A Computational Study of the Ionic Liquid-Induced Destabilization of the Miniprotein Trp-Cage.
Fundamental understanding of protein stability away from physiological conditions is important due to its evolutionary implications and relevance to industrial processing and storage of biological materials. The molecular mechanisms of stabilization/destabilization by environmental perturbations are incompletely understood. We use replica-exchange molecular dynamics simulations and thermodynamic analysis to investigate the effects of ionic liquid-induced perturbations on the folding/unfolding thermodynamics of the Trp-cage miniprotein. We find that ionic liquid-induced denaturation resembles cold unfolding, where the unfolded states are populated by compact, partially folded structures in which elements of the secondary structure are conserved, while the tertiary structure is disrupted. Our simulations show that the intrusion of ions and water into Trp-cage's hydrophobic core is facilitated by the disruption of its salt bridge and 310-helix by specific ion-residue interactions. Despite the swelling and widening of the hydrophobic core, however, Trp-cage's α-helix remains stable. We further show that ionic liquid disrupts protein-protein and protein-water hydrogen bonds while favoring the formation of ion-protein bonds, shifting the equilibrium of conformational states and promoting denaturation near room temperature.


A qualitative study examining tensions in interdoctor telephone consultations.
Communication skills have gained increasing attention in medical education. Much of the existing literature and medical curricula addresses issues of doctor-patient communication. The critical importance of communication between health professionals, however, is now coming under the spotlight. The interdoctor telephone consultation is a common health care setting in which health professional communication skills are exercised. Breakdowns in this communication commonly occur and, surprisingly, this skill is not formally addressed in medical training. This study sought to clarify the communication issues that can occur during interdoctor telephone consultations in order to inform future educational initiatives in this domain. Data were collected and triangulated among 3 sources: documentation of 129 telephone consults received; 51 hours of field observations of consultants, and semi-structured interviews of 12 callers and 12 consultants. Analysis was performed using grounded theory methodology. Overwhelmingly, participants described tensions with telephone consultation communication. Recurrent theme analysis revealed 5 key sources of tension: discursive features; context; fragmented clinical process; reason for call, and responsibility. Often, callers and consultants viewed similar instances in different and opposite manners, contributing to difficulties in the exchange. Further, a vicious cycle in which a participant's strategies to mitigate tension actually increased tension for the other participant was identified. Interdoctor telephone consultation has become an integral part of medical practice; however, tensions within this exchange can undermine its effectiveness. The results of this study provide a preliminary theory upon which an educational intervention to improve this communication skill can be based.


The application and importance of disability policy research to the mental health field.
This editorial provides an introduction to this unique special issue of the Psychiatric Rehabilitation Journal. Rather than focusing on a particular type of rehabilitative services, it more broadly addresses the subject, methods, and results of disability policy research. This special issue is meant to start a conversation about the role of psychiatric rehabilitation researchers, professionals, and consumers in shaping future policies affecting and affected by mental illness. In particular, this issue focuses on the application of rigorous research methodologies to answer policy-relevant questions to help ensure that decisions affecting our field are evidence-based and address the issues that matter most in the lives of consumers. (PsycINFO Database Record


Role of melatonin in Alzheimer-like neurodegeneration.
Alzheimer disease (AD), an age-related neurodegenerative disorder with progressive loss of memory and deterioration of comprehensive cognition, is characterized by extracellular senile plaques of aggregated beta-amyloid (Abeta), and intracellular neurofibrillary tangles that contain hyperphosphorylated tau protein. Recent studies showed that melatonin, an indoleamine secreted by the pineal gland, may play an important role in aging and AD as an antioxidant and neuroprotector. Melatonin decreases during aging and patients with AD have a more profound reduction in this hormone. Data from clinical trials indicate that melatonin supplementation improves sleep, ameliorates sundowning, and slows down the progression of cognitive impairment in Alzheimer patients. Melatonin efficiently protects neuronal cells from Abeta-mediated toxicity via antioxidant and anti-amyloid properties: it not only inhibits Abeta generation, but also arrests the formation of amyloid fibrils by a structure-dependent interaction with Abeta. Our recent studies have demonstrated that melatonin efficiently attenuates Alzheimer-like tau hyperphosphorylation. Although the exact mechanism is still not fully understood, a direct regulatory influence of melatonin on the activities of protein kinases and protein phosphatases is proposed. Additionally, melatonin also plays a role in protecting cholinergic neurons and in anti-inflammation. Here, the neuroprotective effects of melatonin and the underlying mechanisms by which it exerts its effects are reviewed. The capacity of melatonin to prevent or ameliorate tau and Abeta pathology further enhances its potential in the prevention or treatment of AD.


Activation of RalA is critical for Ras-induced tumorigenesis of human cells.
RalGEFs were recently shown to be critical for Ras-mediated transformed and tumorigenic growth of human cells. We now show that the oncogenic activity of these proteins is propagated by activation of one RalGEF substrate, RalA, but blunted by another closely related substrate, RalB, and that the oncogenic signaling requires binding of the RalBP1 and exocyst subunit effector proteins. Knockdown of RalA expression impeded, if not abolished, the ability of human cancer cells to form tumors. RalA was also commonly activated in a panel of cell lines from pancreatic cancers, a disease characterized by activation of Ras. Activation of RalA signaling thus appears to be a critical step in Ras-induced transformation and tumorigenesis of human cells.


Osteotome-mediated sinus floor elevation: a clinical report.
It was the aim of the present study to clinically evaluate the success of osteotome-mediated sinus floor elevation (OMSFE) using autogenous and xenogenic bone and a variety of screw-type implants. From August 1995 to February 2003, 276 OMSFE procedures with simultaneous implant placement were completed in 167 patients. The mean residual bone height (RBH) of the alveolar ridge was 7.1 mm (range 3 to 10 mm). The mean increase in height of the implant sites using osteotome techniques was 3.8 mm (range 2 to 7 mm). Of the 276 implants placed, 240 had been loaded for an average of 27.9 months (range 1 to 84 months). There were a total of 18 failures: Ten implants failed to integrate, 3 implants were lost within the first 18 months of loading, 1 implant fractured after 3 years in function, and 4 implants demonstrated excessive bone loss. The overall survival rate was 93.5%. When only sites with an RBH of 4 mm or less were considered, the survival rate dropped to 73.3%. Small tears in the schneiderian membrane were clinically assessed at 13 sites, for a detectable perforation rate of 4.7%. The primary determinant in implant survival with OMSFE procedures was the height of the residual alveolar ridge. Implant design, graft material, and the method of sinus floor infracture (direct or bone-cushioned) exerted minimal influence on survival outcome; however, factors such as edentulism, osteoporosis, and an overdenture prosthesis were shown to negatively influence postloading survival of implants placed in areas of limited RBH. OMSFE procedures can be used predictably for implant placement at sites with moderate vertical deficiencies in the posterior maxilla.


Establishing reporting standards for metabolomic and metabonomic studies: a call for participation.
Metabolite concentrations in cellular systems are very much dependent on the physiological, environmental, and genetic status of an organism and are regarded as the ultimate result of cellular regulation, resulting in the visible phenotypes. Therefore, the comprehensive analysis of metabolite levels and fluxes renders a suitable tool for assessing the degree of perturbation in biological systems. Lessons derived from development of other OMICS areas (genomics, proteomics, and transcriptomics) have shown that large-scale comparisons and interpretations will require the re-use of data over long periods of time and by multiple laboratories with different expertise and backgrounds. Reaching this goal will require standardization of reporting structures of metabolomic studies for journal publication purposes, for regulatory deposition, and for database dissemination. An initiative by the Metabolomics Society is presented that aims to define important aspects of metabolomic workflows. These include biological study designs, chemical analysis, and data processing, as well as the ontologies that are necessary in this framework.


Identification and isolation of the cyclooxygenase-2 inhibitory principle in Isatis tinctoria.
Various extracts prepared from the traditional dye and medicinal plant Isatis tinctoria L. were submitted to a broad in vitro screening against 16 anti-inflammatory targets. Dichloromethane (DCM) extracts from dried leaves showed a marked cyclooxygenase (COX) inhibitory activity with a preferential effect on COX-2 catalysed prostaglandin synthesis. A supercritical fluid extraction (SFE) procedure employing CO2-modifier mixtures was developed by which the bioactivity profile and chromatographic fingerprint of the DCM extract could be reproduced. High-resolution activity directed on-line identification of the COX-2 inhibitory principle, using a combination of LC-DAD-MS with a microtitre-based bioassay, led to the identification of tryptanthrin (1) as the constituent responsible for essentially all COX-2 inhibitory activity in the crude extract. Following on-line identification, 1 was isolated at preparative scale and its structure confirmed by comparison with synthetic tryptanthrin. In an assay with lipopolysaccharide stimulated Mono Mac 6 cells, tryptanthrin (1) was of comparable potency (IC50 = 64 nM) than the preferential COX-2 inhibitors nimesulide (IC50 = 39 nM) and NS 398 (IC50 = 2 nM). The SFE extract and 1 showed no cytotoxicity in Mono Mac 6 and RAW 264.7 cells when tested at 100 microg/ml and 10 microM, respectively.


Identification of direct regulatory targets of the transcription factor Sox10 based on function and conservation.
Sox10, a member of the Sry-related HMG-Box gene family, is a critical transcription factor for several important cell lineages, most notably the neural crest stem cells and the derivative peripheral glial cells and melanocytes. Thus far, only a handful of direct target genes are known for this transcription factor limiting our understanding of the biological network it governs. We describe identification of multiple direct regulatory target genes of Sox10 through a procedure based on function and conservation. By combining RNA interference technique and DNA microarray technology, we have identified a set of genes that show significant down-regulation upon introduction of Sox10 specific siRNA into Schwannoma cells. Subsequent comparative genomics analyses led to potential binding sites for Sox10 protein conserved across several mammalian species within the genomic region proximal to these genes. Multiple sites belonging to 4 different genes (proteolipid protein, Sox10, extracellular superoxide dismutase, and pleiotrophin) were shown to directly interact with Sox10 by chromatin immunoprecipitation assay. We further confirmed the direct regulation through the identified cis-element for one of the genes, extracellular superoxide dismutase, using electrophoretic mobility shift assay and reporter assay. In sum, the process of combining differential expression profiling and comparative genomics successfully led to further defining the role of Sox10, a critical transcription factor for the development of peripheral glia. Our strategy utilizing relatively accessible techniques and tools should be applicable to studying the function of other transcription factors.


Association of snoring with chronic bronchitis.
Snoring is more prevalent in patients with chronic bronchitis than in persons without it. Few studies have examined the effect of snoring on chronic bronchitis. We prospectively investigated the association between snoring and the incidence of chronic bronchitis. The baseline study was conducted from June 25, 2001, to January 29, 2003. Members of the study cohort consisted of 5015 male and female Korean citizens aged 40 to 69 years at baseline who participated in a comprehensive health examination and on-site interviews at Korea University Ansan Hospital. Of these, 4270 participants (52% men and 48% women) entered the analysis for the first 2-year follow-up from April 17, 2003, to February 20, 2005, and those who met the same inclusion criteria remained in the analysis for a second 2-year follow-up period from February 21, 2005, to November 17, 2006. We collected information on snoring at baseline and identified incident cases of chronic bronchitis during a 4-year follow-up period. On the baseline questionnaire, we excluded participants who reported the presence of cough and sputum production on most days for at least 3 months a year. During 4 years of follow-up, we documented 314 cases of new-onset chronic bronchitis (27.1 cases per 1000 person-years). After taking into account age, smoking, and other risk factors for chronic bronchitis, the multivariate relative risks of chronic bronchitis were 1.25 (95% confidence interval [CI], 0.95-1.64) for persons snoring 5 times per week or less and 1.68 (95% CI, 1.17-2.42) for those snoring 6 to 7 times per week compared with never snorers (P for trend = .049). The analyses stratified by risk factors, including smoking, occupation, and body mass index, showed a stronger association among never smokers, house workers, and overweight persons. In analysis for the joint effect of smoking and snoring, the relative risks of chronic bronchitis were 1.39 (95% CI, 1.01-1.90) for nonsmoking and snoring, 2.31 (95% CI, 1.38-3.87) for smoking and never snoring, and 2.86 (95% CI, 1.91-4.27) for smoking and snoring compared with nonsmoking and never snoring. This prospective study observed that snoring is associated with chronic bronchitis. Our findings provide support for the hypothesis that snoring influences the development of chronic bronchitis.


Adolescents with Developmental Dyscalculia Do Not Have a Generalized Magnitude Deficit - Processing of Discrete and Continuous Magnitudes.
The link between number and space has been discussed in the literature for some time, resulting in the theory that number, space and time might be part of a generalized magnitude system. To date, several behavioral and neuroimaging findings support the notion of a generalized magnitude system, although contradictory results showing a partial overlap or separate magnitude systems are also found. The possible existence of a generalized magnitude processing area leads to the question how individuals with developmental dyscalculia (DD), known for deficits in numerical-arithmetical abilities, process magnitudes. By means of neuropsychological tests and functional magnetic resonance imaging (fMRI) we aimed to examine the relationship between number and space in typical and atypical development. Participants were 16 adolescents with DD (14.1 years) and 14 typically developing (TD) peers (13.8 years). In the fMRI paradigm participants had to perform discrete (arrays of dots) and continuous magnitude (angles) comparisons as well as a mental rotation task. In the neuropsychological tests, adolescents with dyscalculia performed significantly worse in numerical and complex visuo-spatial tasks. However, they showed similar results to TD peers when making discrete and continuous magnitude decisions during the neuropsychological tests and the fMRI paradigm. A conjunction analysis of the fMRI data revealed commonly activated higher order visual (inferior and middle occipital gyrus) and parietal (inferior and superior parietal lobe) magnitude areas for the discrete and continuous magnitude tasks. Moreover, no differences were found when contrasting both magnitude processing conditions, favoring the possibility of a generalized magnitude system. Group comparisons further revealed that dyscalculic subjects showed increased activation in domain general regions, whilst TD peers activate domain specific areas to a greater extent. In conclusion, our results point to the existence of a generalized magnitude system in the occipito-parietal stream in typical development. The detailed investigation of spatial and numerical magnitude abilities in DD reveals that the deficits in number processing and arithmetic cannot be explained with a general magnitude deficiency. Our results further indicate that multiple neuro-cognitive components might contribute to the explanation of DD.


Cyanobacteria-From the Oceans to the Potential Biotechnological and Biomedical Applications.
Cyanobacteria are photosynthetic prokaryotic organisms which represent a significant source of novel, bioactive, secondary metabolites, and they are also considered an abundant source of bioactive compounds/drugs, such as dolastatin, cryptophycin 1, curacin toyocamycin, phytoalexin, cyanovirin-N and phycocyanin. Some of these compounds have displayed promising results in successful Phase I, II, III and IV clinical trials. Additionally, the cyanobacterial compounds applied to medical research have demonstrated an exciting future with great potential to be developed into new medicines. Most of these compounds have exhibited strong pharmacological activities, including neurotoxicity, cytotoxicity and antiviral activity against HCMV, HSV-1, HHV-6 and HIV-1, so these metabolites could be promising candidates for COVID-19 treatment. Therefore, the effective large-scale production of natural marine products through synthesis is important for resolving the existing issues associated with chemical isolation, including small yields, and may be necessary to better investigate their biological activities. Herein, we highlight the total synthesized and stereochemical determinations of the cyanobacterial bioactive compounds. Furthermore, this review primarily focuses on the biotechnological applications of cyanobacteria, including applications as cosmetics, food supplements, and the nanobiotechnological applications of cyanobacterial bioactive compounds in potential medicinal applications for various human diseases are discussed.


Survival of drug resistant tuberculosis patients in Lithuania: retrospective national cohort study.
Objective To establish risk factors influencing survival of patients with multidrug-resistant and extensively drug-resistant tuberculosis (MDR/XDRTB). Design All MDR/XDRTB cases (n=1809) reported from 2002 to 2008 in Lithuania with a known outcome were included in the survival analysis. Results Median survival for MDRTB and XDRTB patients was 4.1 (95% CI 3.7 to 4.4) and 2.9 (95% CI 2.2 to 3.9) years. In a multivariable analysis adjusting for other patient characteristics, the difference in survival between MDRTB and XDRTB patients was not significant (HR=1.29 (0.91 to 1.81)). Older age (HR=4.80 (3.16 to 7.29)) for 60+ vs <30 years, rural living (HR=1.20 (1.02 to 1.40)), alcohol use (HR=1.49 (1.13 to 1.96)) for alcoholic versus moderate use, unemployment (HR=1.79 (1.31 to 2.46)), lower education levels (HR=1.50 (1.08 to 2.07)) for primary level versus tertiary level, cavitary disease (HR=1.54 (1.29 to 1.83)) and being smear positive at the time of MDR/XDRTB diagnosis (HR=1.47 (1.19 to 1.82)) were associated with poorer survival. HIV positivity significantly affected survival (HR=3.44 (1.92 to 6.19)) for HIV positive versus HIV negative; HR=1.60 (1.28 to 2.01) for HIV not tested versus HIV negative). There was no difference in survival of patients who acquired MDR/XDRTB during treatment compared with patients with primary MDR/XDRTB (HR=1.01 (0.85 to 1.19)). Treatment with a second-line drug improved survival (HR=0.40 (0.34 to 0.47)). In a subgroup with genotyped TB strains, a Beijing family of strains was associated with poorer survival (HR=1.71 (1.19 to 2.47)). Conclusions Social factors, rural living, HIV infection and Beijing strain family impact on survival. Survival of MDR/XDRTB patients is short. Rapid drug resistance identification, early administration of appropriate treatment and achieving high cure rates, expansion of HIV testing and antiretroviral treatment are necessary for optimal management of MDR/XDRTB.


Analysis of 1,3-Dichloropropene for Control of Meloidogyne spp. in a Tobacco Pest Management System.
1,3-Dichloropropene (1,3-D) and nonfumigant nematicides were evaluated for control of Meloidogyne spp. and soil and foliar insects in a tobacco pest management system. In a field with a high Meloidogyne spp. population density (root gall index 4.0 to 4.5 on a 0 to 10 scale in untreated controls), tobacco yields and crop values increased (482 kg/ha and $1,784/ha for 1, 3-D; 326 kg/ha and $1,206/ha for fenamiphos; 252 kg/ha and $933/ha for ethoprop) with nematicide application over an untreated control. In fields with a low population density of Meloidogyne arenaria or M. incognita (root gall index 2.3 to 2.5 in untreated controls), yields ranged from 1,714 to 2,027 kg/ha and were not altered by fumigant or nonfumigant nematicide application. Carbofuran, a soil-applied nonfumigant nematicide/insecticide, reduced the number of foliar insecticide applications required to keep insect populations below treatment threshold (3.8 vs. 4.5, respectively, for treated vs. untreated). Carbofuran reduced the cost ($23/ha) of foliar insecticide treatments when compared to an untreated control. Although nonfumigant nematicides provided some soil and foliar insect control, the cost of using a fumigant plus a lower insecticidal rate of a soil insecticide/nematicide was comparable to the least expensive non-fumigant nematicide when the cost of foliar insecticide applications was included in the cost estimates. Savings in foliar insecticide cost by use of soil-applied nonfumigant nematicide/insecticides were small ($23/ha) in comparison to potential value reductions by root-knot nematodes when the nonfumigant nematicides fenamiphos or ethoprop ($578/ha and $851/ha, respectively) were used instead of 1,3-D.


Past, present, and future directions for defining optimal treatment outcome in depression: remission and beyond.
During the past decade, evidence from research on mood disorders has demonstrated that remission is the optimal outcome of treatment. However, there continues to be considerable variability in the specific characteristics that are accepted as indicators of remission. Increasing knowledge of mood disorders and their underlying mechanisms may allow for the development of a new diagnostic and assessment system that no longer is based solely on symptoms and other descriptive phenomena. Continued advances in neuroscience may allow for more knowledge of the underlying neurobiological status and more accurate assessments of the underlying disease state and response to treatment, thus enabling physicians to use treatments that will most effectively bring patients back to euthymia and a truly disease-free healthy state. Until then, remission should continue to be based on the descriptive and experiential phenomena of symptoms and psychosocial functioning.


Validation of a Deep Learning Algorithm for Continuous, Real-Time Detection of Atrial Fibrillation Using a Wrist-Worn Device in an Ambulatory Environment.
Background Wearable devices may be useful for identification, quantification and characterization, and management of atrial fibrillation (AF). To date, consumer wrist-worn devices for AF detection using photoplethysmography-based algorithms perform only periodic checks when the user is stationary and are US Food and Drug Administration cleared for prediagnostic uses without intended use for clinical decision-making. There is an unmet need for medical-grade diagnostic wrist-worn devices that provide long-term, continuous AF monitoring. Methods and Results We evaluated the performance of a wrist-worn device with lead-I ECG and continuous photoplethysmography (Verily Study Watch) and photoplethysmography-based convolutional neural network for AF detection and burden estimation in a prospective multicenter study that enrolled 117 patients with paroxysmal AF. A 14-day continuous ECG monitor (Zio XT) served as the reference device to evaluate algorithm sensitivity and specificity for detection of AF in 15-minute intervals. A total of 91 857 intervals were contributed by 111 subjects with evaluable reference and test data (18.3 h/d median watch wear time). The watch was 96.1% sensitive (95% CI, 92.7%-98.0%) and 98.1% specific (95% CI, 97.2%-99.1%) for interval-level AF detection. Photoplethysmography-derived AF burden estimation was highly correlated with the reference device burden (R2=0.986) with a mean difference of 0.8% (95% limits of agreement, -6.6% to 8.2%). Conclusions Continuous monitoring using a photoplethysmography-based convolutional neural network incorporated in a wrist-worn device has clinical-grade performance for AF detection and burden estimation. These findings suggest that monitoring can be performed with wrist-worn wearables for diagnosis and clinical management of AF. Registration Information URL: https://www.clinicaltrials.gov; Unique identifier: NCT04546763.


Association Between Preoperative Proteinuria and Postoperative Acute Kidney Injury and Readmission.
Proteinuria indicates renal dysfunction and is a risk factor for morbidity among medical patients, but less is understood among surgical populations. There is a paucity of studies investigating how preoperative proteinuria is associated with surgical outcomes, including postoperative acute kidney injury (AKI) and readmission. To assess preoperative urine protein levels as a biomarker for adverse surgical outcomes. A retrospective, population-based study was conducted in a cohort of patients with and without known preoperative renal dysfunction undergoing elective inpatient surgery performed at 119 Veterans Affairs facilities from October 1, 2007, to September 30, 2014. Data analysis was conducted from April 4 to December 1, 2016. Preoperative dialysis, septic, cardiac, ophthalmology, transplantation, and urologic cases were excluded. Preoperative proteinuria as assessed by urinalysis using the closest value within 6 months of surgery: negative (0 mg/dL), trace (15-29 mg/dL), 1+ (30-100 mg/dL), 2+ (101-300 mg/dL), 3+ (301-1000 mg/dL), and 4+ (>1000 mg/dL). Primary outcome was postoperative predischarge AKI and 30-day postdischarge unplanned readmission. Secondary outcomes included any 30-day postoperative outcome. Of 346 676 surgeries, 153 767 met inclusion criteria, with the majority including orthopedic (37%), general (29%), and vascular procedures (14%). Evidence of proteinuria was shown in 43.8% of the population (trace: 20.6%, 1+: 16.0%, 2+: 5.5%, 3+: 1.6%) with 20.4%, 14.9%, 4.3%, and 0.9%, respectively, of the patients having a normal preoperative estimated glomerular filtration rate (eGFR). In unadjusted analysis, preoperative proteinuria was significantly associated with postoperative AKI (negative: 8.6%, trace: 12%, 1+: 14.5%, 2+: 21.2%, 3+: 27.6%; P < .001) and readmission (9.3%, 11.3%, 13.3%, 15.8%, 17.5%, respectively, P < .001). After adjustment, preoperative proteinuria was associated with postoperative AKI in a dose-dependent relationship (trace: odds ratio [OR], 1.2; 95% CI, 1.1-1.3, to 3+: OR, 2.0; 95% CI, 1.8-2.2) and 30-day unplanned readmission (trace: OR, 1.0; 95% CI, 1.0-1.1, to 3+: OR, 1.3; 95% CI, 1.1-1.4). Preoperative proteinuria was associated with AKI independent of eGFR. Proteinuria was associated with postoperative AKI and 30-day unplanned readmission independent of preoperative eGFR. Simple urine assessment for proteinuria may identify patients at higher risk of AKI and readmission to guide perioperative management.


Molecular Pathogenesis and Targeted Therapies for Intrahepatic Cholangiocarcinoma.
Intrahepatic cholangiocarcinoma (iCCA) is a molecularly heterogeneous hepatobiliary neoplasm with poor prognosis and limited therapeutic options. The incidence of this neoplasm is growing globally. One third of iCCA tumors are amenable to surgical resection, but most cases are diagnosed at advanced stages with chemotherapy as the only established standard of practice. No molecular therapies are currently available for the treatment of this neoplasm. The poor understanding of the biology of iCCA and the lack of known oncogenic addiction loops has hindered the development of effective targeted therapies. Studies with sophisticated animal models defined IDH mutation as the first gatekeeper in the carcinogenic process and led to the discovery of striking alternative cellular origins. RNA- and exome-sequencing technologies revealed the presence of recurrent novel fusion events (FGFR2 and ROS1 fusions) and somatic mutations in metabolic (IDH1/2) and chromatin-remodeling genes (ARID1A, BAP1). These latest advancements along with known mutations in KRAS/BRAF/EGFR and 11q13 high-level amplification have contributed to a better understanding of the landscape of molecular alterations in iCCA. More than 100 clinical trials testing molecular therapies alone or in combination with chemotherapy including iCCA patients have not reported conclusive clinical benefits. Recent discoveries have shown that up to 70% of iCCA patients harbor potential actionable alterations that are amenable to therapeutic targeting in early clinical trials. Thus, the first biomarker-driven trials are currently underway.


Anodic Reactivity of Alkyl S-Glucosides.
A voltammetric study of a series of alkyl and aryl S-glucosides unveiled the reactivity patterns of alkyl S-glucosides toward anodic oxidation and found noteworthy differences with the trends followed by aryl derivatives. The oxidation potential of alkyl S-glucosides, estimated herein from square-wave voltammetry peak potentials (Ep), depends on the steric properties of the aglycone. Glucosides substituted with bulky groups exhibit Ep values at voltages more positive than the values of those carrying small aglycones. This relationship, observed in all analyzed alkyl series, is evidenced by good linear correlations between Ep and Taft's steric parameters (ES) of the respective alkyl substituents. Moreover, the role of the aglycone's steric properties as a primary reactivity modulator is backed by poor correlations between Ep and the radical stabilization energies (RSEs) of the aglycone-derived thiyl radicals (RS•). In contrast, aryl glucosides' Ep values exhibit excellent correlations with the aryl substituents' Hammett parameters (σ+) and the ArS• RSEs, evidencing the inherent stability of the reactive radical intermediate as the primary factor controlling aryl glucoside's electrochemical reactivity. The reactivity differences between alkyl and aryl S-glucosides also extend to the protective group's effect on Ep. Alkyl S-glucosides' reactivity proved to be more sensitive to protective group exchange.


Fever, immunity, and molecular adaptations.
The heat shock response (HSR) is an ancient and highly conserved process that is essential for coping with environmental stresses, including extremes of temperature. Fever is a more recently evolved response, during which organisms temporarily subject themselves to thermal stress in the face of infections. We review the phylogenetically conserved mechanisms that regulate fever and discuss the effects that febrile-range temperatures have on multiple biological processes involved in host defense and cell death and survival, including the HSR and its implications for patients with severe sepsis, trauma, and other acute systemic inflammatory states. Heat shock factor-1, a heat-induced transcriptional enhancer is not only the central regulator of the HSR but also regulates expression of pivotal cytokines and early response genes. Febrile-range temperatures exert additional immunomodulatory effects by activating mitogen-activated protein kinase cascades and accelerating apoptosis in some cell types. This results in accelerated pathogen clearance, but increased collateral tissue injury, thus the net effect of exposure to febrile range temperature depends in part on the site and nature of the pathologic process and the specific treatment provided.


Generating multi-atom entangled W states via light-matter interface based fusion mechanism.
W state is a key resource in quantum communication. Fusion technology has been proven to be a good candidate for preparing a large-size W state from two or more small-size W states in linear optical system. It is of great importance to study how to fuse W states via light-matter interface. Here we show that it is possible to prepare large-size W-state networks using a fusion mechanism in cavity QED system. The detuned interaction between three atoms and a vacuum cavity mode constitute the main fusion mechanism, based on which two or three small-size atomic W states can be fused into a larger-size W state. If no excitation is detected from those three atoms, the remaining atoms are still in the product of two or three new W states, which can be re-fused. The complicated Fredkin gate used in the previous fusion schemes is avoided here. W states of size 2 can be fused as well. The feasibility analysis shows that our fusion processes maybe implementable with the current technology. Our results demonstrate how the light-matter interaction based fusion mechanism can be realized, and may become the starting point for the fusion of multipartite entanglement in cavity QED system.


Quantification of aortic pulse wave velocity from a population based cohort: a fully automatic method.
Aortic pulse wave velocity (PWV) is an indicator of aortic stiffness and is used as a predictor of adverse cardiovascular events. PWV can be non-invasively assessed using magnetic resonance imaging (MRI). PWV computation requires two components, the length of the aortic arch and the time taken for the systolic pressure wave to travel through the aortic arch. The aortic length is calculated using a multi-slice 3D scan and the transit time is computed using a 2D velocity encoded MRI (VE) scan. In this study we present and evaluate an automatic method to quantify the aortic pulse wave velocity using a large population-based cohort. For this study 212 subjects were retrospectively selected from a large multi-center heart-brain connection cohort. For each subject a multi-slice 3D scan of the aorta was acquired in an oblique-sagittal plane and a 2D VE scan acquired in a transverse plane cutting through the proximal ascending and descending aorta. PWV was calculated in three stages: (i) a multi-atlas-based segmentation method was developed to segment the aortic arch from the multi-slice 3D scan and subsequently estimate the length of the proximal aorta, (ii) an algorithm that delineates the proximal ascending and descending aorta from the time-resolved 2D VE scan and subsequently obtains the velocity-time flow curves was also developed, and (iii) automatic methods that can compute the transit time from the velocity-time flow curves were implemented and investigated. Finally the PWV was obtained by combining the aortic length and the transit time. Quantitative evaluation with respect to the length of the aortic arch as well as the computed PWV were performend by comparing the results of the novel automatic method to those obtained manually. The mean absolute difference in aortic length obtained automatically as compared to those obtained manually was 3.3 ± 2.8 mm (p < 0.05), the manual inter-observer variability on a subset of 45 scans was 3.4 ± 3.4 mm (p = 0.49). Bland-Altman analysis between the automataic method and the manual methods showed a bias of 0.0 (-5.0,5.0) m/s for the foot-to-foot approach, -0.1 (-1.2, 1.1) and -0.2 (-2.6, 2.1) m/s for the half-max and the cross-correlation methods, respectively. We proposed and evaluated a fully automatic method to calculate the PWV on a large set of multi-center MRI scans. It was observed that the overall results obtained had very good agreement with manual analysis. Our proposed automatic method would be very beneficial for large population based studies, where manual analysis requires a lot of manpower.


Anti-tumour necrosis factor-induced visceral and cutaneous leishmaniasis: case report and review of the literature.
Leishmaniasis is a chronic protozoan disease in which organisms are found within phagolysosomes of the mononuclear phagocyte system. There are three major forms: cutaneous, mucocutaneous and visceral. We report the first case of visceral leishmaniasis with cutaneous involvement in a patient with rheumatoid arthritis treated with the anti-tumour necrosis factor (anti-TNF) adalimumab. To highlight cutaneous leishmaniasis as the first indicator of a kala-azar disease in a patient treated with anti-TNF and to review the literature on leishmaniasis in the context of anti-TNF therapy. A 59-year-old woman presented with a crusted plaque on the right elbow 34 months after the initiation of adalimumab. A cutaneous biopsy showed intracellular amastigotes. No Leishmania parasites were observed in a bone marrow aspirate, but laboratory tests showed anaemia and impaired liver function, abdominal ultrasonography showed hepatomegaly, and ELISA serology was strongly positive for Leishmania antibodies in serum and urine. Adalimumab was withdrawn and treatment combining intralesional pentavalent antimonials and liposomal amphotericin was started. Eight weeks later, the leishmaniasis had resolved. A skin biopsy disclosing leishmaniasis should prompt tests to rule out visceral leishmaniasis, especially in an area such as the Mediterranean where the prevalence of latent Leishmania infection is high.


Class I HDACs are mediators of smoke carcinogen-induced stabilization of DNMT1 and serve as promising targets for chemoprevention of lung cancer.
DNA methylation is an early event in bronchial carcinogenesis and increased DNA methyltransferase (DNMT)1 protein expression is a crucial step in the oncogenic transformation of epithelia. Here, we investigate the role of class I histone deacetylases (HDAC) 1 to 3 in the stabilization of DNMT1 protein and as a potential therapeutic target for lung cancer chemoprevention. Long-term exposure of immortalized bronchial epithelial cells (HBEC-3KT) to low doses of tobacco-related carcinogens led to oncogenic transformation, increased HDAC expression, cell-cycle independent increased DNMT1 stability, and DNA hypermethylation. Overexpression of HDACs was associated with increased DNMT1 stability and knockdown of HDACs reduced DNMT1 protein levels and induced DNMT1 acetylation. This suggests a causal relationship among increased class I HDACs levels, upregulation of DNMT1 protein, and subsequent promoter hypermethylation. Targeting of class I HDACs with valproic acid (VPA) was associated with reduced HDAC expression and a profound reduction of DNMT1 protein level. Treatment of transformed bronchial epithelial cells with VPA resulted in reduced colony formation, demethylation of the aberrantly methylated SFRP2 promoter, and derepression of SFRP2 transcription. These data suggest that inhibition of HDAC activity may reverse or prevent carcinogen-induced transformation. Finally, immunohistochemistry on human lung cancer specimens revealed a significant increase in DNMT1, HDAC1, HDAC2, and HDAC3 expression, supporting our hypotheses that class I HDACs are mediators of DNMT1 stability. In summary, our study provides evidence for an important role of class I HDACs in controlling the stability of DNMT1 and suggests that HDAC inhibition could be an attractive approach for lung cancer chemoprevention.


Social cognition impairments in relation to general cognitive deficits, injury severity, and prefrontal lesions in traumatic brain injury patients.
Impairments in social behavior are frequently found in moderate to severe traumatic brain injury (TBI) patients and are associated with an unfavorable outcome with regard to return to work and social reintegration. Neuropsychological tests measuring aspects of social cognition are thought to be sensitive to these problems. However, little is known about the effect of general cognitive problems on these tests, nor about their sensitivity to injury severity and frontal lesions. In the present study 28 chronic TBI patients with a moderate to severe TBI were assessed with tests for social cognition (emotion recognition, Theory of Mind, and empathy), and for general, non-social cognition (memory, mental speed, attention, and executive function). The patients performed significantly worse than healthy controls on all measures, with the highest effect size for the emotion recognition test, the Facial Expressions of Emotion-Stimuli and Tests (FEEST). Correlation analyses yielded no significant (partial) correlations between social and non-social cognition tests. Consequently, poor performance on social cognition tests was not due to general cognitive deficits. In addition, the emotion recognition test was the only measure that was significantly related to post-traumatic amnesia (PTA) duration, Glasgow Coma Scale (GCS) score, and the presence of prefrontal lesions. Hence, we conclude that social cognition tests are a valuable supplement to a standard neuropsychological examination, and we strongly recommend the incorporation of measurements of social cognition in clinical practice. Preferably, a broader range of social cognition tests would be applied, since our study demonstrated that each of the measures represents a unique aspect of social cognition, but if capacity is limited, at least a test for emotion recognition should be included.


Behavioral measurement of neural poststimulation excitability cycle: pain cells in the brain of the rat.
A new technique in which elicited behavior of the freely moving rat is used to measure the poststimulation excitability cycle of the central neurons mediating that behavior has been adapted from accepted methods of neurophysiology. A continuous train of pairs of brief pulses was delivered to pain systems in the midbrain. Rate of lever pressing to achieve 3-second rests from this stimulation was measured as a function of the interval separating the pulses within pairs. Evidence for latent addition, absolute refractory period, temporal summation, and adaptation was demonstrated. Obtained relationships suggested that three sets of fibers may carry the aversive signal and that synaptic integration of pain in the brain may be related to Stevens' power law functions.


Modelling gas-liquid mass transfer in wastewater treatment: when current knowledge needs to encounter engineering practice and vice versa.
Gas-liquid mass transfer in wastewater treatment processes has received considerable attention over the last decades from both academia and industry. Indeed, improvements in modelling gas-liquid mass transfer can bring huge benefits in terms of reaction rates, plant energy expenditure, acid-base equilibria and greenhouse gas emissions. Despite these efforts, there is still no universally valid correlation between the design and operating parameters of a wastewater treatment plant and the gas-liquid mass transfer coefficients. That is why the current practice for oxygen mass transfer modelling is to apply overly simplified models, which come with multiple assumptions that are not valid for most applications. To deal with these complexities, correction factors were introduced over time. The most uncertain of them is the α-factor. To build fundamental gas-liquid mass transfer knowledge more advanced modelling paradigms have been applied more recently. Yet these come with a high level of complexity making them impractical for rapid process design and optimisation in an industrial setting. However, the knowledge gained from these more advanced models can help in improving the way the α-factor and thus gas-liquid mass transfer coefficient should be applied. That is why the presented work aims at clarifying the current state-of-the-art in gas-liquid mass transfer modelling of oxygen and other gases, but also to direct academic research efforts towards the needs of the industrial practitioners.


The Role of Microbes in the Nutrition of Detritivorous Invertebrates: A Stoichiometric Analysis.
Detritus represents an important pool in the global carbon cycle, providing a food source for detritivorous invertebrates that are conspicuous components of almost all ecosystems. Our knowledge of how these organisms meet their nutritional demands on a diet that is typically comprised of refractory, carbon-rich compounds nevertheless remains incomplete. "Trophic upgrading" of detritus by the attached microbial community (enhancement of zooplankton diet by the inclusion of heterotrophic protozoans) represents a potential source of nutrition for detritivores as both bacteria and their flagellated protistan predators are capable of biosynthesizing essential micronutrients such as polyunsaturated fatty acids (PUFAs). There is however a trade-off because although microbes enhance the substrate in terms of its micronutrient content, the quantity of organic carbon is diminished though metabolic losses as energy passes through the microbial food web. Here, we develop a simple stoichiometric model to examine this trade-off in the nutrition of detritivorous copepods inhabiting the mesopelagic zone of the ocean, focusing on their requirements for carbon and an essential PUFA, docosahexaenoic acid (DHA). Results indicate that feeding on microbes may be a highly favorable strategy for these invertebrates, although the potential for carbon to become limiting when consuming a microbial diet exists because of the inefficiencies of trophic transfer within the microbial food web. Our study highlights the need for improved knowledge at the detritus-microbe-metazoan interface, including interactions between the physiology and ecology of the associated organisms.


Readmissions to Different Hospitals After Common Surgical Procedures and Consequences for Implementation of Perioperative Surgical Home Programs.
We consider whether there should be greater priority of information sharing about postacute surgical resources used: (1) at skilled nursing facilities or inpatient rehabilitation hospitals to which patients are transferred upon discharge (when applicable) versus (2) at different hospitals where readmissions occur. Obtaining and storing data electronically from these 2 sources for Perioperative Surgical Home initiatives are dissimilar; both can be challenging depending on the country and health system. Using the 2013 US Nationwide Readmissions Database, we studied discharges of surgical diagnosis-related group (DRG) with US national median length of stay (LOS) ≥ 3 days and ≥ 10 hospitals each with ≥ 100 discharges for the Medicare Severity DRG. Nationwide, 16.15% (95% confidence interval [CI], 15.14%-17.22%) of discharges were with a disposition of "not to home" (ie, transfer to a skilled nursing facility or an inpatient rehabilitation hospital). Within 30 days, 0.88% of discharges (0.82%-0.95%) were followed by readmission and to a different hospital than the original hospital where the surgery was performed. Among all discharges, disposition "not to home" versus "to home" was associated with greater odds that the patient would have readmission within 30 days and to a different hospital than where the surgery was performed (2.11, 95% CI, 1.96-2.27; P < .0001). In part, this was because disposition "not to home" was associated with greater odds of readmission to any hospital (1.90, 95% CI, 1.82-1.98; P < .0001). In addition, among the subset of discharges with readmission within 30 days, disposition "not to home" versus "to home" was associated with greater odds that the readmission was to a different hospital than where the surgery was performed (1.20, 95% CI, 1.11-1.31; P < .0001). There was no association between the hospitals' median LOS for the DRG and the odds that readmission was to a different hospital (P = .82). The odds ratio per each 1 day decrease in the hospital median LOS was 1.01 (95% CI, 0.91-1.12). Departments and hospitals wishing to demonstrate the value of their Perioperative Surgical Home initiatives, or to calculate risk assumption contracts, should ensure that their informatics priorities include obtaining accurate data on resource use at postacute care facilities such as skilled nursing facilities. Although approximately a quarter of readmissions are to different hospitals than where surgery was performed, provided that is recognized, obtaining those missing data is of less importance.


Morbidity mortality paradox of 1st generation Greek Australians.
There is evidence in Australia that 1st generation Greek Australians (GA), despite their high prevalence of cardiovascular disease (CVD) risk factors (e.g. obesity, diabetes, hyperlipidaemia, smoking, hypertension, sedentary lifestyles) continue to display more than 35% lower mortality from CVD and overall mortality compared with the Australian-born after at least 30 years in Australia. This has been called a 'morbidity mortality paradox' or 'Greek-migrant paradox'. Retrospective data from elderly Greek migrants participating in the International Union of Nutrition Sciences Food Habits in Later Life (FHILL) study suggests that diets changed on migration due to the: (i) lack of familiar foods in the new environment; (ii) abundant and cheap animal foods (iii) memories of hunger before migration; and (iv) status ascribed to energy dense foods (animal foods, white bread and sweets) and 'plumpness' as a sign of affluence and plant foods (legumes, vegetable dishes, grainy bread) and 'thinness' as a sign of poverty. This apparently resulted in traditional foods (e.g. olive oil) being replaced with 'new' foods (e.g. butter), 'traditional' plant dishes being made more energy dense, larger serves of animal foods, sweets and fats being consumed, and increased frequency of celebratory feasts. This shift in food pattern contributed to significant weight gain in GA. Despite these potentially adverse changes, data from Greece in the 1960s (seven countries study) and from Australia in the 1990s (FHILL study) has shown that Greek migrants have continued to eat large serves of putatively protective foods (leafy vegetables, onions, garlic, tomatoes, capsicum, lemon juice, herbs, legumes, fish) prepared according to Greek cuisine (e.g. vegetables stewed in oil). Furthermore, GA were found to return to the traditional Greek food pattern with advancing years. We suspect that these factors may explain why GA have recently been found to have over double the circulating concentrations of antioxidant carotenoids, especially lutein, compared with Australians of Anglo-Celtic ancestry. This in turn may have helped to make the CVD risk factors 'benign' and reduce the risk of death. This raises the question whether specific dietary guidelines need to be developed for recent migrants to Australia, encouraging them to retain the best of their traditional cultures and include the best of the mainstream culture.


Female sexual dysfunction: therapeutic options and experimental challenges.
Female sexual dysfunction (FSD) is a prevalent problem, afflicting approximately 40% of women and there are few treatment options. FSD is more typical as women age and is a progressive and widespread condition. Common symptoms associated with FSD include diminished vaginal lubrication, pain and discomfort upon intercourse, decreased sense of arousal and difficulty in achieving orgasm. Only a small percentage of women seek medical attention. In comparison to the overwhelming research and treatment for erectile dysfunction in males, specifically with the development of phosphodiesterase type 5 inhibitors, significantly less has been explored regarding FSD and treatment is primarily limited to psychological therapy. Several cardiovascular diseases have been linked with FSD including atherosclerosis, peripheral arterial disease and hypertension, all of which are also pathological conditions associated with aging and erectile dysfunction in men. Using animal models, we have expanded our understanding of FSD, however a tremendous amount is still to be learned in order to properly treat women suffering from FSD. The aim of this review is to provide the most current knowledge on FSD, advances in basic science addressing this dysfunction, and explore developing therapeutic options.


A review of diffusion tensor imaging studies in schizophrenia.
Both post-mortem and neuroimaging studies have contributed significantly to what we know about the brain and schizophrenia. MRI studies of volumetric reduction in several brain regions in schizophrenia have confirmed early speculations that the brain is disordered in schizophrenia. There is also a growing body of evidence suggesting that a disturbance in connectivity between different brain regions, rather than abnormalities within the separate regions themselves, are responsible for the clinical symptoms and cognitive dysfunctions observed in this disorder. Thus an interest in white matter fiber tracts, subserving anatomical connections between distant, as well as proximal, brain regions, is emerging. This interest coincides with the recent advent of diffusion tensor imaging (DTI), which makes it possible to evaluate the organization and coherence of white matter fiber tracts. This is an important advance as conventional MRI techniques are insensitive to fiber tract direction and organization, and have not consistently demonstrated white matter abnormalities. DTI may, therefore, provide important new information about neural circuitry, and it is increasingly being used in neuroimaging studies of psychopathological disorders. Of note, in the past five years 18 DTI studies in schizophrenia have been published, most describing white matter abnormalities. Questions still remain, however, regarding what we are measuring that is abnormal in this disease, and how measures obtained using one method correspond to those obtained using other methods? Below we review the basic principles involved in MR-DTI, followed by a review of the different methods used to evaluate diffusion. Finally, we review MR-DTI findings in schizophrenia.


Laparoscopic Technique in the Management of High Anorectal Malformations: A Propensity Score-Matched Outcome Study Using a Large Inpatient Database.
Background: Posterior sagittal anorectoplasty (PSARP) has been the standard for management of children with high anorectal malformations (ARMs). Recently, there has been an increase in the use of laparoscopy in its management. We analyzed the outcomes of laparoscopically assisted anorectal pull-through (LAARP) compared to PSARP using a large inpatient database. Methods: Kids' Inpatient Database was analyzed for ARM (ICD-9-CM 751.2) between 1997 and 2012. Perineal fistulas and low/intermediate ARM were excluded. Propensity score (PS)-matched analyses were performed using 37 variables. Cases were weighted to provide national estimates. Results: Of the overall 29,106 cases, 7428 patients <2 years underwent surgical repair. LAARP was performed in 178 patients. Eighty-eight percent were male. Most were of Caucasian (n = 71; 45%), followed by Hispanic (n = 41; 26%) descent. Most were performed in 2009 and 2012 (n = 149; 83%). Most were covered by Medicaid (88; 49%), followed by private insurance (80; 45%). Median length of stay (LOS) was 4 (interquartile range = 3) days. The majority were performed in a children's hospital (n = 90; 88%). On PS-matched analysis, LAARP had shorter median LOS (4 [3]) compared to PSARP (6 [15]) days, P = .003. Rates of reoperation, wound infection, wound dehiscence, and mortality were unchanged between approaches. Cost was lower for LAARP (47,969 [49,450]) versus PSARP (56,110 [160,314]) U.S. dollar , P = .002, whereas total charges did not differ significantly. Conclusions: A minimal access approach to a complex procedure requires significant time and resources to be adopted as standard. PSARP is an important example, as increased availability of laparoscopy, and therefore, access to the procedure for patients will greatly affect resource utilization and recovery for the patient. As demonstrated, the LOS and cost is significantly lower for the LAARP procedure in comparison to the traditional approach. Future research will clarify boundaries to introducing the laparoscopic approach as a potential standard technique in the next decade.


Homologues of the Arabidopsis thaliana SHI/STY/LRP1 genes control auxin biosynthesis and affect growth and development in the moss Physcomitrella patens.
The plant hormone auxin plays fundamental roles in vascular plants. Although exogenous auxin also stimulates developmental transitions and growth in non-vascular plants, the effects of manipulating endogenous auxin levels have thus far not been reported. Here, we have altered the levels and sites of auxin production and accumulation in the moss Physcomitrella patens by changing the expression level of homologues of the Arabidopsis SHI/STY family proteins, which are positive regulators of auxin biosynthesis genes. Constitutive expression of PpSHI1 resulted in elevated auxin levels, increased and ectopic expression of the auxin response reporter GmGH3pro:GUS, and in an increased caulonema/chloronema ratio, an effect also induced by exogenous auxin application. In addition, we observed premature ageing and necrosis in cells ectopically expressing PpSHI1. Knockout of either of the two PpSHI genes resulted in reduced auxin levels and auxin biosynthesis rates in leafy shoots, reduced internode elongation, delayed ageing, a decreased caulonema/chloronema ratio and an increased number of axillary hairs, which constitute potential auxin biosynthesis sites. Some of the identified auxin functions appear to be analogous in vascular and non-vascular plants. Furthermore, the spatiotemporal expression of the PpSHI genes and GmGH3pro:GUS strongly overlap, suggesting that local auxin biosynthesis is important for the regulation of auxin peak formation in non-vascular plants.


Complete genes may pass from food to human blood.
Our bloodstream is considered to be an environment well separated from the outside world and the digestive tract. According to the standard paradigm large macromolecules consumed with food cannot pass directly to the circulatory system. During digestion proteins and DNA are thought to be degraded into small constituents, amino acids and nucleic acids, respectively, and then absorbed by a complex active process and distributed to various parts of the body through the circulation system. Here, based on the analysis of over 1000 human samples from four independent studies, we report evidence that meal-derived DNA fragments which are large enough to carry complete genes can avoid degradation and through an unknown mechanism enter the human circulation system. In one of the blood samples the relative concentration of plant DNA is higher than the human DNA. The plant DNA concentration shows a surprisingly precise log-normal distribution in the plasma samples while non-plasma (cord blood) control sample was found to be free of plant DNA.


Top-down attention selection is fine grained.
Although much is known about the sources and modulatory effects of top-down attentional signals, the information capacity of these signals is less known. Here, we investigate the granularity of top-down attentional signals. Previous theories in psychophysics have provided conflicting evidence on whether top-down guidance is coarse grained (i.e., one gain control term per feature dimension) or fine grained (i.e., multiple gain control terms per dimension). We resolve the conflict by designing new experiments that disentangle top-down from bottom-up contributions, thereby avoiding confounds existing in previous studies. The results of our eye-tracking experiments show that subjects can selectively saccade to items belonging to the relevant feature interval compared with irrelevant intervals within a dimension. This suggests that top-down signals can specify not only the relevant feature dimension but also the relevant feature interval within a dimension. We conclude that top-down signals are fine grained and can specify multiple gain control terms per dimension.


Sources of health insurance and characteristics of the uninsured: analysis of the March 2009 Current Population Survey.
This Issue Brief provides historical data through 2008 on the number and percentage of nonelderly individuals with and without health insurance. Based on EBRI estimates from the U.S. Census Bureau's March 2009 Current Population Survey (CPS), it reflects 2008 data. It also discusses trends in coverage for the 1994-2008 period and highlights characteristics that typically indicate whether an individual is insured. HEALTH COVERAGE RATE CONTINUES TO DECREASE: The percentage of the nonelderly population (under age 65) with health insurance coverage decreased to 82.6 percent in 2008. Increases in health insurance coverage have been recorded in only four years since 1994, when 36.5 million nonelderly individuals were uninsured; in 2008, the uninsured population was 45.7 million. EMPLOYMENT-BASED COVERAGE REMAINS DOMINANT SOURCE OF HEALTH COVERAGE, BUT CONTINUES TO SLOWLY ERODE: Employment-based health benefits remain the most common form of health coverage in the United States. In 2008, 61.1 percent of the nonelderly population had employment-based health benefits, down from 68.4 percent in 2000. Between 1994 and 2000, the percentage of the nonelderly population with employment-based coverage expanded. PUBLIC PROGRAM COVERAGE IS GROWING: Public program health coverage expanded as a percentage of the population in 2008, accounting for 19.4 percent of the nonelderly population. Enrollment in Medicaid and the State Children's Health Insurance Program increased, reaching a combined 39.2 million in 2008, and covering 14.9 percent of the nonelderly population, significantly above the 10.5 percent level of 1999. INDIVIDUAL COVERAGE STABLE: Individually purchased health coverage was unchanged in 2008 and has basically hovered in the 6-7 percent range since 1994. MOST/LEAST LIKELY TO HAVE HEALTH INSURANCE: Full-time, full-year workers, public-sector workers, workers employed in manufacturing, managerial and professional workers, and individuals living in high-income families are most likely to have employment-based health benefits. Poor families are most likely to be covered by public coverage programs such as Medicaid or S-CHIP. RETHINKING THE VALUE OF OFFERING HEALTH INSURANCE: Research illustrates the advantages to consumers of having health insurance and the benefits to employers of offering it. In general, the availability of health insurance allows consumers to avoid unnecessary pain and suffering and improves the quality of life, and employers report that offering benefits has a positive impact on worker recruitment, retention, health status, and productivity. Employers may believe in the business case for providing health benefits today, but in the future they may rethink the value that offering coverage provides, especially if health costs continue to escalate sharply or if health reform changes the value proposition.


Gallstone disease after extended (D2) lymph node dissection for gastric cancer.
Few studies have reported the incidence and clinical outcomes of gallstone disease after extended (D2) lymph node dissection for gastric cancer. The present study was designed to retrospectively compare limited (D1) and D2 dissections in terms of gallstone formation, presentation of gallstones, and surgery for gallstone disease. A total of 805 Japanese gastric cancer patients (595 male, 210 female) who underwent curative resection with D1 (n = 490) or D2 (n = 315) dissection were retrospectively reviewed. Of those subjects followed for 70.5 +/- 44.3 months (range: 2-196 months), 102 (12.7%) developed gallstones. The incidence of gallstone formation was higher in the D2 group than in the D1 group (17.8% vs. 9.4%, p = 0.001). The interval between gastrectomy and detection of gallstones was shorter in the D2 group than in the Dl group (18.8 +/- 11.4 months vs. 29.4 +/- 18.3 months, p = 0.002). Of those with gallstones followed for 48.0 +/- 28.6 months (range: 1-158 months), 74 (72.5%) remained asymptomatic, and 15 (14.7%) experienced mild biliary pain. Thirteen patients (12.7%) developed recurrent biliary pain (n = 3) or biliary complications (n = 10; 6 acute cholecystitis, 3 obstructive jaundice, and 1 cholangitis), and required surgical treatment. Surgery was more frequently sought in the D2 group than in the D1 group (19.5% vs. 4.3%, p = 0.033). In conclusion, patients with D2 dissection developed gallstones more frequently and earlier than patients with D1 dissection. Of those with gallstones, patients with D2 dissection required surgery more often than patients with D1 dissection. A closer follow-up should be mandatory for gallstone disease after D2 dissection, but further studies are needed before generalizations can be made.


Acute and chronic pancreatitis: surgical management.
Pancreatitis is becoming increasingly prevalent in children, posing new challenges to pediatric health care providers. Although some general adult treatment paradigms are applicable in the pediatric population, diagnostic workup and surgical management of acute and chronic pancreatitis have to be tailored to anatomic and pathophysiological entities peculiar to children. Nonbiliary causes of acute pancreatitis in children are generally managed nonoperatively with hydration, close biochemical and clinical observation, and early initiation of enteral feeds. Surgical intervention including cholecystectomy or endoscopic retrograde cholangiopancreatography is often required in acute biliary pancreatitis, whereas infected pancreatic necrosis remains a rare absolute indication for pancreatic debridement and drainage via open, laparoscopic, or interventional radiologic procedure. Chronic pancreatitis is characterized by painful irreversible changes of the parenchyma and ducts, which may result in or be caused by inadequate ductal drainage. A variety of surgical procedures providing drainage, denervation, resection, or a combination thereof are well established to relieve pain and preserve pancreatic function.


Clinical, hemodynamic and endomyocardial biopsy findings in idiopathic restrictive cardiomyopathy.
Restrictive cardiomyopathy is uncommon and in its overt form is associated with heart failure, characterized primarily by abnormalities in diastolic function and preserved or nearly preserved systolic function. It may be associated with amyloidosis, hemochromatosis or endomyocardial fibrosis. We describe five patients with restrictive cardiomyopathy, ages ranging from 35 to 71 (mean 49), three of whom were men. Fatigue, dyspnea on exertion and chest pain were the most frequent symptoms. Only one patient had overt heart failure, and three had normal or near-normal hemodynamics at rest that became greatly abnormal with exercise. Four of the five patients are alive now 9 to 77 (mean 33) months following the onset of symptoms. Despite prior emphasis on specific causes, restrictive cardiomyopathy in this series had no definable cause. Moreover, the presence of a "latent" form of restriction (abnormalities only with exercise) suggests that the incidence of the disease may be higher than previously appreciated.


The efficacy and safety of febuxostat for urate lowering in gout patients ≥65 years of age.
The incidence of gout rises with increasing age. Management of elderly (≥65 years) gout patients can be challenging due to high rates of comorbidities, such as renal impairment and cardiovascular disease, and concomitant medication use. However, there is little data specifically addressing the efficacy and safety of available urate-lowering therapies (ULT) in the elderly. The objective of this post hoc analysis was to examine the efficacy and safety of ULT with febuxostat or allopurinol in a subset of elderly subjects enrolled in the CONFIRMS trial. Hyperuricemic (serum urate [sUA] levels ≥ 8.0 mg/dL) gout subjects were enrolled in the 6-month, double-blind, randomized, comparative CONFIRMS trial and randomized, 1:1:1, to receive febuxostat, 40 mg or 80 mg, or allopurinol (200 mg or 300 mg based on renal function) once daily. Flare prophylaxis was provided throughout the study duration.Study endpoints were the percent of elderly subjects with sUA <6.0 mg/dL at the final visit, overall and by renal function status, percent change in sUA from baseline to final visit, flare rates, and rates of adverse events (AEs). Of 2,269 subjects enrolled, 374 were elderly. Febuxostat 80 mg was significantly more efficacious (82.0%) than febuxostat 40 mg (61.7%; p < 0.001) or allopurinol (47.3%; p < 0.001) for achieving the primary efficacy endpoint. Febuxostat 40 mg was also superior to allopurinol in this population (p = 0.029). In subjects with mild-to-moderate renal impairment, significantly greater ULT efficacy was observed with febuxostat 40 mg (61.6%; p = 0.028) and febuxostat 80 mg (82.5%; p < 0.001) compared to allopurinol 200/300 mg (46.9%). Compared to allopurinol 200/300 mg, the mean percent change in sUA from baseline was significantly greater for both febuxostat 80 mg (p < 0.001) and febuxostat 40 mg (p = 0.011) groups. Flare rates declined steadily in all treatment groups. Rates of AEs were low and comparable across treatments. These data suggest that either dose of febuxostat is superior to commonly prescribed fixed doses of allopurinol (200/300 mg) in subjects ≥65 years of age with high rates of renal dysfunction. In addition, in this high-risk population, ULT with either drug was well tolerated. clinicaltrials.gov NCT#00430248.


Prognostic factors and patterns of treatment failure in dogs with unresectable differentiated thyroid carcinomas treated with megavoltage irradiation.
To determine quality and duration of progression-free survival (PFS) time in dogs with unresectable thyroid carcinomas treated with definitive megavoltage irradiation and analyze prognostic factors of PFS and patterns of failure (local recurrence vs metastasis). Prospective clinical trial. 25 dogs with locally advanced thyroid carcinomas and no evidence of metastasis. Dogs were treated with 48 Gy during 4 weeks on an alternate-day schedule of 4 Gy/fraction. Irradiation was safe and effective for treatment of large unresectable thyroid carcinomas. Progression-free survival rates were 80% at 1 year and 72% at 3 years. Time to maximum tumor size reduction ranged from 8 to 22 months. Factors affecting PFS were not found. Twenty-eight percent (7/25) of dogs developed metastasis. Dogs with bilateral tumors had 16 times the risk of developing metastases, compared with dogs with a single tumor. Dogs with no evidence of tumor progression had 15 times less risk of developing metastases. Radiation-induced hypothyroidism was suspected in 2 dogs 13 and 29 months after irradiation. Irradiation is effective for local control of thyroid tumors, despite their slow regression rate. Results provided evidence that local tumor control affects metastatic outcome in dogs with thyroid carcinomas and is a strong basis for the development of new approaches that include irradiation in the management of dogs with advanced thyroid carcinomas. Improvements in local tumor control alone may be insufficient to improve survival times because of the high risk of metastatic spread before an initial diagnosis is made, which warrants initiation of early systemic treatment.


Transforming growth factor beta as a virulence mechanism for Leishmania braziliensis.
Transforming growth factor beta (TGF-beta) has potent down-regulating effects on macrophages and is thus capable of influencing the fate of intramacrophage parasites, including leishmanias. We report the development of a mouse model for the study of the human pathogen Leishmania braziliensis and demonstrate, both in vitro and in vivo, a key regulatory role for TGF-beta in the pathogenesis of infection with this parasite. Recombinant TGF-beta added to cultures of murine peritoneal macrophages led to increased intracellular L. braziliensis replication, whereas addition of neutralizing anti-TGF-beta monoclonal antibody decreased levels of infection. Macrophages infected with L. braziliensis produced biologically active TGF-beta, with a direct correlation between amounts of TGF-beta induced by two parasite isolates and their relative virulence. In vivo, treatment with recombinant TGF-beta rendered avirulent parasites virulent and activated latent L. braziliensis infection. Activation of parasite replication was observed in mice which had been infected with L. braziliensis 15 weeks previously but had not developed lesions or had healed lesions, depending on the parasite isolate used to infect the mice. The exacerbation of L. braziliensis infection in vivo was associated with an increase of interleukin 10 mRNA in the draining lymph node. These results demonstrate that TGF-beta is able to alter the course of in vitro and in vivo infections with L. braziliensis, the latter being characterized by an increase in interleukin 10, an important Th2 helper-T-cell cytokine.


Association between DPYD c.1129-5923 C>G/hapB3 and severe toxicity to 5-fluorouracil-based chemotherapy in stage III colon cancer patients: NCCTG N0147 (Alliance).
Severe (grade≥3) adverse events (AEs) to 5-fluorouracil (5-FU)-based chemotherapy regimens can result in treatment delays or cessation, and, in extreme cases, life-threatening complications. Current genetic biomarkers for 5-FU toxicity prediction, however, account for only a small proportion of toxic cases. In the current study, we assessed DPYD variants suggested to correlate with 5-FU toxicity, a deep intronic variant (c.1129-5923 C>G), and four variants within a haplotype (hapB3) in 1953 stage III colon cancer patients who received adjuvant FOLFOX±cetuximab. Logistic regression was used to assess multivariable associations between DPYD variant status and AEs common to 5-FU (5FU-AEs). In our study cohort, 1228 patients (62.9%) reported any grade≥3 AE (overall AE), with 638 patients (32.7%) reporting any grade≥3 5FU-AE. Only 32 of 78 (41.0%) patients carrying DPYD c.1129-5923 C>G and the completely linked hapB3 variants c.1236 C>G and c.959-51 T>C showed at least one grade≥3 5FU-AE, resulting in no statistically significant association (adjusted odds ratio=1.47, 95% confidence interval=0.90-2.43, P=0.1267). No significant associations were identified between c.1129-5923 C>G/hapB3 and overall grade≥3 AE rate. Our results suggest that c.1129-5923 C>G/hapB3 have limited predictive value for severe toxicity to 5-FU-based combination chemotherapy.


Assessment of primary care facilities for cardiovascular disease preparedness in Madhya Pradesh, India.
Government of India has launched National Program for Prevention & Control of Cancer, Diabetes, Cardiovascular Diseases and Stroke (NPCDCS) to address high prevalence of non-communicable diseases (NCDs) in India. Cardiovascular diseases (CVDs) constitute a significant portion of NCD burden. While this program is yet to be launched in all districts of Madhya Pradesh state of India, we performed this study to understand facility-level gaps that need to be addressed to improve CVD services in primary care provided by the public sector. This is a cross-sectional questionnaire based study. A standardized questionnaire was self-administered to 85 medical officers from as many primary care facilities from 24 districts of the state. These medical officers were working in two types of primary care facilities - primary health center (PHC) and community health centers (CHC). Facilities were assessed for 36 items in 5 domains (human-resource, equipment, drug supplies, point-of-care tests and laboratory services) with a focus on management of hypertension and diabetes mellitus in primary-care. Each item was to be answered as either present or absent at the facility where medical officer was working. We compared availability of an item across two levels of primary care facilities. All statistical analysis were done using Microsoft Excel. Availability of facilities was least in laboratory services, and human resource domains followed by drugs, and better in equipment and point-of-care supply domains. Across these domains, availability of items in CHCs was (37.1, 49.0, 56.1, 67.9 and 80.9 % respectively) and in PHCs (11.8, 18.2, 44.2, 55.1, and 55.3 % respectively). Current facility assessment study shows critical gaps in key items required for management of NCDs at primary care level. Human resource and laboratory services need to be strengthened the most, followed by sustained availability of all required drug classes, equipment and related supplies, and upgrading point-of-care testing. There are larger gaps in PHCs, which are level 1 facilities, as compared to CHCs, which are level 2 facilities in primary-care. Increasing burden of NCDs like hypertension and diabetes mellitus necessitates public health response through health systems. Therefore health system preparedness in form of trained human resources, functional laboratories and well stocked pharmacies are essential in primary care facilities.


Cross-talk between Schwann cells and neuroblasts influences the biology of neuroblastoma xenografts.
Neuroblastoma (NB) tumors with abundant schwannian stroma have a differentiated phenotype, low vascularity, and are associated with a favorable prognosis. These observations suggest that cross-talk between Schwann cells and neuroblasts may influence tumor biology. To test this hypothesis, we developed a novel NB xenograft model with infiltrating mouse Schwann cells. Human SMS-KCNR NB cells were injected intrafascicularly (sciatic nerve-engrafted NB, n = 19) or outside the sciatic nerve (control, n = 12). Xenografts were harvested 4 to 12 weeks after tumor cell inoculation for histological studies. Schwann cells were immunostained with S-100 and species-specific p75(NGFR), major histocompatibility complex, and human leukocyte antigen antibodies. The number of proliferating cells, infiltrating Schwann cells, apoptotic cells, differentiated neuroblasts, and blood vessels in the sciatic nerve-engrafted NB tumors were compared to controls. Significantly more Schwann cells were detected in the sciatic nerve-engrafted NB xenografts than controls (P < 0.001). The infiltrating Schwann cells were S-100-positive and reacted with anti-mouse major histocompatibility complex class Ib and p75(NGFR) but not anti-human p75(NGFR) and human leukocyte antigen class I antibodies. The sciatic nerve-engrafted tumors also had lower numbers of proliferating neuroblasts, higher numbers of differentiated neuroblasts and apoptotic cells, and decreased vascular density compared to controls. Our results indicate that infiltrating Schwann cells of mouse origin are capable of promoting human neuroblast differentiation, inducing apoptosis, and inhibiting proliferation and angiogenesis in vivo.


Validation study of portable device for the diagnosis of obstructive sleep apnea according to the new AASM scoring criteria: Watch-PAT 100.
Watch-PAT may provide an accurate and clinically effective portable monitoring method for the diagnosis of obstructive sleep apnea (OSA). This study was designed to assess the accuracy and clinical efficacy of a wrist-worn portable device (Watch-PAT 100) to diagnose OSA. Twenty-seven participants with suspected OSA underwent full polysomnography (PSG). Finally, 25 subjects successfully underwent portable monitoring using Watch-PAT after full PSG. The study population consisted of 21 males and 4 females, mean age 40.9 +/- 11.2 years (range 21-59). Mean body mass index (BMI) was 26.2 +/- 2.6 kg/m(2) (range 21.2-32.3). All PSG were manually scored according to the new scoring manual of the American Academy of Sleep Medicine (2007) and the Watch-PAT data were analyzed by the automatic algorithm. There was a high correlation of apnea-hypopnea index (AHI) (r = 0.94, p < 0.001) and lowest oxygen saturation (LSAT) (r = 0.90, p < 0.001) between the PSG and the Watch-PAT. A good agreement was also found between PSG AHI, PSG LSAT and PAT AHI, PAT LSAT, respectively. There was a significantly high concordance of the severity of AHI (Kendall tau-b = 0.897, p < 0.001) between the PSG and the Watch-PAT.


Concentrations of stromal cell-derived factor-1 in serum, plasma, and synovial fluid of horses with osteochondral injury.
To determine whether stromal cell-derived factor-1 (SDF-1) concentrations in serum, plasma, and synovial fluid differed among untrained, race-trained, and osteochondral-injured Thoroughbred racehorses. 22 racehorses without osteochondral injury and 37 racehorses with osteochondral injury. Horses without osteochondral injury were examined before and after 5 to 6 months of race training. Horses with osteochondral injury were undergoing arthroscopic surgery for removal of osteochondral fragments from carpal or metacarpophalangeal or metatarsophalangeal joints (fetlock joints). Serum, plasma, and fetlock or carpal synovial fluid samples were obtained and analyzed for SDF-1 concentration by use of an ELISA. In horses with fetlock or carpal joint injury, mean synovial fluid SDF-1 concentrations were significantly higher, serum SDF-1 concentrations were significantly lower, and synovial fluid-to-serum SDF-1 ratios were significantly higher than in untrained and trained horses. Synovial fluid SDF-1 concentrations were not significantly different between trained and untrained horses. Plasma SDF-1 concentrations were not different among the 3 groups. Results obtained with serum, compared with synovial fluid and plasma, had better sensitivity for differentiating between osteochondral-injured horses and uninjured horses. In horses with fetlock joint osteochondral injury, serum SDF-1 concentrations were correlated with radiographic and arthroscopic inflammation scores, but not arthroscopic cartilage scores. Results suggested that serum SDF-1 concentrations were more sensitive than plasma and synovial fluid concentrations for detection of osteochondral injury in the fetlock or carpal joint of racehorses. Analysis of serum and synovial SDF-1 concentrations in horses with experimentally induced joint injury may help define the onset and progression of post-traumatic osteoarthritis and aid in the evaluation of anti-inflammatory treatments.


Characterization of xanthophyll pigments, photosynthetic performance, photon energy dissipation, reactive oxygen species generation and carbon isotope discrimination during artemisinin-induced stress in Arabidopsis thaliana.
Artemisinin, a potent antimalarial drug, is phytotoxic to many crops and weeds. The effects of artemisinin on stress markers, including fluorescence parameters, photosystem II photochemistry, photon energy dissipation, lipid peroxidation, reactive oxygen species generation and carbon isotope discrimination in Arabidopsis thaliana were studied. Arabidopsis ecotype Columbia (Col-0) seedlings were grown in perlite and watered with 50% Hoagland nutrient solution. Adult plants of Arabidopsis were treated with artemisinin at 0, 40, 80, 160 μM for one week. Artemisinin, in the range 40-160 μM, decreased the fresh biomass, chl a, b and leaf mineral contents. Photosynthetic efficiency, yield and electron transport rate in Arabidopsis were also reduced following exposure to 80 and 160 μM artemisinin. The ΦNPQ and NPQ were less than control. Artemisinin treatment caused an increase in root oxidizability and lipid peroxidation (MDA contents) of Arabidopsis. Calcium and nitrogen contents decreased after 80 and 160 μM artemisinin treatment compared to control. δ13C values were less negative following treatment with artemisinin as compared to the control. Artemisinin also decreased leaf protein contents in Arabidopsis. Taken together, these data suggest that artemisinin inhibits many physiological and biochemical processes in Arabidopsis.


The internal structure of stopping as revealed by a sensory detection task.
An important aspect of everyday behaviour is the ability to cancel a prepared movement. In Experiment 1, subjects prepared a response, and then either executed it in response to a subsequent Go signal, or cancelled the movement if a NoGo signal occurred. Subjects had to detect weak shocks, which were delivered after the signals on some trials. Results were compared to a prior instruction condition in which subjects knew at the start of the trial if they should move or not. We found that detection rates on move trials were lower than on non-move trials, consistent with sensory suppression. There was no difference between conditions in detection for move trials. However, detection rates for non-move trials were significantly lower in the NoGo than in the prior instruction condition, suggesting an element of sensory suppression associated with actions, which are prepared, but then inhibited before execution. In Experiment 2, the delay between the NoGo signal and shock was varied. Detection rates improved monotonically as the interval increased from 0 up to 200 ms. The recovery from sensory suppression offers a new way of measuring the processes triggered by a NoGo signal. Our results suggest that when a prepared movement is inhibited the dismantling of the sensory consequences of the motor command takes at least 200 ms.


Hidden spontaneous polarisation in the chalcohalide photovoltaic absorber Sn2SbS2I3.
Perovskite-inspired materials aim to replicate the optoelectronic performance of lead-halide perovskites, while eliminating issues with stability and toxicity. Chalcohalides of group IV/V elements have attracted attention due to enhanced stability provided by stronger metal-chalcogen bonds, alongside compositional flexibility and ns2 lone pair cations - a performance-defining feature of halide perovskites. Following the experimental report of solution-grown tin-antimony sulfoiodide (Sn2SbS2I3) solar cells, with power conversion efficiencies above 4%, we assess the structural and electronic properties of this emerging photovoltaic material. We find that the reported centrosymmetric Cmcm crystal structure represents an average over multiple polar Cmc21 configurations. The instability is confirmed through a combination of lattice dynamics and molecular dynamics simulations. We predict a large spontaneous polarisation of 37 μC cm-2 that could be active for electron-hole separation in operating solar cells. We further assess the radiative efficiency limit of this material, calculating ηmax > 30% for film thicknesses t > 0.5 μm.


Effects of BMI, fat mass, and lean mass on asthma in childhood: a Mendelian randomization study.
Observational studies have reported associations between body mass index (BMI) and asthma, but confounding and reverse causality remain plausible explanations. We aim to investigate evidence for a causal effect of BMI on asthma using a Mendelian randomization approach. We used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ y in the Avon Longitudinal Study of Parents and Children (ALSPAC). A weighted allele score based on 32 independent BMI-related single nucleotide polymorphisms (SNPs) was derived from external data, and associations with BMI, fat mass, lean mass, and asthma were estimated. We derived instrumental variable (IV) estimates of causal risk ratios (RRs). 4,835 children had available data on BMI-associated SNPs, asthma, and BMI. The weighted allele score was strongly associated with BMI, fat mass, and lean mass (all p-values<0.001) and with childhood asthma (RR 2.56, 95% CI 1.38-4.76 per unit score, p = 0.003). The estimated causal RR for the effect of BMI on asthma was 1.55 (95% CI 1.16-2.07) per kg/m2, p = 0.003. This effect appeared stronger for non-atopic (1.90, 95% CI 1.19-3.03) than for atopic asthma (1.37, 95% CI 0.89-2.11) though there was little evidence of heterogeneity (p = 0.31). The estimated causal RRs for the effects of fat mass and lean mass on asthma were 1.41 (95% CI 1.11-1.79) per 0.5 kg and 2.25 (95% CI 1.23-4.11) per kg, respectively. The possibility of genetic pleiotropy could not be discounted completely; however, additional IV analyses using FTO variant rs1558902 and the other BMI-related SNPs separately provided similar causal effects with wider confidence intervals. Loss of follow-up was unlikely to bias the estimated effects. Higher BMI increases the risk of asthma in mid-childhood. Higher BMI may have contributed to the increase in asthma risk toward the end of the 20th century. Please see later in the article for the Editors' Summary.


Survival in the Rockies of an endangered hybrid swarm from diverged caribou (Rangifer tarandus) lineages.
In North America, caribou (Rangifer tarandus) experienced diversification in separate refugia before the last glacial maximum. Geographical isolation produced the barren-ground caribou (Rangifer tarandus groenlandicus) with its distinctive migratory habits, and the woodland caribou (Rangifer tarandus caribou), which has sedentary behaviour and is now in danger of extinction. Herein we report on the phylogenetics, population structure, and migratory habits of caribou in the Canadian Rockies, utilizing molecular and spatial data for 223 individuals. Mitochondrial DNA analyses show the occurrence of two highly diverged lineages; the Beringian-Eurasian and North American lineages, while microsatellite data reveal that present-day Rockies' caribou populations have resulted from interbreeding between these diverged lineages. An ice-free corridor at the end of the last glaciation likely allowed, for the first time, for barren-ground caribou to migrate from the North and overlap with woodland caribou expanding from the South. The lack of correlation between nuclear and mitochondrial data may indicate that different environmental forces, which might also include human-caused habitat loss and fragmentation, are currently reshaping the population structure of this postglacial hybrid swarm. Furthermore, spatial ecological data show evidence of pronounced migratory behaviour within the study area, and suggest that the probability of being migratory may be higher in individual caribou carrying a Beringian-Eurasian haplotype which is mainly associated with the barren-ground subspecies. Overall, our analyses reveal an intriguing example of postglacial mixing of diverged lineages. In a landscape that is changing due to climatic and human-mediated factors, an understanding of these dynamics, both past and present, is essential for management and conservation of these populations.


Three-dimensional force measurements with mandibular overdentures connected to implants by ball-shaped retentive anchors. A clinical study.
The purpose of this in vivo study was to determine maximum and functional forces simultaneously in three dimensions on mandibular implants supporting overdentures. The anchorage system for overdenture connection was the ball-shaped retentive anchor. Five edentulous patients, each with two mandibular ITI implants, were selected as test subjects. A novel miniaturized piezo-electric force transducer was developed for specific use with ITI implants. Force magnitudes and directions were registered under various test conditions by means of electrostatic plotter records. The test modalities were maximum biting in centric occlusion, maximum biting on a bite plate, grinding, and chewing bread. Maximum forces measured in centric occlusion and on the ipsilateral implant when using a bite plate were slightly increased in vertical and backward-forward dimension (z-, y-axis) compared to the lateral-medial direction (x-axis). On the contralateral implant, equally low values were found in all three dimensions. This may be the effect of a nonsplinted anchorage device. With the use of a bite plate, force magnitudes on the ipsilateral implant were significantly higher on the z- and y-axis than mean maximum forces in centric occlusion (P < .001). Chewing and grinding resulted in lower forces compared to maximum biting, particularly in the vertical direction. The transverse force component in backward-forward direction, however, reached magnitudes that exceeded the vertical component by 100% to 300% during chewing function. This chewing pattern had not been observed in previous investigations with bars and telescopes, and therefore appears to be specific for retentive ball anchors. The prevalent or exclusive force direction registered on both implants in the vertical direction was downward under all test conditions. In the transverse direction during maximum biting the forward direction was more frequently registered, while no obvious prevalence of transverse force direction was observed during chewing and grinding.


Central nervous system.
Several different types of tumors, benign and malignant, have been identified in the central nervous system (CNS). The prognoses for these tumors are related to several factors, such as the age of the patient and the location and histology of the tumor. In adults, about half of all CNS tumors are malignant, whereas in pediatric patients, more than 75% are malignant. For most benign CNS tumors that require treatment, neurosurgeons can offer curative resections or at least provide significant relief from mass effect. Unfortunately, we still lack effective treatments for most primary and secondary malignant CNS tumors. However, the past decade has witnessed an explosion in the understanding of the early molecular events in malignant primary CNS tumors, and for the first time in history, oncologists are seeing that a plethora of new therapies targeting these molecular events are being tested in clinical trials. There is hope on the horizon for the fight against these deadly tumors. The distribution of CNS tumors by location has remained constant for numerous years. The majority of primary CNS tumors arise in the major cortical lobes. Twenty nine percent of primary CNS tumors arise from the dural meninges that encase the CNS structures. The vast majority of these are meningiomas, of which over 90% are benign. About 10% of primary CNS tumors are found in the sella turcica region, where the pituitary gland resides. Other much less common sites of primary CNS tumors include the pineal region, ventricular system, cerebellum, brain stem, cranial nerves, and spinal cord. The distribution of CNS tumors by histology has seen a slight increase in more malignant tumors over the past decade, possibly due to increased neuroimaging practices or environmental exposures. Arising from glial cells, gliomas represent over 36% of all primary CNS tumors and consist of astrocytomas, oligodendrogliomas, ependymomas, mixed gliomas, and neuroepithelial tumors. The benign meningiomas make up 32% of primary CNS tumors, followed by nerve sheath tumors and pituitary tumors. Primary CNS lymphomas, embryonal tumors, and craniopharyngiomas are uncommon. The most common gliomas are astrocytomas, and these tumors are typically classified by the World Health Organization (WHO) as Grades I through IV. Grade IV, the most malignant grade of astrocytoma, includes glioblastoma multiforme (GBM), the most common malignant primary CNS glioma in adults, which represents 51% of all CNS gliomas. GBM is unfortunately the most challenging to effectively treat and has the worst patient survival. This chapter is therefore primarily devoted to the current understanding of this topic. Here we describe the molecular and cellular events associated with malignant glioma initiation and progression. We also review the importance of glioma stem cell biology and tumor immunology in early gliomagenesis. In addition, we present a brief description of the most common malignant primary CNS glioma in pediatric patients - medulloblastoma, as well as familial cancer syndromes that include gliomas as part of the syndrome.


Pak1 as a novel therapeutic target for antihypertrophic treatment in the heart.
Stress-induced hypertrophic remodeling is a critical pathogenetic process leading to heart failure. Although many signal transduction cascades are demonstrated as important regulators to facilitate the induction of cardiac hypertrophy, the signaling pathways for suppressing hypertrophic remodeling remain largely unexplored. In this study, we identified p21-activated kinase 1 (Pak1) as a novel signaling regulator that antagonizes cardiac hypertrophy. Hypertrophic stress applied to primary neonatal rat cardiomyocytes (NRCMs) or murine hearts caused the activation of Pak1. Analysis of NRCMs expressing constitutively active Pak1 or in which Pak1 was silenced disclosed that Pak1 played an antihypertrophic role. To investigate the in vivo role of Pak1 in the heart, we generated mice with a cardiomyocyte-specific deletion of Pak1 (Pak1(cko)). When subjected to 2 weeks of pressure overload, Pak1(cko) mice developed greater cardiac hypertrophy with attendant blunting of JNK activation compared with controls, and these knockout mice underwent the transition into heart failure when prolonged stress was applied. Chronic angiotensin II infusion also caused increased cardiac hypertrophy in Pak1(cko) mice. Moreover, we discovered that the Pak1 activator FTY720, a sphingosine-like analog, was able to prevent pressure overload-induced hypertrophy in wild-type mice without compromising their cardiac functions. Meanwhile, FTY720 failed to exert such an effect on Pak1(cko) mice, suggesting that the antihypertrophic effect of FTY720 likely acts through Pak1 activation. These results, for the first time, establish Pak1 as a novel antihypertrophic regulator and suggest that it may be a potential therapeutic target for the treatment of cardiac hypertrophy and heart failure.