Food Photography Is Not an Accurate Measure of Energy Intake in Obese, Pregnant Women.
To improve weight management in pregnant women, there is a need to deliver specific, data-based recommendations on energy intake. This cross-sectional study evaluated the accuracy of an electronic reporting method to measure daily energy intake in pregnant women compared with total daily energy expenditure (TDEE). Twenty-three obese [mean ± SEM body mass index (kg/m2): 36.9 ± 1.3] pregnant women (aged 28.3 ±1.1 y) used a smartphone application to capture images of their food selection and plate waste in free-living conditions for ≥6 d in early (13-16 wk) and late (35-37 wk) pregnancy. Energy intake was evaluated by the smartphone application SmartIntake and compared with simultaneous assessment of TDEE obtained by doubly labeled water. Accuracy was defined as reported energy intake compared with TDEE (percentage of TDEE). Ecological momentary assessment prompts were used to enhance data reporting. Two-one-sided t tests for the 2 methods were used to assess equivalency, which was considered significant when accuracy was >80%. Energy intake reported by the SmartIntake application was 63.4% ± 2.3% of TDEE measured by doubly labeled water (P = 1.00). Energy intake reported as snacks accounted for 17% ± 2% of reported energy intake. Participants who used their own phones compared with participants who used borrowed phones captured more images (P = 0.04) and had higher accuracy (73% ± 3% compared with 60% ± 3% of TDEE; P = 0.01). Reported energy intake as snacks was significantly associated with the accuracy of SmartIntake (P = 0.03). To improve data quality, excluding erroneous days of likely underreporting (<60% TDEE) improved the accuracy of SmartIntake, yet this was not equivalent to TDEE (-22% ± 1% of TDEE; P = 1.00). Energy intake in obese, pregnant women obtained with the use of an electronic reporting method (SmartIntake) does not accurately estimate energy intake compared with doubly labeled water. However, accuracy improves by applying criteria to eliminate erroneous data. Further evaluation of electronic reporting in this population is needed to improve compliance, specifically for reporting frequent intake of small meals. This trial was registered at www.clinicaltrials.gov as NCT01954342.


Translating research into action: an international study of the role of research funders.
It is widely accepted that research can lead to improved health outcomes. However, translating research into meaningful impacts in peoples' lives requires actions that stretch well beyond those traditionally associated with knowledge creation. The research reported in this manuscript provides an international review of health research funders' efforts to encourage this process of research uptake, application and scaling, often referred to as knowledge translation. We conducted web-site review, document review and key informant interviews to investigate knowledge translation at 26 research funding agencies. The sample comprises the regions of Australia, Europe and North America, and a diverse range of funder types, including biomedical, clinical, multi-health domain, philanthropic, public and private organisations. The data builds on a 2008 study by the authors with the same international sample, which permitted longitudinal trend analysis. Knowledge translation is an objective of growing significance for funders across each region studied. However, there is no clear international consensus or standard on how funders might support knowledge translation. We found that approaches and mechanisms vary across region and funder type. Strategically tailored funding opportunities (grants) are the most prevalent modality of support. The most common funder-driven strategy for knowledge translation within these grants is the linking of researchers to research users. Funders could not to provide empirical evidence to support the majority of the knowledge translation activities they encourage or undertake. Knowledge translation at a research funder relies on context. Accordingly, we suggest that the diversity of approaches uncovered in our research is fitting. We argue that evaluation of funding agency efforts to promote and/or support knowledge translation should be prioritised and actioned. It is paradoxical that funders' efforts to get evidence into practice are not themselves evidence based.


Epigenetic alteration of microRNAs in DNMT3B-mutated patients of ICF syndrome.
Immunodeficiency, Centromeric region instability, Facial anomalies (ICF; OMIM #242860) syndrome, due to mutations in the DNMT3B gene, is characterized by inheritance of aberrant patterns of DNA methylation and heterochromatin defects. Patients show variable agammaglobulinemia and a reduced number of T cells, making them prone to infections and death before adulthood. Other variable symptoms include facial dysmorphism, growth and mental retardation. Despite the recent advances in identifying the dysregulated genes, the molecular mechanisms, which underlie the altered gene expression causing ICF phenotype complexity, are not well understood. Held the recently-shown tight correlation between epigenetics and microRNAs (miRNAs), we searched for miRNAs regulated by DNMT3B activity, comparing cell lines from ICF patients with those from healthy individuals. We observe that eighty-nine miRNAs, some of which involved in immune function, development and neurogenesis, are dysregulated in ICF (LCLs) compared to wild-type cells. Significant DNA hypomethylation of miRNA CpG islands was not observed in cases of miRNA up-regulation in ICF cells, suggesting a more subtle effect of DNMT3B deficiency on their regulation; however, a modification of histone marks, especially H3K27 and H3K4 trimethylation, and H4 acetylation, was observed concomitantly with changes in microRNA expression. Functional correlation between miRNA and mRNA expression of their targets allow us to suppose a regulation either at mRNA level or at protein level. These results provide a better understanding of how DNA methylation and histone code interact to regulate the class of microRNA genes and enable us to predict molecular events possibly contributing to ICF condition.


Role of O2 in the Growth of Rhizobium leguminosarum bv. viciae 3841 on Glucose and Succinate.
Insertion sequencing (INSeq) analysis of Rhizobium leguminosarum bv. viciae 3841 (Rlv3841) grown on glucose or succinate at both 21% and 1% O2 was used to understand how O2 concentration alters metabolism. Two transcriptional regulators were required for growth on glucose (pRL120207 [eryD] and RL0547 [phoB]), five were required on succinate (pRL100388, RL1641, RL1642, RL3427, and RL4524 [ecfL]), and three were required on 1% O2 (pRL110072, RL0545 [phoU], and RL4042). A novel toxin-antitoxin system was identified that could be important for generation of new plasmidless rhizobial strains. Rlv3841 appears to use the methylglyoxal pathway alongside the Entner-Doudoroff (ED) pathway and tricarboxylic acid (TCA) cycle for optimal growth on glucose. Surprisingly, the ED pathway was required for growth on succinate, suggesting that sugars made by gluconeogenesis must undergo recycling. Altered amino acid metabolism was specifically needed for growth on glucose, including RL2082 (gatB) and pRL120419 (opaA, encoding omega-amino acid:pyruvate transaminase). Growth on succinate specifically required enzymes of nucleobase synthesis, including ribose-phosphate pyrophosphokinase (RL3468 [prs]) and a cytosine deaminase (pRL90208 [codA]). Succinate growth was particularly dependent on cell surface factors, including the PrsD-PrsE type I secretion system and UDP-galactose production. Only RL2393 (glnB, encoding nitrogen regulatory protein PII) was specifically essential for growth on succinate at 1% O2, conditions similar to those experienced by N2-fixing bacteroids. Glutamate synthesis is constitutively activated in glnB mutants, suggesting that consumption of 2-ketoglutarate may increase flux through the TCA cycle, leading to excess reductant that cannot be reoxidized at 1% O2 and cell death. Rhizobium leguminosarum, a soil bacterium that forms N2-fixing symbioses with several agriculturally important leguminous plants (including pea, vetch, and lentil), has been widely utilized as a model to study Rhizobium-legume symbioses. Insertion sequencing (INSeq) has been used to identify factors needed for its growth on different carbon sources and O2 levels. Identification of these factors is fundamental to a better understanding of the cell physiology and core metabolism of this bacterium, which adapts to a variety of different carbon sources and O2 tensions during growth in soil and N2 fixation in symbiosis with legumes.


The AHF SCENE II Preceptorship Program: rationale and design of an educational program to optimize management of advanced heart failure.
Advanced heart failure requires specialized treatment to improve symptoms, increase survival, and reverse or slow disease progression. The Advanced Heart Failure Shared Clinical Experiences Network, or AHF SCENE, was founded in 1995 to provide small groups of health care professionals with better advanced heart failure management strategies by sharing clinical experiences from centers treating large numbers of patients. The original AHF SCENE program has since been modified to provide health care professionals with more information on current strategies for advanced heart failure management and to better serve the educational needs of professionals who care for these patients. AHF SCENE II promotes new methods, programs, procedures, and pharmacologic interventions and also describes strategies for tracking and improving clinical and economic outcomes in the management of advanced heart failure. AHF SCENE II supports the understanding that rapid, aggressive medical management is essential and is more effective in the context of a well designed program that spans the continuum of care. (c)2000 by CHF, Inc.


DEPDC5 variants increase fibrosis progression in Europeans with chronic hepatitis C virus infection.
Chronic hepatitis C virus (HCV) infection may progress to cirrhosis and hepatocellular carcinoma (HCC). Recently, two genetic variants, DEPDC5 rs1012068 and MICA rs2596542, were associated with the onset of HCC in Asian subjects with chronic HCV infection. The aim of the present study was to analyze whether DEPDC5 and MICA genetic variants were associated with liver disease progression in European subjects with chronic HCV infection. In a Northern Italian discovery cohort (n = 477), neither DEPDC5 rs1012068 nor MICA rs2596542 were associated with HCC (n = 150). However, DEPDC5 rs1012068 was independently associated with cirrhosis (n = 300; P = 0.049). The association of rs1012068 with moderate to severe fibrosis was confirmed in an independent cross-sectional German cohort (n = 415; P = 0.006). Furthermore, DEPDC5 rs1012068 predicted faster fibrosis progression in a prospective cohort (n = 247; P = 0.027). Next, we examined the distribution of nonsynonymous DEPDC5 variants in the overall cross-sectional cohort (n = 912). The presence of at least one variant increased the risk of moderate/severe fibrosis by 54% (P = 0.040). To understand the molecular mechanism underlying the genetic association of DEPDC5 variants with fibrosis progression, we performed in vitro studies on immortalized hepatic stellate cells (LX-2). In these cells, down-regulation of DEPDC5 resulted in increased expression of β-catenin and production of its target matrix metallopeptidase 2 (MMP2), a secreted enzyme involved in fibrosis progression. DEPDC5 variants increase fibrosis progression in European subjects with chronic HCV infection. Our findings suggest that DEPDC5 down-regulation may contribute to HCV-related fibrosis by increasing MMP2 synthesis through the β-catenin pathway.


Impact of gender on in-hospital outcomes following contemporary percutaneous intervention for peripheral arterial disease.
Percutaneous peripheral arterial intervention (PPAI) has emerged as an effective and less invasive alternative to surgery for peripheral arterial disease (PAD), however, data on gender differences in outcome of PPAI, especially in the stent era, are limited. The purpose of this study was to assess the gender differences on in-hospital outcomes of patients undergoing PPAI. We analyzed data on 268 consecutive patients (women: 122; men: 146) who underwent PPAI for PAD between October 2001 and January 2004. A total of 405 lesions (women: 184; men: 221) were treated. Background characteristics were similar except for less prevalent prior coronary intervention in women (18.0% versus 28.8%; p = 0.04), and more prevalent current smokers in women (22.1% versus 12.3%; p = 0.03). Upper extremities interventions were performed more often in women (9.2% versus 3.2%; p = 0.01). Procedure success was achieved in 89.3% of women and 89.7% of men (p = NS). In-hospital mortality was similar between women and men (1.6% versus 0.7%; p = NS). However, hemorrhagic complications occurred more frequently in women (7.4% versus 0.7%; p = 0.006). The blood transfusion rate was significantly higher in women (6.6% versus 0.7%; p = 0.013). Female gender was the only independent predictor of hemorrhagic complications (OR = 12.2; 95% CI = 1.39-111.1; p = 0.024). Percutaneous intervention for PAD can be performed in women with similar success rates as in men, albeit with a greater than 10-fold higher risk of hemorrhagic complications.


Genetics of acquired long QT syndrome.
The QT interval is the electrocardiographic manifestation of ventricular repolarization, is variable under physiologic conditions, and is measurably prolonged by many drugs. Rarely, however, individuals with normal base-line intervals may display exaggerated QT interval prolongation, and the potentially fatal polymorphic ventricular tachycardia torsade de pointes, with drugs or other environmental stressors such as heart block or heart failure. This review summarizes the molecular and cellular mechanisms underlying this acquired or drug-induced form of long QT syndrome, describes approaches to the analysis of a role for DNA variants in the mediation of individual susceptibility, and proposes that these concepts may be generalizable to common acquired arrhythmias.


Inhibitor of protein synthesis phase shifts a circadian pacemaker in mammalian SCN.
The suprachiasmatic nucleus (SCN) of the hypothalamus contains a circadian pacemaker that regulates many circadian rhythms in mammals. Experimental work in microorganisms and invertebrates suggests that protein synthesis is required for the function of the circadian oscillator, and recent experiments in golden hamsters suggest an acute inhibition of protein synthesis can induce phase shifts in a mammalian circadian pacemaker. To determine whether protein synthesis in the SCN region is involved in the generation of circadian rhythms in mammals, a protein synthesis inhibitor, anisomycin, was microinjected into the SCN region, and the effect on the circadian rhythm of locomotor activity of hamsters was measured. A single injection of anisomycin into the SCN region induced phase shifts in the circadian activity rhythm that varied systematically as a function of the phase of injection within the circadian cycle. These results suggest that protein synthesis may be involved in the generation of circadian rhythms in mammals and that the anatomic site of action of anisomycin is within the hypothalamic suprachiasmatic region.


Possible loss of length conservation and reciprocity during recombination or conversion in tandem arrays.
Recombination or conversion between arrays of repeated sequences need not be conservative for length because two single strands of DNA from one chromatid may form heteroduplexes in different registers on the other participating duplex. This can cause an overall change in repeat number. Loss of length conservation is equally possible whether models of recombination initiated by single-strand transfer or double-strand break are applicable. Length changing conversion will frequently produce a characteristic insertion within a deletion, often appearing as a double deletion such as are frequently found in new variants of human minisatellite MS32. There is no apparent means of preserving parity during length-changing conversion or recombination, and if the changes are biased then the overall copy number will increase or decrease according to that bias. The observation that arrays persist suggests that any bias in these arrays will be toward gains. An equilibrium may be reached where gains, which may be largely independent of array length, equal losses from the array-length-dependent processes of intrachromatid recombination and repeated unequal sister chromatid exchanges.


Rational improvement of the affinity and selectivity of integrin binding of grafted lasso peptides.
Integrins moderate diverse important functions in the human body and are promising targets in cancer therapy. Hence, the selective inhibition of specific integrins is of great medicinal interest. Here, we report the optimization of a grafted lasso peptide, yielding MccJ25(RGDF), which is a highly potent and selective αvβ3 integrin inhibitor. Furthermore, its NMR structure was elucidated and employed in a molecular dynamics approach, revealing information about the integrin binding mode and selectivity profile of MccJ25(RGDF).


The human locus coeruleus: computer reconstruction of cellular distribution.
Quantitative neuroanatomical techniques were developed to map the distribution of norepinephrine-containing locus coeruleus (LC) neurons in the adult human brain. These neurons reside in the dorsolateral pontine tegmentum and are identifiable by their neuromelanin pigment content. Five brains, ranging in age from 60 to 104 years, were examined. Outlines of coronal or sagittal sections containing the LC were entered into a computer along with the location of each cell, certain neuroanatomical landmarks, and cell size. Sections were aligned with specific neuroanatomical landmarks so that the computer-generated distribution of cells was representative of the in situ distribution of cells. Analysis of (1) the number of cells in sections throughout the rostrocaudal extent of the nucleus, (2) cell size, (3) 3-dimensional reconstructions of the distribution of cells within the brain stem, and (4) 2-dimensional cell-frequency maps, make it possible to quantitatively characterize the distribution of cells within this large nucleus. The total estimated number of LC cells on both sides of the brain ranged from 45,562 to 18,940 (youngest to oldest), and mean soma area ranged from 835 to 718 micron 2 (youngest to oldest). The nucleus is "tube-like" in shape, has a rostrocaudal extent of approximately 16 mm, and is bilaterally symmetrical. Two-dimensional cell-frequency maps were developed to illustrate the regional distribution of cell frequencies at any rostrocaudal/mediolateral point on the horizontal plane; the total unilateral area of the LC ranged from 32.8 to 17.2 mm2 (youngest to oldest). The techniques developed to characterize the 2- and 3-dimensional distributions of LC neurons can be used in future studies to quantitatively examine the effects of aging and disease on this and other brain nuclei.


Differential effects of Cytomegalovirus carriage on the immune phenotype of middle-aged males and females.
The elderly population is more susceptible to infections as a result of an altered immune response, commonly referred to as immunosenescence. Cytomegalovirus (CMV)-infection associated changes in blood lymphocytes are known to impact this process, but the interaction with gender remains unclear. Therefore, we analysed the effects and interaction of gender and CMV on the absolute numbers of a comprehensive set of naive and memory T- and B-cell subsets in people between 50 and 65 years of age. Enumeration and characterisation of lymphocyte subsets by flow cytometry was performed on fresh whole blood samples from 255 middle-aged persons. CMV-IgG serostatus was determined by ELISA. Gender was a major factor affecting immune cell numbers. CMV infection was mainly associated with an expansion of late-differentiated T-cell subsets. CMV+ males carried lower numbers of total CD4+, CD4+ central memory (CM) and follicular helper T-cells than females and CMV- males. Moreover, CMV+ males had significantly lower numbers of regulatory T (Treg)-cells and memory B-cells than CMV+ females. We here demonstrate an interaction between the effects of CMV infection and gender on T- and B-cells in middle-aged individuals. These differential effects on adaptive immunity between males and females may have implications for vaccination strategies at middle-age.


Effect of feeding systems on omega-3 fatty acids, conjugated linoleic acid and trans fatty acids in Australian beef cuts: potential impact on human health.
The influence of feeding systems on the levels of functional lipids and other fatty acid concentrations in Australian beef was examined. Rump, strip loin and blade cuts obtained from grass feeding, short-term grain feeding (80 days; STGF) and long-term grain feedlot rations (150-200 days; LTFL) were used in the present study. The typical Australian feedlot ration contains more than 50% barley and/or sorghum and balanced with whole cottonseed and protein meals were used as feed for STGF and LTFL regimens. Meat cuts from 18 cattle for each feeding regimen were trimmed of visible fat and connective tissue and then minced (300 g lean beef); replicate samples of 7 g were used for fatty acid (FA) analysis. There was a significantly higher level of total omega-3 (n-3) and long chain n-3 FA in grass-fed beef (P< 0.0001) than the grain-fed groups regardless of cut types. Cuts from STGF beef had significantly reduced levels of n-3 FA and conjugated linoleic acid (CLA) and similar levels of saturated, monounsaturated and n-6 FA compared with grass feeding (P < 0.001). Cuts from LTFL beef had higher levels of saturated, monounsaturated,n-6 FA and trans 18:1 than similar cuts from the other two groups (P<0.01), indicating that increased length of grain feeding was associated with more fat deposited in the carcass. There was a step-wise increase in trans 18:1 content from grass to STGF to LTGF, suggesting grain feeding elevates trans FA in beef, probably because of increased intake of 18:2n-6. Only grass-fed beef reached the target of more than 30mg of long chain n-3 FA/100 g muscle as recommended by Food Standard Australia and New Zealand for a food to be considered a source of omega-3 fatty acids. The proportions of trans 18:1 and n-6 FA were higher (P<0.001) for both grain-fed beef groups than grass-fed beef. Data from the present study show that grain feeding decreases functional lipid components (long chain n-3 FA and CLA) in Australian beef regardless of meat cuts, while increasing total trans 18:1 and saturated FA levels.


Choosing orientation: influence of cargo geometry and ActA polarization on actin comet tails.
Networks of polymerizing actin filaments can propel intracellular pathogens and drive movement of artificial particles in reconstituted systems. While biochemical mechanisms activating actin network assembly have been well characterized, it remains unclear how particle geometry and large-scale force balance affect emergent properties of movement. We reconstituted actin-based motility using ellipsoidal beads resembling the geometry of Listeria monocytogenes. Beads coated uniformly with the L. monocytogenes ActA protein migrated equally well in either of two distinct orientations, with their long axes parallel or perpendicular to the direction of motion, while intermediate orientations were unstable. When beads were coated with a fluid lipid bilayer rendering ActA laterally mobile, beads predominantly migrated with their long axes parallel to the direction of motion, mimicking the orientation of motile L. monocytogenes. Generating an accurate biophysical model to account for our observations required the combination of elastic-propulsion and tethered-ratchet actin-polymerization theories. Our results indicate that the characteristic orientation of L. monocytogenes must be due to polarized ActA rather than intrinsic actin network forces. Furthermore, viscoelastic stresses, forces, and torques produced by individual actin filaments and lateral movement of molecular complexes must all be incorporated to correctly predict large-scale behavior in the actin-based movement of nonspherical particles.


Dose-related effects of magnesium on myocardial function in the neonate.
The antagonistic effects of magnesium ion as a calcium ion blocker may decrease calcium influx associated with ischemia. However, the effect of magnesium on the preischemic neonatal myocardium has not been investigated previously. The purpose of this study was to investigate the effects of the administration of increasing doses of magnesium on left ventricular performance in the neonate. We assessed left ventricular function (pressure-volume data obtained by the conductance catheter/micromanometer technique) in three groups (n = 6 in each) of newborn pigs (3 to 5 days old) differing with respect to magnesium concentrations. End-systolic elastance did not change during infusion in group A (magnesium = 1.2 mmol/L), whereas in groups B (magnesium = 8 mmol/L) and C (magnesium = 16 mmol/L) it decreased significantly (P < .05) to 67 +/- 6% and 44 +/- 8% of baseline, respectively. The decrease in end-systolic elastance was associated with a significant reduction in cardiac output (P < .05) and stroke work (P < .05) in group C. After administration of magnesium, end-systolic elastance returned to baseline in group B in contrast to group C (78 +/- 3% of baseline value, P < .05). The slope constant of the end-diastolic pressure-volume relation decreased significantly (P < .05) from the preinfusion baseline values of 0.42 +/- 0.08 mL-1 in group B and 0.46 +/- 0.05 mL-1 in group C to 0.3 +/- 0.04 and 0.26 +/- 0.03 mL-1, respectively, versus no change in group A.(ABSTRACT TRUNCATED AT 250 WORDS)


Stand Out in Class: restructuring the classroom environment to reduce sitting time - findings from a pilot cluster randomised controlled trial.
Excessive sedentary behaviour (sitting) is a risk factor for poor health in children and adults. Incorporating sit-stand desks in the classroom environment has been highlighted as a potential strategy to reduce children's sitting time. The primary aim of this study was to examine the feasibility of conducting a cluster randomised controlled trial (RCT) of a sit-stand desk intervention within primary school classrooms. We conducted a two-armed pilot cluster RCT involving 8 primary schools in Bradford, United Kingdom. Schools were randomised on a 1:1 basis to the intervention or usual practice control arm. All children (aged 9-10 years) in participating classes were eligible to take part. Six sit-stand desks replaced three standard desks (sitting 6 children) in the intervention classrooms for 4.5-months. Teachers were encouraged to use a rotation system to ensure all pupils were exposed to the sit-stand desks for > 1 h/day on average. Trial feasibility outcomes (assessed using quantitative and qualitative measures) included school and participant recruitment and attrition, intervention and outcome measure completion rates, acceptability, and preliminary effectiveness of the intervention for reducing sitting time. A weighted linear regression model compared changes in weekday sitting time (assessed using the activPAL accelerometer) between trial arms. School and child recruitment rates were 33% (n = 8) and 75% (n = 176). At follow-up, retention rates were 100% for schools and 97% for children. Outcome measure completion rates ranged from 63 to 97%. A preliminary estimate of intervention effectiveness revealed a mean difference in change in sitting of - 30.6 min/day (95% CI: - 56.42 to - 4.84) in favour of the intervention group, after adjusting for baseline sitting and wear time. Qualitative measures revealed the intervention and evaluation procedures were acceptable to teachers and children, except for some problems with activPAL attachment. This study provides evidence of the acceptability and feasibility of a sit-stand desk intervention and evaluation methods. Preliminary evidence suggests the intervention showed potential in reducing children's weekday sitting but some adaptations to the desk rotation system are needed to maximize exposure. Lessons learnt from this trial will inform the planning of a definitive trial. ISRCTN12915848 (registered: 09/11/16).


Estrogenic pyrethroid pesticides regulate expression of estrogen receptor transcripts in mouse Sertoli cells differently from 17beta-estradiol.
Studies suggested that exposure to agricultural pesticides may affect male fertility. Pyrethroids are widely used pesticides due to their insecticidal potency and low mammalian toxicity. A recombinant yeast assay system incorporating the human alpha-estrogen receptor was used to analyze the estrogenicity of a range of readily available pyrethroid pesticides. The commercial product Ripcord Plus showed estrogenic activity by this assay. To determine whether pyrethroid compounds might exert an effect on male fertility, mouse Sertoli cells were exposed in vitro to the endogenous estrogen, 17beta-estradiol, and selected estrogenic pyrethroids. Following exposure, transcript levels of the alpha- and beta-estrogen receptors were assessed. Exposure of Sertoli cells to the pyrethroid compounds, both at high and at low published serum concentrations, affected the expression of the two estrogen receptors; however, the influence on estrogen receptor gene expression was different from the effect from exposure to 17beta-estradiol. These results from our model systems suggest that (1) estrogenic pyrethroid pesticides affect the estrogen receptors, and therefore potentially the endocrine system, in a different manner from that of endogenous estrogen, and (2) should cells in the male testes be exposed to pyrethroid pesticides, male fertility may be affected through molecular mechanisms involving estrogen receptors.


A three dimensional integral equation approach for fluids under confinement: Argon in zeolites.
In this work, we explore the ability of an inhomogeneous integral equation approach to provide a full three dimensional description of simple fluids under conditions of confinement in porous media. Explicitly, we will consider the case of argon adsorbed into silicalite-1, silicalite-2, and an all-silica analogue of faujasite, with a porous structure composed of linear (and zig-zag in the case of silicalite-1) channels of 5-8 Å diameter. The equation is based on the three dimensional Ornstein-Zernike approximation proposed by Beglov and Roux [J. Chem. Phys. 103, 360 (1995)] in combination with the use of an approximate fluid-fluid direct correlation function furnished by the replica Ornstein-Zernike equation with a hypernetted chain closure. Comparison with the results of grand canonical Monte Carlo/molecular dynamics simulations evidences that the theory provides an accurate description for the three dimensional density distribution of the adsorbed fluid, both at the level of density profiles and bidimensional density maps across representative sections of the porous material. In the case of very tight confinement (silicalite-1 and silicalite-2), solutions at low temperatures could not be found due to convergence difficulties, but for faujasite, which presents substantially larger channels, temperatures as low as 77 K are accessible to the integral equation. The overall results indicate that the theoretical approximation can be an excellent tool to characterize the microscopic adsorption behavior of porous materials.


Revision anterior cruciate ligament reconstruction with doubled semitendinosus and gracilis tendons and lateral extra-articular reconstruction.
The outcome of revision anterior cruciate ligament reconstruction has only rarely been reported. The purpose of this study was to evaluate the results of revision anterior cruciate ligament surgery with use of an autogenous doubled semitendinosus and gracilis graft in association with an extra-articular procedure. Between 1997 and 2003, thirty patients underwent a repeat reconstruction of a previously reconstructed torn anterior cruciate ligament with use of a doubled semitendinosus and gracilis graft combined with an extra-articular reconstruction. Primary reconstruction had been done with an autogenous patellar tendon graft in twenty-six patients and with a prosthetic ligament in four patients; the average time from the primary reconstruction to the revision was five years. Functional outcomes, graft survival, and radiographic outcomes were evaluated at a mean of five years. A graft was considered to have failed when a revision was done or when the side-to-side difference on KT-1000 arthrometer testing was >5 mm and/or the pivot-shift test grade was greater than a trace. One patient underwent another revision reconstruction because of graft failure at three years postoperatively. The mean International Knee Documentation Committee (IKDC) subjective knee score for the remaining twenty-nine patients was 84 +/- 12 points, and the mean Lysholm knee score was 90 +/- 10 points. The side-to-side difference as measured with the KT-1000 arthrometer with maximum manual force was <3 mm in twenty patients (of the twenty-eight who returned for follow-up), between 3 and 5 mm in six patients, and >5 mm in two patients. The result of the pivot shift examination was normal in fifteen patients, slightly positive in eleven patients, and positive in two patients. Twenty-five percent of the patients showed no radiographic signs of degenerative joint disease. Revision anterior cruciate ligament reconstruction with use of an autogenous doubled semitendinosus and gracilis graft combined with an extra-articular procedure provided satisfactory functional outcomes, with a failure rate of 10%.


Application of electronic diaries in patients with schizophrenia and bipolar disorders.
Despite the dissemination of second generation antipsychotics for schizophrenia and bipolar disorder, outcomes remain suboptimal, largely due to poor treatment and drug adherence. The primary aim of the current study was to assess the tolerability, validity and feasibility of the pocket-sized electronic diary Medicus®. Our case observations attempted to evaluate eighteen patients suffering from schizophrenia and bipolar disorder. All of the patients were treated with the second generation antipsychotic quetiapine. We followed them up in two German medical centers over two years. The present results display an improvement of mood-stability in all patients treated with quetiapine. All patients were in regular contact to their psychiatrist over a period of 24 months. A complete description of the coherences between the symptoms was essential for estimation, which was conducted by Medicus®. Moreover, Medicus® seem to be useful for improving compliance within a medication regimen. Although uncontrolled case observations can only be interpreted with caution, Medicus® seems to deserve further investigation and may hold the potential to optimize treatment and drug adherence in patients suffering from schizophrenia and bipolar disorders.


How to Integrate Personalized Medicine into Prevention? Recommendations from the Personalized Prevention of Chronic Diseases (PRECeDI) Consortium.
Medical practitioners are increasingly adopting a personalized medicine (PM) approach involving individually tailored patient care. The Personalized Prevention of Chronic Diseases (PRECeDI) consortium project, funded within the Marie Skłodowska Curie Action (MSCA) Research and Innovation Staff Exchange (RISE) scheme, had fostered collaboration on PM research and training with special emphasis on the prevention of chronic diseases. From 2014 to 2018, the PRECeDI consortium trained 50 staff members on personalized prevention of chronic diseases through training and research. The acquisition of skills from researchers came from dedicated secondments from academic and nonacademic institutions aimed at training on several research topics related to personalized prevention of cancer and cardiovascular and neurodegenerative diseases. In detail, 5 research domains were addressed: (1) identification and validation of biomarkers for the primary prevention of cardiovascular diseases, secondary prevention of Alzheimer disease, and tertiary prevention of head and neck cancer; (2) economic evaluation of genomic applications; (3) ethical-legal and policy issues surrounding PM; (4) sociotechnical analysis of the pros and cons of informing healthy individuals on their genome; and (5) identification of organizational models for the provision of predictive genetic testing. Based on the results of the research carried out by the PRECeDI consortium, in November 2018, a set of recommendations for policy makers, scientists, and industry has been issued, with the main goal to foster the integration of PM approaches in the field of chronic disease prevention.


A single 13-kilobase divergent locus in the Kaposi sarcoma-associated herpesvirus (human herpesvirus 8) genome contains nine open reading frames that are homologous to or related to cellular proteins.
Two small fragments of a novel human gammaherpesvirus genome known as Kaposi's sarcoma (KS)-associated herpesvirus or human herpesvirus 8 (HHV-8) have been shown to be present in virtually all AIDS and non-AIDS KS lesions, as well as in body cavity-based lymphomas (BCBL) and in multicentric Castleman's disease. We have extended those studies by identifying and sequencing a third fragment of HHV-8 DNA encoding a viral thymidylate synthetase (TS) gene. Use of this viral TS fragment as a probe led to the identification and mapping of a cluster of overlapping phage lambda clones from a BCBL tumor DNA genomic library that spanned 48 kb on the left-hand side of the HHV-8 genome between the equivalents of open reading frame 6 (ORF6) and ORF31 of herpesvirus saimiri (HVS). DNA sequencing of a 17-kb segment encompassing a gammaherpesvirus divergent locus (DL-B) between ORF11 and ORF17 revealed the presence of nine viral ORFs with predicted gene products related to cellular proteins. These include the complete TS gene and a dihydrofolate reductase (DHFR) gene, four novel cytokine genes (encoding viral interleukin-6, viral MIP-1A, viral MIP-1B, and BCK) that have not previously been found to be encoded by a virus, and a bcl-2 homolog. This region in HHV-8 also contains the T1.1 abundant lytic cycle nuclear RNA gene and encompasses two genes (or exons) encoding proteins with C4HC3 zinc finger domains of the PHD/leukemia-associated protein subtype. The latter are related to the spliced immediate-early IE1 protein of the gamma-2 class herpesvirus bovine herpesvirus type 4 and a similar motif found in HVS ORF12. Although genes for TS and DHFR enzymes are also encoded by HVS (ORF70 and ORF2), both occur at different genomic loci than in HHV-8, and the HHV-8 DHFR protein is much farther diverged from human DHFR than is the HVS version, implying that they were probably acquired as host cell cDNAs by independent evolutionary events. Transcripts from the IE1-A, IE1-B, DHFR, and MIP-1B genes were all detected by Northern blot hybridization analysis in a BCBL cell line at 12 h after induction with butyrate but were not present before induction, indicating that these are all primarily lytic cycle genes. We conclude that the DL-B locus of gammaherpesviruses displays considerably more variability that previously appreciated and that expression of many of these genes is likely to have important implications for HHV-8 biology and therapy.


Notch activation is dispensable for D, L-sulforaphane-mediated inhibition of human prostate cancer cell migration.
D, L-Sulforaphane (SFN), a synthetic racemic analog of broccoli constituent L-sulforaphane, is a highly promising cancer chemopreventive agent with in vivo efficacy against chemically-induced as well as oncogene-driven cancer in preclinical rodent models. Cancer chemopreventive effect of SFN is characterized by G(2)/M phase cell cycle arrest, apoptosis induction, and inhibition of cell migration and invasion. Moreover, SFN inhibits multiple oncogenic signaling pathways often hyperactive in human cancers, including nuclear factor-κB, Akt, signal transducer and activator of transcription 3, and androgen receptor. The present study was designed to determine the role of Notch signaling, which is constitutively active in many human cancers, in anticancer effects of SFN using prostate cancer cells as a model. Exposure of human prostate cancer cells (PC-3, LNCaP, and/or LNCaP-C4-2B) to SFN as well as its naturally-occurring thio-, sulfinyl-, and sulfonyl-analogs resulted in cleavage (activation) of Notch1, Notch2, and Notch4, which was accompanied by a decrease in levels of full-length Notch forms especially at the 16- and 24-hour time points. The SFN-mediated cleavage of Notch isoforms was associated with its transcriptional activation as evidenced by RBP-Jk-, HES-1A/B- and HEY-1 luciferase reporter assays. Migration of PC-3 and LNCaP cells was decreased significantly by RNA interference of Notch1 and Notch2, but not Notch4. Furthermore, SFN-mediated inhibition of PC-3 and LNCaP cell migration was only marginally affected by knockdown of Notch1 and Notch2. Strikingly, SFN administration to Transgenic Adenocarcinoma of Mouse Prostate transgenic mice failed to increase levels of cleaved Notch1, cleaved Notch2, and HES-1 proteins in vivo in prostatic intraepithelial neoplasia, well-differentiated carcinoma or poorly-differentiated prostate cancer lesions. These results indicate that Notch activation is largely dispensable for SFN-mediated inhibition of cell migration, which should be viewed as a therapeutic advantage as Notch activation is frequent in human prostate cancers.


Survival and echocardiographic data in dogs with congestive heart failure caused by mitral valve disease and treated by multiple drugs: a retrospective study of 21 cases.
This retrospective study reports the survival time [onset of congestive heart failure (CHF) to death from any cause] of 21 dogs with mitral regurgitation (MR) and CHF treated with a combination of furosemide, angiotensin-converting enzyme inhibitor (ACEI, benazepril, or enalapril), pimobendan, spironolactone, and amlodipine. Baseline echocardiographic data: end-systolic and end-diastolic volume indices (ESVI and EDVI), left atrium to aorta ratio (LA/Ao), and regurgitant fraction (RF) are reported. Median survival time (MST) was 430 d. Initial dosage of furosemide (P = 0.0081) and LA/Ao (P = 0.042) were negatively associated with survival. Baseline echocardiographic indices (mean ± standard deviation) were 40.24 ± 16.76 for ESVI, 161.48 ± 44.49 mL/m(2) for EDVI, 2.11 ± 0.75 for LA/Ao, and 64.71 ± 16.85% for RF. Combining furosemide, ACEI, pimobendan, spironolactone, and amlodipine may result in long survival times in dogs with MR and CHF. Severity of MR at onset of CHF is at least moderate.


[Fluorescent derivatives of diphtheria toxin subunit B and their interaction with Vero cells].
Diphtheria toxin's B subunit provides toxin interaction with its receptor on the cell surface and translocation of toxin's A subunit from endosome to cytozole of sensitive cells. Functional analogues of B subunit with fluorescent label are considered as perspective tools for studying the above mentioned processes. The aim of the work was to obtain fluorescent B subunit analogues and to detect the specificity of their interaction with Vero line cells. B subunit fluorescent analogues were obtained in two different ways. The first one was B subunit chemical conjugation with fluorescein isothiocyanate and the second one was genetic fusion of recombinant B subunit chain with enhanced green fluorescent protein chain. Specific interaction of B subunit fluorescent derivatives with Vero cells was studied by flow cytometry and confocal microscopy. Using competitive analysis it was shown that B subunit fluorescent analogues possessed different affinity for cells. The affinity of EGFP-SbB was higher than FITC-SbB. Our results indicate the possibility to use the fluorescent derivatives of B subunit as tools for identification of diphtheria toxin's receptor (HB-EGF) expression on the cell surface as well as for studying the interaction and penetration of diphtheria toxin to the cell.


Thermally assisted recording of holographic gratings in semicrystalline azobenzene-containing polymers.
We examine optically induced birefringence in semicrystalline azopolymer films that are held at glass-transition temperature Tg. The birefringence increases markedly after interception of the pump beam; the saturation value depends on exposure time. In addition, the induced birefringence is completely erased by irradiation with a circularly polarized beam at Tg. Using this thermally assisted method, we demonstrate the holographic recording of a test image. The intensity of the diffracted beam also increases after interception of the writing beams. Furthermore, the retrieved image is found to have a resolution of approximately 30 lp/mm. This resolution is comparable with that of the optical setup that is used. Accordingly, the thermally assisted recording by use of semicrystalline azopolymers is a promising method for reversible holographic storage.


Mineralocorticoid Receptor Antagonists in the Management of Heart Failure and Resistant Hypertension: A Review.
Heart failure (HF), with or without reduced ejection fraction, and multidrug-resistant hypertension (RHT) are major worldwide health problems of ever-increasing proportions. The mineralocorticoid receptor antagonists (MRAs) spironolactone and eplerenone have proved valuable additions to the overall management of these disorders in patients without significant renal dysfunction. Neurohormonal activation, including aldosteronism, in HF and RHT, has provided the pathophysiologic basis for the inclusion of MRA in the overall management of these disorders and the respective survival benefit and control of blood pressure. Furthermore, MRAs attenuate the appearance of secondary hyperparathyroidism that accompanies excretory Ca2+ losses induced by aldosteronism in which elevated parathyroid hormone levels raise the risk of adverse cardiovascular events and atraumatic bone fracture. Serial surveillance of serum electrolytes and creatinine levels is mandated to avoid serious hyperkalemia (potassium concentration >5.5 mEq/L) and its attendant risks in patients receiving MRAs. Mineralocorticoid receptor antagonists are a valuable addition to the practice of medicine. Their judicious use in patients with HF or RHT can improve treatment of these patients.


Experience-dependent modulation of antennal sensitivity and input to antennal lobes in male moths (Spodoptera littoralis) pre-exposed to sex pheromone.
Sex pheromones are intraspecific olfactory signals emitted by one sex to attract a potential mating partner. Behavioural responses to sex pheromones are generally highly stereotyped. However, they can be modulated by experience, as male moths previously exposed to female sex pheromone respond with a lower threshold upon further detection, even after long delays. Here, we address the question of the neural mechanisms underlying such long-term modulation. As previous work has shown increased responses to pheromone in central olfactory neurons, we asked whether brief exposure to the pheromone increases input activity from olfactory receptor neurons. Males pre-exposed to sex pheromone exhibited increased peripheral sensitivity to the main pheromone component. Among nine antennal genes targeted as putatively involved in pheromone reception, one encoding a pheromone-binding protein showed significant upregulation upon exposure. In the primary olfactory centre (antennal lobe), the neural compartment processing the main pheromone component was enlarged after a brief pheromone exposure, thus suggesting enduring structural changes. We hypothesise that higher peripheral sensitivity following pre-exposure leads to increased input to the antennal lobe, thus contributing to the structural and functional reorganization underlying a stable change in behaviour.


Chromosomal biomarkers for detection of human papillomavirus associated genomic instability in epithelial cells of cervical cytology specimens.
The goal of this study was to compare how accumulation of chromosomal aberrations in human papillomavirus (HPV)-infected cells correlates with the severity of cervical dysplastic lesions. We assessed the frequency of genomic alterations for 35 different loci in a pilot biopsy study and selected two loci (3q26 and 8q24) with the highest frequency of copy number gains found in high-grade dysplasia and cancer. These probes were labeled with gold and red fluorophores and combined with HPV biotin-labeled probes for subsequent detection using a tyramide signal amplification system with a green fluorophore. Cells that were both HPV positive and chromosomally abnormal were designated as "double-positive cells." Cervical cytology specimens from 235 patients were used for this blinded study. The average number of double-positive cells increased from two cells in patients with a cytological interpretation of atypical squamous cells of undetermined significance to 22 cells in low-grade squamous intraepithelial lesion and 99 cells in high-grade squamous intraepithelial lesion, reflecting an accumulation of chromosomal abnormality with disease progression. Using a cutoff of four or more double-positive cells as the criterion for the presence of a cervical intraepithelial neoplasia 2 or 3 lesion, we demonstrated that low-grade squamous intraepithelial lesion and high-grade squamous intraepithelial lesion cytology specimens with underlying cervical intraepithelial neoplasia 2/3 histology showed positive test results in more than 80% of cases. Correlation of 3q26 and 8q24 aneusomy with concurrent HPV infection may thus serve as a biomarker of genetic instability in HPV-infected cells.


Optimization of selective stimulation parameters for multi-contact electrodes.
Multi-contact stimulating electrodes are gaining acceptance as a means for interfacing with the peripheral nervous system. These electrodes can potentially activate many independent populations of motor units within a single peripheral nerve, but quantifying their recruitment properties and the overlap in stimulation between contacts is difficult and time consuming. Further, current methods for quantifying overlap between contacts are ambiguous and can lead to suboptimal selective stimulation parameters. This study describes a novel method for optimizing stimulation parameters for multi-contact peripheral stimulating electrodes to produce strong, selective muscle contractions. The method is tested with four-contact spiral nerve-cuff electrodes implanted on bilateral femoral nerves of two individuals with spinal cord injury, but it is designed to be extendable to other electrode technologies with higher densities of contacts. To optimize selective stimulation parameters for multi-contact electrodes, first, recruitment and overlap are characterized for all contacts within an electrode. Recruitment is measured with the twitch response to single stimulus pulses, and overlap between pairs of contacts is quantified by the deviation in their combined response from linear addition of individual responses. Simple mathematical models are fit to recruitment and overlap data, and a cost function is defined to maximize recruitment and minimize overlap between all contacts. Results are presented for four-contact nerve-cuff electrodes stimulating bilateral femoral nerves of two human subjects with spinal cord injury. Knee extension moments between 11.6 and 43.2 Nm were achieved with selective stimulation through multiple contacts of each nerve-cuff with less than 10% overlap between pairs of contacts. The overlap in stimulation measured in response to selective stimulation parameters was stable at multiple repeated time points after implantation. These results suggest that the method described here can provide an automated means of determining stimulus parameters to achieve strong muscle contractions via selective stimulation through multi-contact peripheral nerve electrodes.


Human and swine hosts share vancomycin-resistant Enterococcus faecium CC17 and CC5 and Enterococcus faecalis CC2 clonal clusters harboring Tn1546 on indistinguishable plasmids.
VRE isolates from pigs (n = 29) and healthy persons (n = 12) recovered during wide surveillance studies performed in Portugal, Denmark, Spain, Switzerland, and the United States (1995 to 2008) were compared with outbreak/prevalent VRE clinical strains (n = 190; 23 countries; 1986 to 2009). Thirty clonally related Enterococcus faecium clonal complex 5 (CC5) isolates (17 sequence type 6 [ST6], 6 ST5, 5 ST185, 1 ST147, and 1 ST493) were obtained from feces of swine and healthy humans. This collection included isolates widespread among pigs of European Union (EU) countries since the mid-1990s. Each ST comprised isolates showing similar pulsed-field gel electrophoresis (PFGE) patterns (≤6 bands difference; >82% similarity). Some CC5 PFGE subtype strains from swine were indistinguishable from hospital vancomycin-resistant enterococci (VRE) causing infections. A truncated variant of Tn1546 (encoding resistance to vancomycin) and tcrB (coding for resistance to copper) were consistently located on 150- to 190-kb plasmids (rep(pLG1)). E. faecium CC17 (ST132) isolates from pig manure and two clinical samples showed identical PFGE profiles and contained a 60-kb mosaic plasmid (rep(Inc18) plus rep(pRUM)) carrying diverse Tn1546-IS1216 variants. The only Enterococcus faecalis isolate obtained from pigs (CC2-ST6) corresponded to a multidrug-resistant clone widely disseminated in hospitals in Italy, Portugal, and Spain, and both animal and human isolates harbored an indistinguishable 100-kb mosaic plasmid (rep(pRE25) plus rep(pCF10)) containing the whole Tn1546 backbone. The results indicate a current intra- and international spread of E. faecium and E. faecalis clones and their plasmids among swine and humans.


A computer-aided drug discovery system for chemistry teaching.
The Schools Malaria Project (http://emalaria.soton.ac.uk/) brings together school students with university researchers in the hunt for a new antimalaria drug. The design challenge being offered to students is to use a distributed drug search and selection system to design potential antimalaria drugs. The system is accessed via a Web interface. This e-science project displays the results of the trials in an accessible manner, giving students an opportunity for discussion and debate both with peers and with the university contacts. The project has been implemented by using distributed computing techniques, spreading computer load over a network of machines that cross institutional boundaries, forming a grid. This provides access to greater computing power and allows a much more complex and detailed formulation of the drug design problem to be tackled for research, teaching, and learning.


Ionic homeostasis in brain conditioning.
Most of the current focus on developing neuroprotective therapies is aimed at preventing neuronal death. However, these approaches have not been successful despite many years of clinical trials mainly because the numerous side effects observed in humans and absent in animals used at preclinical level. Recently, the research in this field aims to overcome this problem by developing strategies which induce, mimic, or boost endogenous protective responses and thus do not interfere with physiological neurotransmission. Preconditioning is a protective strategy in which a subliminal stimulus is applied before a subsequent harmful stimulus, thus inducing a state of tolerance in which the injury inflicted by the challenge is mitigated. Tolerance may be observed in ischemia, seizure, and infection. Since it requires protein synthesis, it confers delayed and temporary neuroprotection, taking hours to develop, with a pick at 1-3 days. A new promising approach for neuroprotection derives from post-conditioning, in which neuroprotection is achieved by a modified reperfusion subsequent to a prolonged ischemic episode. Many pathways have been proposed as plausible mechanisms to explain the neuroprotection offered by preconditioning and post-conditioning. Although the mechanisms through which these two endogenous protective strategies exert their effects are not yet fully understood, recent evidence highlights that the maintenance of ionic homeostasis plays a key role in propagating these neuroprotective phenomena. The present article will review the role of protein transporters and ionic channels involved in the control of ionic homeostasis in the neuroprotective effect of ischemic preconditioning and post-conditioning in adult brain, with particular regards to the Na(+)/Ca2(+) exchangers (NCX), the plasma membrane Ca2(+)-ATPase (PMCA), the Na(+)/H(+) exchange (NHE), the Na(+)/K(+)/2Cl(-) cotransport (NKCC) and the acid-sensing cation channels (ASIC). Ischemic stroke is the third leading cause of death and disability. Up until now, all clinical trials testing potential stroke neuroprotectants failed. For this reason attention of researchers has been focusing on the identification of brain endogenous neuroprotective mechanisms activated after cerebral ischemia. In this context, ischemic preconditioning and ischemic post-conditioning represent two neuroprotecive strategies to investigate in order to identify new molecular target to reduce the ischemic damage.


Postsynaptic modulation of rectifying electrical synaptic inputs to the LG escape command neuron in crayfish.
The lateral giant (LG) tail-flip escape system of crayfish is organized to provide a massive convergence of mechanosensory inputs onto the LG command neuron through electrical synapses from both mechanosensory afferents and interneurons. We used electrophysiological techniques to show that the connections between three major mechanosensory interneurons and LG rectify, and that their inputs to LG can be reduced by postsynaptic depolarization and increased by postsynaptic hyperpolarization. The mechanosensory afferents and interneurons are excited by sensory nerve shock, and the components of the resulting LG PSP can be similarly modulated by the same postsynaptic potential changes. Because these inputs are all made through electrical synapses, we conclude that they are rectifying connections, as well. To test the physical plausibility of this conclusion, we developed an electrical model of the rectifying connection between a mechanosensory interneuron and LG, and found that it can reproduce all the qualitative features of the orthodromic and antidromic experimental responses. The ability of postsynaptic membrane potential to modulate inputs through rectifying electrical synapses is used in the escape system to enhance LG's relative sensitivity to novel, phasic stimuli. Postsynaptic depolarization of LG produced by earlier inputs "reverse-biases" the rectifying input synapses and reduces their strength relative to times when LG is at rest.


Automatic relevance determination in nonnegative matrix factorization with the β-divergence.
This paper addresses the estimation of the latent dimensionality in nonnegative matrix factorization (NMF) with the β-divergence. The β-divergence is a family of cost functions that includes the squared euclidean distance, Kullback-Leibler (KL) and Itakura-Saito (IS) divergences as special cases. Learning the model order is important as it is necessary to strike the right balance between data fidelity and overfitting. We propose a Bayesian model based on automatic relevance determination (ARD) in which the columns of the dictionary matrix and the rows of the activation matrix are tied together through a common scale parameter in their prior. A family of majorization-minimization (MM) algorithms is proposed for maximum a posteriori (MAP) estimation. A subset of scale parameters is driven to a small lower bound in the course of inference, with the effect of pruning the corresponding spurious components. We demonstrate the efficacy and robustness of our algorithms by performing extensive experiments on synthetic data, the swimmer dataset, a music decomposition example, and a stock price prediction task.


"Invisible Voices": A Critical Incident Study of Family Caregivers' Experience of Nursing Homes After Their Elder Relative's Death.
The literature provides few examples of family caregivers' retrospective evaluation of nursing home services. This study aimed at analyzing narratives of Italian family caregivers of elders who experienced nursing home placement. Data were gathered through in-depth interviews with family members after their relatives' death. The interviews were based on the Critical Incident Technique, which allowed the categorization of the most memorable positive and negative events from the perspective of family members of elders deceased in nursing homes. Interviews were interpreted with a phenomenologically inspired thematic analysis approach. Participants were screened for complicated grief disorder as a confounding variable in relatives' accounts of the treatment. Results suggested that positive long-term recollection of the nursing home was associated with different themes emerging from the interviews: medical reliability and expertise, active demonstrations of care that extend beyond the contract with the facility, individualized attention, responsiveness, openness to dialog with family members about routines, management of the first impression, and family engagement. Lack of professionals' expertise and medical failures, lack of care for patients' personal goods, lack of family involvement, lack of individualized attention, lack of responsiveness, poor patient surveillance, and structural limits of the facilities were the themes that were more frequently negatively associated with the nursing home experience. Focusing on the key dimensions connected to the quality of the experience of family members can enrich the quality of existing nursing home services and allow healthcare policymakers and managers to design better facilities for the patients.


[Human pluripotent stem cells and liver disorders].
The liver is associated with many diseases including metabolic and cholestatic diseases, cirrhosis as well as chronic and acute hepatitis. However, knowledge about the mechanisms involved in the pathophysiology of these diseases remains limited due to the restricted access to liver biopsies and the lack of cellular models derived from patients. The liver is the main organ responsible for the elimination of xenobiotics and thus hepatocytes have a key role in toxicology and pharmacokinetics. The induced pluripotent stem cells generated from patients with monogenic metabolic disorders, for which the corresponding gene is identified, are relevant in vitro models for the study of the mechanisms involved in generation of pathologies and also for drug screening. Towards this aim, robust protocols for generating liver cells, such as hepatocytes and cholangiocytes, are essential. Our study focused on familial hypercholesterolemia disease modeling, as well as on establishing a protocol for generation of functional cholangiocytes from pluripotent stem cells.


A unique proteolytic fragment of alpha1-antitrypsin is elevated in ductal fluid of breast cancer patient.
By comparison of mass spectra from a small cohort of nipple aspiration fluids (NAF), we previously discovered a panel of five candidate breast cancer biomarkers among them an unidentified 4.7 kD peptide BF5. The purposes of the present study were to verify the presence of BF5 in an independent cohort; to determine the protein identity of BF5; and to provide insight into the biology of BF5 production and elevation in tumor-associated NAF. We prospectively collected bilaterally matched NAF from patients with unilateral Stage I/II breast cancer (IBC-31), ductal carcinoma in situ (DCIS-6), atypical ductal hyperplasia (ADH-5), and presumed healthy women who came to routine mammography and had a normal exam (31). Following the consolidation of its cancer-associated expression on SELDI-mass spectrometry, BF5 was isolated by gel electrophoresis and sequenced by tandem mass spectrometry. BF5 was elevated in 15-25% of women with IBC, DCIS, or ADH vs. 0% of controls. This elevation was restricted to the affected breasts. BF5 was identified as 41/42-aa C-terminal peptide of alpha1-antitrypsin (AAT), the principle inhibitor of serine protease neutrophile elastase. The full length AAT showed a consistent expression pattern as C-41/42, and C-41/42 can be generated in vitro by MMP-7 cleavage. In conclusion, elevated C-41/42 is likely the result of elevated AAT synthesis, and the activity of specific MMPs present within the tumor. As other C-terminal fragments of AAT are reported to function as tumor-derived suppressors to the host immune-system, elevated C-41/42 may also be predictive of a poor outcome.


Clinical utility of existing and second-generation interferon-γ release assays for diagnostic evaluation of tuberculosis: an observational cohort study.
The clinical utility of interferon-γ release assays (IGRAs) for diagnosis of active tuberculosis is unclear, although they are commonly used in countries with a low incidence of tuberculosis. We aimed to resolve this clinical uncertainty by determining the accuracy and utility of commercially available and second-generation IGRAs in the diagnostic assessment of suspected tuberculosis in a low-incidence setting. We did a prospective cohort study of adults with suspected tuberculosis in routine secondary care in England. Patients were tested for Mycobacterium tuberculosis infection at baseline with commercially available (T-SPOT.TB and QuantiFERON-TB Gold In-Tube [QFT-GIT]) and second-generation (incorporating novel M tuberculosis antigens) IGRAs and followed up for 6-12 months to establish definitive diagnoses. Sensitivity, specificity, positive and negative likelihood ratios, and predictive values of the tests were determined. Of the 1060 adults enrolled in the study, 845 were included in the analyses and 363 were diagnosed with tuberculosis. Sensitivity of T-SPOT.TB for all tuberculosis diagnosis, including culture-confirmed and highly probable cases, was 81·4% (95% CI 76·6-85·3), which was higher than QFT-GIT (67·3% [62·0-72·1]). Second-generation IGRAs had a sensitivity of 94·0% (90·0-96·4) for culture-confirmed tuberculosis and 89·2% (85·2-92·2) when including highly probable tuberculosis, giving a negative likelihood ratio for all tuberculosis cases of 0·13 (95% CI 0·10-0·19). Specificity ranged from 86·2% (95% CI 82·3-89·4) for T-SPOT.TB to 80·0% (75·6-83·8) for second-generation IGRAs. Commercially available IGRAs do not have sufficient accuracy for diagnostic evaluation of suspected tuberculosis. Second-generation tests, however, might have sufficiently high sensitivity, low negative likelihood ratio, and correspondingly high negative predictive value in low-incidence settings to facilitate prompt rule-out of tuberculosis. National Institute for Health Research.


Effects of calcium supplementation during pregnancy on maternal, fetal and birth outcomes.
Gestational hypertensive disorders are the second leading cause of maternal death worldwide. Epidemiological and clinical studies have shown that an inverse relationship exists between calcium intake and development of hypertension in pregnancy. The purpose of this review was to evaluate preventive effect of calcium supplementation during pregnancy on gestational hypertensive disorders and related maternal and neonatal morbidity and mortality. A literature search was carried out on PubMed, WHOLIS, PAHO and Cochrane Library. Only randomised trials were included in the review. Data were extracted into a standardised Excel sheet. Primary outcomes were pre-eclampsia, preterm birth and birthweight. Other neonatal outcomes such as neonatal mortality, small-for-gestational age and low birthweight were also evaluated. A total of 15 randomised controlled trials were included in this review. Pooled analysis showed that calcium supplementation during pregnancy reduced risk of pre-eclampsia by 52% [relative risk (RR) 0.48; 95% confidence interval (CI) 0.34, 0.67] and that of severe pre-eclampsia by 25% (RR 0.75 [95% CI 0.57, 0.98]). There was no effect on incidence of eclampsia (RR 0.73 [95% CI 0.41, 1.27]). There was a significant reduction for risk of maternal mortality/severe morbidity (RR 0.80 [95% CI 0.65, 0.97]). Calcium supplementation during pregnancy was also associated with a significant reduction in risk of pre-term birth (RR 0.76 [95% CI 0.60, 0.97]). There was an extra gain of 85 g in the intervention group compared with control (mean difference 85 g [95% CI 37, 133]). There was no effect of calcium supplementation on perinatal mortality (RR 0.90 [95% CI 0.74, 1.09]). There was a statistically non-significant increased risk of urolithiasis in the intervention group compared with control (RR 1.52 [95% CI 0.06, 40.67]). In conclusion, calcium supplementation during pregnancy is associated with a reduction in risk of gestational hypertensive disorders and pre-term birth and an increase in birthweight. There is no increased risk of kidney stones.


Action potential amplitude as a noninvasive indicator of motor unit-specific hypertrophy.
Skeletal muscle fibers hypertrophy in response to strength training, with type II fibers generally demonstrating the greatest plasticity in regards to cross-sectional area (CSA). However, assessing fiber type-specific CSA in humans requires invasive muscle biopsies. With advancements in the decomposition of surface electromyographic (sEMG) signals recorded using multichannel electrode arrays, the firing properties of individual motor units (MUs) can now be detected noninvasively. Since action potential amplitude (APSIZE) has a documented relationship with muscle fiber size, as well as with its parent MU's recruitment threshold (RT) force, our purpose was to examine if MU APSIZE, as a function of its RT (i.e., the size principle), could potentially be used as a longitudinal indicator of MU-specific hypertrophy. By decomposing the sEMG signals from the vastus lateralis muscle of 10 subjects during maximal voluntary knee extensions, we noninvasively assessed the relationship between MU APSIZE and RT before and immediately after an 8-wk strength training intervention. In addition to significant increases in muscle size and strength (P < 0.02), our data show that training elicited an increase in MU APSIZE of high-threshold MUs. Additionally, a large portion of the variance (83.6%) in the change in each individual's relationship between MU APSIZE and RT was explained by training-induced changes in whole muscle CSA (obtained via ultrasonography). Our findings suggest that the noninvasive, electrophysiological assessment of longitudinal changes to MU APSIZE appears to reflect hypertrophy specific to MUs across the RT continuum.


The distribution of HLA class II haplotypes reveals that the Sardinian population is genetically differentiated from the other Caucasian populations.
In this study we have established the frequencies of the DRB1-DQA1-DQB1 haplotypes in a large cohort of Sardinian new-borns and found that the most frequent haplotypes were detected at frequencies unique to the Sardinians. Other haplotypes, common in other Caucasian populations, are rare or absent across the island. Next, the DRB1-DQA1-DQB1 haplotype frequencies obtained in Sardinians and those reported in other human populations were used to compute genetic distances and construct phylogenetic trees. A clear-cut pattern appeared with a split between the three major human groups: Caucasians, Asians and Blacks. Among the Caucasians there were three major clusters: a group representing the North-Africans, a group including most of the European-derived populations and a group encompassing Bulgaria, Greece and Sardinia. When we increased the resolution of the tree using the genetic distances calculated from both DRB1-DQA1-DQB1 haplotypes and class I HLA A, B, C allelic frequencies, the Sardinians clearly emerged as the major outlier among the various European populations considered in this study. These results indicate that the genetic structure of the present Sardinian population is the result of a fixation of haplotypes, which are very rare elsewhere, and are most likely to have originated from a relatively large group of founders.


Women's Health Australia: recruitment for a national longitudinal cohort study.
The Women's Health Australia (WHA) project is a longitudinal study of several cohorts of Australian women, which aims to examine the relationships between biological, psychological, social and lifestyle factors and women's physical health, emotional well-being, and their use of and satisfaction with health care. Using the Medicare database as a sampling frame (with oversampling of women from rural and remote areas), 106,000 women in the three age groups 18-23, 45-50 and 70-75 were sent an invitation to participate and a 24-page self-complete questionnaire. Reminder letters, a nation-wide publicity campaign, information brochures, a freecall number for inquiries, and the option of completing the questionnaire by telephone in English or in the respondent's own language, were used to encourage participation. Statutory regulations precluded telephone follow-up of non-respondents. Response rates were 41% (N = 14,792), 54% (N = 14,200) and 36% (N = 12,614) for the three age groups. Comparison with Australian census data indicated that the samples are reasonably representative of Australian women in these age groups, except for a somewhat higher representation of women who are married or in a defacto relationship, and of women with post-school education. The most common reason for non-participation was lack of interest or time. Personal circumstances, objections to the questionnaire or specific items in it, and concerns about confidentiality were the other main reasons. Recruitment of three representative age-group cohorts of women, and the maintenance of these cohorts over a number of years, will provide a valuable opportunity to examine associations over time between aspects of women's lives and their physical and emotional health and well-being.


Clinical efficacy of octreotide in the treatment of metastatic neuroendocrine tumors. A study by the Italian Trials in Medical Oncology Group.
The unsatisfactory control of neuroendocrine tumor growth with chemotherapy and/or interferon (IFN-2a) stimulated us to investigate the role of the somatostatin analogue octreotide (SMS 201.995), which is reported to be highly effective in controlling carcinoid syndrome symptoms. Octreotide has been used in a wide range of doses, and it was postulated that higher doses might lead to an objective response. The aim of the present multicenter Phase II study was to determine the safety and efficacy of SMS 201.995 in controlling carcinoids and other neuroendocrine tumors. Fifty-eight patients were treated subcutaneously with 2 sequential doses of the drug (Sandostatina, Sandoz, Inc., S.b.A. Pharmaceuticals, Basel, Switzerland). The first 23 patients received 500 micrograms 3 times a day and the remaining 35 patients received 1000 micrograms 3 times a day. The treatment was continued until the tumor progressed. All of the patients were adequately treated and evaluated. The predominant histotype was carcinoid, although there were instances of medullary thyroid carcinoma, pancreatic islet cell tumors, and Merkel cell carcinoma. Carcinoid syndrome was documented in 16 patients and abnormal urinary 5-hydroxyindoloacetic acid excretion in 15. The median treatment duration was 5 months (range, 2-31 months). The responses were evaluated in three categories: tumor regression for tumor growth control, symptom response, and biochemical response. There was an effect on tumor growth in two patients with carcinoids. Symptomatic control was achieved in 73% of patients and a biochemical response in 77% of patients. In twenty-seven patients, the disease stabilized for at least 6 months (range, 6-32+). The median survival time for all patients was 22 months (range, 1-32+). In terms of tumor regression, octreotide is disappointing (partial response: 3%); symptomatic response and biochemical control are satisfactory. These data confirm that somatostatin analogues are comparable to interferons in the treatment of carcinoid syndrome, although other efforts are necessary to control tumor regression.


Irritable urethral syndrome: follow up study in general practice.
Two years after a microbiological study of the urethral syndrome 25 of 31 women had had further symptoms, but only two had sought medical help for their symptoms in the year after the study. Analysis of patients' records showed that women with the urethral syndrome had higher consultation and sterilisation rates and more psychosomatic symptoms and relationship problems than matched control patients. Using the Nottingham health profile women with the urethral syndrome were more likely to mention that health problems affected their sex lives and were more likely to see themselves as having health problems than control patients. Women who have the urethral syndrome are considerable drain on the doctor's time, and management needs to be directed towards the anxious patient who makes such demands. Seeing the condition as the "irritable urethral syndrome" may help both doctor and patient to recognize the psychosomatic aspect of the problem.


Sativex(®) (tetrahydrocannabinol + cannabidiol), an endocannabinoid system modulator: basic features and main clinical data.
Sativex(®) (nabiximols, USAN name) oromucosal spray contains the two main active constituents of Cannabis sativa, tetrahydrocannabinol and cannabidiol in a 1:1 molecular ratio, and acts as an endocannabinoid system modulator. Randomized, controlled clinical trials of Sativex as add-on therapy provide conclusive evidence of its efficacy in the treatment of more than 1500 patients with multiple sclerosis (MS)-related resistant spasticity. The primary end point in clinical trials was the mean change from baseline in the 0-10 numerical rating scale (NRS) spasticity score. The first pivotal clinical trial included 189 patients treated for 6 weeks with Sativex (n = 124) or placebo (n = 65). At study end, there was a significant reduction from baseline in patient-recorded NRS spasticity scores with Sativex compared with placebo (-1.18 vs -0.63; p = 0.048). In the second pivotal trial, 337 patients with MS-related resistant spasticity received Sativex (n = 167) or placebo (n = 170) over a 15-week period. In the per-protocol analysis (79% of the patient population), mean baseline NRS spasticity score was reduced significantly in patients receiving Sativex compared with placebo: -1.3 versus -0.8 points (p = 0.035). The third pivotal clinical trial, evaluating the sustained efficacy of Sativex, had a two-phase study design: in phase A (n = 572), 47% of patients were initial responders (improvement ≥ 20%) after 4 weeks of single-blind Sativex treatment who then entered phase B, a randomized, double-blind, 12-week placebo comparison. At the end of phase B, the change in NRS spasticity score improved by a further 0.04 units in initial responders treated with Sativex, but decreased by 0.81 units in placebo recipients (p = 0.0002). Significant improvements in quality-of-life measures from baseline to week 16 were also observed in patients receiving Sativex. The most common treatment-related adverse events with Sativex were mild-to moderate and transient episodes of dizziness, fatigue or somnolence. Sativex does not exhibit the side effects typically associated with recreational cannabis use and there are no signs of drug tolerance or withdrawal syndrome, or any evidence of drug misuse or abuse. Sativex oromucosal spray appears to be a useful and welcomed option for the management of resistant spasticity in MS patients. Although the management of MS has been improved by the availability of disease-modifying agents that target the underlying pathophysiological processes of the disease, a clear need remains for more effective symptomatic treatments, especially as regards MS-related spasticity and pain.


Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy: A Novel Meningoencephalomyelitis.
A novel astrocytic autoantibody has been identified as a biomarker of a relapsing autoimmune meningoencephalomyelitis that is immunotherapy responsive. Seropositivity distinguishes autoimmune glial fibrillary acidic protein (GFAP) meningoencephalomyelitis from disorders commonly considered in the differential diagnosis. To describe a novel IgG autoantibody found in serum or cerebrospinal fluid that is specific for a cytosolic intermediate filament protein of astrocytes. Retrospective review of the medical records of seropositive patients identified in the Mayo Clinic Neuroimmunology Laboratory from October 15, 1998, to April 1, 2016, in blinded comprehensive serologic evaluation for autoantibody profiles to aid the diagnosis of neurologic autoimmunity (and predict cancer likelihood). Frequency and definition of novel autoantibody, the autoantigen's immunochemical identification, clinical and magnetic resonance imaging correlations of the autoantibody, and immunotherapy responsiveness. Of 103 patients whose medical records were available for review, the 16 initial patients identified as seropositive were the subject of this study. Median age at neurologic symptom onset was 42 years (range, 21-73 years); there was no sex predominance. The novel neural autoantibody, which we discovered to be GFAP-specific, is disease spectrum restricted but not rare (frequency equivalent to Purkinje cell antibody type 1 [anti-Yo]). Its filamentous pial, subventricular, and perivascular immunostaining pattern on mouse tissue resembles the characteristic magnetic resonance imaging findings of linear perivascular enhancement in patients. Prominent clinical manifestations are headache, subacute encephalopathy, optic papillitis, inflammatory myelitis, postural tremor, and cerebellar ataxia. Cerebrospinal fluid was inflammatory in 13 of 14 patients (93%) with data available. Neoplasia was diagnosed within 3 years of neurologic onset in 6 of 16 patients (38%): prostate and gastroesophageal adenocarcinomas, myeloma, melanoma, colonic carcinoid, parotid pleomorphic adenoma, and teratoma. Neurologic improvement followed treatment with high-dose corticosteroids, with a tendency of patients to relapse without long-term immunosuppression. Glial fibrillary acidic protein-specific IgG identifies a distinctive, corticosteroid-responsive, sometimes paraneoplastic autoimmune meningoencephalomyelitis. It has a lethal canine equivalent: necrotizing meningoencephalitis. Expression of GFAP has been reported in some of the tumor types identified in paraneoplastic cases. Glial fibrillary acidic protein peptide-specific cytotoxic CD8+ T cells are implicated as effectors in a transgenic mouse model of autoimmune GFAP meningoencephalitis.


Identifying the Machine Translation Error Types with the Greatest Impact on Post-editing Effort.
Translation Environment Tools make translators' work easier by providing them with term lists, translation memories and machine translation output. Ideally, such tools automatically predict whether it is more effortful to post-edit than to translate from scratch, and determine whether or not to provide translators with machine translation output. Current machine translation quality estimation systems heavily rely on automatic metrics, even though they do not accurately capture actual post-editing effort. In addition, these systems do not take translator experience into account, even though novices' translation processes are different from those of professional translators. In this paper, we report on the impact of machine translation errors on various types of post-editing effort indicators, for professional translators as well as student translators. We compare the impact of MT quality on a product effort indicator (HTER) with that on various process effort indicators. The translation and post-editing process of student translators and professional translators was logged with a combination of keystroke logging and eye-tracking, and the MT output was analyzed with a fine-grained translation quality assessment approach. We find that most post-editing effort indicators (product as well as process) are influenced by machine translation quality, but that different error types affect different post-editing effort indicators, confirming that a more fine-grained MT quality analysis is needed to correctly estimate actual post-editing effort. Coherence, meaning shifts, and structural issues are shown to be good indicators of post-editing effort. The additional impact of experience on these interactions between MT quality and post-editing effort is smaller than expected.


A novel method for determining and improving the quality of a quadrupolar fiber gyro coil under temperature variations.
We introduce a parameter called pointing error thermal sensitivity (PETS) for quantitatively determining the quality of a quadrupolar (QAD) fiber coil under radial temperature variations. We show both analytically and experimentally that the pointing error of a fiber gyro incorporating the fiber coil is linearly proportional to the final radial thermal gradient on the coil, with PETS as the proportional constant. We further show that PETS is linearly proportional to another parameter called effective asymmetric length of the coil. By thermally inducing different radial thermal gradients on the fiber coil and measuring the corresponding pointing errors in a gyroscopic measurement setup, we can confidently determine the PETS of the fiber coil and its associated effective asymmetric length caused by imperfections in coil winding. Consequently, we are able to precisely trim the coil to achieve best thermal performance.


The use of dipyrone (metamizol) as an analgesic in children: What is the evidence? A review.
Dipyrone has analgesic, spasmolytic, and antipyretic effects and is used to treat pain. Due to a possible risk of agranulocytosis with the use of dipyrone, it has been banned in a number of countries. The most commonly used data for the use of dipyrone are related to adults. Information relating to the use of dipyrone in children is scarce. Given the potential added value of dipyrone in the treatment of pain, a review of the literature was conducted to obtain more insight into the analgesic efficacy of dipyrone in children as well as the safety of dipyrone in terms of adverse events. A literature search was done for original articles (in English, German, or Spanish language) which met the following criteria: the use of dipyrone for pain and children up to the age of 17 years old. All titles and abstracts retrieved were reviewed, independently, by two of the authors, for their suitability for inclusion. The references of the selected articles were also checked for additional relevant papers. The publications were categorized into case reports, observational studies, or randomized controlled trials. To assess the methodological quality of the studies, the Jadad score was used. In the limited available data, the analgesic efficacy of intravenous dipyrone appears similar to that of intravenous paracetamol. Evidence is lacking to support the claim that dipyrone is equivalent or even superior to Non-Steroid-Anti-Inflammatory-Drugs in pediatric pain. While the absolute risk of agranulocytosis with dipyrone in children, based on available literature, cannot be determined, case reports suggest that this risk is not negligible.


The TB REACH Initiative: Supporting TB Elimination Efforts in the Asia-Pacific.
After many years of TB 'control' and incremental progress, the TB community is talking about ending the disease, yet this will only be possible with a shift in the way we approach the TB response. While the Asia-Pacific region has the highest TB burden worldwide, it also has the opportunity to lead the quest to end TB by embracing the four areas laid out in this series: using data to target hotspots, initiating active case finding, provisioning preventive TB treatment, and employing a biosocial approach. The Stop TB Partnership's TB REACH initiative provides a platform to support partners in the development, evaluation and scale-up of new and innovative technologies and approaches to advance TB programs. We present several approaches TB REACH is taking to support its partners in the Asia-Pacific and globally to advance our collective response to end TB.


From Maps to Multi-dimensional Network Mechanisms of Mental Disorders.
The development of advanced neuroimaging techniques and their deployment in large cohorts has enabled an assessment of functional and structural brain network architecture at an unprecedented level of detail. Across many temporal and spatial scales, network neuroscience has emerged as a central focus of intellectual efforts, seeking meaningful descriptions of brain networks and explanatory sets of network features that underlie circuit function in health and dysfunction in disease. However, the tools of network science commonly deployed provide insight into brain function at a fundamentally descriptive level, often failing to identify (patho-)physiological mechanisms that link system-level phenomena to the multiple hierarchies of brain function. Here we describe recently developed techniques stemming from advances in complex systems and network science that have the potential to overcome this limitation, thereby contributing mechanistic insights into neuroanatomy, functional dynamics, and pathology. Finally, we build on the Research Domain Criteria framework, highlighting the notion that mental illnesses can be conceptualized as dysfunctions of neural circuitry present across conventional diagnostic boundaries, to sketch how network-based methods can be combined with pharmacological, intermediate phenotype, genetic, and magnetic stimulation studies to probe mechanisms of psychopathology.


Identification of cellular pathways affected by Sortin2, a synthetic compound that affects protein targeting to the vacuole in Saccharomyces cerevisiae.
Sortin2 is a low mass compound that interferes with vacuolar delivery of proteins in plants and yeast. The Sortin2 phenotype was tested in Arabidopsis thaliana and found to be reversible upon drug removal, demonstrating the ability of chemical genomics to induce reversible phenotypes that would be difficult to achieve using conventional genetics 1. However, standard genetic methods can be used to identify drug target pathways in a high-throughput manner. In this study, we analyzed structure-function relationships of Sortin2 using structural analogues. The results show the key roles of sulphite substitution and a benzoic acid group. A Sortin 2 hypersensitivity screen for the induced secretion of a vacuolar cargo protein was done utilizing a yeast haploid deletion library. Using bioinformatics approaches, we highlighted functional information about the cellular pathways affected by drug treatment which included protein sorting and other endomembrane system-related processes. Chemical, genomic and genetics approaches were used to understand the mode of action of Sortin2, a bioactive chemical that affects the delivery of a vacuolar protein. Critical features of Sortin2 structure necessary for bioactivity suggest a binding pocket that may recognize two ends of Sortin2. The genome-wide screen shows that Sortin2 treatment in yeast affects primarily components within the endomembrane system. This approach allowed us to assign putative functions in protein sorting for fifteen genes of previously unknown function.


Anti-Viral Therapy and Decreased Sexual Desire in Patients with Chronic Hepatitis C.
Peg-interferon (PegIFN)α2a or PegIFNα2b plus ribavirin (RBV) is the standard therapy for chronic hepatitis C virus (HCV) infection in Taiwan and Asia. It is commonly associated with adverse effects, but the issue of sexual and mental health is not well reported. This study aimed to evaluate the impact of anti-viral therapy with PegIFNα plus RBV on sexual desire and depression. This prospective cohort study from 2009 to 2014 enrolled 181 patients with HCV who received PegIFNα2a (180 mcg/week) or PegIFNα2b (1.5 mcg/Kg/week) plus RBV (800-1200 mg/day) according to response-guide therapy for 24 to 48 weeks in a tertiary medical center. Patients with decreased sexual desire (DSD) before PegIFNα plus RBV were excluded. Patients were evaluated at baseline (week 0) and after 2, 4, 8, 12, 16, 20, and 24 weeks of PegIFNα plus RBV treatment using the structured Mini-International Neuropsychiatric Interview, for the diagnosis of a major depressive episode, and the 21-item Beck Depression Inventory (BDI), for monitoring depressive symptoms. The 21st item of the BDI was used to evaluate DSD. During therapy, 124 (68.5%) patients had DSD. The BDI score peaked at 14.8 weeks. The severity of DSD was greatest at 16 weeks of treatment. The average score of the 21st item of the BDI correlated with DSD. Depression history and the prevalence of subsequent major depressive disorder after anti-viral therapy was correlated to DSD (p = 0.05 and 0.001). Male patients complained of DSD more significantly than females (p = 0.031). Decreased sexual desire is common but is usually neglected in patients with chronic hepatitis C undergoing anti-viral therapy, especially among male patients. Physicians must be monitoring the side effects of sexual health and depression.


The Impact of Sotagliflozin on Renal Function, Albuminuria, Blood Pressure, and Hematocrit in Adults With Type 1 Diabetes.
In people with type 2 diabetes, sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce cardiovascular risk and progression of diabetic kidney disease. Our aim was to determine whether sotagliflozin (SOTA), a dual SGLT1i and SGLT2i, had favorable effects on clinical biomarkers suggestive of kidney protection in adults with type 1 diabetes. In this 52-week pooled analysis, 1,575 adults enrolled in the inTandem1 and inTandem2 trials were randomized to SOTA 200 mg, 400 mg, or placebo in addition to optimized insulin therapy. Changes in cardiorenal biomarkers were assessed. At 52 weeks, in response to SOTA 200 and 400 mg, the placebo-corrected least squares mean change from baseline in estimated glomerular filtration rate was -2.0 mL/min/1.73 m2 (P = 0.010) and -0.5 mL/min/1.73 m2 (P = 0.52), respectively. Systolic blood pressure difference was -2.9 and -3.6 mmHg (P < 0.0001 for both); diastolic blood pressure changed by -1.4 (P = 0.0033) and -1.6 mmHg (P = 0.0008). In participants with baseline urinary albumin-to-creatinine ratio (UACR) ≥30 mg/g, UACR decreased by 23.7% (P = 0.054) and 18.3% (P = 0.18) for SOTA 200 and SOTA 400 mg, respectively, versus placebo. Increases in serum albumin and hematocrit and reductions in uric acid were observed throughout 52 weeks with both SOTA doses. SOTA was associated with short- and long-term renal hemodynamic changes, which were similar to those seen with SGLT2i in type 2 diabetes. Further investigation around cardiorenal effects of SOTA in people with type 1 diabetes is justified.


Paradoxical Personality and Academic Achievement in College Students From Buenos Aires.
This paper presents a study on paradoxical personality, defined as a distinctive feature in creative persons, developed with 350 college students from Buenos Aires. Goals aimed at describing and analysing possible significant differences of paradoxical traits in students from diverse majors representing seven different fields of study, and examining the relationship between each bipolar trait and academic achievement. The sample was composed of 7 groups (n = 50 by group) representing fields of study typically offered in public universities, Biology, Computer Science, Engineering, Law, Nutrition, Psychology, and History of Art. Analyses by career provided descriptive information about students of these majors, concerning their paradoxical personality profiles. Correlational studies verified significant associations between academic achievement and most paradoxical traits in majors such as Computer Science, Nutrition and Psychology. Results are discussed regarding practical outcomes and teaching programs.


Histamine modulates calcium current in guinea pig ventricular myocytes.
In the present work we have examined the effects of histamine on electrophysiological parameters of isolated cardiocytes acutely dissociated from adult guinea pigs. The whole cell patch clamp technique was used to examine action potential and currents. Stable recordings of calcium current (average peak amplitude of 563 +/- 256 pA per cell, n = 83) were obtained. Application of histamine (5 nM-10 microM) resulted in marked modification of action potentials and calcium current. Calcium current was enhanced by histamine in a concentration-dependent manner (half-maximal dose, 10 nM) up to 315% of the control level. Action potentials were prolonged by small doses of histamine whereas larger doses caused voltage instabilities and spontaneous arrhythmic bursts. Histamine effects were reduced by cimetidine and ranitidine (1 microM), two H2-receptor antagonists. After the calcium current was increased by intracellular perfusion of micromolar cyclic AMP saturating doses of histamine had no effect. Micromolar concentrations of acetylcholine rapidly antagonized the histamine effect. The latter results indicate that the response to histamine is based on H2-receptor-mediated activation of adenylate cyclase and cyclic AMP regulation of phosphorylation of calcium channel.


STARD 2015: An Updated List of Essential Items for Reporting Diagnostic Accuracy Studies.
Incomplete reporting has been identified as a major source of avoidable waste in biomedical research. Essential information is often not provided in study reports, impeding the identification, critical appraisal, and replication of studies. To improve the quality of reporting of diagnostic accuracy studies, the Standards for Reporting of Diagnostic Accuracy Studies (STARD) statement was developed. Here we present STARD 2015, an updated list of 30 essential items that should be included in every report of a diagnostic accuracy study. This update incorporates recent evidence about sources of bias and variability in diagnostic accuracy and is intended to facilitate the use of STARD. As such, STARD 2015 may help to improve completeness and transparency in reporting of diagnostic accuracy studies.