I, and 5 +/- 1 and 48 +/- 5 mm for T310S. Compared with wild-type Glut1, we determined the following. (a). Zero-trans and equilibrium exchange influx values of 3-OMG were significantly decreased, respectively, 15 and 5% in T310A, 8 and 3% in T310I, and 40 and 34% in T310S mutants. (b). Zero-trans efflux of 3-OMG and dehydroascorbic acid uptake were significantly decreased in mutants. (c). The relative Pf values for T310A, T310I, and T310S were increased 3-, 4.8-, and 3.5-fold compared with wild-type values. We found a very high negative correlation between the rate of glucose uptake and Pf (-0.93), and between hydropathy and uptake (-0.92), a moderate correlation between hydropathy and Pf (0.73), and a minimal correlation between uptake, Pf, and molecular weight. These findings are consistent with a central role for hydropathy rather than size at position 310 of this mutation.


Sleep disturbances and cause-specific mortality: Results from the GAZEL cohort study.
Poor sleep is an increasing problem in modern society, but most previous studies on the association between sleep and mortality rates have addressed only duration, not quality, of sleep. The authors prospectively examined the effects of sleep disturbances on mortality rates and on important risk factors for mortality, such as body mass index, hypertension, and diabetes. A total of 16,989 participants in the GAZEL cohort study were asked validated questions on sleep disturbances in 1990 and were followed up until 2009, with <1% loss to follow-up. Body mass index, hypertension, and diabetes were measured annually through self-reporting. During follow-up, a total of 1,045 men and women died. Sleep disturbances were associated with a higher overall mortality risk in men (P = 0.005) but not in women (P = 0.33). This effect was most pronounced for men <45 years of age (≥3 symptoms vs. none: hazard ratio = 2.03, 95% confidence interval: 1.24, 3.33). There were no clear associations between sleep disturbances and cardiovascular mortality rates, although men and women with sleep disturbances were more likely to develop hypertension and diabetes (P < 0.001). Compared with people with no sleep disturbances, men who reported ≥3 types of sleep disturbance had an almost 5 times' higher risk of committing suicide (hazard ratio = 4.99, 95% confidence interval: 1.59, 15.7). Future strategies to prevent premature deaths may benefit from assessment of sleep disturbances, especially in younger individuals.


Restoration of Function With Acupuncture Following Severe Traumatic Brain Injury: A Case Report.
This case report illustrates the improvement of an acupuncture-treated patient who incurred a severe traumatic brain injury (TBI) from a snowboarding accident. Over 4 years, the patient progressed from initially not being able to walk, having difficulty with speech, and suffering from poor eyesight to where he has now regained significant motor function, speech, and vision and has returned to snowboarding. A core acupuncture protocol plus specific points added to address the patient's ongoing concerns was used. This case adds to the medical literature by demonstrating the potential role of acupuncture in TBI treatment.


Neuroprotective Effects of Cannabidiol in Hypoxic Ischemic Insult. The Therapeutic Window in Newborn Mice.
A relevant therapeutic time window (TTW) is an important criterion for considering the clinical relevance of a substance preventing newborn hypoxic-ischemic (HI) brain damage. To test the TTW of the neuroprotective effects of cannabidol (CBD), a non-psychoactive cannabinoid in a model of newborn HI brain damage. 9-10 day-old C57BL6 mice underwent a HI insult (10% oxygen for 90 min after left carotid artery electrocoagulation). Then, CBD 1 mg/kg or vehicle were administered s.c. 15 min, or 1, 3, 6, 12, 18 or 24 h after the end of the HI insult. Seven days later brain damage was assessed using T2W Magnetic Resonance Imaging scan (ipsilateral hemisphere volume loss, IVHL) and histological studies: Nissl staining (neuropathological score), TUNEL staining (apoptotic damage) and immunohistochemistry with glial fibrillary acidic protein (astrocyte viability) or ionized calcium binding adaptor molecule (microglial activation). CBD administered up to 18 h after HI reduced IHVL and neuropathological score by 60%, TUNEL+ count by 90% and astrocyte damage by 50%. In addition, CBD blunted the HI-induced increase in microglial population. When CBD administration was delayed 24 h, however, the neuroprotective effect was lost in terms of IHVL, apoptosis or astrogliosis reduction. CBD shows a TTW of 18 h when administered to HI newborn mice, which represents a broader TTW than reported for other neuroprotective treatments including hypothermia.


High-fidelity copying is not necessarily the key to cumulative cultural evolution: a study in monkeys and children.
The unique cumulative nature of human culture has often been explained by high-fidelity copying mechanisms found only in human social learning. However, transmission chain experiments in human and non-human primates suggest that cumulative cultural evolution (CCE) might not necessarily depend on high-fidelity copying after all. In this study, we test whether defining properties of CCE can emerge in a non-copying task. We performed transmission chain experiments in Guinea baboons and human children where individuals observed and produced visual patterns composed of four squares on touchscreen devices. In order to be rewarded, participants had to avoid touching squares that were touched by a previous participant. In other words, they were rewarded for innovation rather than copying. Results nevertheless exhibited fundamental properties of CCE: an increase over generations in task performance and the emergence of systematic structure. However, these properties arose from different mechanisms across species: children, unlike baboons, converged in behaviour over generations by copying specific patterns in a different location, thus introducing alternative copying mechanisms into the non-copying task. In children, prior biases towards specific shapes led to convergence in behaviour across chains, while baboon chains showed signs of lineage specificity. We conclude that CCE can result from mechanisms with varying degrees of fidelity in transmission and thus that high-fidelity copying is not necessarily the key to CCE.


Partial deletion of ANKRD11 results in the KBG phenotype distinct from the 16q24.3 microdeletion syndrome.
KBG syndrome (OMIM 148050) is a very rare genetic disorder characterized by macrodontia, distinctive craniofacial abnormalities, short stature, intellectual disability, skeletal, and neurologic involvement. Approximately 60 patients have been reported since it was first described in 1975. Recently mutations in ANKRD11 have been documented in patients with KBG syndrome, and it has been proposed that haploinsufficiency of ANKRD11 is the cause of this syndrome. In addition, copy number variation in the 16q24.3 region that includes ANKRD11 results in a variable phenotype that overlaps with KBG syndrome and also includes autism spectrum disorders and other dysmorphic facial features. In this report we present a 2½-year-old African American male with features highly suggestive of KBG syndrome. Genomic microarray identified an intragenic 154 kb deletion at 16q24.3 within ANKRD11. This child's mother was mosaic for the same deletion (present in approximately 38% of cells) and exhibited a milder phenotype including macrodontia, short stature and brachydactyly. This family provides additional evidence that ANKRD11 causes KBG syndrome, and the mild phenotype in the mosaic form suggests that KBG phenotypes might be dose dependent, differentiating it from the more variable 16q24.3 microdeletion syndrome. This family has additional features that might expand the phenotype of KBG syndrome.


Complementary and Alternative Medicines for the Postoperative Patient.
The Medical-Surgical Nursing Certification Board (MSNCB) is a professional organization whose mission is to validate excellence in medical-surgical nursing. MSNCB administers the Certified Medical-Surgical Registered Nurse (CMSRN®) and Certified in Care Coordination and Transition Management (CCCTM) certification programs because certification is the recognized path for registered nurses to build and demonstrate commitment, confidence, and credibility. Certification provides an added credential beyond licensure. It demonstrates, by examination, that the registered nurse adheres to specialized nursing standards and has acquired a core body of specialized knowledge in his or her practice or specialty. The topic of this article is part of the comprehensive examination given by MSNCB. The following scenario and questions offer an example that potential certificants may use to test their knowledge. For more information about MSNCB, visit www.msncb.org.


NADPH oxidase-2 inhibition restores contractility and intracellular calcium handling and reduces arrhythmogenicity in dystrophic cardiomyopathy.
Duchenne muscular dystrophy may affect cardiac muscle, producing a dystrophic cardiomyopathy in humans and the mdx mouse. We tested the hypothesis that oxidative stress participates in disrupting calcium handling and contractility in the mdx mouse with established cardiomyopathy. We found increased expression (fivefold) of the NADPH oxidase (NOX) 2 in the mdx hearts compared with wild type, along with increased superoxide production. Next, we tested the impact of NOX2 inhibition on contractility and calcium handling in isolated cardiomyocytes. Contractility was decreased in mdx myocytes compared with wild type, and this was restored toward normal by pretreating with apocynin. In addition, the amplitude of evoked intracellular Ca(2+) concentration transients that was diminished in mdx myocytes was also restored with NOX2 inhibition. Total sarcoplasmic reticulum (SR) Ca(2+) content was reduced in mdx hearts and normalized by apocynin treatment. Additionally, NOX2 inhibition decreased the production of spontaneous diastolic calcium release events and decreased the SR calcium leak in mdx myocytes. In addition, nitric oxide (NO) synthase 1 (NOS-1) expression was increased eightfold in mdx hearts compared with wild type. Nevertheless, cardiac NO production was reduced. To test whether this paradox implied NOS-1 uncoupling, we treated cardiac myocytes with exogenous tetrahydrobioterin, along with the NOX inhibitor VAS2870. These agents restored NO production and phospholamban phosphorylation in mdx toward normal. Together, these results demonstrate that, in mdx hearts, NOX2 inhibition improves the SR calcium handling and contractility, partially by recoupling NOS-1. These findings reveal a new layer of nitroso-redox imbalance in dystrophic cardiomyopathy.


Phosphorylation of RNA polymerase II is independent of P-TEFb in the C. elegans germline.
RNA polymerase II (Pol II) elongation in metazoans is thought to require phosphorylation of serine 2 (Ser2-P) of the Pol II C-terminal domain (CTD) by the P-TEFb complex, CDK-9/cyclin T. Another Ser2 kinase complex, CDK-12/cyclin K, which requires upstream CDK-9 activity has been identified in Drosophila and human cells. We show that regulation of Ser2-P in C. elegans soma is similar to other metazoan systems, but Ser2-P in the germline is independent of CDK-9, and largely requires only CDK-12. The observed differences are not due to differential tissue expression as both kinases and their cyclin partners are ubiquitously expressed. Surprisingly, loss of CDK-9 from germ cells has little effect on Ser2-P, yet CDK-9 is essential for germline development. By contrast, loss of CDK-12 and Ser2-P specifically from germ cells has little impact on germline development or function, although significant loss of co-transcriptional H3K36 trimethylation is observed. These results show a reduced requirement for Pol II Ser2-P in germline development and suggest that generating Ser2-P is not the essential role of CDK-9 in these cells. Transcriptional elongation in the C. elegans germline thus appears to be uniquely regulated, which may be a novel facet of germline identity.


Physical fitness and psychological benefits of strength training in community dwelling older adults.
Previous studies concerning psychological benefits of exercise among the elderly has focused predominantly on the effects of aerobic exercise. In the present study, psychological and behavioral adaptations in response to 12-weeks of strength training were examined in medically healthy but sedentary 42 older adults (mean age = 68 years). The purpose of this study was to evaluate the effects of high and low intensity resistance training intensity on a) muscular fitness, b) psychological affect, and c) neurocognitive functioning. Subjects were randomly assigned to high intensity/low volume (EXH: 2 sets of 8 to 10 repetitions for 75 to 85% of 1 RM), low intensity/high volume (EXL: 2 sets of 14 to 16 repetitions for 55 to 65% of 1 RM), or no exercise control programs. Prior to and following the 12-week program, subjects underwent comprehensive physiological and psychological evaluations. Physiological assessment included measurements of blood pressure, heart rate, arm and leg muscle strength, body composition, and oxygen consumption (VO2max). Psychological measures included evaluations of mood, anxiety, and physical self-efficacy as well as cognitive functioning. The results of this study indicated that both high and low intensity strength programs were associated with marked improvements in physiological fitness and psychological functioning. Specifically, subjects in the strength training programs increased overall muscle strength by 38.6% and reduced percent body fat by 3.0%. Favorable psychological changes in the strength-trained subjects included improvements in positive and negative mood, trait anxiety, and perceived confidence for physical capability. The treatment effects of neurocognitive functioning were not significant. In summary, this study demonstrated that participation in 12-weeks of high or low intensity strength training can improve overall physical fitness, mood, and physical self-efficacy in older adults while cognitive functioning remains constant.


Mass fatality preparedness in the death care sector.
To characterize mass fatality preparedness of the death care sector (ie, funeral industry organizations) and to determine the workforce's ability and willingness to report to duty during a hypothetical high fatality pandemic event. Anonymous, Web-based, cross-sectional survey of a national funeral industry sample. Preparedness was characterized using descriptive statistics. Factors significantly associated with ability and willingness were identified using chi-squared bivariate analysis. Respondents (N = 492) generally rated their organizational preparedness planning as suboptimal; only six of thirteen preparedness checklist items were typically in place. In contrast, response intentions were uniformly high; more than 80% of the respondents were willing to report to work, although high prevalence of secondary obligations might hinder this. Preparedness strategies that address interorganizational, surge capacity, and personal emergency planning are likely to be most efficacious. STATEMENT OF CLINICAL SIGNIFICANCE: Occupational medicine plays an important role in emergency preparedness and response. Funeral industry organizations could benefit from skills and resources of occupational medicine, including training, fit testing, development of plans, and coordination and hosting of planning exercises.


Photodynamic antimicrobial chemotherapy on Streptococcus mutans using curcumin and toluidine blue activated by a novel LED device.
Photodynamic antimicrobial chemotherapy (PACT) is an antimicrobial approach that uses photosensitizers (PS) in combination with light sources at specific wavelengths aiming the production of reactive oxygen species. The long illumination time necessary to active PS is a challenge in PACT. Thus, this study investigated the antimicrobial effect of a novel single source of light-emitting diode (LED) light that covers the entire spectrum of visible light beyond interchangeable probes at high power intensity. Blue and red LED probes were used into different exposure times to active different concentrations of curcumin (C) and toluidine blue (T) on planktonic suspensions of Streptococcus mutans UA 159 (S. mutans). S. mutans were standardized and submitted to (1) PACT treatment at three concentrations of C and T exposure at three radiant exposures of a blue LED (BL) (C+BL+) and a red LED (RL) (T+RL+), (2) C (C+BL-) or T alone (T+RL-), (3) both LED lights (C-BL+ and T-RL+), and (4) neither PS nor LED illumination (control group: C-BL- and T-RL-). Aliquots of the suspensions were diluted and cultured on blood agar plates. The number of colony-forming units was calculated after 48 h. The groups submitted to PACT presented a lethal photokilling rate to all PS concentrations at tested dosimetries. The comparison to control group when PS and LED lights used alone demonstrated no decrease in the number of viable bacterial counts. The novel LED device in combination with curcumin and toluidine blue promoted an effective photoinactivation of S. mutans suspensions at ultrashort light illumination times.


Guggulsterone for Chemoprevention of Cancer.
Guggulsterone [4, 17(20)-pregnadiene-3, 16-dione] is a plant sterol derived from the gum resin of the tree Commiphora wightii. The gum resin of the guggul tree has been used in traditional medicine for centuries to treat obesity, liver disorders, internal tumors, malignant sores, ulcers, urinary complaints, intestinal worms, leucoderma, sinus, edema and sudden paralytic seizures. Guggulsterone has been shown to modulate the nuclear receptors, farnesoid X receptor, pregnane X receptor, CYP 2b10 gene expression, and the bile salt export pump for cholesterol elimination. Recent research indicates that the active components of gum guggul, E- and Zguggulsterone have the potential to both prevent and treat cancers. Guggulsterone inhibits the growth of a wide variety of tumor cells and induces apoptosis through down regulation of antiapoptotic gene products (IAP1, xIAP, Bfl-1/A1, Bcl-2, cFLIP, and survivin), modulation of cell cycle proteins (cyclin D1 and c-Myc), activation of caspases, inhibition of Akt, and activation of JNK. Guggulsterone modulates the expression of gene products involved in metastasis (MMP-9, COX-2, and VEGF) of tumor cells. Guggulsterone mediates gene expression through the modulation of several transcription factors, including NF-κB, STAT3, C/EBPα, androgen receptor, and glucocorticoid receptors. This review describes the anti-cancer properties, molecular targets, and the apoptotic effects of guggulsterone.


Flattened cortisol rhythms in metastatic breast cancer patients.
Allostatic load, the physiological accumulation of the effects of chronic stressors, has been associated with multiple adverse health outcomes. Flattened diurnal cortisol rhythmicity is one of the prototypes of allostatic load, and has been shown to predict shorter survival among women with metastatic breast cancer. The current study compared diurnal cortisol slope in 17 breast cancer patients and 31 controls, and tested associations with variables previously found to be related to cortisol regulation, i.e, abdominal adiposity, perceived stress, social support, and explicit memory. Women with metastatic breast cancer had significantly flatter diurnal cortisol rhythms than did healthy controls. Patients with greater disease severity showed higher mean cortisol levels, smaller waist circumference, and a tendency toward flatter diurnal cortisol rhythms. There were no relations between cortisol slope and psychological or cognitive functioning among patients. In contrast, controls with flatter rhythms showed the expected allostatic load profile of larger waist circumference, poorer performance on explicit memory tasks, lower perceived social support, and a tendency toward higher perceived stress. These findings suggest that the cortisol diurnal slope may have important but different correlates in healthy women versus those with breast cancer.


Mutants of the RNA-dependent protein kinase (PKR) lacking double-stranded RNA binding domain I can act as transdominant inhibitors and induce malignant transformation.
Recently we reported that introduction of catalytically inactive PKR molecules into NIH 3T3 cells causes malignant transformation and the development of tumors in nude mice. We have proposed that PKR may be a tumor suppressor gene possibly because of its translational inhibitory properties. We have now designed and characterized a number of PKR mutants encoding proteins that retain their catalytic competence but are mutated in their regulatory double-stranded RNA (dsRNA) binding domains (RBDs). RNA binding analysis revealed that PKR proteins either lacking or with point mutations in the first RBD (RBD-1) bound negligible amounts of dsRNA activator or adenovirus VAI RNA inhibitor. Despite the lack of binding, such variants remained functionally competent but were much less active than wild-type PKR. PKR variants completely lacking RBD-1 were largely unresponsive to dsRNA in activation assays but could be activated by heparin. To complement these studies, we evaluated the effects of point mutations in RBD-1 or the removal of either RBD-1 or RBD-2 on the proliferation rate of mouse 3T3 cells. We were unsuccessful at isolating stably transformed cells expressing RBD-1 point mutants or RBD-2-minus mutants. In contrast, NIH 3T3 cells, which constitutively expressed PKR proteins that lacked RBD-1, were selected. These cells displayed a transformed phenotype and caused tumors after inoculation in nude mice. Further, levels of endogenous eIF-2 alpha phosphorylation in RBD-1-minus cell lines were reduced, suggesting that such mutants act in a dominant negative manner to inhibit the function of endogenous PKR. These results emphasize the importance of RBD-1 in PKR control of cell growth and provide additional evidence for the critical role played by PKR in the regulation of malignant transformation.


Infidelity of DNA synthesis in vitro: screening for potential metal mutagens or carcinogens.
Thirty-one metal salts have been tested for their ability to affect the accuracy of DNA synthesis in vitro. All ten salts of metal carcinogens decreased the fidelity of DNA synthesis. Of the three metals which beforehand were considered to be possible mutagens or carcinogens, only one decreased fidelity. In contrast, 17 noncarcinogenic metal salts did not affect fidelity even when present at concentrations that were clearly inhibitory.


Oxidative targets in the stratum corneum. A new basis for antioxidative strategies.
As the outermost layer of skin, the stratum corneum (SC) is continuously exposed to an oxidative environment, including air pollutants, ultraviolet radiation, chemical oxidants, and aerobic microorganisms. Human SC reveals characteristic antioxidant and protein oxidation gradients with increasing antioxidant depletion and protein oxidation towards the outer layers. SC antioxidants, lipids, and proteins are oxidatively modified upon treatments with ultraviolet A/ultraviolet B, ozone, and benzoyl peroxide. alpha-Tocopherol represents the predominating SC antioxidant with respect to its concentration and its unique susceptibility to the various oxidative challenges tested. In sites rich in sebaceous glands, alpha-tocopherol is physiologically delivered to the surface via secretion of sebum. Oxidative damage in the human SC represents an early pathophysiological event preceding barrier disruption and inflammation in environmentally challenged skin. Furthermore, oxidative gradients in SC proteins may have implications for the process of desquamation in human skin.


Is body size a biomarker for optimizing dosing of omega-3 polyunsaturated fatty acids in the treatment of patients with IgA nephropathy?
Re-analysis of the North American IgA Nephropathy Study suggested that efficacy of omega-3 polyunsaturated fatty acids (omega-3 PUFA) was dosage-dependent on the basis of body size and plasma omega-3/omega-6 and eicosapentaenoic acid (EPA)/arachidonic acid (AA) ratios. The objective of this study was to confirm these assertions. Data from a previously reported randomized 2-yr clinical trial in which two dosages of an ethyl ester omega-3 PUFA (Omacor) were given to 73 high-risk patients with IgA nephropathy were reviewed. Omacor also was used in the North American IgA Nephropathy Study. Parameters included body weight; body mass index (BMI); plasma phospholipid AA, EPA, and docosahexanoic acid (DHA) levels and serum creatinine and 24-h urine protein (UP) levels during the 2-yr trial; and time to ESRD after 6.4 yr. Plasma phospholipid levels of EPA, DHA, and EPA/AA ratios were significantly inversely correlated with increasing body weight and BMI in the Omacor 4-g dosage group but not in the Omacor 8-g dosage group. Conversely, increasing levels of lipid parameters were observed with increasing dosages of Omacor (EPA+DHA) in grams per kilogram of body weight at 6 wk of treatment. None of the plasma omega-3 PUFA levels, EPA/AA ratios, or Omacor dosage per kilogram was significantly associated with reciprocal serum creatinine or UP slopes during the 2-yr trial or with ESRD. This post hoc analysis of body weight and BMI, plasma omega-3 PUFA status, and renal outcome did not find that treatment efficacy of omega-3 PUFA was dosage dependent on the basis of body size.


Myocardial potassium channels: electrophysiological and molecular diversity.
Myocardial K+ currents function to control resting membrane potentials, the heights and durations of action potentials, and refractoriness and automaticity. They are important targets for the actions of transmitters and hormones or drugs known, or postulated, to modulate cardiac functioning. A variety of K+ currents that subserve these functions have now been identified in myocardial cells isolated from different species, as well as in cells isolated from different regions of the heart in the same species. These currents include the voltage-gated K+ types, such as the transient outward (Ito) and delayed rectifier (IK) currents, as well as the inwardly rectifying currents, IK1, IK(ACh), and IK(ATP). The physiological and functional properties of the various K+ currents/channels expressed in different myocardial cell types are the focus of this review. Advances made in cloning K+ channel subunits of the Kv, eag, Kir, and IsK families are discussed, and progress made in identifying the K+ channel subunits expressed in the mammalian myocardium is summarized. The relationships between the various cloned K+ channel subunits and the functional K+ channels characterized electrophysiologically in myocardial cells are explored.


Nucleosome landscape and control of transcription in the human malaria parasite.
In eukaryotic cells, chromatin reorganizes within promoters of active genes to allow the transcription machinery and various transcription factors to access DNA. In this model, promoter-specific transcription factors bind DNA to initiate the production of mRNA in a tightly regulated manner. In the case of the human malaria parasite, Plasmodium falciparum, specific transcription factors are apparently underrepresented with regards to the size of the genome, and mechanisms underlying transcriptional regulation are controversial. Here, we investigate the modulation of DNA accessibility by chromatin remodeling during the parasite infection cycle. We have generated genome-wide maps of nucleosome occupancy across the parasite erythrocytic cycle using two complementary assays--the formaldehyde-assisted isolation of regulatory elements to extract protein-free DNA (FAIRE) and the MNase-mediated purification of mononucleosomes to extract histone-bound DNA (MAINE), both techniques being coupled to high-throughput sequencing. We show that chromatin architecture undergoes drastic upheavals throughout the parasite's cycle, contrasting with targeted chromatin reorganization usually observed in eukaryotes. Chromatin loosens after the invasion of the red blood cell and then repacks prior to the next cycle. Changes in nucleosome occupancy within promoter regions follow this genome-wide pattern, with a few exceptions such as the var genes involved in virulence and genes expressed at early stages of the cycle. We postulate that chromatin structure and nucleosome turnover control massive transcription during the erythrocytic cycle. Our results demonstrate that the processes driving gene expression in Plasmodium challenge the classical eukaryotic model of transcriptional regulation occurring mostly at the transcription initiation level.


Tidal volume reduction in patients with acute lung injury when plateau pressures are not high.
Use of a volume- and pressure-limited mechanical ventilation strategy improves clinical outcomes of patients with acute lung injury and acute respiratory distress syndrome (ALI/ARDS). However, the extent to which tidal volumes and inspiratory airway pressures should be reduced to optimize clinical outcomes is a controversial topic. This article addresses the question, "Is there a safe upper limit to inspiratory plateau pressure in patients with ALI/ARDS?" We reviewed data from animal models with and without preexisting lung injury, studies of normal human respiratory system mechanics, and the results of five clinical trials of lung-protective mechanical ventilation strategies. We also present an original analysis of data from the largest of the five clinical trials. The available data from each of these assessments do not support the commonly held view that inspiratory plateau pressures of 30 to 35 cm H2O are safe. We could not identify a safe upper limit for plateau pressures in patients with ALI/ARDS.


Cognitive bias modification of interpretation in children with social anxiety disorder.
Negative (or a lack of positive) interpretation of ambiguous social situations has been hypothesised to maintain social anxiety disorder in children, yet there is currently limited evidence to support this. Cognitive Bias Modification of Interpretation (CBM-I) provides a means to explore the causal influence of interpretation bias on social anxiety disorder, and has been associated with a reduction in social anxiety symptoms in adults. Seven to twelve year old children with a diagnosis of social anxiety disorder completed CBM-I training, adapted from materials designed for socially anxious children in the community, or no training. Effects on interpretation bias and social anxiety were assessed. The adapted CBM-I training was not associated with significant changes in benign or negative interpretation. Unsurprisingly given the lack of successful interpretation training, there were no significant changes in child or parent reported social anxiety symptoms, clinician-rated severity or diagnoses and change in interpretation was not significantly associated with change in social anxiety. These findings contrast with some studies with community populations although it is possible that more intensive CBM-I training is required to fully test this hypothesis among clinical groups.


Spike-timing error backpropagation in theta neuron networks.
The main contribution of this letter is the derivation of a steepest gradient descent learning rule for a multilayer network of theta neurons, a one-dimensional nonlinear neuron model. Central to our model is the assumption that the intrinsic neuron dynamics are sufficient to achieve consistent time coding, with no need to involve the precise shape of postsynaptic currents; this assumption departs from other related models such as SpikeProp and Tempotron learning. Our results clearly show that it is possible to perform complex computations by applying supervised learning techniques to the spike times and time response properties of nonlinear integrate and fire neurons. Networks trained with our multilayer training rule are shown to have similar generalization abilities for spike latency pattern classification as Tempotron learning. The rule is also able to train networks to perform complex regression tasks that neither SpikeProp or Tempotron learning appears to be capable of.


Conformability in everolimus-eluting bioresorbable scaffolds compared with metal platform coronary stents in long lesions.
The aim of this study was to determine if there are significant differences in curvature of the treated vessel after the deployment of a polymeric BRS or MPS in long lesions. The impact of long polymeric bioresorbable scaffolds (BRS) compared with metallic platform stents (MPS) on vessel curvature is unknown. This retrospective study compares 32 patients who received a single everolimus-eluting BRS with 32 patients treated with a single MPS of 28 mm. Quantitative coronary angiography (QCA) was used to evaluate curvature of the treatment and peri-treatment region before and after percutaneous coronary intervention (PCI). Baseline demographic and angiographic characteristics were similar between the BRS and MPS groups. Pretreatment lesion length was 22.19 versus 20.38 mm in the BRS and MPS groups respectively (p = 0.803). After treatment, there was a decrease in median diastolic curvature in the MPS group (from 0.257 to 0.199 cm-1, p = 0.001). A similar trend was observed in the BRS group but did not reach statistical significance (median diastolic curvature from 0.305 to 0.283 cm-1, p = 0.056). Median Percentage relative change in diastolic curvature was lower in the BRS group compared with the MPS group (BRS vs. MPS: 7.48 vs. 29.4%, p = 0.013). By univariate analysis, use of MPS was an independent predictor of change in diastolic curvature (p = 0.022). In the deployment of long coronary scaffolds/stents (28 mm in length), BRS provides better conformability compared with MPS.


Complete upper urinary tract obstruction caused by penetrating pellet injury of the ureterintroduction.
Ureteral injuries due to gunshots are tend to be misdiagnosed because of concomitant vascular and intraabdominal organ wounds. Our case is a 23-year-old man who was admitted to the hospital with multiple abdominal gunshot wounds. Laboratory findings showed worsening anemia, and the computed tomography (CT) scan showed multiple lead bullets inside the abdomen and retroperitoneum. Patient was then taken to the operation room for laparatomy. There were many intestinal injuries and also a stable retroperitoneal hematoma. There was no ureteral injury mentioned in the operation note or the initial CT report. Two weeks after this operation, the patient developed significant urine leakage from the abdominal wounds. Ureteral J stent placement was our first choice of treatment. This was complicated with a late ureteral obstruction. The final treatment was an ureteroureterostomy. Diagnosing ureteral injuries due to traumatic causes can be hard in most of the cases. Physicians should consider early evaluation of the patient for ureteral leakage if there is suspicion about ureteral injury.


Time-division color electroholography using one-chip RGB LED and synchronizing controller.
We propose time-division based color electroholography with a one-chip RGB Light Emitting Diode (LED) and a low-priced synchronizing controller. In electroholography, although color reconstruction methods via time-division have already been proposed, the methods require an LCD with a high refresh rate and output signals from the LCD for synchronizing the RGB reference lights such as laser sources, which consequently increase the development cost. Instead of using such an LCD, the proposed method is capable of using a general LCD panel with a normal refresh rate of 60 Hz. In addition, the LCD panel used in the proposed method does not require the output signals from the LCD. Instead, we generated synchronized signals using an external controller developed by a low-priced one-chip microprocessor, and, use a one-chip RGB LED instead of lasers as the RGB reference lights. The one-chip LED allows us to decrease the development cost and to facilitate optical-axis alignment. Using this method, we observed a multi-color 3D reconstructed movie at a frame rate of 20 Hz.


PRC1: a human mitotic spindle-associated CDK substrate protein required for cytokinesis.
We have identified a novel human protein, PRC1, that is involved in cytokinesis. PRC1 is a good substrate for several CDKs in vitro and is phosphorylated in vivo at sites that are phosphorylated by CDK in vitro, strongly suggesting that PRC1 is an in vivo CDK substrate. PRC1 has sequence homology to the budding yeast anaphase spindle elongation factor Ase1p. Like Ase1p, PRC1 protein levels are high during S and G2/M and drop dramatically after cells exit mitosis and enter G1. PRC1 is a nuclear protein in interphase, becomes associated with mitotic spindles in a highly dynamic manner during mitosis, and localizes to the cell mid-body during cytokinesis. Microinjection of anti-PRC1 antibodies into HeLa cells blocked cellular cleavage, but not nuclear division, indicating a functional role for PRC1 in the process of cytokinesis.


Ultrasound imaging in spondyloathropathies: from imaging to diagnostic intervention.
Ultrasound has developed significantly over the past decade, becoming a potent imaging modality for the assessment of inflammatory arthritis. Until recently, few published data were available with respect to the use of ultrasound imaging in patients with spondyloarthropathy. This review examines the current state of ultrasound imaging with respect to spondyloarthritis and describes some of the limitations that need to be addressed. Ultrasound imaging has been shown to be more sensitive than clinical examination in detecting many features of spondyloarthritis, such as synovitis and enthesitis. The ability to detect subclinical disease and demonstrate a clear response to therapeutic intervention makes this imaging modality a potential tool for both diagnostic and monitoring purposes. Despite this, a number of issues including a lack of standardization of ultrasound assessment of musculoskeletal disorders continue to hamper its progress. New three-dimensional technology is a promising development, which may allow this problem to be addressed. Improving the ability of the rheumatologist to predict prognosis and guide therapeutic intervention is a long-term goal to which ultrasound may be able to provide a significant contribution. The addition of a novel imaging modality to currently available assessment tools may provide rheumatologists with a more precise working framework, which may be exploited for the benefits of the patients.


Outpatient surgical utilization in Veterans Affairs hospitals, 1981-1989.
In the 1980s, there was a large increase in the percentage of surgical operations performed in the United States without an overnight hospital admission. This shift may have been related to changes in reimbursement for outpatient surgery; studies of this relationship have had conflicting results. The Department of Veterans Affairs (VA) has a budgeting strategy significantly different from reimbursement strategies used by nonfederal hospitals. The VA strategy underwent changes in terms of budgeting for outpatient surgery in the 1980s. Data from the American Hospital Association (AHA) Annual Survey of Hospitals collected during the years 1981 through 1989 inclusive were analyzed in an effort to examine VA outpatient surgical utilization and to compare changes in VA outpatient surgical utilization with changes in outpatient surgical utilization in the nonfederal sector. The VA had an apparent rapid expansion of outpatient surgical utilization in the mid-1980s compared with the nonfederal sector. This increase occurred without a concomitant decrease in inpatient surgical procedures. This apparent rapid expansion may represent a combination of real changes in surgical utilization, changes in utilization of services not traditionally thought to be surgical but counted as such by VA hospitals, and changes in VA record-keeping. All of the components of this expansion may have been accelerated by the implementation of the VA Resource Allocation Methodology in 1985 and 1986.


Comfort from suicidal cognition in recurrently depressed patients.
Previous research has suggested that some individuals may obtain comfort from their suicidal cognitions. This study explored clinical variables associated with comfort from suicidal cognition using a newly developed 5 item measure in 217 patients with a history of recurrent depression and suicidality, of whom 98 were followed up to at least one relapse to depression and reported data on suicidal ideation during the follow-up phase. Results indicated that a minority of patients, around 15%, reported experiencing comfort from suicidal cognitions and that comfort was associated with several markers of a more severe clinical profile including both worst ever prior suicidal ideation and worst suicidal ideation over a 12 month follow-up period. Few patients self-harmed during the follow-up period preventing an examination of associations between comfort and repetition of self-harm. These results, although preliminary, suggest that future theoretical and clinical research would benefit from further consideration of the concept of comfort from suicidal thinking.


Pou2f1 and Pou2f2 cooperate to control the timing of cone photoreceptor production in the developing mouse retina.
Multipotent retinal progenitor cells (RPCs) generate various cell types in a precise chronological order, but how exactly cone photoreceptor production is restricted to early stages remains unclear. Here, we show that the POU-homeodomain factors Pou2f1/Pou2f2, the homologs of Drosophila temporal identity factors nub/pdm2, regulate the timely production of cones in mice. Forcing sustained expression of Pou2f1 or Pou2f2 in RPCs expands the period of cone production, whereas misexpression in late-stage RPCs triggers ectopic cone production at the expense of late-born fates. Mechanistically, we report that Pou2f1 induces Pou2f2 expression, which binds to a POU motif in the promoter of the rod-inducing factor Nrl to repress its expression. Conversely, conditional inactivation of Pou2f2 in RPCs increases Nrl expression and reduces cone production. Finally, we provide evidence that Pou2f1 is part of a cross-regulatory cascade with the other temporal identity factors Ikzf1 and Casz1. These results uncover Pou2f1/2 as regulators of the temporal window for cone genesis and, given their widespread expression in the nervous system, raise the possibility of a general role in temporal patterning.This article has an associated 'The people behind the papers' interview.


Increased mortality risk in patients with phenotypic hereditary hemochromatosis but not in their first-degree relatives.
Hereditary hemochromatosis (HH) is an autosomal-recessive disorder characterized by iron overload. Relatives of HH patients were screened and those with HH-associated mutations and an increased iron load were identified. However, little is known about their mortality or strategies for their management. We assessed mortality among Swedish patients with HH and their first-degree relatives using health and census registers. We performed a matched population-based cohort study of 3832 patients with HH and their 14,496 first-degree relatives using data collected from 1990 through 2007. Mortality data from these groups were compared with that of 38,969 population controls and their 143,349 first-degree relatives using Cox regression analyses. Patients identified on the basis of hospitalization with HH had an increased risk (relative risk [RR]) for death (RR, 2.45; 95% confidence interval [CI], 2.27-2.64; 857 deaths). Patients identified through other means had a mortality risk that was lower than those identified in the hospital but higher than controls (RR, 1.15; 95% CI, 1.00-1.33; 216 deaths). Their first-degree relatives had only a marginally increased mortality risk (RR, 1.05; 95% CI, 1.01-1.10); this RR was similar to that of patients' spouses (RR, 1.09; 95% CI, 0.86-1.38; 82 deaths). Patients with HH who also had a family history of HH did not have an increased mortality risk compared with other groups (RR, 1.05; 95% CI, 0.67-1.62; 21 deaths). Patients with HH have a modestly increased mortality risk compared with controls. The mortality of relatives is increased marginally compared with controls, and is similar among biological and nonbiological relatives.


Spatial Clustering Properties in the Temporal Variation of Suicide Rates/Numbers among Japanese Citizens: A Comprehensive Comparison and Discussion.
The number of suicides in Japan has remained high for many years. To effectively resolve this problem, firm understanding of the statistical data is required. Using a large quantity of wide-ranging data on Japanese citizens, the purpose of this study was to analyze the geographical clustering properties of suicides and how suicide rates have evolved over time, and to observe detailed patterns and trends in a variety of geographic regions. Using adjacency data from 2008, the spatial and temporal/spatial clustering structure of geographic statistics on suicides were clarified. Echelon scans were performed to identify regions with the highest-likelihood ratio of suicide as the most likely suicide clusters. In contrast to results obtained using temporal/spatial analysis, the results of a period-by-period breakdown of evolving suicide rates demonstrated that suicides among men increased particularly rapidly during 1988-1992, 1993-1997, and 1998-2002 in certain cluster regions located near major metropolitan areas. For women, results identified cluster regions near major metropolitan areas in 1993-1997, 1998-2002, and 2003-2007. For both men and women, the cluster regions identified are located primarily near major metropolitan areas, such as greater Tokyo and Osaka.


Refractory depression - cost-effectiveness of radically open dialectical behaviour therapy: findings of economic evaluation of RefraMED trial.
Refractory depression is a major contributor to the economic burden of depression. Radically open dialectical behaviour therapy (RO DBT) is an unevaluated new treatment targeting overcontrolled personality, common in refractory depression, but it is not yet known whether the additional expense of RO DBT is good value for money.AimsTo estimate the cost-effectiveness of RO DBT plus treatment as usual (TAU) compared with TAU alone in people with refractory depression (trial registration: ISRCTN85784627). We undertook a cost-effectiveness analysis alongside a randomised trial evaluating RO DBT plus TAU versus TAU alone for refractory depression in three UK secondary care centres. Our economic evaluation, 12 months after randomisation, adopted the perspective of the UK National Health Service (NHS) and personal social services. It evaluated cost-effectiveness by comparing the net cost of RO DBT with the net gain in quality-adjusted life-years (QALYs), estimated using the EQ-5D-3L measure of health-related quality of life. The additional cost of RO DBT plus TAU compared with TAU alone was £7048 and was associated with a difference of 0.032 QALYs, yielding an incremental cost-effectiveness ratio (ICER) of £220 250 per QALY. This ICER was well above the National Institute for Health and Care Excellence (NICE) upper threshold of £30 000 per QALY. A cost-effectiveness acceptability curve indicated that RO DBT had a zero probability of being cost-effective compared with TAU at the NICE £30 000 threshold. In its current resource-intensive form, RO DBT is not a cost-effective use of resources in the UK NHS.Declaration of interestR.H. is co-owner and director of Radically Open Ltd, the RO DBT training and dissemination company. D.K. reports grants outside the submitted work from the National Institute for Health Research (NIHR). T.L. receives royalties from New Harbinger Publishing for sales of RO DBT treatment manuals, speaking fees from Radically Open Ltd, and a grant outside the submitted work from the Medical Research Council. He was co-director of Radically Open Ltd between November 2014 and May 2015 and is married to Erica Smith-Lynch, the principal shareholder and one of two directors of Radically Open Ltd. H.O'M. reports personal fees outside the submitted work from the Charlie Waller Institute and Improving Access to Psychological Therapy. S.R. provides RO DBT supervision through her company S C Rushbrook Ltd. I.R. reports grants outside the submitted work from NIHR and Health & Care Research Wales. M. Stanton reports personal fees outside the submitted work from British Isles DBT Training, Stanton Psychological Services Ltd and Taylor & Francis. M. Swales reports personal fees outside the submitted work from British Isles DBT Training, Guilford Press, Oxford University Press and Taylor & Francis. B.W. was co-director of Radically Open Ltd between November 2014 and February 2015.


Psychosocial care for hospitalized young survivors after the terror attack on Utøya Island: A qualitative study of the survivors' experiences.
The objective of the study was to explore hospitalized youths' experiences with psychosocial care in the hospital after the shooting on Utøya Island, Norway, in 2011. 17 hospitalized youths were interviewed face-to-face 30-31 months after the attack. The interviews were analysed using interpretative phenomenological analysis (IPA). The initial reading and coding of the interviews was carried out inductively. To explore the emphasis placed on everyday conversation and ordinary interaction detected during the initial reading, the text was re-read while bearing in mind concepts from the research field of sociology concerning the therapeutic potential in commonplace conversations and situations. The youths highlighted the need for health care workers to embrace essential aspects of their past, present and future. Therefore, three overarching categories emerged related to 1) Remembering the past, 2) Dealing with the present and 3) Preparing for the future. For each temporal category, two related subcategories were identified: Past:Engaging in the trauma narrative; Understanding the trauma reminders; Present: Bringing back normalcy; Being there; Future: Supporting confidence; Instilling trust. For the youths in the current study, talking with the hospital staff about their traumatic experiences was mostly perceived as positive and linked to various helpful outcomes. In addition to engaging in the trauma narrative, the staff needed to comprehend and address how the traumatic experiences and the hospitalization resulted in the survivors' extended fear and changed appraisals about the world and themselves. Having the time to stay physically and mentally close to the youths and engage in everyday interaction was crucial in rebuilding their sense of safety and bringing back normalcy. The hospital staff played a significant role in strengthening the survivors' confidence in own capabilities and trust in others. The different professionals in the hospital contributed to various aspects of psychosocial care, and both trauma-focused interventions and commonplace conversations and actions were emphasized as important and meaningful approaches.


Left Ventricular Ejection Fraction and Risk of Stroke and Cardiac Events in Heart Failure: Data From the Warfarin Versus Aspirin in Reduced Ejection Fraction Trial.
In heart failure (HF), left ventricular ejection fraction (LVEF) is inversely associated with mortality and cardiovascular outcomes. Its relationship with stroke is controversial, as is the effect of antithrombotic treatment. We studied the relationship of LVEF with stroke and cardiovascular events in patients with HF and the effect of different antithrombotic treatments. In the Warfarin Versus Aspirin in Reduced Ejection Fraction (WARCEF) trial, 2305 patients with systolic HF (LVEF≤35%) and sinus rhythm were randomized to warfarin or aspirin and followed for 3.5±1.8 years. Although no differences between treatments were observed on primary outcome (death, stroke, or intracerebral hemorrhage), warfarin decreased the stroke risk. The present report compares the incidence of stroke and cardiovascular events across different LVEF and treatment subgroups. Baseline LVEF was inversely and linearly associated with primary outcome, mortality and its components (sudden and cardiovascular death), and HF hospitalization, but not myocardial infarction. A relationship with stroke was only observed for LVEF of <15% (incidence rates: 2.04 versus 0.95/100 patient-years; P=0.009), which more than doubled the adjusted stroke risk (adjusted hazard ratio, 2.125; 95% CI, 1.182-3.818; P=0.012). In warfarin-treated patients, each 5% LVEF decrement significantly increased the stroke risk (adjusted hazard ratio, 1.346; 95% CI, 1.044-1.737; P=0.022; P value for interaction=0.04). In patients with systolic HF and sinus rhythm, LVEF is inversely associated with death and its components, whereas an association with stroke exists for very low LVEF values. An interaction with warfarin treatment on stroke risk may exist. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00041938.


Prevalence and risk factors for hepatitis C virus infection among young Thai men.
Epidemiologic studies of hepatitis C virus (HCV) infection are unusual in developing countries, especially Thailand. We evaluated the prevalence and risk factors for HCV among military conscripts, including a sample of 5,246 men (1:30 sample), and human immunodeficiency virus (HIV)-1 positive men (N = 500) between 2005 and 2008. The HCV prevalence was 2.2% in the sampled group and 8.4% in HIV-1 sero-positives. Among the sampled group, HIV-1 infection, injection drug use (IDU) history, and unsafe injections were associated with HCV infection; adjusted prevalence rate ratios [RRs; 95% confidence intervals (CIs)] were 3.7 (1.04-12.77), 1.9 (1.04-3.54), and 1.8 (1.02-3.11), respectively. Among HIV-1 sero-positives, an IDU history and residence in southern Thailand were associated with HCV prevalence; adjusted RRs (95% CIs) were 3.5 (1.71-7.24) and 2.6 (1.18-5.61), respectively. Public health measures to prevent HCV in Thailand should focus on reducing injection drug use and other exposures to unsafe injections among young Thai men.


Toxicity of sediment cores collected from the Ashtabula River in Northeastern Ohio, USA, to the amphipod Hyalella azteca.
This study was conducted to support a Natural Resource Damage Assessment and Restoration project associated with the Ashtabula River in Ohio. The objective of the study was to evaluate the chemistry and toxicity of 50 sediment samples obtained from five cores collected from the Ashtabula River (10 samples/core, with each 10-cm-diameter core collected to a total depth of about 150 cm). Effects of chemicals of potential concern (COPCs) measured in the sediment samples were evaluated by measuring whole-sediment chemistry and whole-sediment toxicity in the sediment samples (including polycyclic aromatic hydrocarbons [PAHs], polychlorinated biphenyls [PCBs], organochlorine pesticides, and metals). Effects on the amphipod Hyalella azteca at the end of a 28-day sediment toxicity test were determined by comparing survival or length of amphipods in individual sediment samples in the cores to the range of responses of amphipods exposed to selected reference sediments that were also collected from the cores. Mean survival or length of amphipods was below the lower limit of the reference envelope in 56% of the sediment samples. Concentrations of total PCBs alone in some samples or concentrations of total PAHs alone in other samples were likely high enough to have caused the reduced survival or length of amphipods (i.e., concentrations of PAHs or PCBs exceeded mechanistically based and empirically based sediment quality guidelines). While elevated concentrations of ammonia in pore water may have contributed to the reduced length of amphipods, it is unlikely that the reduced length was caused solely by elevated ammonia (i.e., concentrations of ammonia were not significantly correlated with the concentrations of PCBs or PAHs and concentrations of ammonia were elevated both in the reference sediments and in the test sediments). Results of this study show that PAHs, PCBs, and ammonia are the primary COPCs that are likely causing or substantially contributing to the toxicity to sediment-dwelling organisms.


Ca2+, autophagy and protein degradation: thrown off balance in neurodegenerative disease.
Substantial progress has been made throughout the last decades in the elucidation of the key players and mechanisms responsible for Ca2+ signal generation in both excitable and non-excitable cells. Importantly, these studies led also to the recognition that a close correlation exists between the deregulation of cellular Ca2+ homeostasis and the development of several human pathologies, including neurodegenerative disease. Notwithstanding this advances, much less is certain about the targets and mechanisms by which compromised Ca2+ signaling exerts its effects on cell function and survival. Recently it has been proposed that deregulation of cellular energy metabolism and protein turnover (synthesis, folding and degradation) are also fundamental pathomechanisms of neurodegenerative disease, pointing to the pivotal role of autophagy, a major cellular pathway controlling metabolic homeostasis. Indeed, activation of autophagy has been shown to represent a highly successful strategy to restore normal neuronal function in a variety of models of neurodegenerative disease. Here we review recent advances in elucidating Ca2+ regulation of autophagy and will highlight its relationship to neurodegeneration.


Molecular signatures of thyroid follicular neoplasia.
The molecular pathways leading to thyroid follicular neoplasia are incompletely understood, and the diagnosis of follicular tumors is a clinical challenge. To provide leads to the pathogenesis and diagnosis of the tumors, we examined the global transcriptome signatures of follicular thyroid carcinoma (FC) and normofollicular adenoma (FA) as well as fetal/microFA (fetal adenoma). Carcinomas were strongly enriched in transcripts encoding proteins involved in DNA replication and mitosis corresponding to increased number of proliferating cells and depleted number of transcripts encoding factors involved in growth arrest and apoptosis. In the latter group, the combined loss of transcripts encoding the nuclear orphan receptors NR4A1 and NR4A3, which were recently shown to play a causal role in hematopoetic neoplasia, was noteworthy. The analysis of differentially expressed transcripts provided a mechanism for cancer progression, which is why we exploited the results in order to generate a molecular classifier that could identify 95% of all carcinomas. Validation employing public domain and cross-platform data demonstrated that the signature was robust and could diagnose follicular nodules originating from different geographical locations and platforms with similar accuracy. We came to the conclusion that down-regulation of factors involved in growth arrest and apoptosis may represent a decisive step in the pathogenesis of FC. Moreover, the described molecular pathways provide an accurate and robust genetic signature for the diagnosis of FA and FC.


Identification of three distinct allelic forms of bovine CD4.
The CD4-specific monoclonal antibody (mAb) CC26, when tested on a total of 143 cattle, failed to react with T cells from 16% of animals and gave reduced intensity staining in a further 35% of animals. The results of family studies with groups of half- and full-siblings indicated that CC26 recognizes an allele of CD4 which is co-dominantly expressed in heterozygous animals. This was confirmed by sequential immunoprecipitation and by selecting transfectants expressing the CC26+ and CC26- allelic forms of CD4 following transfection of genomic DNA from a heterozygous animal. Biochemical studies also revealed an allelic difference in the relative molecular weight (M(r)) of the CD4 molecule, one allele giving 49,000/52,000 MW bands and the other 52,000/57,000 MW bands in sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). Treatment of CD4+ cell lines with tunicamycin resulted in the appearance of a 47,000 MW band for both allelic forms indicating that the difference in M(r) is due to glycosylation. All of the CC26+ alleles examined were of the low molecular weight form (M(r)low) whereas both M(r)low and M(r)high alleles were represented in CC26- animals. Thus, on the basis of M(r) and reactivity with mAb CC26, three allelic forms of bovine CD4 can be identified, namely CC26+ M(r)low, CC26- M(r)low and CC26- M(r)high; it is proposed that these alleles are designated CD4.1, CD4.2 and CD4.3, respectively. The allelic difference detected by CC26 was present in both Bos taurus and B. indicus cattle indicating that it had arisen prior to divergence of these subspecies. The M(r)high allele (CD4.3) was detected only in B. indicus animals.