Transcriptomics of dorso-ventral axis determination in Xenopus tropicalis.
Amphibian embryos provide a powerful system to study early cell fate determination because their eggs are externally fertilised, large, and easy to manipulate. Ultraviolet (UV) or lithium chloride (LiCl) treatment are classic embryonic manipulations frequently used to perturb specification of the dorso-ventral (DV) axis by affecting the stability of the maternal Wnt mediator β-catenin. Such treatments result in the formation of so-called ventralised or dorsalised embryos. Although these phenotypes have been well described with respect to their morphology and some aspects of gene expression, their whole transcriptomes have never been systematically characterised and compared. Here we show that at the early gastrula stage UV-treated embryos are transcriptionally more closely related to untreated embryos than to LiCl-treated embryos. Transcriptional comparisons with dissected ventral and dorsal regions of unperturbed gastrula embryos indicate that UV and LiCl treatments indeed enrich for ventral and dorsal cells, respectively. However, these treatments also affect the balance of neural induction in the ectodermal germ layer, with LiCl stimulating pro-neural BMP inhibition and UV preferentially generating epidermis because of elevated BMP levels. Thus the transcriptomes of UV- and LiCl-treated embryos can best be described as ventro-epidermalised and dorso-neuralised. These descriptions notwithstanding, our profiling reveals several hitherto uncharacterized genes with differential expression along the DV axis. At least one of these genes, a RNF220-like ubiquitin ligase, is activated dorsally by β-catenin. Our analysis of UV/LiCl-mediated axis perturbation will enhance the mechanistic understanding of DV axis determination in vertebrates.


Intermittent preventive treatment with sulfadoxine-pyrimethamine does not modify plasma cytokines and chemokines or intracellular cytokine responses to Plasmodium falciparum in Mozambican children.
Cytokines and chemokines are key mediators of anti-malarial immunity. We evaluated whether Intermittent Preventive Treatment in infants with Sulfadoxine-Pyrimethamine (IPTi-SP) had an effect on the acquisition of these cellular immune responses in Mozambican children. Multiple cytokines and chemokines were quantified in plasma by luminex, and antigen-specific cytokine production in whole blood was determined by intracellular cytokine staining and flow cytometry, at ages 5, 9, 12 and 24 months. IPTi-SP did not significantly affect the proportion of CD3+ cells producing IFN-γ, IL-4 or IL-10. Overall, plasma cytokine or chemokine concentrations did not differ between treatment groups. Th1 and pro-inflammatory responses were higher than Th2 and anti-inflammatory responses, respectively, and IFN-γ:IL-4 ratios were higher for placebo than for SP recipients. Levels of cytokines and chemokines varied according to age, declining from 5 to 9 months. Plasma concentrations of IL-10, IL-12 and IL-13 were associated with current infection or prior malaria episodes. Higher frequencies of IFN-γ and IL-10 producing CD3+ cells and elevated IL-10, IFN-γ, MCP-1 and IL-13 in plasma were individually associated with increased malaria incidence, at different time points. When all markers were analyzed together, only higher IL-17 at 12 months was associated with lower incidence of malaria up to 24 months. Our work has confirmed that IPTi-SP does not negatively affect the development of cellular immune response during early childhood. This study has also provided new insights as to how these cytokine responses are acquired upon age and exposure to P. falciparum, as well as their associations with malaria susceptibility. ClinicalTrials.gov: NCT00209795.


Effects of a synthetic facial pheromone on behavior of cats.
TO evaluate the effects of a synthetic feline facial pheromone (FFP) on behavior and food intake of healthy versus clinically ill cats. Original study. 20 cats were used in each of 2 studies. In each study, 7 cats were considered healthy, and 13 cats were determined to be clinically ill. In study 1, cats were assigned either to exposure to FFP (treated group; 4 healthy, 6 ill cats) or to exposure to the vehicle (70% ethanol solution; control group; 3 healthy, 7 ill cats). Cats were placed in a cage containing a small cotton towel that had been sprayed with FFP or vehicle 30 minutes previously. Cats were then videotaped for 125 minutes, and food intake was measured during this period. Videotapes were scored at 5-minute intervals for various behaviors. In study 2, cats were categorized in 1 of 2 groups; group 1 (2 healthy, 8 ill cats) had a cat carrier placed in their cages, and group 2 (5 healthy, 5 ill cats) did not. All cats were exposed to FFP, and 24-hour food intake was measured. Differences between behaviors of healthy versus clinically ill cats were not identified. In the first study, significant increases in grooming and interest in food were found in cats exposed to FFP compared with vehicle. For all cats, significant positive correlations were detected between grooming and facial rubbing, walking and facial rubbing, interest in food and facial rubbing, eating and facial rubbing, grooming and interest in food, and grooming and eating. In the second study, 24-hour food intake was significantly greater in cats exposed to FFP and the cat carrier, compared with cats exposed to FFP alone. Results suggest that exposure to FFP may be useful to increase food intake of hospitalized cats.


Dynamics of Ca2+ and guanosine 5'-[gamma-thio]triphosphate action on insulin secretion from alpha-toxin-permeabilized HIT-T15 cells.
The time course of Ca2+ and GTP-analogue effects on insulin secretion was investigated in HIT-T15 cells permeabilized with Staphylococcus alpha-toxin. These cells responded to Ca2+ in the range 0.1-10 microM and could be used in a dynamic perifusion system because of the minimal run-down of the secretory response. High Ca2+ (10 microM) elicited a monophasic ATP-dependent stimulation of insulin secretion that reached a peak within 5 min (approximately 20-fold increase) and rapidly decreased during the subsequent 15 min to a plateau remaining above basal rates (0.1 microM Ca2+). The decrease in Ca(2+)-induced insulin secretion with time could not be attributed to decreased capacity to respond to Ca2+ after prolonged perfusion at low Ca2+ (run-down), nor to depletion of a particular secretory-granule pool. It was rather due to desensitization of the secretory machinery to Ca2+ that was not reversed by selective inhibition of the Ca2+/calmodulin-dependent kinase II with KN-62. However, an intermediate Ca2+ concentration (2 microM) increased insulin secretion to stable level without causing any desensitization. Imposed oscillations of Ca2+ (0.1-10 microM) produced phasic oscillations of insulin secretion, but did not prevent desensitization to Ca2+. Poorly hydrolysable GTP analogues increased insulin secretion at low Ca2+, whereas they strongly inhibited Ca(2+)-induced insulin secretion. By contrast, GTP did not affect basal secretion, and slightly increased Ca(2+)-evoked secretion. These results indicate the following. (1) Oscillations of insulin secretion are tightly coupled to cytosolic Ca2+ oscillations. (2) Oscillations of Ca2+ do not prevent high-Ca(2+)-induced desensitization to Ca2+; this result does not support the idea of a greater efficiency of oscillations compared with sustained Ca2+ rises in triggering exocytosis. (3) Activation of G-proteins modulates exocytosis in a bimodal manner.


De novo assembly of the perennial ryegrass transcriptome using an RNA-Seq strategy.
Perennial ryegrass is a highly heterozygous outbreeding grass species used for turf and forage production. Heterozygosity can affect de-Bruijn graph assembly making de novo transcriptome assembly of species such as perennial ryegrass challenging. Creating a reference transcriptome from a homozygous perennial ryegrass genotype can circumvent the challenge of heterozygosity. The goals of this study were to perform RNA-sequencing on multiple tissues from a highly inbred genotype to develop a reference transcriptome. This was complemented with RNA-sequencing of a highly heterozygous genotype for SNP calling. De novo transcriptome assembly of the inbred genotype created 185,833 transcripts with an average length of 830 base pairs. Within the inbred reference transcriptome 78,560 predicted open reading frames were found of which 24,434 were predicted as complete. Functional annotation found 50,890 transcripts with a BLASTp hit from the Swiss-Prot non-redundant database, 58,941 transcripts with a Pfam protein domain and 1,151 transcripts encoding putative secreted peptides. To evaluate the reference transcriptome we targeted the high-affinity K+ transporter gene family and found multiple orthologs. Using the longest unique open reading frames as the reference sequence, 64,242 single nucleotide polymorphisms were found. One thousand sixty one open reading frames from the inbred genotype contained heterozygous sites, confirming the high degree of homozygosity. Our study has developed an annotated, comprehensive transcriptome reference for perennial ryegrass that can aid in determining genetic variation, expression analysis, genome annotation, and gene mapping.


Tutorial on removing the shackles of regression analysis: How to stay true to your theory of binary response probabilities.
Statistical analyses of data often add some additional constraints to a theory and leave out others, so as to convert the theory into a testable hypothesis. In the case of binary data, such as yes/no responses, or such as the presence/absence of a symptom or a behavior, theories often actually predict that certain response probabilities change monotonically in a specific direction and/or that certain response probabilities are bounded from above or below in specific ways. A regression analysis is not really true to such a theory in that it may leave out parsimonious constraints and in that extraneous assumptions like linearity or log-linearity, or even the assumption of a functional relationship, are dictated by the method rather than the theory. That mismatch may well bias the results of empirical analysis and jeopardize attempts at meaningful replication of psychological research. This tutorial shows how contemporary order-constrained methods can shed more light on such questions, using far weaker auxiliary assumptions, while also formulating more detailed, nuanced, and concise hypotheses, and allowing for quantitative model selection. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


On the origin of vanillyl alcohol oxidases.
Vanillyl alcohol oxidase (VAO) is a fungal flavoenzyme that converts a wide range of para-substituted phenols. The products of these conversions, e.g. vanillin, coniferyl alcohol and chiral aryl alcohols, are of interest for several industries. VAO is the only known fungal member of the 4-phenol oxidising (4PO) subgroup of the VAO/PCMH flavoprotein family. While the enzyme has been biochemically characterised in great detail, little is known about its physiological role and distribution in fungi. We have identified and analysed novel, fungal candidate VAOs and found them to be mostly present in Pezizomycotina and Agaricomycotina. The VAOs group into three clades, of which two clades do not have any characterised member. Interestingly, bacterial relatives of VAO do not form a single outgroup, but rather split up into two separate clades. We have analysed the distribution of candidate VAOs in fungi, as well as their genomic environment. VAOs are present in low frequency in species of varying degrees of relatedness and in regions of low synteny. These findings suggest that fungal VAOs may have originated from bacterial ancestors, obtained by fungi through horizontal gene transfer. Because the overall conservation of fungal VAOs varies between 60 and 30% sequence identity, we argue for a more reliable functional prediction using critical amino acid residues. We have defined a sequence motif P-x-x-x-x-S-x-G-[RK]-N-x-G-Y-G-[GS] that specifically recognizes 4PO enzymes of the VAO/PCMH family, as well as additional motifs that can help to further narrow down putative functions. We also provide an overview of fingerprint residues that are specific to VAOs.


Quantitation and prediction of sorptive losses during toxicity testing of polycyclic aromatic hydrocarbon (PAH) and nitrated PAH (NPAH) using polystyrene 96-well plates.
Developing zebrafish are increasingly being used for rapid assessments of chemical toxicity, and these assays are frequently conducted in multi-well plastic plates. This study investigated the sorptive behavior of polycyclic aromatic hydrocarbons (PAHs) and nitrated PAHs (NPAHs) to uncoated 96-well polystyrene plates typically used for zebrafish (Danio rerio) testing. We measured the percent sorption in the presence and absence of zebrafish embryos, at two exposure concentrations, as well as using two different procedures (addition of embryos to polystyrene plates either before analyte addition, or allowing 24h of equilibrium between analyte addition and embryo addition to the polystyrene plates). Following exposure, the plates were extracted with hexane and analyzed using gas chromatography coupled with mass spectrometry (GC/MS). Allowing 24h of pre-incubation between the addition of analytes and embryos did not significantly impact the percent sorption. The percent sorption was higher for both PAHs and NPAHs at the lower exposure concentration, and sorption was lower in the presence of zebrafish embryos. A mass balance model was developed to predict the sorption to polystyrene plates, based on the PAH and NPAH mass distribution ratios between polystyrene and water. While PAH sorption was significantly correlated with subcooled liquid solubility, NPAH sorption did not correlate with any of the physical-chemical properties investigated. This indicates the need to better understand the sorptive behavior of hydrophobic analytes to plastics, and to better account for sorptive losses during toxicity testing in polystyrene plates.


Nicotinic stomatitis: positive correlation with heat in maté tea drinks and smoking.
The etiology of nicotinic stomatitis is strongly linked with nicotine compounds; however, high temperature can be synergistic to the damage of tobacco compounds. The aim of the present study was to evaluate the separate and combined effects of smoking and heat applied by hot drinks as predictors for the development of nicotinic stomatitis in a population from southern Brazil. In a case-control study, 53 patients of both sexes with a median age of 43 years (18 to 83 years) with the clinical diagnosis of nicotinic stomatitis were selected consecutively. They were paired with 53 control subjects, matched for sex, race, and smoking and tea, maté (chimarrão), alcohol, and coffee consumption. The collected data were analyzed by means of descriptive statistics; chi-square test and risk estimation were also employed. The independent variables considered significant were analyzed using a multivariate model of multinomial logistic regression (P < .05 was considered statistically significant). Nicotinic stomatitis was more prevalent in smokers (60.00%) than nonsmokers (39.21%) (OR = 2.32; CI 95% 1.06-5.06), and in subjects who drank hot drinks (maté drink and regular tea or coffee) than in subjects who did not drink this combination (OR = 2.84; CI 95% 1.05-7.63). The combination of smoking and heat from hot drinks could best predict the appearance of nicotinic stomatitis.


Cryo-electron tomography reveals conserved features of doublet microtubules in flagella.
The axoneme forms the essential and conserved core of cilia and flagella. We have used cryo-electron tomography of Chlamydomonas and sea urchin flagella to answer long-standing questions and to provide information about the structure of axonemal doublet microtubules (DMTs). Solving an ongoing controversy, we show that B-tubules of DMTs contain exactly 10 protofilaments (PFs) and that the inner junction (IJ) and outer junction between the A- and B-tubules are fundamentally different. The outer junction, crucial for the initiation of doublet formation, appears to be formed by close interactions between the tubulin subunits of three PFs with unusual tubulin interfaces; other investigators have reported that this junction is weakened by mutations affecting posttranslational modifications of tubulin. The IJ consists of an axially periodic ladder-like structure connecting tubulin PFs of the A- and B-tubules. The recently discovered microtubule inner proteins (MIPs) on the inside of the A- and B-tubules are more complex than previously thought. They are composed of alternating small and large subunits with periodicities of 16 and/or 48 nm. MIP3 forms arches connecting B-tubule PFs, contrary to an earlier report that MIP3 forms the IJ. Finally, the "beak" structures within the B-tubules of Chlamydomonas DMT1, DMT5, and DMT6 are clearly composed of a longitudinal band of proteins repeating with a periodicity of 16 nm. These findings, discussed in relation to genetic and biochemical data, provide a critical foundation for future work on the molecular assembly and stability of the axoneme, as well as its function in motility and sensory transduction.


Structure of human serum lipoproteins: nuclear magnetic resonance supports a micellar model.
High-resolution proton nuclear magnetic resonance spectra of low- and high-density lipoproteins from human serum closely resemble those of dispersions of lipoprotein lipids in water. Linewidths of hydrocarbon proton absorptions are not increased in the lipoproteins. In contrast, apolar binding of lysolecithin on serum albumin causes extensive line-broadening and an upfield chemical shift of the hydrocarbon proton resonances of lysolecithin. The results are consistent with a predominantly micellar structure for the lipoproteins rather than with extensive hydrophobic association of lipid and protein.


[Eating disorders (II)--dental aspects].
Patients suffering from eating disorders exhibit oral symptoms indicative to the otherwise concealed illness. The most striking features are the intrinsic erosions due to the regular surreptitious vomiting. They occur in very typical locations within the dental arches and have been termed "perimolysis". Dental professionals are often the first to discover and diagnose eating disorders by detecting perimolysis and consequently face the difficult task to motivate the patients--who often deny their illness--to seek psychiatric help and dental care. Such motivation must be done while respecting the patients' integrity and sense of self-worth. The primary goal of dental care is to preserve the remaining teeth and to prevent further erosive loss of dental hard tissue. The key elements of a dental preventive programme based on pathophysiologic grounds are to enhance local defence mechanisms, to offer chemical and mechanical protection and to diminish abrasive and erosive challenges. Dental restorative therapy must be part of a combined medical and dental treatment plan and should not be started before the eating disorder has been treated and the patients are considered to have stable prognosis. In view of the young age of the patients, the large extension of the erosive lesions and in order to avoid endodontological treatment of mostly sound pulps, non-invasive restorative concepts using adhesive technology should be preferably used. Prophylactic measures and restorative treatment are covered by health insurance (KGV; KLV 18c, 7) if the patients undergo psychiatric or similar adequate treatment.


Improvement in Cognition Following Double-Blind Randomized Micronutrient Interventions in the General Population.
The impact of poor nutrition on physiological health is well understood (Costarelli et al., 2013). Less is known about the effects of diet on brain function and cognition in the general population (Ames, 2010; Parletta et al., 2013; White et al., 2017) and we are still in the early stages of understanding the role of specific nutrients to normal and pathological neuronal functioning. In the present study, the putative effect of a multivitamin/mineral or vitamin D supplement on cognitive function over an 8-week period was compared with volunteers taking vitamin C. Healthy adults (N = 60) were recruited, age range 21-59 years ( x ¯ = 39.07 years, SD = 11.46), with participants randomly allocated to conditions in a double-blind protocol. Participants also completed a 14-day food diary to gather information on micronutrient intake. The cognitive test battery included measures from the Wechsler Adult Intelligence Scale-III (WAIS-III; Wechsler et al., 2008), Wechsler Memory Scale-IV (WMS-IV; Wechsler, 2009) and Delis-Kaplan Executive Function System (D-KEFS; Delis et al., 2001), along with the Doors and People (Baddeley et al., 1994) and a serial reaction time task. Analyses showed better performance on some tasks in all groups following the intervention period, notably on measures of verbal and visual memory and visuomotor processing speed. The Multivitamin group showed significant improvements on tasks of visual strategy generation (along with the Vitamin C group), motor planning, explicit and implicit learning, and working memory. This evidence suggests that sub-optimal micronutrient intake may have a negative effect on cognition across the lifespan.


Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study.
Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown antitumour activity in patients with advanced pancreatic neuroendocrine tumours. We aimed to assess the combination of everolimus plus octreotide long-acting repeatable (LAR) in patients with low-grade or intermediate-grade neuroendocrine tumours (carcinoid). We did a randomised, double-blind, placebo-controlled, phase 3 study comparing 10 mg per day oral everolimus with placebo, both in conjunction with 30 mg intramuscular octreotide LAR every 28 days. Randomisation was by interactive voice response systems. Participants were aged 18 years or older, with low-grade or intermediate-grade advanced (unresectable locally advanced or distant metastatic) neuroendocrine tumours, and disease progression established by radiological assessment within the past 12 months. Our primary endpoint was progression-free survival. Adjusted for two interim analyses, the prespecified boundary at final analysis was p≤0·0246. This study is registered at ClinicalTrials.gov, number NCT00412061. 429 individuals were randomly assigned to study groups; 357 participants discontinued study treatment and one was lost to follow-up. Median progression-free survival by central review was 16·4 (95% CI 13·7-21·2) months in the everolimus plus octreotide LAR group and 11·3 (8·4-14·6) months in the placebo plus octreotide LAR group (hazard ratio 0·77, 95% CI 0·59-1·00; one-sided log-rank test p=0·026). Drug-related adverse events (everolimus plus octreotide LAR vs placebo plus octreotide LAR) were mostly grade 1 or 2, and adverse events of all grades included stomatitis (62%vs 14%), rash (37%vs 12%), fatigue (31%vs 23%), and diarrhoea (27%vs 16%). Everolimus plus octreotide LAR, compared with placebo plus octreotide LAR, improved progression-free survival in patients with advanced neuroendocrine tumours associated with carcinoid syndrome. Novartis Pharmaceuticals.


Scale for Space and Time Experience in Psychosis: Converging Phenomenological and Psychopathological Perspectives.
Abnormalities in the experience of space and time are fundamental to understanding schizophrenia spectrum disorders, but the precise relation between such abnormalities and psychopathological symptoms is still unclear. Therefore, the aim of our study was to introduce a novel scale for space and time experience in psychosis (STEP), specifically devised to assess schizophrenia spectrum disorders. The STEP scale is a semiquantitative instrument developed on the basis of several items from previous scales and phenomenological reports addressing the experience of space and time. We applied the STEP scale to three groups of subjects (patients with schizophrenia spectrum disorders, patients with predominant affective symptoms, and healthy control subjects), to whom we also applied other more general psychopathological scales, such as the Positive and Negative Syndrome Scale and the Ego-Psychopathology Inventory. Patients with schizophrenia spectrum disorders scored significantly higher on general psychopatho<X00_Del_TrennDivis>--</X00_Del_TrennDivis>logical scales relative to subjects belonging to the other groups. The STEP scale provided good psychometric properties regarding reliability. We also tested convergent and divergent validity of the STEP scale and found that space and time subscale scores of STEP significantly correlated with each other, as well as with the remaining general psychopathological scores. We introduced the STEP scale as a novel instrument for the assessment of experience of space and time. Its psychometric properties showed high validity and reliability to identify psychopathological symptoms and enabled to differentiate patients with predominantly psychotic symptoms from those with predominantly affective symptoms. The STEP scale provides a standardized measure for assessing disturbances in the experience of space and time. Furthermore, it probably represents a leap forward toward the establishment of an additional dimension of symptoms proposed as "spatiotemporal psychopathology."


White tea - A cost effective alternative to EGCG in fight against benzo(a)pyrene (BaP) induced lung toxicity in SD rats.
Tea is a natural resource of catechins and exhibits antioxidative and anticancer activities. This study was designed to elucidate the comparative efficacy of white tea and pure EGCG in containing benzo (a) pyrene (BaP)-induced pulmonary stress. Rats were treated with white tea extract (WT) (1%) and pure EGCG at a dose of 80μg/ml in drinking water on alternate days for 12 weeks (4 weeks prior, during and after BaP treatment). BaP(50 mg/kg b. wt) was administered to rats orally in olive oil twice a week for four weeks. The indices such as stress biomarkers (LPO, PCC & ROS), antioxidant enzymes (SOD, CAT, GSH, GST, GR, GPx) activities and lung histoarchitecture were assessed. BaP administration enhanced the levels of inflammatory markers (NO and citrulline) and reduced activities of antioxidant enzymes. We observed similar antioxidant efficacy by both WT and EGCG as seen by their ameliorative action in restoring BaP induced oxidative and inflammatory stress as well as lung histoarchitecture. Our findings suggest that WT is equally beneficial as EGCG in maintaining the integrity of alveoli and is a potential candidate to be used as a cost effective and protective agent in conditions of BaP-induced lung damage.


Formation Mechanism and Cohesive Energy Analysis of Metal-Coated Graphene Nanocomposites Using In-Situ Co-Reduction Method.
Nanocomposite powders based on metal-coated graphene were synthesized using an in-situ co-reduction method in order to improve wettability and interfacial bonding between graphene and metal. Graphene oxide (GO) of 2~3 atomic layers was synthesized using the Hummer's method with graphite as a raw material and then dispersed into a dispersing agent solution mixed with N-Methyl pyrrolidone and deionized water to form a homogeneous GO suspension, which was finally added into electroless plating solutions for the reduction process. Copper-coated graphene (Cu@graphene) and nickel-coated graphene (Ni@graphene) were synthesized using this one-step and co-reduction method by mixing salt solutions containing metal ions and GOs into the plating solution. The Cu ions or Ni ions were adsorbed and bonded onto the edges and surfaces of graphene, which was reduced from the GOs using a strong reducing agent of ascorbic acid or sodium borohydride. Crystalline Cu particles with an average size of about 200 nm were formed on the surface of graphene, whereas amorphous or nanocrystalline Ni particles with an average size of 55 nm were formed on the surface of graphene. Distribution of these metal particles on the graphene is homogeneous and highly dispersed, which can effectively improve the sinterability of composite powders. Cohesive energy distribution between graphene and metal interface was analyzed using first-principle calculation method. Formation mechanism of metal coated graphene was identified to be that both the GO and metal ions were simultaneously reduced in the reducing agents and thus a chemical bonding of graphene/metal was formed between the metal particles and graphene.


Pancreatic Cancer-Induced Cachexia and Relevant Mouse Models.
Pancreatic cancer is the third leading cause of cancer death in the United States, with projections that it will become the second leading cause by the year 2030. It carries a dismal prognosis with a 5-year overall survival rate of less than 9% and is associated with numerous comorbidities, the most notable being cachexia. Defined as the loss of muscle mass not reversible by conventional nutritional support, cachexia is seen in over 85% of pancreatic cancer patients and contributes significantly to mortality, where nearly 30% of pancreatic cancer deaths are due to cachexia rather than tumor burden. Therefore, there is an urgent need to identify the mechanisms behind the development of muscle wasting in pancreatic cancer patients and design novel therapeutics targeting cachexia. This review highlights the current understanding surrounding the mechanisms underpinning the development of cachexia in pancreatic cancer, as well as the current mouse models of pancreatic cancer-induced muscle wasting described in the literature.


Associations between urinary organophosphate pesticide metabolite levels and reproductive parameters in men from an infertility clinic.
Organophosphate (OP) pesticides are compounds used for pest control at home or in agriculture activities. Almost all OP pesticides are metabolized to at least one of six possible dialkylphosphates (DAPs). Despite wide use, their potential effects on human reproductive health have not yet been fully characterized. The aim of this study was to evaluate the associations between urinary concentrations of six DAP metabolites and reproductive parameters in men. All men were attended an infertility clinic and provided urine, serum and semen samples on the same day. Six DAP metabolites were measured in urine (dimethylphosphate [DMP], dimethylthiophosphate [DMTP], dimethyldithiophosphate [DMDTP], diethylphosphate [DEP], diethylthiophosphate [DETP], and diethyldithiophosphate [DEDTP]). Sperm quality was assessed by measuring volume, concentration, total sperm count (TSC), motility and morphology, and serum samples were analyzed for reproductive hormones, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, prolactin and estradiol. Pearson correlations were used for unadjusted analyses, and multiple linear regression analysis was performed controlling for appropriate covariates. All men presented detectable concentrations of at least one urinary OP metabolite. After adjustment by important covariates, there was a significant positive association between DEDTP concentrations and LH [(β)=11.4; 95% CI 0.81-22.1] as well as FSH levels [(β)=3.2; 95% CI 0.08-6.2]. Sperm concentration and TSC were both significantly inversely associated with DMP, DMDP, DMDTP and ∑DAP in multivariate analysis. Besides, there was a significant inverse association between percentage of motile sperm and DMTP, DMDTP and DEP metabolite concentrations. Our results suggest that exposure to OP pesticides may be associated with decreased sperm counts and motility and altered reproductive hormone levels in male partners of couples seeking for infertility treatment. However, further studies are warranted to confirm and extent these findings.


Review of the first year of an overseas military gambling treatment program.
This study provides descriptive information and preliminary first-year outcome data on the only overseas military gambling treatment option currently available. Implemented in January 2003 within the Substance Abuse Rehabilitation Program, U.S. Naval Hospital, Okinawa, Japan, gambling treatment was developed as a specific track within the overall substance abuse program. The present study explores the various considerations and requirements for setting up such a program, as well as a description of individuals seeking gambling treatment and preliminary outcome data. Participants consisted of all gambling referrals (N = 35, 26 males; mean age, 33.2 years; SD = 8.93) obtained over the first year that gambling services were offered. A significant degree of depression, suicidality, and substance abuse problems were observed in the sample. Results revealed that the gambling program was easily implemented within an established substance abuse program. The program was effective in preventing suicides in both military members and eligible beneficiaries and was effective in facilitating the retention of military members with gambling problems.


Body Mass Index Is Prognostic in Metastatic Colorectal Cancer: Pooled Analysis of Patients From First-Line Clinical Trials in the ARCAD Database.
In recent retrospective analyses of early-stage colorectal cancer (CRC), low and high body mass index (BMI) scores were associated with worsened outcomes. Whether BMI is a prognostic or predictive factor in metastatic CRC (mCRC) is unclear. Individual data from 21,149 patients enrolled onto 25 first-line mCRC trials during 1997 to 2012 were pooled. We assessed both prognostic and predictive effects of BMI on overall survival and progression-free survival, and we accounted for patient and tumor characteristics and therapy type (targeted v nontargeted). BMI was prognostic for overall survival (P < .001) and progression-free survival (P < .001), with an L-shaped pattern. That is, risk of progression and/or death was greatest for low BMI; risk decreased as BMI increased to approximately 28 kg/m(2), and then it plateaued. Relative to obese patients, patients with a BMI of 18.5 kg/m(2) had a 27% increased risk of having a PFS event (95% CI, 20% to 34%) and a 50% increased risk of death (95% CI, 43% to 56%). Low BMI was associated with poorer survival for men than women (interaction P < .001). BMI was not predictive of treatment effect. Low BMI is associated with an increased risk of progression and death among the patients enrolled on the mCRC trials, with no increased risk for elevated BMI, in contrast to the adjuvant setting. Possible explanations include negative effects related to cancer cachexia in patients with low BMI, increased drug delivery or selection bias in patients with high BMI, and potential for an interaction between BMI and molecular signaling pathways.


Construction of rice chromosome segment substitution lines harboring Oryza barthii genome and evaluation of yield-related traits.
Rice (Oryza sativa L.) is one of the most important staple food in the world. To meet the increasing demand for food, a strategy for improving rice yield is needed. Alleles of wild relatives are useful because they confer adaptation to plants under diverse harsh environments and have the potential to improve rice. O. barthii is a wild rice species endemic to Africa and the known progenitor of the African cultivated rice, O. glaberrima. To explore the genetic potential of the O. barthii as a genetic resource, 40 chromosome segment substitution lines (CSSL) of O. barthii in the background of the elite japonica cultivar Koshihikari were developed and evaluated to identify QTLs associated with 10 traits related to flag leaf morphology, grain yield and other agronomic traits. More than 90% of the entire genome of the donor parent was represented in contiguous or overlapping chromosome segments in the CSSLs. Evaluation of the CSSLs for several agriculturally important traits identified candidate chromosome segments that harbors QTLs associated with yield and yield-related traits. These results suggest that alleles from O. barthii might be used as a novel genetic resource for improving the yield-related traits in cultivars of O. sativa.


Recovering sound sources from embedded repetition.
Cocktail parties and other natural auditory environments present organisms with mixtures of sounds. Segregating individual sound sources is thought to require prior knowledge of source properties, yet these presumably cannot be learned unless the sources are segregated first. Here we show that the auditory system can bootstrap its way around this problem by identifying sound sources as repeating patterns embedded in the acoustic input. Due to the presence of competing sounds, source repetition is not explicit in the input to the ear, but it produces temporal regularities that listeners detect and use for segregation. We used a simple generative model to synthesize novel sounds with naturalistic properties. We found that such sounds could be segregated and identified if they occurred more than once across different mixtures, even when the same sounds were impossible to segregate in single mixtures. Sensitivity to the repetition of sound sources can permit their recovery in the absence of other segregation cues or prior knowledge of sounds, and could help solve the cocktail party problem.


Prevalence of rheumatic symptoms, rheumatoid arthritis, ankylosing spondylitis, and gout in Shanghai, China: a COPCORD study.
To carry out a cross-sectional survey on prevalence of musculoskeletal symptoms, rheumatoid arthritis (RA), ankylosing spondylitis (AS), and gout. In Shanghai, 4 communities comprising 7603 inhabitants over 15 years of age in an urban population were randomly selected from 13 communities. Interviews were conducted from September 1997 to March 1998 by trained physicians using the COPCORD Core Questionnaire. Physical and radiographic examinations and serologic tests were carried out when required to classify categories of rheumatic diseases. The diagnoses of RA, systemic lupus erythematosus (SLE), and gout were based on American Rheumatism Association criteria. The diagnosis of AS strictly followed the modified New York criteria of 1984. Crude prevalence rates were standardized according to a standard Chinese population for age and sex structure. A total of 6584 adults (3394 women, 3190 men) were interviewed, and response rate was 86.6%. The age and sex standardized prevalence rate of rheumatic symptoms at any site amounted to 13.3% (95% CI 12.5-14.1%). Symptoms occurred more frequently in the following sites: knee 7.0% (95% CI 6.4-7.6%), lower back 5.6% (95% CI 5.0-6.2%), shoulder 4.7% (95% CI 4.2-5.2%), and neck 2.4% (95% CI 2.0-2.8%). Women complained of rheumatic symptoms more frequently than men. The standardized rates of RA, AS, gout, symptomatic knee osteoarthritis, and soft tissue rheumatism were 0.28% (95% CI 0.15-0.41%), 0.11% (95% CI 0.03-0.19%), 0.22% (95% CI 0.11-0.33%), 4.1% (95% CI 3.6-4.6%), and 3.4% (95% CI 3.0-3.8%), respectively. Two cases of SLE, one case of dermatomyositis, and one case of systemic sclerosis were found. Compared with rates in European and Western countries the prevalence rates of RA, AS, and gout are low in Shanghai, China, although the prevalence rates of rheumatic symptoms are high.


Autologous blood versus fibrin glue for conjunctival autograft adherence in sutureless pterygium surgery: a randomised controlled trial.
To assess the efficacy of securing conjunctival autograft (CAG) without glue or sutures, using the patient's own blood at the surgical site, and to compare it with the current accepted standard of using fibrin glue for graft adherence, in pterygium surgery. A single-centre, prospective, randomised controlled trial was carried out in 200 eyes of patients with primary pterygia who were advised pterygium excision with CAG. Enrolled participants were assigned to Group I or II by randomisation. After excision of pterygium, they underwent CAG with autologous blood in Group I (100 eyes) and CAG with fibrin glue in Group II (100 eyes). During follow-up of 1 year, the eyes were assessed for graft adherence and recurrence. Of the 200 eyes randomised, 6 eyes that did not complete intended follow-up were excluded from final analysis. Of the 194 eyes (Group I n=96, Group II n=98), on the first postoperative day, 3 eyes in Group I (3.13%) had total graft dislodgement requiring regrafting from another site or reattachment with glue. In Group II also 2 eyes (2.04%) had graft dislodgement on the first postoperative day requiring regrafting from another site. During the 1-year follow-up, 6 eyes in Group I (6.25%) and 8 eyes in Group II (8.16%) developed recurrence. Feasibilty of adherence of the graft without glue in pterygium surgery is promising and has results comparable with the fibrin glue technique in terms of long-term outcome and recurrence, suggesting the potential for autologous blood to replace fibrin glue in graft fixation. Clinical Trial Registry, India: CTRI/2013/06/003764 and UTN: U1111-1140-6572.


Clinical and prognostic significance of elevated ferritin levels in hospitalised adults.
Elevated ferritin levels are associated with a variety of infectious, malignant and inflammatory diseases. We aimed to investigate the prognostic value of markedly elevated ferritin levels in hospitalised patients with various medical conditions. Retrospective analysis of patients with a ferritin level higher than 2000 ng/mL hospitalised in Sheba Medical Center between 1 January 2007 and 31 December 2015. Medical conditions of these patients were recorded. In-hospital, 30-day and 1-year mortality rates were evaluated according to ferritin ranges and clinical categories. The study included 722 patients (63.4% men) with a mean age of 63.9±16.7 years. The most common clinical conditions associated with markedly elevated ferritin were infectious diseases and malignancies. The highest mean ferritin levels were associated with rheumatological/inflammatory conditions (16 241.3 ng/dL), particularly in patients with macrophage activation syndrome (MAS) (96 615.5 ng/dL). In-hospital, 30-day and 1-year mortality rates were 32.3%, 46.7% and 70.8%, respectively. The highest in-hospital, 30-day and 1-year mortality rates were observed among patients with solid malignancies (40.1%, 64.7% and 90.3%, respectively), whereas the lowest rates were found among patients with rheumatological/inflammatory conditions, including MAS (21.4%, 38.1% and 45.2%, respectively). Ferritin levels were not associated with mortality. In hospitalised patients, ferritin levels higher than 2000 ng/mL are mainly associated with infectious and malignant diseases but do not predict mortality.


Hypothalamic responses to peripheral glucose infusion in food-restricted sheep are influenced by photoperiod.
Nutritional feedback provided by systemic hormones, such as insulin and leptin, influences reproductive neuroendocrine output within the hypothalamus, yet the mechanisms and their interaction with photoperiodic cues remain unresolved in seasonal species. Here, peripheral glucose (G) infusion was used to increase endogenous concentrations of insulin and leptin in food-restricted sheep kept in either long-day (LD) or short-day (SD) photoperiod, and responses were examined in terms of pulsatile luteinising hormone (LH) (gonadotrophin-releasing hormone by inference) output and hypothalamic gene expression for nutritionally sensitive neuropeptides and receptors. We addressed the hypothesis that these hypothalamic responses were correlated and influenced by photoperiod. Oestradiol-implanted, castrated male sheep were kept 16 weeks in SD (8 h light/day) or LD (16 h light/day) and then transferred to the opposite photoperiods for 8 weeks, during which food was restricted to 90% requirement to maintain body weight (maintenance). For the final 6 days, food was reduced to 75% maintenance, and sheep in both photoperiods were infused intravenously with G (60 mM/h) or saline (S) (n = 8/group). G-infused sheep had higher mean plasma concentrations of G, insulin and leptin than S-infused sheep, with no effect of photoperiod. In LD, but not in SD, G infusion increased LH pulse frequency and pulse amplitude. In LD, but not in SD, gene expression in the hypothalamic arcuate nucleus was lower in G- than S-infused sheep for neuropeptide Y (NPY) and agouti-related peptide (AGRP) and was higher in G- than S-infused sheep for pro-opiomelanocortin (POMC). Gene expression for leptin and insulin receptors was not affected by photoperiod or infusion. These results are consistent with the involvement of NPY, AGRP and POMC in mediating the reproductive neuroendocrine response to increased systemic nutritional feedback, and they support the hypothesis that hypothalamic responses to nutritional feedback are influenced by photoperiod in sheep.


Inactivation of TGFbeta signaling in neural crest stem cells leads to multiple defects reminiscent of DiGeorge syndrome.
Specific inactivation of TGFbeta signaling in neural crest stem cells (NCSCs) results in cardiovascular defects and thymic, parathyroid, and craniofacial anomalies. All these malformations characterize DiGeorge syndrome, the most common microdeletion syndrome in humans. Consistent with a role of TGFbeta in promoting non-neural lineages in NCSCs, mutant neural crest cells migrate into the pharyngeal apparatus but are unable to acquire non-neural cell fates. Moreover, in neural crest cells, TGFbeta signaling is both sufficient and required for phosphorylation of CrkL, a signal adaptor protein implicated in the development of DiGeorge syndrome. Thus, TGFbeta signal modulation in neural crest differentiation might play a crucial role in the etiology of DiGeorge syndrome.


Bundle branch block as a predictor of long-term survival after acute myocardial infarction.
Using a community-based population of patients with acute myocardial infarction (AMI), we sought to: (1) determine the prevalence of bundle branch block (BBB) on the presenting electrocardiogram (ECG), (2) compare the clinical characteristics and the treatment administered to patients with and without BBB, and (3) determine the association of BBB with mortality. We analyzed the admission ECGs of 894 consecutive patients with AMI from Olmsted County, Minnesota, seen at our institution from January 1988 to March 1998. Of these, 53 had left BBB (LBBB) (5.9%) and 60 had right BBB (RBBB) (6.7%). Patients with BBB were more likely to be older, have a history of AMI or hypertension, and to be in Killip class >I at presentation. They were less likely to receive primary reperfusion therapy, beta blockers, or heparin, but more likely to receive angiotensin-converting enzyme inhibitors. They had lower mean predischarge ejection fractions (38 +/- 16% vs 50 +/- 15%, p <0.0001). In-hospital mortality was 13.3%, 17.0%, and 9.1% for patients with RBBB, LBBB, and no BBB, respectively (p = 0.11). Respective postdischarge survival at 1, 3, and 5 years was 80%, 60%, and 50% in the RBBB group, 78%, 56%, and 51% in the LBBB group, and 92%, 85%, and 76% in the group without BBB (p <0.0001). Although BBB was not an independent predictor of mortality on multivariate analysis, the presence of transient or persistent BBB with AMI is an easily recognized clinical marker of increased mortality. Our conclusion from this study is that in a community-based population, patients who had LBBB or RBBB at the time of AMI had lower predischarge ejection fractions and higher in-hospital and long-term unadjusted mortality.


Mutations of the SLX4 gene in Fanconi anemia.
Fanconi anemia is a rare recessive disorder characterized by genome instability, congenital malformations, progressive bone marrow failure and predisposition to hematologic malignancies and solid tumors. At the cellular level, hypersensitivity to DNA interstrand crosslinks is the defining feature in Fanconi anemia. Mutations in thirteen distinct Fanconi anemia genes have been shown to interfere with the DNA-replication-dependent repair of lesions involving crosslinked DNA at stalled replication forks. Depletion of SLX4, which interacts with multiple nucleases and has been recently identified as a Holliday junction resolvase, results in increased sensitivity of the cells to DNA crosslinking agents. Here we report the identification of biallelic SLX4 mutations in two individuals with typical clinical features of Fanconi anemia and show that the cellular defects in these individuals' cells are complemented by wildtype SLX4, demonstrating that biallelic mutations in SLX4 (renamed here as FANCP) cause a new subtype of Fanconi anemia, Fanconi anemia-P.


Gender identity, race/ethnicity and eating pathology in a treatment-seeking community sample.
Despite the wide-reaching impact of eating disorders (EDs), less is known about eating pathology among individuals across racial/ethnic groups whose gender identity differs from the binary categorization. Examining ED pathology both across binary and minority-gender groups, and relative to racial/ethnic identification is necessary to inform screening and culturally-sensitive intervention efforts. This study investigated patterns of ED symptomology among youth and adults (N = 13658) who telephoned treatment centers in the United States when seeking clinical support for ED symptoms. Analyses examined data from participants who completed a semi-structured clinical interview. Results indicated that Anorexia nervosa was the most common diagnosis in each gender category and for a majority of race/ethnic groups; Black individuals had elevated rates of binge eating disorder. Compared to females, males were less likely to endorse all ED symptoms (ps < .001); gender minority status was also associated with decreased report of a majority of ED symptoms. Asian and Black individuals were less likely than Whites to endorse most ED symptoms. When compared to Whites, Hispanic/Latinx and Bi/Multi-racial participants did not demonstrate significant differences in presentation across a majority of ED symptoms. Overall findings suggest individuals with female gender and White race may seek treatment from an ED treatment facility with greater frequency than other demographic groups. Noted exceptions include Hispanic/Latinx and Bi/Multi-racial individuals, for whom ED pathology may be represented comparably to Whites. While findings confirm traditional patterns in gender and racial/ethnic representation in EDs, current study findings also underscore that EDs are not culture bound.


Point: fluoroquinolone-based antibacterial chemoprophylaxis in neutropenic cancer patients works for defined outcomes in defined populations, but must be used wisely.
Fluoroquinolone-based antibacterial chemoprophylaxis administered in situations in which the prevalence of fluoroquinolone-resistant Escherichia coli is low (< 3% to 5%) can reliably reduce the risk for invasive gram-negative bacillary infection, and, if supplemented by gram-positive agents such as rifampin, penicillin, or macrolides, can reduce the risk of developing invasive infections caused by gram-positive microorganisms, including Viridans streptococci and coagulase-negative staphylococci. In the published literature, fluoroquinolone-based chemoprophylaxis does not reliably reduce the incidence of febrile neutropenic episodes, neutropenic episode-related mortality, or physician-initiated systemic antimicrobial prescribing behavior. Prophylaxis should only be prescribed in defined patient populations from the first day of cytotoxic therapy until neutrophil regeneration in environments in which the prevalence of gram-negative bacillary resistance to the prophylaxis strategy is low. Small phase II clinical trials suggest that empirical antibacterial therapy of unexplained fevers in neutropenic patients receiving effective fluoroquinolone-based prophylaxis under defined epidemiologic circumstances may be safely discontinued early. Better discriminators of infection in febrile neutropenic patients are needed.


Evidence-based approach to the maintenance of laboratory and medical equipment in resource-poor settings.
Much of the laboratory and medical equipment in resource-poor settings is out-of-service. The most commonly cited reasons are (1) a lack of spare parts and (2) a lack of highly trained technicians. However, there is little data to support these hypotheses, or to generate evidence-based solutions to the problem. We studied 2,849 equipment-repair requests (of which 2,529 were out-of-service medical equipment) from 60 resource-poor hospitals located in 11 nations in Africa, Europe, Asia, and Central America. Each piece of equipment was analyzed by an engineer or an engineering student and a repair was attempted using only locally available materials. If the piece was placed back into service, we assumed that the engineer's problem analysis was correct. A total of 1,821 pieces of medical equipment were placed back into service, or 72%, without requiring the use of imported spare parts. Of those pieces repaired, 1,704 were sufficiently documented to determine what knowledge was required to place the equipment back into service. We found that six domains of knowledge were required to accomplish 99% of the repairs: electrical (18%), mechanical (18%), power supply (14%), plumbing (19%), motors (5%), and installation or user training (25%). A further analysis of the domains shows that 66% of the out-of-service equipment was placed back into service using only 107 skills covering basic knowledge in each domain; far less knowledge than that required of a biomedical engineer or biomedical engineering technician. We conclude that a great majority of laboratory and medical equipment can be put back into service without importing spare parts and using only basic knowledge. Capacity building in resource-poor settings should first focus on a limited set of knowledge; a body of knowledge that we call the biomedical technician's assistant (BTA). This data set suggests that a supported BTA could place 66% of the out-of-service laboratory and medical equipment in their hospital back into service.


Isolation of the human chromosomal band Xq28 within somatic cell hybrids by fragile X site breakage.
The chromosomal fragile-site mapping to Xq27.3 is associated with a frequent form of mental retardation and is prone to breakage after induced deoxyribonucleotide pool perturbation. The human hypoxanthine phosphoribosyltransferase (HPRT) and glucose-6-phosphate dehydrogenase (G6PD) genes flank the fragile X chromosome site and can be used to monitor integrity of the site in human-hamster somatic cell hybrids deficient in the rodent forms of these activities. After induction of the fragile X site, negative selection for HPRT and positive enrichment for G6PD resulted in 31 independent colonies of HPRT-,G6PD+ phenotype. Southern blot analysis demonstrated the loss of all tested markers proximal to the fragile X site with retention of all tested human Xq28 loci in a majority of the hybrids. In situ hybridization with a human-specific probe demonstrated the translocation of a small amount of human DNA to rodent chromosomes in these hybrids, suggesting chromosome breakage at the fragile X site and the subsequent translocation of Xq28. Southern blot hybridization of hybrid-cell DNA, resolved by pulsed-field gel electrophoresis, for human-specific repetitive sequences revealed abundant CpG-islands within Xq28, consistent with its known gene density. The electrophoretic banding patterns of human DNA among the hybrids were remarkably consistent, suggesting that fragile X site breakage is limited to a relatively small region in Xq27-28. These somatic cell hybrids, containing Xq27.3-qter as the sole human DNA, will aid the search for DNA associated with the fragile X site and will augment the high resolution genomic analysis of Xq28, including the identification of candidate genes for genetic-disease loci mapping to this region.


Comparing mutational variabilities.
We have reviewed the available data on VM, the amount of genetic variation in phenotypic traits produced each generation by mutation. We use these data to make several qualitative tests of the mutation-selection balance hypothesis for the maintenance of genetic variance (MSB). To compare VM values, we use three dimensionless quantities: mutational heritability, VM/VE, the mutational coefficient of variation, CVM; and the ratio of the standing genetic variance to VM, VC/VM. Since genetic coefficients of variation for life history traits are larger than those for morphological traits, we predict that under MSB, life history traits should also have larger CVM. This is confirmed; life history traits have a median CVM value more than six times higher than that for morphological traits. VC/VM approximates the persistence time of mutations under MSB in an infinite population. In order for MSB to hold, VC/VM must be small, substantially less than 1000, and life history traits should have smaller values than morphological traits. VC/VM averages about 50 generations for life history traits and 100 generations for morphological traits. These observations are all consistent with the predictions of a mutation-selection balance model.


A new approach yields high rates of radiographic progression in knee osteoarthritis.
Progression of knee osteoarthritis (OA) has typically been assessed in the medial tibiofemoral (TF) compartment on the anteroposterior (AP) or posteroanterior (PA) view. We propose a new approach using multiple views and compartments that is likely to be more sensitive to change and reveals progression throughout the knee. We tested our approach in the Multicenter Osteoarthritis Study, a study of persons with OA or at high risk of disease. At baseline and 30 months, subjects provided PA (fixed flexion without fluoro) and lateral weight-bearing knee radiographs. Paired radiographs were read by 2 readers who scored joint space (JS) using a 0-3 atlas-based scale. When JS narrowed but narrowing did not reach a full grade on the scale, readers used half-grades. Change was scored in medial and lateral TF compartments on both PA and lateral views and in the patellofemoral (PF) joint on lateral view. A knee showed progression when there was at least a half-grade worsening in JS width in any compartment at followup. Disagreements were adjudicated by a panel of 3 readers. To validate progression, we tested definitions for TF progression to see if malalignment on long-limb radiographs at baseline (>or=3 degrees malaligned in any direction with nonmalaligned knees being reference) increased risk of progression. A valid definition of progression would show that malalignment strongly predicted progression. We studied 842 knees with either Kellgren-Lawrence grade>or=2 or PF OA at baseline in 606 subjects (age range 50-79 yrs, mean 63.9 yrs; 66.6% women). Mean body mass index was 31.9, and 32.8% of knees had frequent knee pain at baseline. Of these, 500 knees (59.4%) showed progression. Of the 500, 75 (15%) had progression only in the PF joint, while the remainder had progression in the TF joint. Malalignment increased the risk of overall progression in TF joint and increased the risk of half-grade progression, suggesting that half-grade progression had validity. PA and lateral views obtained in persons at high risk of OA progression can produce a cumulative incidence of progression above 50% at 30 months. Keys to increasing the yield include imaging PF and lateral compartments, using semiquantitative scales designed to detect change, and examining more than one radiographic view.


Epigenetic regulation in chondrogenesis.
Epigenetics is an essential mechanism to control gene expression and fundamental cellular processes. DNA methylation in CpG-rich promoters correlates with gene silencing. Histone modification including histone acetylation and deacetylation determines the stability of the chromatin structure. Condensed chromatin (heterochromatin), which has a higher-order histone-DNA structure, prevents the access of transcriptional activators to their target genes. The fundamental unit of eukaryotic chromatin consists of 146 bp of DNA wrapped around a histone octamer. Posttranslational modifications of the histone tail and the chromatin remodeling complex disrupt histone-DNA contacts and induce nucleosome mobilization. Histone acetylation of specific lysine residues in the histone tail plays a crucial role in epigenetic regulation. Histone acetylation is a dynamic process regulated by the antagonistic actions of 2 families of enzymes - the histone acetyltransferases (HATs) and the histone deacetylases (HDACs). The balance between histone acetylation and deacetylation serves as a key epigenetic mechanism for transcription factor-dependent gene expression and the developmental process. We review emerging evidence that DNA methylation, histone acetylation modified by HAT and/or HDAC, and transcription factor-associated molecules contribute to a mechanism that can alter chromatin structure, gene expression, and cellular differentiation during chondrogenesis.


Intracranial pressure monitoring: fundamental considerations and rationale for monitoring.
Traumatic brain injury (TBI) is a major cause of death and disability worldwide. In large part critical care for TBI is focused on the identification and management of secondary brain injury. This requires effective neuromonitoring that traditionally has centered on intracranial pressure (ICP). The purpose of this paper is to review the fundamental literature relative to the clinical application of ICP monitoring in TBI critical care and to provide recommendations on how the technique maybe applied to help patient management and enhance outcome. A PubMed search between 1980 and September 2013 identified 2,253 articles; 244 of which were reviewed in detail to prepare this report and the evidentiary tables. Several important concepts emerge from this review. ICP monitoring is safe and is best performed using a parenchymal monitor or ventricular catheter. While the indications for ICP monitoring are well established, there remains great variability in its use. Increased ICP, particularly the pattern of the increase and ICP refractory to treatment is associated with increased mortality. Class I evidence is lacking on how monitoring and management of ICP influences outcome. However, a large body of observational data suggests that ICP management has the potential to influence outcome, particularly when care is targeted and individualized and supplemented with data from other monitors including the clinical examination and imaging.


Swine influenza virus antibodies in humans, western Europe, 2009.
Serologic studies for swine influenza viruses (SIVs) in humans with occupational exposure to swine have been reported from the Americas but not from Europe. We compared levels of neutralizing antibodies against 3 influenza viruses--pandemic (H1N1) 2009, an avian-like enzootic subtype H1N1 SIV, and a 2007-08 seasonal subtype H1N1--in 211 persons with swine contact and 224 matched controls in Luxembourg. Persons whose profession involved contact with swine had more neutralizing antibodies against SIV and pandemic (H1N1) 2009 virus than did the controls. Controls also had antibodies against these viruses although exposure to them was unlikely. Antibodies against SIV and pandemic (H1N1) 2009 virus correlated with each other but not with seasonal subtype H1N1 virus. Sequential exposure to variants of seasonal influenza (H1N1) viruses may have increased chances for serologic cross-reactivity with antigenically distinct viruses. Further studies are needed to determine the extent to which serologic responses correlate with infection.


The harpooning mechanism as evidenced in the oxidation reaction of the Al atom.
The harpooning mechanism has long been proposed for elementary reaction dynamics involving metals. It is characterized by an initial electron transfer (ET) process from the metal to the oxidant molecule. For the titled reaction Al + O2, the ET distance can be predicted to be 2.6 Å by simply calculating the energy difference between the ionization energy of the Al atom and the electron affinity of the O2 molecule. Hereby we experimentally derived the maximum impact parameter bmax of 2.5 ± 0.2 Å for the titled reaction, in consistency with the predicted ET distance. This derivation of bmax was achieved by using the crossed molecular beam experiment at a collision energy of 507 cm-1 (i.e. 1.45 kcal mol-1) with a high resolution time-sliced ion velocity imaging detection of the state-selective AlO products based on the (1 + 1) resonance-enhanced multiphoton ionization. The small rotational constant of the AlO(X2Σ+) radical (Be = 0.6413 cm-1) facilitated the formation of the AlO(v = 0) products in high rotational levels up to the energetically limited state, Nmax = 52, with an almost zero velocity mapping. Hence, in this extreme angular momentum disposal case, the collisional orbital angular momentum l was nearly completely channeled into the product rotational angular momentum as a consequence of the conservations of energy and angular momentum, offering a reaction system that breaks the restriction of kinematically favored mass combination in order to obtain information on the impact parameters. The present study yields the first direct derivation of bmax from the maximum rotational level of products under the experimental condition with the recoil energy E'T ≈ 0. This, in turn, provides solid evidence in supporting the harpooning mechanism.


Commentary on pedophilia diagnostic criteria in DSM-5.
Human beings differ in sexual makeup. Most adults are not sexually attracted to prepubescent children, but some are. Societal values can be of relevance in determining whether such a difference is considered to be a psychiatric condition. Were a society to believe that adult-child sexual interactions should not be prohibited, such a difference might not be viewed as a disorder. According to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), a difference in sexual makeup can be considered a disorder when it causes interpersonal difficulty or marked distress. In contemporary society, pedophilia can do both. According to DSM-IV-TR, for a diagnosis of pedophilia, there must be both a qualitative difference in sexual makeup (i.e., sexualized urges directed toward children) and a quantitative difference (i.e., the sexualized urges must be intense). However, just as a heterosexual man with low (i.e., nonintense) sexual urges is still heterosexual, DSM-5 should similarly allow that individuals with low sexual urges in response to children qualify for a diagnosis of pedophilia.


Hepatitis E, Helicobacter pylori, and gastrointestinal symptoms in workers exposed to waste water.
Workers exposed to sewage may have an increased risk of infection by Helicobacter pylori and hepatitis E virus (HEV). To assess the prevalence of clinical hepatitis E (HE) and peptic ulcer disease as well as the seroprevalence of antibodies to H pylori and HEV in workers with and without sewage exposure and to look for symptoms due to exposure to endotoxin. In the first year of a prospective cohort study 349 sewage exposed workers and 429 municipal manual workers (participation: 61%) underwent a complete medical examination. Travelling to endemic areas, socioeconomic level, age, country in which childhood was spent, and number of siblings were considered as the main confounding factors. Peptic ulcer disease and clinical HE did not occur more often in workers exposed to sewage. Prevalence of antibodies to HEV was 3.3% and overall prevalence of IgG antibodies to H pylori was 42% with large differences between subgroups. Logistic regression did not show an increased risk of seropositivity or antibodies to parietal cells in sewage exposed workers, but disentangling the effect of exposure from that of confounders was extremely difficult. No increase of symptoms due to exposure to endotoxin was found in sewage workers, with the exception of diarrhoea. No clear increased risk of infection by H pylori or by HEV in workers exposed to sewage was found in this cross-sectional study, but these results need to be confirmed by follow up.


Rearrangement of the transcription factor gene CHOP in myxoid liposarcomas with t(12;16)(q13;p11).
Most myxoid liposarcomas (MLS) are characterized cytogenetically by a t(12;16)(q13;p11). It is reasonable to assume that this translocation corresponds to the consistent rearrangement of one or two genes in 12q13 and/or 16p11, and that the loci thus affected are important in the normal control of fat cell differentiation and proliferation. We have used Southern blot technique to test whether a gene of the CCAAT/enhancer binding protein (C/EBP) family, CHOP, which maps to 12q13 and is assumed to be involved in adipocyte differentiation, could be the 12q gene in question. Using a cDNA probe that spans the CHOP coding region, we detected one rearranged and one wild type allele in nine of nine MLS with t(12;16). Using PCR generated, site-specific probes corresponding to the non-coding exons 1 and 2 and intron 2 of CHOP, rearrangements in five of seven tumors mapped to the 2.4 and 1.6 kbp PstI fragments that contain the first two exons and introns of the gene and the upstream promoter region. In contrast to the findings in MLS, no tumor without a t(12;16) exhibited aberrant CHOP restriction digest patterns. These tumors included one highly differentiated liposarcoma with abnormal karyotype but no involvement of 12q13, seven lipomas with various cytogenetic aberrations of 12q13-15, two uterine leiomyomas with t(12;14) (q14-15;q23-24), and one hemangiopericytoma and one chondroma, both of which also had 12q13 changes.(ABSTRACT TRUNCATED AT 250 WORDS)


Dose-dependent effects of epidermal growth factor on corneal wound healing.
The dose-dependent effect of epidermal growth factor (EGF) on the development of wound tensile strength following full-thickness corneal wounds was evaluated in 60 adult rabbits. One eye from each rabbit received a single 7-mm long corneal incision. After injury each rabbit was treated three times daily for 5 or 10 days with either EGF at 0.001 mg/ml (10 eyes), 0.01 mg/ml (10 eyes), 0.1 mg/ml (10 eyes), 1.0 mg/ml (15 eyes), or vehicle (15 eyes). The tensile strength of the wound was evaluated using a 5-mm wide strip of cornea mounted on a tensiometer. We found that EGF at 0.1 mg/ml and at 0.01 mg/ml increased wound strength by 100% at 5 days and by 60% at 10 days (P less than 0.05 and P less than 0.05). However, EGF at 0.001 mg/ml and 1.0 mg/ml appeared to have no effect on wound strength. Histologic examination of full-thickness wounds in a separate series showed an increase in wound fibroblastic response and a diminished fibrin clot at 5 days in rabbits treated with 0.1 mg/ml and 0.01 mg/ml. We conclude that EGF enhances the wound strength of full-thickness corneal wounds in a dose-dependent manner which may be explained in part by an increased fibroblastic response. Concentrations of EGF greater or less than an optimal dose may be less effective in enhancing corneal wound strength.


Laboratory study of stationary accretion shock relevant to astrophysical systems.
Accretion processes play a crucial role in a wide variety of astrophysical systems. Of particular interest are magnetic cataclysmic variables, where, plasma flow is directed along the star's magnetic field lines onto its poles. A stationary shock is formed, several hundred kilometres above the stellar surface; a distance far too small to be resolved with today's telescopes. Here, we report the results of an analogous laboratory experiment which recreates this astrophysical system. The dynamics of the laboratory system are strongly influenced by the interplay of material, thermal, magnetic and radiative effects, allowing a steady shock to form at a constant distance from a stationary obstacle. Our results demonstrate that a significant amount of plasma is ejected in the lateral direction; a phenomenon that is under-estimated in typical magnetohydrodynamic simulations and often neglected in astrophysical models. This changes the properties of the post-shock region considerably and has important implications for many astrophysical studies.


Evaluation of image quality of DWIBS versus DWI sequences in thoracic MRI at 3T.
To compare diffusion weighted imaging with background suppression (DWIBS) sequence with classic spectral diffusion sequence (DWI) with and without respiratory gating in mediastinal lymph node analysis at 3T. 26 patients scheduled for mediastinoscopic lymph node analysis, prospectively undergone a thoracic 3T MRI with DWIBS (FatSat=STIR; TR/TE=6674.1/44.7ms; IR=260 ms) and DWI sequences (FatSat=SPIR; TR/TE=1291/59.6 ms) (b=0-400-800 s/mm2) with and without (free breathing) respiratory gating. Images at b=800 were analyzed by two radiologists. They performed qualitative analysis of fat-sat homogeneity and motion artifacts, rated from 0 to 4, and quantitative evaluation by studying signal to background (STB) of lymph nodes. Quality of fat suppression was significantly higher for DWIBS than for DWI both for free-breathing (score 3.48±0.65 vs. 1.76±0.96, p<0.0001) and respiratory-gated scans (3.17±0.77 vs. 1.72±0.73, p=0.0001). Similarly, artifacts were reduced with DWIBS (3.16±0.47 vs. 1.76±0.59, p<0.0001; 3.0±0.73 vs. 2.04±0.53, p=0.0001). Quantitative analysis showed higher STB with DWIBS (3.26±1.83 vs. 0.98±0.44, p<0.0001; 3.56±, 2.09 vs. 0.92±0.59, p<0.0001). Gating did not improve image quality and STB on DWIBS (p>0.05). In thoracic MRI, ungated DWIBS sequence improves fat-sat homogeneity, reduces motion artifacts and increases STB of lymph nodes. Respiratory gating does not improve DWIBS image quality.


Computational redesign of protein-protein interaction specificity.
We developed a 'computational second-site suppressor' strategy to redesign specificity at a protein-protein interface and applied it to create new specifically interacting DNase-inhibitor protein pairs. We demonstrate that the designed switch in specificity holds in in vitro binding and functional assays. We also show that the designed interfaces are specific in the natural functional context in living cells, and present the first high-resolution X-ray crystallographic analysis of a computer-redesigned functional protein-protein interface with altered specificity. The approach should be applicable to the design of interacting protein pairs with novel specificities for delineating and re-engineering protein interaction networks in living cells.


Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes.
Adaptive features of innate immunity, recently described as "trained immunity," have been documented in plants, invertebrate animals, and mice, but not yet in humans. Here we show that bacille Calmette-Guérin (BCG) vaccination in healthy volunteers led not only to a four- to sevenfold increase in the production of IFN-γ, but also to a twofold enhanced release of monocyte-derived cytokines, such as TNF and IL-1β, in response to unrelated bacterial and fungal pathogens. The enhanced function of circulating monocytes persisted for at least 3 mo after vaccination and was accompanied by increased expression of activation markers such as CD11b and Toll-like receptor 4. These training effects were induced through the NOD2 receptor and mediated by increased histone 3 lysine 4 trimethylation. In experimental studies, BCG vaccination induced T- and B-lymphocyte-independent protection of severe combined immunodeficiency SCID mice from disseminated candidiasis (100% survival in BCG-vaccinated mice vs. 30% in control mice). In conclusion, BCG induces trained immunity and nonspecific protection from infections through epigenetic reprogramming of innate immune cells.


Effects of exercise training on mitochondrial function in patients with type 2 diabetes.
Type 2 diabetes is characterized by a decreased ability of insulin to facilitate glucose uptake into insulin sensitive tissue, i.e., skeletal muscle. The mechanism behind this is at the moment unresolved. It has been suggested that increased amount of lipids inside the skeletal muscle (intramuscular triglyceride, diacylglycerol and ceramides) will impair insulin action in skeletal muscle, but data are not consistent in the human literature. It has also been hypothesized that the impaired insulin sensitivity is due to a dysfunction in the mitochondria resulting in an impaired ability to oxidize lipids, but the majority of the literature is not supporting this hypothesis. Recently it has been suggested that the production of reactive oxygen species play an essential role in skeletal muscle insulin sensitivity. It is well accepted that physical activity (endurance, strength and high intensity training) improves insulin sensitivity in healthy humans and in patients with type 2 diabetes. Whether patients with type 2 diabetes have the same beneficial effects (same improvement) as control subjects, when it comes to regular physical activity in regard to mitochondrial function, is not established in the literature. This review will focus only on the effect of physical activity on skeletal muscle (mitochondrial function) in patients with type 2 diabetes.


Geographic and socioeconomic factors in patients with malignant pleural mesothelioma in New South Wales and their impact upon clinical outcomes.
Whilst the impact of clinicopathological factors on the prognosis of malignant pleural mesothelioma (MPM) is well understood, socioeconomic and geographic factors have received less attention. We analysed the relationship between geographic and socioeconomic factors upon survival and treatment provision in a large series of patients with MPM. We assessed MPM patients awarded compensation between 2002 and 2009 with additional MPM incidence data from the New South Wales (NSW) Cancer Registry. The impact of geographic remoteness, distance from oncological multidisciplinary team (MDT) and Index of Relative Socioeconomic Advantage and Disadvantage (IRSAD) upon survival, clinical features and treatment received was analysed. We identified 910 patients (67% residing in major cities; 92% <50 km from MDT). Median overall survival was 10.0 months. On multivariate analysis, age >70 (hazard ratio (HR) = 1.39), male gender (HR =1.36), non-epithelioid histological subtype (HR = 2.18) and IRSAD status by decreasing quintile (HR = 1.06) were independent prognostic factors. There was no significant advantage for patients residing in major cities (10.6 months vs 8.8 months; P = 0.162) or within 50 km of MDT (10.3 months vs 7.8 months; P = 0.539). Patient's geographic location and distance to MDT did not impact chemotherapy, adjuvant radiotherapy or extrapleural pneumonectomy provision. Socioeconomically disadvantaged patients were significantly less likely to receive chemotherapy (37.4% vs 54.8%; P = 0.001). This study provides evidence for differences in the treatment and survival according to socioeconomic status for compensated MPM patients in NSW. Further research is warranted to seek additional explanations for the differences noted by comparing the treatments and outcomes of compensated and non-compensated MPM patients in NSW.


[Clinical re-evaluation of pediatric inflammatory disorders of the central nervous system:a study based on the new classification criteria proposed by the International Pediatric MS Study Group].
A retrospective analysis of the clinical and MRI features in 20 Japanese children diagnosed with central nervous system inflammatory demyelinating disorders was performed. Using the new criteria proposed by International Pediatric MS Study Group, half of children were reclassified into clinical isolated demyelinating syndrome (CIS). Presence of seizures and a pattern of diffuse bilateral lesions on brain MRIs are more frequent in children with ADEM than in CIS. However we suggest these features and encephalopathy may be associated with the age of patients. Furthermore, though persistence of abnormal MRI lesions is significantly more likely in the group of CIS, none of these patients had a subsequent recurrence or developed MS during the follow-up period. The prediction of patient prognosis seems to be difficult even based on the new criteria, and the nationwide multicenter analysis may be necessary in Japan for acquiring the definite conclusion.


Primary hepatic carcinoid: a case report and literature review.
Carcinoids are tumors derived from neuroendocrine cells and often produce functional peptide hormones. Approximately 54.5% arise in the gastrointestinal tract and frequently metastasize to the liver. Primary hepatic carcinoid tumors (PHCT) are extremely rare; only 95 cases have been reported. A 65-year-old man came to our attention due to occasional ultrasound findings in absence of clinical manifestations. His previous medical history, since 2003, included an echotomography of the dishomogeneous parenchymal area but no focal lesions. A computed tomography scan performed in 2005 showed an enhanced pseudonodular-like lesion of about 2 cm. Cholangio-magnetic resonance imaging identified the lesion as a possible cholangiocarcinoma. No positive findings were obtained with positron emission tomography. Histology suggested a secondary localization in the liver caused by a low-grade malignant neuroendocrine tumor. Immunohistochemistry was positive for anti chromogranin antibodies, Ki67 antibodies and synaptophysin. Octreoscan scintigraphy indicated intense activity in the lesion. Endoscopic investigations were performed to exclude the presence of extrahepatic neoplasms. Diagnosis of PHCT was established. The patient underwent left hepatectomy, followed by hormone therapy with sandostatine LAR. Two months after surgery he had a lymph nodal relapse along the celiac trunk and caudate lobe, which was histologically confirmed. The postoperative clinical course was uneventful, with a negative follow-up for hematochemical, clinical and radiological investigations at 18 mo post-surgery. Diagnosis of PHCT is based principally on the histopathological confirmation of a carcinoid tumor and the exclusion of a non-hepatic primary tumor. Surgical resection is the recommended primary treatment for PHCT. Recurrence rate and survival rate in patients treated with resection were 18% and 74%, respectively.


An Update on Surgical versus Expectant Management of Ovarian Endometriomas in Infertile Women.
Ovarian endometriomas are a common manifestation of endometriosis that can represent a more severe stage of the disease. There is much debate over the treatment of these cysts in infertile women, particularly before use of assisted reproductive technologies. Evidence exists that supports surgical excision of ovarian endometriomas, as well as evidence that cautions against surgical intervention. Certain factors need to be examined closely before proceeding with surgery or continuing with expectant management. These include the patient's symptoms, age, ovarian reserve, size and laterality of the cyst, prior surgical treatment, and level of suspicion for malignancy. The most recent evidence appears to suggest that certain patient profiles may benefit from proceeding directly to in vitro fertilization (IVF). These include symptomatic infertile patients, especially those that are older, those that have diminished ovarian reserve, those that have bilateral endometriomas, or those that have had prior surgical treatment. Although endometriomas can be detrimental to the ovarian reserve, surgical therapy may further lower a woman's ovarian reserve. Nevertheless, the presence of an endometrioma does not appear to adversely affect IVF outcomes, and surgical excision of endometriomas does not appear to improve IVF outcomes. Regardless of treatment plan, infertile patients with endometriomas must be counseled appropriately before choosing either treatment path.


TH1/TH2 Cytokine profile in relapsing-remitting multiple sclerosis patients treated with Glatiramer acetate or Natalizumab.
The balance between T helper cells Th2- and Th1-related cytokines plays a key role in multiple sclerosis (MS). A shift from a Th1 towards a Th2 cytokine profile could have a beneficial effect on the clinical course of the disease. The objective of this study was to assess Th2/Th1 cytokine profile in relapsing-remitting MS (RRMS) patients receiving an immunosuppressive treatment with natalizumab (NAT), or an immunomodulatory treatment with glatiramer acetate (GA) after one year of treatment. This was an observational cross-sectional study. All consecutive patients diagnosed with RRMS who had received GA or NAT for 12 months were included in the study. We determined serum levels of Th1 and Th2 cytokines (interleukin [IL]-1a, IL-1b, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-13, monocyte chemotactic protein [MCP]-1, tumor-necrosis factor [TNF]-α, interferon [IFN]-γ and granulocyte macrophage colony stimulating factor [GM-CSF]) by flow cytometry. Th2/Th1 bias was defined based on the ratio of IL-4, IL-5, IL-6 or IL-10 Th2 cytokines and proinflammatory INF-γ or TNF-α Th1 cytokines. Eleven patients under treatment with NAT and 12 patients treated with GA were evaluated. RRMS patients treated with NAT showed significantly higher levels of IL-6 (p < 0.05), MCP-1 (p < 0.01), and GM-CSF (p < 0.05) compared to GA patients after one year of treatment. A trend for increasing of IL-12p70, IL-1b, TNF- α and IFN- γ levels was also found in patients receiving NAT compared to GA patients. IL-4/IFN-γ, IFN-γ/TNF-α and IL-10/IFN-γ ratios as markers of Th2/Th1 ratio were significantly elevated in GA patients compared to those receiving NAT (p < 0.05). In conclusion, our findings suggest that GA promotes a superior Th2-biased anti-inflammatory response as compared with NAT in the systemic circulation of RRMS patients. Future studies with larger cohorts will determine whether this immune Th2 shift in GA patients is associated with a beneficial effect on disease outcome.


Palliative radiation oncology in pediatric patients.
Radiation therapy (RT) provides an effective and often rapid means to alleviate symptomatic progression in pediatric patients with advanced or metastatic cancer. As part of a comprehensive, multimodality approach to pediatric palliative care, RT can be a useful tool to manage pain, spinal cord compression, dyspnea, neurologic compromise, bleeding, and bowel or urinary obstruction. Whether such symptoms present earlier in the disease course or in children and adolescents approaching the end of life, they can significantly impact the quality of life of patients and caregivers. Control of symptoms is therefore an important aspect in maximizing end of life care. Outcomes for palliative RT in both children and adults are favorable. While RT has been widely adopted as a component of palliative oncologic care for many adult malignancies, it remains infrequently utilized in pediatric patients despite the relative radiosensitivity of many pediatric tumors. Potential barriers to palliative radiation for pediatric patients include insufficient understanding by care providers regarding the utility of RT for a given symptom, lack of comfort in discussing a transition away from definitive management, concern over radiation-related side effects, and hesitancy toward radiation treatment on the part of parents and caregivers. Delivery of palliative RT can also be impeded by logistical obstacles including lack of on-site radiation facilities, unavailability of radiation oncologists comfortable with pediatric treatments, and the potential need for specialized medical care such as pediatric anesthesia. The aim of this review is to foster a more complete understanding of the benefits and limitations of palliative RT in the pediatric oncology setting, including common symptoms experienced by children and adolescents with cancer that may be indications for the integration of RT into palliative care paradigms, as well as the expected efficacy of treatment. We describe the logistics, delivery, common doses for palliative radiation regimens, and management of potential side effects. While palliative RT is generally well tolerated in the pediatric population, we also discuss potential side effects of RT to various body sites and approaches for prevention or mitigation.


What is the Ocular phenotype associated with a dystrophin deletion of exons 12-29?
Duchenne muscular dystrophy (DMD) is a result of a X-linked recessive inherited mutation of the DMD gene which contains 79 exons. This rare disease is passed on by the mother who is called a carrier. Primarily it affects boys, but in rare cases it can affect girls. Dystrophin protein is mostly located in skeletal and cardiac muscles, which explains muscular and cardiac manifestations in symptomatic female DMD-carriers. Dystrophin is also present in extramuscular tissues. Some dystrophin isoforms are exclusively or predominantly expressed in the brain or the retina. It has been reported that DMD patients and DMD-carriers present normal visual acuity, but abnormal electroretinographic findings. As symptomatic female DMD are very rare, ophthalmic screening of the female patient with deletions of exons 12- 29 is valuable. Studying the functional relationship between ocular symptoms and related different deletions of exons dystrophin gene may further elucidate the pathophysiology in DMD.


Does negative-pressure wound therapy influence subjacent bacterial growth? A systematic review.
Negative-pressure wound therapy is a ubiquitous wound management resource. The influence of NPWT on the bacterial bioburden of the subjacent wound remains unclear. We sought to examine the evidence. MEDLINE, Embase, PubMed, the Cochrane Database of Systematic Reviews and the Cochrane Controlled Trials Register were searched for articles quantitatively evaluating bacterial load under NPWT. Twenty-four studies met the inclusion criteria including 4 randomised controlled trials, 8 clinical series and 12 experimental studies. Twenty studies evaluated conventional NPWT, while 4 evaluated infiltration-based NPWT. While 8 studies using conventional NPWT failed to demonstrate an observable effect on bacterial load, 7 studies reported that NPWT was inherently bacteriostatic and 5 others reported species selectivity with suppression of non-fermentative gram-negative bacilli (NFGNB), including Pseudomonas spp. Simultaneously, there was some evidence of enhanced proliferation of gram-positive cocci where the niche was cleared of NFGNB. Two of the 4 studies using infiltration-based NPWT also reported selectively impaired proliferation of Pseudomonas spp. The assumption that NPWT suppresses bacterial proliferation is oversimplified. There is evidence that NPWT exhibits species selectivity, suppressing the proliferation of NFGNB. However, this may depopulate the niche for exploitation by gram-positive cocci. This, in turn, has implications for the use of NPWT where highly virulent strains of gram-positive cocci have been isolated and the duration of NPWT therapy and frequency of dressing changes.


Hypertension screening, awareness, treatment, and control in India: A nationally representative cross-sectional study among individuals aged 15 to 49 years.
Evidence on where in the hypertension care process individuals are lost to care, and how this varies among states and population groups in a country as large as India, is essential for the design of targeted interventions and to monitor progress. Yet, to our knowledge, there has not yet been a nationally representative analysis of the proportion of adults who reach each step of the hypertension care process in India. This study aimed to determine (i) the proportion of adults with hypertension who have been screened, are aware of their diagnosis, take antihypertensive treatment, and have achieved control and (ii) the variation of these care indicators among states and sociodemographic groups. We used data from a nationally representative household survey carried out from 20 January 2015 to 4 December 2016 among individuals aged 15-49 years in all states and union territories (hereafter "states") of the country. The stages of the care process-computed among those with hypertension at the time of the survey-were (i) having ever had one's blood pressure (BP) measured before the survey ("screened"), (ii) having been diagnosed ("aware"), (iii) currently taking BP-lowering medication ("treated"), and (iv) reporting being treated and not having a raised BP ("controlled"). We disaggregated these stages by state, rural-urban residence, sex, age group, body mass index, tobacco consumption, household wealth quintile, education, and marital status. In total, 731,864 participants were included in the analysis. Hypertension prevalence was 18.1% (95% CI 17.8%-18.4%). Among those with hypertension, 76.1% (95% CI 75.3%-76.8%) had ever received a BP measurement, 44.7% (95% CI 43.6%-45.8%) were aware of their diagnosis, 13.3% (95% CI 12.9%-13.8%) were treated, and 7.9% (95% CI 7.6%-8.3%) had achieved control. Male sex, rural location, lower household wealth, and not being married were associated with greater losses at each step of the care process. Between states, control among individuals with hypertension varied from 2.4% (95% CI 1.7%-3.3%) in Nagaland to 21.0% (95% CI 9.8%-39.6%) in Daman and Diu. At 38.0% (95% CI 36.3%-39.0%), 28.8% (95% CI 28.5%-29.2%), 28.4% (95% CI 27.7%-29.0%), and 28.4% (95% CI 27.8%-29.0%), respectively, Puducherry, Tamil Nadu, Sikkim, and Haryana had the highest proportion of all adults (irrespective of hypertension status) in the sampled age range who had hypertension but did not achieve control. The main limitation of this study is that its results cannot be generalized to adults aged 50 years and older-the population group in which hypertension is most common. Hypertension prevalence in India is high, but the proportion of adults with hypertension who are aware of their diagnosis, are treated, and achieve control is low. Even after adjusting for states' economic development, there is large variation among states in health system performance in the management of hypertension. Improvements in access to hypertension diagnosis and treatment are especially important among men, in rural areas, and in populations with lower household wealth.


The hnRNP C proteins contain a nuclear retention sequence that can override nuclear export signals.
Nascent pre-mRNAs associate with the abundant heterogeneous nuclear RNP (hnRNP) proteins and remain associated with them throughout the time they are in the nucleus. The hnRNP proteins can be divided into two groups according to their nucleocytoplasmic transport properties. One group is completely restricted to the nucleus in interphase cells, whereas the other group, although primarily nuclear at steady state, shuttles between the nucleus and the cytoplasm. Nuclear export of the shuttling hnRNP proteins is mediated by nuclear export signals (NESs). Mounting evidence indicates that NES-bearing hnRNP proteins are mediators of mRNA export. The hnRNP C proteins are representative of the nonshuttling group of hnRNP proteins. Here we show that hnRNP C proteins are restricted to the nucleus not because they lack an NES, but because they bear a nuclear retention sequence (NRS) that is capable of overriding NESs. The NRS comprises approximately 78 amino acids and is largely within the auxiliary domain of hnRNP C1. We suggest that the removal of NRS-containing hnRNP proteins from pre-mRNA/mRNA is required for mRNA export from the nucleus and is an essential step in the pathway of gene expression.


High-dose ondansetron reduces activation of interoceptive and sensorimotor brain regions.
Several psychiatric disorders involve abnormalities of interoception and associated neural circuitry centered on the insula. The development of interventions modulating interoceptive circuits could lead to novel treatment approaches for these disorders. The 5-HT3 receptor antagonist ondansetron is a good candidate for the modulation of interoceptive circuits, as 5-HT3 receptors are located abundantly on sensory pathways and ondansetron has shown some clinical utility in disorders characterized by sensory and interoceptive abnormalities. The present study tested the ability of three different doses of ondansetron to engage neural regions involved in interoception to determine the drug's utility as a therapeutic agent to target circuit abnormalities in patients. Fifty-three healthy subjects were randomized to receive a single 8-mg (n = 18), 16-mg (n = 17), or 24-mg (n = 18) dose of ondansetron and placebo before MRI scanning on separate days. Subjects performed an fMRI task previously shown to engage interoceptive circuitry in which they viewed videos depicting body movements/sensation and control videos. The results revealed a highly significant relationship between dosage and activation in bilateral insula, somatosensory and premotor regions, cingulate cortex, and temporal cortex for control but not body-focused videos. These effects were driven by a robust reduction in activation for ondansetron compared to placebo for the 24-mg group, with weaker effects for the 16-mg and 8-mg groups. In conclusion, high-dose ondansetron reduces activation of several areas important for interoception, including insula and sensorimotor cortical regions. This study reveals the potential utility of this drug in modulating hyperactivity in these regions in patients.


Plasma noradrenaline as a measure of baroreflex sensitivity in hypertensive man.
1. Changes in plasma noradrenaline levels and heart rate were used as measures of baroreflex sensitivity in six hypertensive subjects given serial incremental doses of sodium nitroprusside (intravenously) to lower blood pressure. 2. The rises in both heart rate and plasma noradrenaline concentration were linearly related to the decrement in blood pressure and inversely related to the severity of the hypertension. 3. A positive correlation between rise in heart rate and rise in plasma noradrenaline was found for each subject. With increasing severity of hypertension, a greater increase in heart rate occurred for each increment in plasma noradrenaline concentration. 4. Baroreflex sensitivity can be assessed by relating changes in heart rate to change in arterial pressure; however, this method does not distinguish the relative contributions of the vagal and sympathetic components of the autonomic neural response or variations in the chronotropic response to sympathetic stimulation. 5. Changes in plasma noradrenaline levels in response to graded reductions in blood pressure may be a more appropriate measure of baroreflex sensitivity than the methods currently used in clinical investigation.