Snf1 dependence of peroxisomal gene expression is mediated by Adr1.
Eukaryotes utilize fatty acids by beta-oxidation, which occurs in the mitochondria and peroxisomes in higher organisms and in the peroxisomes in yeast. The AMP-activated protein kinase regulates this process in mammalian cells, and its homolog Snf1, together with the transcription factors Adr1, Oaf1, and Pip2, regulates peroxisome proliferation and beta-oxidation in yeast. A constitutive allele of Adr1 (Adr1(c)) lacking the glucose- and Snf1-regulated phosphorylation substrate Ser-230 was found to be Snf1-independent for regulation of peroxisomal genes. In addition, it could compensate for and even suppress the requirement for Oaf1 or Pip2 for gene induction. Peroxisomal genes were found to be regulated by oleate in the presence of glucose, as long as Adr1(c) was expressed, suggesting that the Oaf1/Pip2 heterodimer is Snf1-independent. Consistent with this observation, Oaf1 binding to promoters in the presence of oleate was not reduced in a snf1Delta strain. Exploring the mechanism by which Adr1(c) permits Snf1-independent peroxisomal gene induction, we found that strength of promoter binding did not correlate with transcription, suggesting that stable binding is not a prerequisite for enhanced transcription. Instead, enhanced transcriptional activation and suppression of Oaf1, Pip2, and Snf1 by Adr1(c) may be related to the ability of Adr1(c) to suppress the requirement for and enhance the recruitment of transcriptional coactivators in a promoter- and growth medium-dependent manner.


Identifying genetically driven clinical phenotypes using linear mixed models.
We hypothesized that generalized linear mixed models (GLMMs), which estimate the additive genetic variance underlying phenotype variability, would facilitate rapid characterization of clinical phenotypes from an electronic health record. We evaluated 1,288 phenotypes in 29,349 subjects of European ancestry with single-nucleotide polymorphism (SNP) genotyping on the Illumina Exome Beadchip. We show that genetic liability estimates are primarily driven by SNPs identified by prior genome-wide association studies and SNPs within the human leukocyte antigen (HLA) region. We identify 44 (false discovery rate q<0.05) phenotypes associated with HLA SNP variation and show that hypothyroidism is genetically correlated with Type I diabetes (rG=0.31, s.e. 0.12, P=0.003). We also report novel SNP associations for hypothyroidism near HLA-DQA1/HLA-DQB1 at rs6906021 (combined odds ratio (OR)=1.2 (95% confidence interval (CI): 1.1-1.2), P=9.8 × 10(-11)) and for polymyalgia rheumatica near C6orf10 at rs6910071 (OR=1.5 (95% CI: 1.3-1.6), P=1.3 × 10(-10)). Phenome-wide application of GLMMs identifies phenotypes with important genetic drivers, and focusing on these phenotypes can identify novel genetic associations.


Hepatitis B viral replication influences the expression of natural killer cell ligands.
Hepatitis B virus (HBV) is accounting for over one million deaths annually due to immune-mediated chronic liver damage. Natural killer (NK) cells are abundant in the liver and contribute in HBV persistence. NK cytotoxic effects are controlled by signals from activating and inhibitory receptors. HBV may circumvent host antiviral immunity via the regulation of NK receptors and their ligands. We investigated the effect of viral replication and HBeAg mutations on NK mediators expression in the livers of chronic HBV (CHB) patients and in cell cultures. HBV monomers bearing hotspot mutations in the basal core promoter and precore region were transfected into HepG2 cells using a plasmid-free assay. Serum viremia and liver HBV RNA were measured in 19 CHB patients. The expression of HBV RNA and of NKG2D ligands, B7H6, DNAX accessory molecule-1, lectin-like transcript 1 (LLT1), LFA-1 and TRAIL was measured in the livers of CHB patients and transfected cells. In general, high HBV replication in CHB patients and cell lines upregulated the mRNA of all NK cell ligands and particularly the inhibitory NK cell ligand, LLT1. The exception was the NKG2D ligand, MICA, that was significantly decreased in patients with high serum viremia and intrahepatic HBV RNA levels. HBV replication has differential effects on NK cell ligands suggesting a potential escape mechanisms through up-regulation of LLT1 and down-regulation of MICA. A general trend towards upregulating NK cell ligands can be counteracted by decreasing MICA and hence weakening NK surveillance.


SU-E-J-146: Time Series Prediction of Lung Cancer Patients' Breathing Pattern Based on Nonlinear Dynamics.
Prediction methods for breathing patterns, which are crucial to deal with system latency in treatments of moving lung tumors using state-space methodologies based on non-linear dynamics are contrasted to linear predictive methods. In our previous work we established that breathing patterns can be described as a 5-6 dimensional nonlinear, stationary and deterministic system that exhibits sensitive dependence on initial conditions. In this work, nonlinear prediction methods are used to predict the short-term evolution of the respiratory system for 3 patients. Single step and N-point multi step prediction are performed for sampling rates of 5Hz, 10Hz, and 30Hz. We compare the employed nonlinear prediction methods with respect to prediction accuracy to Infinite Impulse Response (IIR) prediction filters. The simplest form of local prediction is finding similar segments of scalar time series data in a higher dimensional embedding space. Hence, we predict the future value x(t)of N-time steps ahead by simply finding the average of nearest neighbor points to the point x(t) in the past and using them to estimate x(t+N), yielding a local average model (LAM). Local linear models (LLM) which are linear autoregressive models that hold only for a region around the target point formed by the nearest neighbor points is combined with a set of linear regularization techniques to solve ill-posed regression problems are also implemented. For all sampling frequencies, both single step and N-point multi step prediction results obtained using LAM and LLM with regularization methods are better than IIR prediction filters for the selected sample patients. The use of non-linear prediction methods for predicting the breathing pattern of lung cancer patients may lead to improved, robust and accurate long-term prediction to account for system latencies.


Abrupt withdrawal of inhaled corticosteroids does not result in spirometric deterioration in chronic obstructive pulmonary disease: Effect of phenotyping?
Some studies show a decline of FEV(1) only one month after withdrawal of inhaled corticosteroids (ICS), while others show no decline. We speculate that the presence of an asthma phenotype in the Chronic Obstructive Pulmonary Disease (COPD) population, and that its exclusion may result in no spirometric deterioration. We performed a prospective clinical observation study on 32 patients who fulfilled the Global Initiative for Chronic Obstructive lung disease definition of COPD (Grade II-IV). They were divided into two phenotypic groups. 1. Irreversible asthma (A and B) (n = 13): A. Asthma: Bronchial biopsy shows diffuse thickening of basement membrane (≥ 6.6 μm). B. Airflow limitation (AFL) likely to be asthma: KCO > 80% predicted if the patient refused biopsy. 2. COPD (A and B) (n = 19): A. COPD: hypercapneic respiratory failure with raised bicarbonate, panlobular emphysema with multiple bullas, or bronchial biopsy showing squamous metaplasia and epithelial/subepithelial inflammation without thickening of the basement membrane. B. AFL likely to be COPD: KCO < 80% predicted. The asthma phenotype was significantly younger, had a strong association with hypertrophy of nasal turbinates, and registered a significant improvement of FEV(1) (350 ml) vs a decline of - 26.5 ml in the COPD phenotype following therapy with budesonide/formoterol for one year. Withdrawal of budesonide for 4 weeks in the COPD phenotype resulted in FEV(1) + 1.33% (SD ± 5.71) and FVC + 1.24% (SD ± 5.32); a change of <12% in all patients. We recorded no spirometric deterioration after exclusion of the asthma phenotype from a COPD group.


Nitrogen-doped graphene: effect of graphite oxide precursors and nitrogen content on the electrochemical sensing properties.
Graphene, produced via chemical methods, has been widely applied for electrochemical sensing due to its structural and electrochemical properties as well as its ease of production in large quantity. While nitrogen-doped graphenes are widely studied materials, the literature showing an effect of graphene oxide preparation methods on nitrogen quantity and chemical states as well as on defects and, in turn, on electrochemical sensing is non-existent. In this study, the properties of nitrogen-doped graphene materials, prepared via hydrothermal synthesis using graphite oxide produced by various classical methods using permanganate or chlorate oxidants Staudenmaier, Hummers, Hofmann and Brodie oxidation methods, were studied; the resulting nitrogen-doped graphene oxides were labeled as ST-GO, HU-GO, HO-GO and BR-GO, respectively. The electrochemical oxidation of biomolecules, such as ascorbic acid, uric acid, dopamine, nicotinamide adenine nucleotide and DNA free bases, was carried out using cyclic voltammetry and differential pulse voltammetry techniques. The nitrogen content in doped graphene oxides increased in the order ST-GO < BR-GO < HO-GO < HU-GO. In the same way, the pyridinic form of nitrogen increased and the electrocatalytic effect of N-doped graphene followed this trend, as shown in the cyclic voltammograms. This is a very important finding that provides insight into the electrocatalytic effect of N-doped graphene. The nitrogen-doped graphene materials exhibited improved sensitivity over bare glassy carbon for ascorbic acid, uric acid and dopamine detection. These studies will enhance our understanding of the effects of graphite oxide precursors on the electrochemical sensing properties of nitrogen-doped graphene materials.


Local re-inversion coronary MR angiography: arterial spin-labeling without the need for subtraction.
To implement a double-inversion bright-blood coronary MR angiography sequence using a cylindrical re-inversion prepulse for selective visualization of the coronary arteries. Local re-inversion bright-blood magnetization preparation was implemented using a nonselective inversion followed by a cylindrical aortic re-inversion prepulse. After an inversion delay that allows for in-flow of the labeled blood-pool into the coronary arteries, three-dimensional radial steady-state free-precession (SSFP) imaging (repetition/echo time, 7.2/3.6 ms; flip angle, 120 degrees, 16 profiles per RR interval; field of view, 360 mm; matrix, 512, twelve 3-mm slices) is performed. Coronary MR angiography was performed in three healthy volunteers and in one patient on a commercial 1.5 Tesla whole-body MR System. In all subjects, coronary arteries were selectively visualized with positive contrast. In addition, a middle-grade stenosis of the proximal right coronary artery was seen in one patient. A novel T1 contrast-enhancement strategy is presented for selective visualization of the coronary arteries without extrinsic contrast medium application. In comparison to former arterial spin-labeling schemes, the proposed magnetization preparation obviates the need for a second data set and subtraction.


Surgical treatment of liver injury with microwave tissue coagulation: an experimental study.
The purpose of this study was to examine whether microwave tissue coagulation (MTC) therapy is capable of stopping bleeding from severe liver injury in pigs. Ten pigs (38 +/- 4 kg) underwent a 30-mL/kg isovolemic exchange transfusion with 3% low-molecular-weight dextran to produce dilutional coagulopathy, and then a through-and-through laceration injury measuring approximately 8 cm in length was induced in the right hepatic lobe. Immediately after inflicting the injury, the animals were randomly divided into two groups: Group A (n = 5, MTC was repeated along the liver laceration at intervals of 2.0 cm with manual compression) or Group B (n = 5, the injured lobe was manually compressed without MTC therapy for 1 minute). All animals received lactated Ringer's solution to maintain the mean arterial pressure at 75 mm Hg for 1 hour after the abdominal closure. The intraperitoneal blood loss, mean arterial pressure, volume of lactated Ringer's solution, and hematologic variables were compared between the groups. For further laboratory evaluation, three additional experimental animals were treated with the MTC therapy after inflicting the injury and then were allowed to survive for 14 days. Mean arterial pressure declined from a mean value of 88 +/- 10 mm Hg (range, 75-107 mm Hg) to 62 +/- 3 mm Hg (range, 50-75 mm Hg) after the induction of liver injury. The total blood loss in Group A was 192 +/- 58 g (range, 120-250 g), which was lower (p < 0.01) than that of 448 +/- 138 g (range, 260-650 g) in Group B. The resuscitation fluid volume of Group A animals was 304 +/- 204 mL (range, 100-600 mL), which was smaller (p < 0.01) than that of 1,320 +/- 654 mL (range, 900-2,250 mL) in Group B. At 14 days, all three animals that were treated in the additional study were found to be in good health. Their necropsies showed no evidence of an intrahepatic abscess, hematoma, or biloma. MTC therapy was thus found to provide simple, rapid, and definitive hemorrhage control in cases of severe liver injury without the need for reoperation.


Genetic variation in genes associated with arsenic metabolism: glutathione S-transferase omega 1-1 and purine nucleoside phosphorylase polymorphisms in European and indigenous Americans.
Individual variability in human arsenic metabolism has been reported frequently in the literature. This variability could be an underlying determinant of individual susceptibility to arsenic-induced disease in humans. Recent analysis revealing familial aggregation of arsenic metabolic profiles suggests that genetic factors could underlie interindividual variation in arsenic metabolism. We screened two genes responsible for arsenic metabolism, human purine nucleoside phosphorylase (hNP), which functions as an arsenate reductase converting arsenate to arsenite, and human glutathione S-transferase omega 1-1 (hGSTO1-1), which functions as a monomethylarsonic acid (MMA) reductase, converting MMA(V) to MMA(III), to develop a comprehensive catalog of commonly occurring genetic polymorphisms in these genes. This catalog was generated by DNA sequencing of 22 individuals of European ancestry (EA) and 24 individuals of indigenous American (IA) ancestry. In (Italic)hNP(/Italic), 48 polymorphic sites were observed, including 6 that occurred in exons, of which 1 was nonsynonymous (G51S). One intronic polymorphism occurred in a known enhancer region. In hGSTO1-1, 33 polymorphisms were observed. Six polymorphisms occurred in exons, of which 4 were nonsynonymous. In contrast to hNP, in which the IA group was more polymorphic than the EA group, in hGSTO1-1 the EA group was more polymorphic than the IA group, which had only 1 polymorphism with a frequency > 10%. Populations representing genetic admixture between the EA and IA groups, such as Mexican Hispanics, could vary in the extent of polymorphism in these genes based upon the extent of admixture. These data provide a framework in which to conduct genetic association studies of these two genes in relevant populations, thereby allowing hNP and hGSTO1-1 to be evaluated as potential susceptibility genes in human arsenicism.


The frequent evolutionary birth and death of functional promoters in mouse and human.
Promoters are central to the regulation of gene expression. Changes in gene regulation are thought to underlie much of the adaptive diversification between species and phenotypic variation within populations. In contrast to earlier work emphasizing the importance of enhancer evolution and subtle sequence changes at promoters, we show that dramatic changes such as the complete gain and loss (collectively, turnover) of functional promoters are common. Using quantitative measures of transcription initiation in both humans and mice across 52 matched tissues, we discriminate promoter sequence gains from losses and resolve the lineage of changes. We also identify expression divergence and functional turnover between orthologous promoters, finding only the latter is associated with local sequence changes. Promoter turnover has occurred at the majority (>56%) of protein-coding genes since humans and mice diverged. Tissue-restricted promoters are the most evolutionarily volatile where retrotransposition is an important, but not the sole, source of innovation. There is considerable heterogeneity of turnover rates between promoters in different tissues, but the consistency of these in both lineages suggests that the same biological systems are similarly inclined to transcriptional rewiring. The genes affected by promoter turnover show evidence of adaptive evolution. In mice, promoters are primarily lost through deletion of the promoter containing sequence, whereas in humans, many promoters appear to be gradually decaying with weak transcriptional output and relaxed selective constraint. Our results suggest that promoter gain and loss is an important process in the evolutionary rewiring of gene regulation and may be a significant source of phenotypic diversification.


Adaptive deep brain stimulation as advanced Parkinson's disease treatment (ADAPT study): protocol for a pseudo-randomised clinical study.
Adaptive deep brain stimulation (aDBS), based on the detection of increased beta oscillations in the subthalamic nucleus (STN), has been assessed in patients with Parkinson's disease (PD) during the immediate postoperative setting. In these studies, aDBS was shown to be at least as effective as conventional DBS (cDBS), while stimulation time and side effects were reduced. However, the effect of aDBS on motor symptoms and stimulation-induced side effects during the chronically implanted phase (after the stun effect of DBS placement has disappeared) has not yet been determined. This protocol describes a single-centre clinical study in which aDBS will be tested in 12 patients with PD undergoing battery replacement, with electrodes implanted in the STN, and as a proof of concept in the internal globus pallidus. Patients included will be allocated in a pseudo-randomised fashion to a three-condition (no stimulation/cDBS/ aDBS), cross-over design. A battery of tests will be conducted and recorded during each condition, which aim to measure the severity of motor symptoms and side effects. These tests include a tablet-based tapping test, a subscale of the Movement Disorder Society-unified Parkinson's disease rating scale (subMDS-UPDRS), the Speech Intelligibility Test (SIT) and a tablet-based version of the Stroop test. SubMDS-UPDRS and SIT recordings will be blindly assessed by independent raters. Data will be analysed using a linear mixed-effects model. This protocol was approved by the Ethical Committee of the University Medical Centre Groningen, where the study will be carried out. Data management and compliance to research policies and standards of our centre, including data privacy, storage and veracity, will be controlled by an independent monitor. All the scientific findings derived from this protocol are aimed to be made public through publication of articles in international journals. NTR 5456; Pre-results.


Optimum control of blood glucose for prevention and treatment of ischemic and hemorrhagic stroke.
Stroke is the most common cause of disability and a major cause of mortality. Each year, more than 500,000 Americans sustain a stroke. Reperfusion and antithrombotic therapies are still of limited benefit, hence increasing interest has been focused on therapeutic approaches that prevent and/or modulate infarct evolution. Hyperglycemia in acute stroke has a poor prognosis and is associated with significant morbidity and mortality. However, it remains unclear whether intensive lowering of blood glucose levels in the hyperacute and acute phases of stroke improves clinical outcomes. Experimental data suggest that elevated blood glucose may contribute to infarct expansion directly through a number of maladaptive metabolic pathways and that treatment with insulin may attenuate these adverse effects. Despite some controversy surrounding the optimal level of blood glucose control, much of the evidence to date supports rigorous blood glucose control and comprehensive cardiovascular risk factor management to prevent stroke in patients with diabetes. The current recommendation is to aim for strict control of blood pressure, glucose, and lipids along with lifestyle modification to improve cardiovascular health. However, there remains a distinct paucity of information concerning secondary stroke prevention. To date, the overwhelming evidence suggests that aggressive glucose management should be the standard of care in all patients with stroke and hyperglycemia. This article presents an overview of the recommendations for the optimum control of blood glucose for prevention and treatment of ischemic and hemorrhagic stroke.


Recurrent miscarriages, innate immunity, and autoimmune reaction to chlamydial 60-kDa heat shock protein--is there an association?
To evaluate a potential association of immunity to the Chlamydia trachomatis 60kDa heat shock protein (ChlamHSP60) and recurrent miscarriages. Prospective study. Outpatient miscarriage clinic of a university-based hospital. 120 asymptomatic women with a history of recurrent miscarriages. None. Determination of serum immunoglobulin G (IgG) antibodies (Ab) to ChlamHSP60 and human HSP60 and, in parallel, mannose-binding lectin (MBL) and the total hemolytic complement (CH50); medical history and clinical examination, including multiple relevant laboratory determinants. ChlamHSP60 Ab were detected in 24 (20%) of 120 patients. Antibodies to human HSP60 were found in 19 (15.8%) of 120 patients, and more frequently in individuals who tested positive for ChlamHSP60. ChlamHSP60 were statistically significantly associated with antichlamydial IgG Ab. However, antibodies to ChlamHSP60 were not related to medical history, the number of abortions, or the time frame of fetal loss. ChlamHSP60 antibodies were not associated with the relevant variables of the coagulation cascade, a panel of autoimmune parameters including thyroid autoimmunity, deficiencies of the complement system (low MBL), or with antibodies to common infectious diseases. No statistically significant differences were was found when comparing the prevalence of ChlamHSP60 Ab in the study group with recurrent miscarriages and 90 controls (women attending for an annual pelvic examination). Immunity to ChlamHSP60 does not play a major role in the etiology of recurrent miscarriages.


Determination of dosage compensation of the mammalian X chromosome by RNA-seq is dependent on analytical approach.
An enduring question surrounding sex chromosome evolution is whether effective hemizygosity in the heterogametic sex leads inevitably to dosage compensation of sex-linked genes, and whether this compensation has been observed in a variety of organisms. Incongruence in the conclusions reached in some recent reports has been attributed to different high-throughput approaches to transcriptome analysis. However, recent reports each utilizing RNA-seq to gauge X-linked gene expression relative to autosomal gene expression also arrived at diametrically opposed conclusions regarding X chromosome dosage compensation in mammals. Here we analyze RNA-seq data from X-monosomic female human and mouse tissues, which are uncomplicated by genes that escape X-inactivation, as well as published RNA-seq data to describe relative X expression (RXE). We find that the determination of RXE is highly dependent upon a variety of computational, statistical and biological assumptions underlying RNA-seq analysis. Parameters implemented in short-read mapping programs, choice of reference genome annotation, expression data distribution, tissue source for RNA and RNA-seq library construction method have profound effects on comparing expression levels across chromosomes. Our analysis shows that the high number of paralogous gene families on the mammalian X chromosome relative to autosomes contributes to the ambiguity in RXE calculations, RNA-seq analysis that takes into account that single- and multi-copy genes are compensated differently supports the conclusion that, in many somatic tissues, the mammalian X is up-regulated compared to the autosomes.


Photometry unlocks 3D information from 2D localization microscopy data.
We developed a straightforward photometric method, temporal, radial-aperture-based intensity estimation (TRABI), that allows users to extract 3D information from existing 2D localization microscopy data. TRABI uses the accurate determination of photon numbers in different regions of the emission pattern of single emitters to generate a z-dependent photometric parameter. This method can determine fluorophore positions up to 600 nm from the focal plane and can be combined with biplane detection to further improve axial localization.


P2X7-regulated protection from exacerbations and loss of control is independent of asthma maintenance therapy.
The function of the P2X(7) nucleotide receptor protects against exacerbation in people with mild-intermittent asthma during viral illnesses, but the impact of disease severity and maintenance therapy has not been studied. To evaluate the association between P2X(7), asthma exacerbations, and incomplete symptom control in a more diverse population. A matched P2RX7 genetic case-control was performed with samples from Asthma Clinical Research Network trial participants enrolled before July 2006, and P2X(7) pore activity was determined in whole blood samples as an ancillary study to two trials completed subsequently. A total of 187 exacerbations were studied in 742 subjects, and the change in asthma symptom burden was studied in an additional 110 subjects during a trial of inhaled corticosteroids (ICS) dose optimization. African American carriers of the minor G allele of the rs2230911 loss-of-function single nucleotide polymorphism were more likely to have a history of prednisone use in the previous 12 months, with adjustment for ICS and long-acting β(2)-agonists use (odds ratio, 2.7; 95% confidence interval, 1.2-6.2; P = 0.018). Despite medium-dose ICS, attenuated pore function predicted earlier exacerbations in incompletely controlled patients with moderate asthma (hazard ratio, 3.2; confidence interval, 1.1-9.3; P = 0.033). After establishing control with low-dose ICS in patients with mild asthma, those with attenuated pore function had more asthma symptoms, rescue albuterol use, and FEV(1) reversal (P < 0.001, 0.03, and 0.03, respectively) during the ICS adjustment phase. P2X(7) pore function protects against exacerbations of asthma and loss of control, independent of baseline severity and the maintenance therapy.


Canine visceral leishmaniasis caused by Leishmania infantum in Senegal: risk of emergence in humans?
In the context of global warming and the risk of spreading arthropod-borne diseases, the emergence and reemergence of leishmaniasis should not be neglected. In Senegal, over the past few years, cases of canine leishmaniasis have been observed. We aim to improve the understanding of the transmission cycle of this zoonosis, to determine the responsible species and to evaluate the risk for human health. An epidemiological and serological study on canine and human populations in the community of Mont Rolland (Thiès area) was conducted. The data showed a high seroprevalence of canine leishmaniasis (>40%) and more than 30% seropositive people. The dogs' seroprevalence was confirmed by PCR data (concordance > 0.85, Kappa > 0.7). The statistical analysis showed strong statistical associations between the health status of dogs and seropositivity, the number of positive PCRs, clinical signs and the number of Leishmania isolates. For the first time, the discriminative PCRs performed on canine Leishmania strains clearly evidenced that the pathogenic agent is Leishmania infantum. The results obtained show that transmission of this species is well established in this area. That the high incidence of seropositivity in humans may be a consequence of infection with this species is discussed.


Lactobacillus reuteri DSM 17938 and Magnesium Oxide in Children with Functional Chronic Constipation: A Double-Blind and Randomized Clinical Trial.
Chronic functional constipation is a frequent condition. The aim of the study was to evaluate the efficacy of the probiotic Lactobacillus (L.) reuteri DSM 17938 and magnesium oxide (MgO) for relieving chronic functional constipation in children. A prospective, double-blind, placebo-controlled, randomized, and parallel-group trial was conducted in five pediatric outpatient clinics in Japan. Sixty patients who were more than six months old and under six years of age with a diagnosis of functional constipation according to Rome IV criteria were randomly divided into three groups: group A (n = 20) received L. reuteri DSM 17938 and lactose hydrate as a placebo of MgO; group B (n = 19) received L. reuteri DSM 17938 and MgO; and group C (n = 21) received a placebo of L. reuteri DSM 17938 and MgO. All three groups exhibited significant improvement in defecation frequency in the fourth week compared with the baseline condition (group A: p < 0.05; group B: p < 0.05; group C: p < 0.05). The MgO group and combination group showed a significant decrease in stool consistency, but the L. reuteri DSM 17938 group did not (group A: p = 0.079; group B: p < 0.05; group C: p < 0.05). MgO significantly suppressed the presence of the genus Dialister. Defecation frequency negatively correlated with the frequency of Clostridiales-belonging bacteria among the gut microbiome. L. rueteri DSM 17938 and MgO were both effective in the management of functional constipation in young children. MgO caused an imbalance in the gastrointestinal microbiome, which was not the case in the probiotic group.


Kupffer Cells Support Hepatitis B Virus-Mediated CD8+ T Cell Exhaustion via Hepatitis B Core Antigen-TLR2 Interactions in Mice.
Hepatitis B virus (HBV) persistence is a fundamental process in chronic HBV infection and a key factor in all related liver diseases; however, the mechanisms have yet to be elucidated. We studied the role of TLR2 in HBV persistence using a well-established HBV-carrier mouse model generated by hydrodynamically injecting a phospho-adeno-associated virus/HBV1.2 plasmid into mice. We found that a genetic deficiency in TLR2 improves HBV elimination, whereas activating TLR2 led to more stable HBV persistence, suggesting that TLR2 activation is critical in HBV persistence. Furthermore, we noted that TLR2 activation could inhibit CD8(+) T cell function, causing the exhaustion phenotype in HBV-carrier mice, because TLR2 deficiency might rescue CD8(+) T cell function in a cellular adoptive experiment. TLR2 expression on Kupffer cells (KCs) was upregulated in HBV-carrier mice, which accounts for HBV persistence, because the difference in anti-HBV immunity between HBV-carrier wild-type and Tlr2(-/-) mice did not exist after KC depletion. In addition, similar to TLR2 deficiency, after KC depletion, CD8(+) T cells were more efficiently activated in HBV-carrier mice, leading to rapid HBV elimination. KCs produced more IL-10 upon TLR2 activation in response to direct hepatitis B core Ag stimulation, and the elevated IL-10 inhibited CD8(+) T cell function in HBV-carrier mice, because IL-10 deficiency or anti-IL-10R treatment resulted in CD8(+) T cells with stronger antiviral function. In conclusion, KCs support liver tolerance by inducing anti-HBV CD8(+) T cell exhaustion via IL-10 production after TLR2 activation by hepatitis B core Ag stimulation.


[Do different interpretative methods used for evaluation of checkerboard synergy test affect the results?].
In recent years, owing to the presence of multi-drug resistant nosocomial bacteria, combination therapies are more frequently applied. Thus there is more need to investigate the in vitro activity of drug combinations against multi-drug resistant bacteria. Checkerboard synergy testing is among the most widely used standard technique to determine the activity of antibiotic combinations. It is based on microdilution susceptibility testing of antibiotic combinations. Although this test has a standardised procedure, there are many different methods for interpreting the results. In many previous studies carried out with multi-drug resistant bacteria, different rates of synergy have been reported with various antibiotic combinations using checkerboard technique. These differences might be attributed to the different features of the strains. However, different synergy rates detected by checkerboard method have also been reported in other studies using the same drug combinations and same types of bacteria. It was thought that these differences in synergy rates might be due to the different methods of interpretation of synergy test results. In recent years, multi-drug resistant Acinetobacter baumannii has been the most commonly encountered nosocomial pathogen especially in intensive-care units. For this reason, multidrug resistant A.baumannii has been the subject of a considerable amount of research about antimicrobial combinations. In the present study, the in vitro activities of frequently preferred combinations in A.baumannii infections like imipenem plus ampicillin/sulbactam, and meropenem plus ampicillin/sulbactam were tested by checkerboard synergy method against 34 multi-drug resistant A.baumannii isolates. Minimum inhibitory concentration (MIC) values for imipenem, meropenem and ampicillin/sulbactam were determined by the broth microdilution method. Subsequently the activity of two different combinations were tested in the dilution range of 4 x MIC and 0.03 x MIC in 96-well checkerboard plates. The results were obtained separately using the four different interpretation methods frequently preferred by researchers. Thus, it was aimed to detect to what extent the rates of synergistic, indifferent and antagonistic interactions were affected by different interpretation methods. The differences between the interpretation methods were tested by chi-square analysis for each combination used. Statistically significant differences were detected between the four different interpretation methods for the determination of synergistic and indifferent interactions (p< 0.0001). Highest rates of synergy were observed with both combinations by the method that used the lowest fractional inhibitory concentration index of all the non-turbid wells along the turbidity/non-turbidity interface. There was no statistically significant difference between the four methods for the detection of antagonism (p> 0.05). In conclusion although there is a standard procedure for checkerboard synergy testing it fails to exhibit standard results owing to different methods of interpretation of the results. Thus, there is a need to standardise the interpretation method for checkerboard synergy testing. To determine the most appropriate method of interpretation further studies investigating the clinical benefits of synergic combinations and additionally comparing the consistency of the results obtained from the other standard combination tests like time-kill studies, are required.


Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets.
Interleukin-7 (IL-7) is a homeostatic cytokine for resting T cells with increasing serum and tissue levels during T cell depletion. In preclinical studies, IL-7 therapy exerts marked stimulating effects on T cell immune reconstitution in mice and primates. First-in-human clinical studies of recombinant human IL-7 (rhIL-7) provided the opportunity to investigate the effects of IL-7 therapy on lymphocytes in vivo. rhIL-7 induced in vivo T cell cycling, bcl-2 up-regulation, and a sustained increase in peripheral blood CD4(+) and CD8(+) T cells. This T cell expansion caused a significant broadening of circulating T cell receptor (TCR) repertoire diversity independent of the subjects' age as naive T cells, including recent thymic emigrants (RTEs), expanded preferentially, whereas the proportions of regulatory T (T reg) cells and senescent CD8(+) effectors diminished. The resulting composition of the circulating T cell pool more closely resembled that seen earlier in life. This profile, distinctive among cytokines under clinical development, suggests that rhIL-7 therapy could enhance and broaden immune responses, particularly in individuals with limited naive T cells and diminished TCR repertoire diversity, as occurs after physiological (age), pathological (human immunodeficiency virus), or iatrogenic (chemotherapy) lymphocyte depletion.


Enhanced access to early visual processing of perceptual simultaneity in autism spectrum disorders.
We compared judgements of the simultaneity or asynchrony of visual stimuli in individuals with autism spectrum disorders (ASD) and typically-developing controls using Magnetoencephalography (MEG). Two vertical bars were presented simultaneously or non-simultaneously with two different stimulus onset delays. Participants with ASD distinguished significantly better between real simultaneity (0 ms delay between two stimuli) and apparent simultaneity (17 ms delay between two stimuli) than controls. In line with the increased sensitivity, event-related MEG activity showed increased differential responses for simultaneity versus apparent simultaneity. The strongest evoked potentials, observed over occipital cortices at about 130 ms, were correlated with performance differences in the ASD group only. Superior access to early visual brain processes in ASD might underlie increased resolution of visual events in perception.


Association of Specific Dietary Fats With Total and Cause-Specific Mortality.
Previous studies have shown distinct associations between specific dietary fat and cardiovascular disease. However, evidence on specific dietary fat and mortality remains limited and inconsistent. To examine the associations of specific dietary fats with total and cause-specific mortality in 2 large ongoing cohort studies. This cohort study investigated 83 349 women from the Nurses' Health Study (July 1, 1980, to June 30, 2012) and 42 884 men from the Health Professionals Follow-up Study (February 1, 1986, to January 31, 2012) who were free of cardiovascular disease, cancer, and types 1 and 2 diabetes at baseline. Dietary fat intake was assessed at baseline and updated every 2 to 4 years. Information on mortality was obtained from systematic searches of the vital records of states and the National Death Index, supplemented by reports from family members or postal authorities. Data were analyzed from September 18, 2014, to March 27, 2016. Total and cause-specific mortality. During 3 439 954 person-years of follow-up, 33 304 deaths were documented. After adjustment for known and suspected risk factors, dietary total fat compared with total carbohydrates was inversely associated with total mortality (hazard ratio [HR] comparing extreme quintiles, 0.84; 95% CI, 0.81-0.88; P < .001 for trend). The HRs of total mortality comparing extreme quintiles of specific dietary fats were 1.08 (95% CI, 1.03-1.14) for saturated fat, 0.81 (95% CI, 0.78-0.84) for polyunsaturated fatty acid (PUFA), 0.89 (95% CI, 0.84-0.94) for monounsaturated fatty acid (MUFA), and 1.13 (95% CI, 1.07-1.18) for trans-fat (P < .001 for trend for all). Replacing 5% of energy from saturated fats with equivalent energy from PUFA and MUFA was associated with estimated reductions in total mortality of 27% (HR, 0.73; 95% CI, 0.70-0.77) and 13% (HR, 0.87; 95% CI, 0.82-0.93), respectively. The HR for total mortality comparing extreme quintiles of ω-6 PUFA intake was 0.85 (95% CI, 0.81-0.89; P < .001 for trend). Intake of ω-6 PUFA, especially linoleic acid, was inversely associated with mortality owing to most major causes, whereas marine ω-3 PUFA intake was associated with a modestly lower total mortality (HR comparing extreme quintiles, 0.96; 95% CI, 0.93-1.00; P = .002 for trend). Different types of dietary fats have divergent associations with total and cause-specific mortality. These findings support current dietary recommendations to replace saturated fat and trans-fat with unsaturated fats.


Lead-induced adverse effects on the reproductive system of rats with particular reference to histopathological changes in uterus.
This study was undertaken to elucidate the adverse effect of lead on female reproductive system following in vivo exposure in rats. Animals of Group II, III and IV received lead acetate in drinking water (30, 100 and 300 ppm, respectively) for 28 days whereas Group I served as control. Lead levels in digested blood and bone samples were measured using atomic absorption spectrophotometer. Marked and a significant decrease in per cent body weight gain was observed in rats of Group IV and III, respectively, compared to that in the control group. Relative uterine weights were found to decrease by 27% in Group III and IV compared to control and low dose lead treated (30 ppm) rats. Lead levels were found to increase in a linear manner in blood along with a marked increase in bone levels in 100 ppm exposure group while there was a decrease in both the blood and bones levels at 300 ppm exposure. Compared to plasma progesterone levels in rats of the control group, a nonsignificant (12.46-21.13%) reduction in plasma progesterone were observed in different lead-treated groups. No apparent gross pathological lesions were observed in any of the vital organs, including uterus. However, histopathological examination of uteri of different groups revealed lead-induced dose-dependent inflammatory changes, which were characterized by thickening of the endometrium, narrowing of uterine lumen, damage to endometrial glands and vacuolar degeneration in endometrial epithelial cells. Findings of this study suggest lead-induced pathophysiological alterations in myometrium, which in turn may affect the reproductive efficiency of animals.


An update on treatment advances for the first-line therapy of metastatic colorectal cancer.
The treatment of metastatic colorectal cancer (mCRC) has evolved significantly over the past 10 years. For nearly 40 years, the fluoropyrimidine 5-fluorouracil (5-FU) was the only agent to be used for advanced metastatic disease. However, since the mid-1990s, the chemotherapy treatment options for patients with mCRC have been greatly facilitated with the introduction of several new cytotoxic and biologic agents. In particular, combination regimens that incorporate infusional schedules of 5-FU in combination with oxaliplatin (FOLFOX) and/or irinotecan (FOLFIRI) have significantly improved clinical efficacy as related to overall response rates, time to tumor progression, and median overall survival. Capecitabine, an oral fluoropyrimidine, has now been shown in several phase III studies to be as effective as infusional 5-FU when combined with oxaliplatin. During this same time frame, intense efforts have focused on integrating novel biologic agents with cytotoxic chemotherapy regimens. These biologic agents target critical signaling pathways such as the vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR). Bevacizumab is a monoclonal antibody targeting VEGF-A, and when combined with fluoropyrimidine-based chemotherapy, which includes oxaliplatin or irinotecan, significantly improves clinical efficacy in the management of patients with mCRC. Cetuximab and panitumumab are monoclonal antibodies targeting EGFR, and each of these agents is approved to treat mCRC patients who have progressed on previous chemotherapy treatments. Recent studies have shown that cetuximab, when combined with cytotoxic chemotherapy, significantly enhances the management of patients with mCRC in the first-, second-, and disease-refractory settings. With these advances in treatment options, much attention is now focused on identifying the critical molecular biomarkers that can predict response and/or toxicity to facilitate the evolution of empiric chemotherapy to individually tailored treatments for patients with mCRC.


Infection and genotype remodel the entire soybean transcriptome.
High throughput methods, such as high density oligonucleotide microarray measurements of mRNA levels, are popular and critical to genome scale analysis and systems biology. However understanding the results of these analyses and in particular understanding the very wide range of levels of transcriptional changes observed is still a significant challenge. Many researchers still use an arbitrary cut off such as two-fold in order to identify changes that may be biologically significant. We have used a very large-scale microarray experiment involving 72 biological replicates to analyze the response of soybean plants to infection by the pathogen Phytophthora sojae and to analyze transcriptional modulation as a result of genotypic variation. With the unprecedented level of statistical sensitivity provided by the high degree of replication, we show unambiguously that almost the entire plant genome (97 to 99% of all detectable genes) undergoes transcriptional modulation in response to infection and genetic variation. The majority of the transcriptional differences are less than two-fold in magnitude. We show that low amplitude modulation of gene expression (less than two-fold changes) is highly statistically significant and consistent across biological replicates, even for modulations of less than 20%. Our results are consistent through two different normalization methods and two different statistical analysis procedures. Our findings demonstrate that the entire plant genome undergoes transcriptional modulation in response to infection and genetic variation. The pervasive low-magnitude remodeling of the transcriptome may be an integral component of physiological adaptation in soybean, and in all eukaryotes.


Overexpression of BUNDLE SHEATH DEFECTIVE 2 improves the efficiency of photosynthesis and growth in Arabidopsis.
Bundle Sheath Defective 2, BSD2, is a stroma-targeted protein initially identified as a factor required for the biogenesis of ribulose 1,5-bisphosphate carboxylase/oxygenase (RuBisCO) in maize. Plants and algae universally have a homologous gene for BSD2 and its deficiency causes a RuBisCO-less phenotype. As RuBisCO can be the rate-limiting step in CO2 assimilation, the overexpression of BSD2 might improve photosynthesis and productivity through the accumulation of RuBisCO. To examine this hypothesis, we produced BSD2 overexpression lines in Arabidopsis. Compared with wild type, the BSD2 overexpression lines BSD2ox-2 and BSD2ox-3 expressed 4.8-fold and 8.8-fold higher BSD2 mRNA, respectively, whereas the empty-vector (EV) harbouring plants had a comparable expression level. The overexpression lines showed a significantly higher CO2 assimilation rate per available CO2 and productivity than EV plants. The maximum carboxylation rate per total catalytic site was accelerated in the overexpression lines, while the number of total catalytic sites and RuBisCO content were unaffected. We then isolated recombinant BSD2 (rBSD2) from E. coli and found that rBSD2 reduces disulfide bonds using reductants present in vivo, for example glutathione, and that rBSD2 has the ability to reactivate RuBisCO that has been inactivated by oxidants. Furthermore, 15% of RuBisCO freshly isolated from leaves of EV was oxidatively inactivated, as compared with 0% in BSD2-overexpression lines, suggesting that the overexpression of BSD2 maintains RuBisCO to be in the reduced active form in vivo. Our results demonstrated that the overexpression of BSD2 improves photosynthetic efficiency in Arabidopsis and we conclude that it is involved in mediating RuBisCO activation.


Dll4/Notch1 signaling from tip/stalk endothelial cell specification to stroma-dependent lung tumor inhibition: a flavor of Dll4/Notch1 pleiotropy in tumor cell biology.
Non-small cell lung cancer (NSCLC) still represents the leading cause of cancer death. Treating this disease with systemic chemotherapy has reached a plateau in effectiveness and is rather toxic to the patients, while molecularly targeted therapies against Epidermal Growth Factor Receptor can lead to resistance. On the other hand, therapies based on tumor angiogenesis inhibition have been recently proposed. Here we will discuss on the pleiotropy of the Dll4/Notch1 cell-to-cell signaling in NSCLC, as alternative target for future therapeutic approaches.


Are well-child visits a risk factor for subsequent influenza-like illness visits?
To determine whether well-child visits are a risk factor for subsequent influenza-like illness (ILI) visits within a child's family. Retrospective cohort. Using data from the Medical Expenditure Panel Survey from the years 1996-2008, we identified 84,595 families. For each family, we determined those weeks in which a well-child visit or an ILI visit occurred. We identified 23,776 well-child-visit weeks and 97,250 ILI-visit weeks. We fitted a logistic regression model, where the binary dependent variable indicated an ILI clinic visit in a particular week. Independent variables included binary indicators to denote a well-child visit in the concurrent week or one of the previous 2 weeks, the occurrence of the ILI visit during the influenza season, and the presence of children in the family in each of the age groups 0-3, 4-7, and 8-17 years. Socioeconomic variables were also included. We also estimated the overall cost of well-child-exam-related ILI using data from 2008. We found that an ILI office visit by a family member was positively associated with a well-child visit in the same or one of the previous 2 weeks (odds ratio, 1.54). This additional risk translates to potentially 778,974 excess cases of ILI per year in the United States, with a cost of $500 million annually. Our results should encourage ambulatory clinics to strictly enforce infection control recommendations. In addition, clinics could consider time-shifting of well-child visits so as not to coincide with the peak of the influenza season.


Spinal interneurons and forelimb plasticity after incomplete cervical spinal cord injury in adult rats.
Cervical spinal cord injury (cSCI) disrupts bulbospinal projections to motoneurons controlling the upper limbs, resulting in significant functional impairments. Ongoing clinical and experimental research has revealed several lines of evidence for functional neuroplasticity and recovery of upper extremity function after SCI. The underlying neural substrates, however, have not been thoroughly characterized. The goals of the present study were to map the intraspinal motor circuitry associated with a defined upper extremity muscle, and evaluate chronic changes in the distribution of this circuit following incomplete cSCI. Injured animals received a high cervical (C2) lateral hemisection (Hx), which compromises supraspinal input to ipsilateral spinal motoneurons controlling the upper extremities (forelimb) in the adult rat. A battery of behavioral tests was used to characterize the time course and extent of forelimb motor recovery over a 16 week period post-injury. A retrograde transneuronal tracer - pseudorabies virus - was used to define the motor and pre-motor circuitry controlling the extensor carpi radialis longus (ECRL) muscle in spinal intact and injured animals. In the spinal intact rat, labeling was observed unilaterally within the ECRL motoneuron pool and within spinal interneurons bilaterally distributed within the dorsal horn and intermediate gray matter. No changes in labeling were observed 16 weeks post-injury, despite a moderate degree of recovery of forelimb motor function. These results suggest that recovery of the forelimb function assessed following C2Hx injury does not involve recruitment of new interneurons into the ipsilateral ECRL motor pathway. However, the functional significance of these existing interneurons to motor recovery requires further exploration.


Association between white matter hyperintensities, cortical volumes, and late-onset epilepsy.
To identify the association between brain vascular changes and cortical volumes on MRI and late-onset epilepsy. In 1993-1995, 1,920 participants (median age 62.7, 59.9% female) in the community-based Atherosclerosis Risk in Communities (ARIC) Study underwent MRI, and white matter hyperintensities were measured. In addition, in 2011-2013, 1,964 ARIC participants (median age 72.4, 61.1% female) underwent MRI, and cortical volumes and white matter hyperintensities were measured. We identified cases of late-onset epilepsy (starting at age 60 or later) from ARIC hospitalization records and Medicare claims data. Using the 1993-1995 MRI, we evaluated the association between white matter hyperintensities and subsequent epilepsy using survival analysis. We used the 2011-2013 MRI to conduct cross-sectional logistic regression to examine the association of cortical volumes and white matter hyperintensities with late-onset epilepsy. All models were adjusted for demographics, hypertension, diabetes, smoking, and APOE ε4 allele status. Ninety-seven ARIC participants developed epilepsy after having an MRI in 1993-1995 (incidence 3.34 per 1,000 person-years). The degree of white matter hyperintensities measured at ages 49-72 years was associated with the risk of late-onset epilepsy (hazard ratio 1.27 per age-adjusted SD, 95% confidence interval [CI] 1.06-1.54). Lower cortical volume scores were associated cross-sectionally with higher odds of late-onset epilepsy (odds ratio 1.87, 95% CI 1.16-3.02) per age-adjusted SD. This study demonstrates associations between earlier-life white matter hyperintensities on MRI and later-life incident epilepsy, and between cortical volumes measured later in life and late-onset epilepsy. These findings may help illuminate the causes of late-onset epilepsy.


Impact of Forward Stroke Volume Response on Clinical and Structural Outcomes After Percutaneous Mitral Valve Repair With MitraClip.
An increase of systolic forward flow was frequently observed after successful MitraClip implantation in patients with significant mitral regurgitation. However, the impact of systolic forward flow improvement on post-MitraClip outcomes remains unknown. Study population included 160 patients who underwent successful MitraClip implantation. The systolic forward flow was noninvasively calculated as the forward stroke volume (FSV) at baseline before the MitraClip procedure and before discharge with pulse-wave Doppler using transthoracic echocardiography. The optimal threshold of discharge/baseline FSV ratio for 3-year all-cause death was assessed. The best cutoff ratio was 1.09 (9% FSV increase from baseline, P=0.006). The FSV responders were defined as those with >9% increase of FSV from baseline (n=93). From discharge to 12-month follow-up, a significant reduction of LV end-diastolic and end-systolic volumes was observed in the responders, whereas no significant change was observed in the nonresponders. Furthermore, the proportion of New York Heart Association functional class III/IV was significantly lower in the responders at 12 months (2.9% versus 14.6%; P=0.03). Among patients with estimated glomerular filtration rate <60 mL/min per 1.73 m2, estimated glomerular filtration rate was significantly improved at 12 months only in the responders. All-cause mortality at 3 years was significantly lower in the responders than in the nonresponders (17.6% versus 42.3%; P=0.002). Multivariable logistic analysis identified higher baseline FSV, less mitral regurgitation severity, and functional mitral regurgitation as independent predictors of the nonresponders. FSV increase after MitraClip implantation was associated with more favorable clinical and anatomic outcomes. Severity and pathogenesis of mitral regurgitation and pre-MitraClip FSV predicted postprocedural FSV response.


Laser speckle correlation technique application for study of aluminum nanopowder combustion.
This paper presents the results of application of the laser speckle correlation (LSC) technique for studying the combustion process of aluminum-based nanopowders. For assessing the results, a combined experimental scheme is proposed with simultaneous application of LSC analyses and another feasible method of nanopowder combustion study, i.e., laser monitoring. In this paper, we present the principle of using the LSC technique to characterize the surface changes of nanopowder during combustion. Calculating the correlation coefficient of image sequencing, it is possible to estimate the time parameters of combustion of aluminum nanopowder and an aluminum mixture with iron nanopowder. Comparing the results obtained with the LSC method and laser monitoring, we conclude that LSC is quite acceptable for investigating the combustion process of metal nanopowders. In contrast with laser monitoring, the LSC method allows us to determine the preheating period preceding the first combustion wave. In practice, the LSC method application for nanopowder combustion control is prospective because of the simple hardware implementation.


Quantitative super-resolution imaging of Bruchpilot distinguishes active zone states.
The precise molecular architecture of synaptic active zones (AZs) gives rise to different structural and functional AZ states that fundamentally shape chemical neurotransmission. However, elucidating the nanoscopic protein arrangement at AZs is impeded by the diffraction-limited resolution of conventional light microscopy. Here we introduce new approaches to quantify endogenous protein organization at single-molecule resolution in situ with super-resolution imaging by direct stochastic optical reconstruction microscopy (dSTORM). Focusing on the Drosophila neuromuscular junction (NMJ), we find that the AZ cytomatrix (CAZ) is composed of units containing ~137 Bruchpilot (Brp) proteins, three quarters of which are organized into about 15 heptameric clusters. We test for a quantitative relationship between CAZ ultrastructure and neurotransmitter release properties by engaging Drosophila mutants and electrophysiology. Our results indicate that the precise nanoscopic organization of Brp distinguishes different physiological AZ states and link functional diversification to a heretofore unrecognized neuronal gradient of the CAZ ultrastructure.


Early intervention in thyroidectomy scars: demographics, symptoms, and prevention.
Although hypertrophic scars are cosmetically problematic for patients following thyroidectomy, the associated risk factors are not well defined. Our objective was to determine the factors associated with hypertrophic scar development following thyroidectomy. A retrospective chart review was performed collecting data on sex, age, body mass index (BMI), operation site, skin characteristics (pigmentation, erythema, elasticity, and hydration), and clinical scar characteristics (itching, tightening, induration, adhesion, and oedema). It was also noted if the patient had early scar intervention with intralesional steroid injection or non-ablative fractional laser irradiation, and preventive topical treatment agents. The effects of these factors were analysed using univariate and multivariate analyses. Data from 1141 patients showed the incidence of hypertrophic scars was 13.9%. Significant variables in univariate analysis were combined for multivariate analysis. Young age, high BMI, itching, tightening, induration, and adhesion were associated with hypertrophic scar formation. Early scar intervention, as well as the use of preventive topical agents, were associated with decreased hypertrophic scar formation. Based on our results, we suggest that dermatologists consider using non-ablative fractional laser, intralesional steroid injection, and topical preventive agents to lower the incidence of hypertrophic scars, especially in young patients or those with high BMI and/or clinical symptoms such as itching, tightening, induration, and adhesion.


Full-Field Calibration of Color Camera Chromatic Aberration using Absolute Phase Maps.
The refractive index of a lens varies for different wavelengths of light, and thus the same incident light with different wavelengths has different outgoing light. This characteristic of lenses causes images captured by a color camera to display chromatic aberration (CA), which seriously reduces image quality. Based on an analysis of the distribution of CA, a full-field calibration method based on absolute phase maps is proposed in this paper. Red, green, and blue closed sinusoidal fringe patterns are generated, consecutively displayed on an LCD (liquid crystal display), and captured by a color camera from the front viewpoint. The phase information of each color fringe is obtained using a four-step phase-shifting algorithm and optimum fringe number selection method. CA causes the unwrapped phase of the three channels to differ. These pixel deviations can be computed by comparing the unwrapped phase data of the red, blue, and green channels in polar coordinates. CA calibration is accomplished in Cartesian coordinates. The systematic errors introduced by the LCD are analyzed and corrected. Simulated results show the validity of the proposed method and experimental results demonstrate that the proposed full-field calibration method based on absolute phase maps will be useful for practical software-based CA calibration.


Tracking SARS-CoV-2 mutations and variants through the COG-UK-Mutation Explorer.
COG-UK Mutation Explorer (COG-UK-ME, https://sars2.cvr.gla.ac.uk/cog-uk/-last accessed date 16 March 2022) is a web resource that displays knowledge and analyses on SARS-CoV-2 virus genome mutations and variants circulating in the UK, with a focus on the observed amino acid replacements that have an antigenic role in the context of the human humoral and cellular immune response. This analysis is based on more than 2 million genome sequences (as of March 2022) for UK SARS-CoV-2 data held in the CLIMB-COVID centralised data environment. COG-UK-ME curates these data and displays analyses that are cross-referenced to experimental data collated from the primary literature. The aim is to track mutations of immunological importance that are accumulating in current variants of concern and variants of interest that could alter the neutralising activity of monoclonal antibodies (mAbs), convalescent sera, and vaccines. Changes in epitopes recognised by T cells, including those where reduced T cell binding has been demonstrated, are reported. Mutations that have been shown to confer SARS-CoV-2 resistance to antiviral drugs are also included. Using visualisation tools, COG-UK-ME also allows users to identify the emergence of variants carrying mutations that could decrease the neutralising activity of both mAbs present in therapeutic cocktails, e.g. Ronapreve. COG-UK-ME tracks changes in the frequency of combinations of mutations and brings together the curated literature on the impact of those mutations on various functional aspects of the virus and therapeutics. Given the unpredictable nature of SARS-CoV-2 as exemplified by yet another variant of concern, Omicron, continued surveillance of SARS-CoV-2 remains imperative to monitor virus evolution linked to the efficacy of therapeutics.


Classifying interval cancers as false negatives or newly occurring in fecal immunochemical testing.
To classify interval colorectal cancers as false negatives or newly occurring cases in a biennial Fecal immunochemical test (FIT) screening program and by various interscreening intervals. Data from the Taiwanese biennial colorectal cancer screening program involving FIT from 2004 to 2014 were used to estimate the incidence rate of asymptomatic colorectal cancer and the rate of its subsequent progression to clinical mode. The sensitivity of detecting asymptomatic colorectal cancers excluding newly developed colorectal cancers was compared to the conventional estimate of sensitivity, the complementary FIT interval cancer rate as a percentage of the expected incidence rate ((1-I/E)%). The relative contribution of newly developed or false-negative cases to FIT interval colorectal cancers was estimated by age and interscreening intervals. The Taiwanese biennial fecal immunochemical test screening program had a conventional sensitivity estimate of 70.2%. After newly developed colorectal cancers were separated from FIT interval cancers, the ability to detect asymptomatic colorectal cancers increased to 75.5%. FIT interval colorectal cancers from the biennial program mainly resulted from newly developed colorectal cancers (68.8%). The corresponding figures decreased to 61.1% for the annual program but increased to 74.7% for the triennial program. The preponderance of newly developed colorectal cancers among FIT interval cancers was more prominent in screenees aged 50-59 than in those aged 60-69. Newly developed colorectal cancers showed a predominance among the FIT interval colorectal cancers in particular in the younger population screened. It is desirable to identify high-risk individuals to offer them a short interscreening interval or advanced detection methods to reduce their odds of developing interval cancer.


Malva parviflora Leaves Mucilage: An Eco-Friendly and Sustainable Biopolymer with Antioxidant Properties.
Malva parviflora L. is an edible and medicinal herb containing mucilaginous cells in its leaves. Mucilage obtained from M. parviflora leaves (MLM) was extracted in distilled water (1:10 w/v) at 70 °C followed by precipitation with alcohol. Preliminary phytochemical tests were performed to assess the purity of the extracted mucilage. Results showed that the yield of mucilage was 7.50%, and it was free from starch, alkaloids, glycosides, saponins, steroids, lipids and heavy metals. MLM had 16.19% carbohydrates, 13.55% proteins and 4.76% amino acids, which indicate its high nutritional value. Physicochemical investigations showed that MLM is neutral and water-soluble, having 5.84% moisture content, 15.60% ash content, 12.33 swelling index, 2.57 g/g water-holding capacity and 2.03 g/g oil-binding capacity. The functional properties, including emulsion capacity, emulsion stability, foaming capacity and stability increased with increased concentrations. Micromeritic properties, such as bulk density, tapped density, Carr's index, Hausner ratio, and angle of repose, were found to be 0.69 g/cm3, 0.84 g/cm3, 17.86%, 1.22 and 28.5, respectively. Scanning electron microscopy (SEM) showed that MLM is an amorphous powder possessing particles of varying size and shape; meanwhile, rheological studies revealed the pseudoplastic behavior of MLM. The thermal transition process of MLM revealed by a differential scanning calorimetry (DSC) thermogram, occurring at a reasonable enthalpy change (∆H), reflects its good thermal stability. The presence of functional groups characteristic of polysaccharides was ascertained by the infrared (IR) and gas chromatography/mass spectrometry (GC/MS) analyses. GC revealed the presence of five neutral monosaccharides; namely, galactose, rhamnose, arabinose, glucose and mannose, showing 51.09, 10.24, 8.90, 1.80 and 0.90 mg/g of MLM, respectively. Meanwhile, galacturonic acid is the only detected acidic monosaccharide, forming 15.06 mg/g of MLM. It showed noticeable antioxidant activity against the DPPH (1,1-diphenyl-2-picrylhydrazyl) radical with an IC50 value of 154.27 µg/mL. It also prevented oxidative damage to DNA caused by the Fenton reagent, as visualized in gel documentation system. The sun protection factor was found to be 10.93 ± 0.15 at 400 µg/mL. Thus, MLM can be used in food, cosmetic and pharmaceutical industry and as a therapeutic agent due to its unique properties.


Multi-targeting Strategies for Alzheimer's Disease Therapeutics: Pros and Cons.
Alzheimer's Disease (AD) is a single major cause of dementia in middle to old age individuals involving several different etiopathological mechanisms that are yet to be properly characterized. Major invariant and characteristic features consist of the progressive cerebral deposition of the Amyloid β-protein (Aβ) and the neurofibrillary degeneration through Neurofibrillary Tangles (NFT) formed by hyperphosphorylation of the tau proteins in the regions of the brain that deal with memory and cognition. There are at least five subgroups of AD that can be identified by determining Cerebrospinal Fluid (CSF) levels of Aβ1-42, tau and ubiquitin. This multifactorial nature of the disease thus demands promising approaches for the development of rational disease-modifying drugs. A large number of agents have been discovered against individual targets but the success rate is very low and the number of compounds progressing to regulatory review is among the lowest found in any therapeutic area. A very promising modern approach solicits the design of Multi-Target-Directed Ligands (MTDLs) based on the "one molecule multiple targets" paradigm that has been specifically adopted for the treatment of disorders with complex pathological mechanisms. AD is one such disorder in which MTDL has found applicability. This review aims at providing an overview of the research carried out in discovering more efficient treatment against AD using MTDL, with a goal to ascertain safer drugs.


Developing a survey to assess factors that contribute to physician involvement in clinical research.
Investment in research, including clinical research, has positive effects both on health of a population and economic growth of a country. Several factors have been suggested as being related to the performance of clinical research. The goal of this work was to develop and perform initial validation of a survey that measures both current research involvement of physicians, as well as previously noted factors and additional informatics factors affecting this involvement. The survey was developed in both English and Spanish with the goal of its use in Latin America. The initial survey was developed primarily from experience with other validated surveys developed for similar purposes. It was validated in three stages with modification or elimination of questions as indicated by this testing. The final survey contains 33 questions in the categories of research experience, education in research, environmental factors, computer experience, and collaboration.


Chromosomal rearrangements in uveal melanoma: Chromothripsis.
Uveal melanoma (UM) is the most common primary intraocular malignancy in the Western world. Recurrent mutations in GNAQ, GNA11, CYSLTR2, PLCB4, BAP1, EIF1AX, and SF3B1 are described as well as non-random chromosomal aberrations. Chromothripsis is a rare event in which chromosomes are shattered and rearranged and has been reported in a variety of cancers including UM. SNP arrays of 249 UM from patients who underwent enucleation, biopsy or endoresection were reviewed for the presence of chromothripsis. Chromothripsis was defined as ten or more breakpoints per chromosome involved. Genetic analysis of GNAQ, GNA11, BAP1, SF3B1, and EIF1AX was conducted using Sanger and next-generation sequencing. In addition, immunohistochemistry for BAP1 was performed. Chromothripsis was detected in 7 out of 249 tumors and the affected chromosomes were chromosomes 3, 5, 6, 8, 12, and 13. The mean total of fragments per chromosome was 39.8 (range 12-116). In 1 UM, chromothripsis was present in 2 different chromosomes. GNAQ, GNA11 or CYSLTR2 mutations were present in 6 of these tumors and 5 tumors harbored a BAP1 mutation and/or lacked BAP1 protein expression by immunohistochemistry. Four of these tumors metastasized and for the fifth only short follow-up data are available. One of these metastatic tumors harbored an SF3B1 mutation. No EIF1AX mutations were detected in any of the tumors. To conclude, chromothripsis is a rare event in UM, occurring in 2.8% of samples and without significant association with mutations in any of the common UM driver genes.


Clinical, Biomarker, and Molecular Delineations and Genotype-Phenotype Correlations of Ataxia With Oculomotor Apraxia Type 1.
Ataxia with oculomotor apraxia type 1 (AOA1) is an autosomal recessive cerebellar ataxia due to mutations in the aprataxin gene (APTX) that is characterized by early-onset cerebellar ataxia, oculomotor apraxia, axonal motor neuropathy, and eventual decrease of albumin serum levels. To improve the clinical, biomarker, and molecular delineation of AOA1 and provide genotype-phenotype correlations. This retrospective analysis included the clinical, biological (especially regarding biomarkers of the disease), electrophysiologic, imaging, and molecular data of all patients consecutively diagnosed with AOA1 in a single genetics laboratory from January 1, 2002, through December 31, 2014. Data were analyzed from January 1, 2015, through January 31, 2016. The clinical, biological, and molecular spectrum of AOA1 and genotype-phenotype correlations. The diagnosis of AOA1 was confirmed in 80 patients (46 men [58%] and 34 women [42%]; mean [SD] age at onset, 7.7 [7.4] years) from 51 families, including 57 new (with 8 new mutations) and 23 previously described patients. Elevated levels of α-fetoprotein (AFP) were found in 33 patients (41%); hypoalbuminemia, in 50 (63%). Median AFP level was higher in patients with AOA1 (6.0 ng/mL; range, 1.1-17.0 ng/mL) than in patients without ataxia (3.4 ng/mL; range, 0.8-17.2 ng/mL; P < .01). Decreased albumin levels (ρ = -0.532) and elevated AFP levels (ρ = 0.637) were correlated with disease duration. The p.Trp279* mutation, initially reported as restricted to the Portuguese founder haplotype, was discovered in 53 patients with AOA1 (66%) with broad white racial origins. Oculomotor apraxia was found in 49 patients (61%); polyneuropathy, in 74 (93%); and cerebellar atrophy, in 78 (98%). Oculomotor apraxia correlated with the severity of ataxia and mutation type, being more frequent with deletion or truncating mutations (83%) than with presence of at least 1 missense variant (17%; P < .01). Mean (SD) age at onset was higher for patients with at least 1 missense mutation (17.7 [11.4] vs 5.2 [2.6] years; P < .001). The AFP level, slightly elevated in a substantial fraction of patients, may constitute a new biomarker for AOA1. Oculomotor apraxia may be an optional finding in AOA1 and correlates with more severe disease. The p.Trp279* mutation is the most frequent APTX mutation in the white population. APTX missense mutations may be associated with a milder phenotype.


Research Strategies for Biomedical and Health Informatics. Some Thought-provoking and Critical Proposals to Encourage Scientific Debate on the Nature of Good Research in Medical Informatics.
Medical informatics, or biomedical and health informatics (BMHI), has become an established scientific discipline. In all such disciplines there is a certain inertia to persist in focusing on well-established research areas and to hold on to well-known research methodologies rather than adopting new ones, which may be more appropriate. To search for answers to the following questions: What are research fields in informatics, which are not being currently adequately addressed, and which methodological approaches might be insufficiently used? Do we know about reasons? What could be consequences of change for research and for education? Outstanding informatics scientists were invited to three panel sessions on this topic in leading international conferences (MIE 2015, Medinfo 2015, HEC 2016) in order to get their answers to these questions. A variety of themes emerged in the set of answers provided by the panellists. Some panellists took the theoretical foundations of the field for granted, while several questioned whether the field was actually grounded in a strong theoretical foundation. Panellists proposed a range of suggestions for new or improved approaches, methodologies, and techniques to enhance the BMHI research agenda. The field of BMHI is on the one hand maturing as an academic community and intellectual endeavour. On the other hand vendor-supplied solutions may be too readily and uncritically accepted in health care practice. There is a high chance that BMHI will continue to flourish as an important discipline; its innovative interventions might then reach the original objectives of advancing science and improving health care outcomes.


[Drop-out from clinical psychotherapeutic treatment of personality problems].
Drop-out is a serious problem in psychotherapy. Earlier studies have shown that the main factors associated with drop-out are young age, low socio-economic status and pathological symptoms such as severity of the problems and problematic substance-abuse. To investigate patient's and pathological characteristics that predict drop-out among patients with predominantly personality problems. Patient's characteristics and pathological characteristics of 372 subjects were ascertained via a retrospective study by means of four databases: intake letters, scid-ii personality questionnaires, scid-i and ii interviews and discharge letters. The association between these characteristics and drop-out was tested by means of bivariate and multivariate analysis. results The drop-out rate was 33.3 %. The main predictors of drop-out were young age, a low Global Assessment of Functioning (gaf)-score and the existence of problematic substance-abuse at discharge. The degree and severity of axis i disorders and the nature of personality problems made hardly any contribution to the prediction of drop-out. These findings indicate that more attention needs to be given to the existence of substance-abuse before psychotherapy begins. Drop-out is still a problem and is difficult to predict and hard to influence.


Nursing research on intimate partner violence in China: A scoping review.
Intimate partner violence (IPV) is a serious public health issue, and nurses have the potential to screen, navigate to interventions, and provide support, but responses to IPV differ greatly in mainland China, Hong Kong, Macao, and Taiwan. We conducted a scoping review to examine the nursing literature on IPV in the above four regions in China. We conducted a comprehensive search of 11 Chinese and English databases from database inception to January 31, 2020, for eligible papers including empirical studies, reviews, reports, and expert opinion articles. We hand searched references lists and other studies published by the first and corresponding authors of included articles. Two reviewers independently screened articles and extracted data, and three reviewers cross-checked the extracted results. We also conducted quality appraisal for applicable empirical studies. A total of 58 Chinese-language and 63 English-language articles were included, 58 from Taiwan, 44 from Hong Kong, 13 from mainland China, and six from institutions outside China, but none from Macao. The quantitative and qualitative studies described the prevalence and complex nature of IPV, comparable to non-nursing and international studies. Nurse-led advocacy and Qigong (traditional Chinese mind-body health practice) interventions showed promise for improving mental health in women in Hong Kong. There was a low level of knowledge and preparedness to respond to IPV among Chinese nurses, especially in mainland China. Mixed methods studies in Hong Kong and Taiwan as complex designs were generally well-conducted. Nursing case reports from Taiwan uniquely supplemented the evidence base. In Hong Kong and Taiwan, varying designs were used to study various facets of IPV, targeting victims, nurses and other key stakeholders. In mainland China and Macao, IPV research was limited in quantity, quality, and diversity. As more research in the area of IPV is needed, factors influencing nursing research on IPV also merit investigation, while taking into consideration socio-economic-political-cultural factors.


R2: a useful measure of model performance when predicting a dichotomous outcome.
R2 has been criticized as a measure of model performance when predicting a dichotomous outcome, both because its value is often low and because it is sensitive to the prevalence of the event of interest. The C statistic is more widely used to measure model performance in a 0/1 setting. We use a simple parametric family of models to illustrate the potential usefulness of models with low R2 values, to clarify the effect of prevalence on both C and R2, and to demonstrate how R2 captures information not picked up by C. We also show that C is subject to a 'random mixing' problem that does not affect R2. Finally, we report both R2 and C values for different risk-adjustment models in situations with different prevalences and show the relationship between the measures and decile death rates, thereby providing a context for interpreting R2 values in a 0/1 setting.


Incorporating variability in point estimates in risk assessment: Bridging the gap between LC50 and population endpoints.
Historically, point estimates such as the median lethal concentration (LC50) have been instrumental in assessing risks associated with toxicants to rare or economically important species. In recent years, growing awareness of the shortcomings of this approach has led to an increased focus on analyses using population endpoints. However, risk assessment of pesticides still relies heavily on large amounts of LC50 data amassed over decades in the laboratory. Despite the fact that these data are generally well replicated, little or no attention has been given to the sometime high levels of variability associated with the generation of point estimates. This is especially important in agroecosystems where arthropod predator-prey interactions are often disrupted by the use of pesticides. Using laboratory derived data of 4 economically important species (2 fruit fly pest species and 2 braconid parasitoid species) and matrix based population models, the authors demonstrate in the present study a method for bridging traditional point estimate risk assessments with population outcomes. The results illustrate that even closely related species can show strikingly divergent responses to the same exposures to pesticides. Furthermore, the authors show that using different values within the 95% confidence intervals of LC50 values can result in very different population outcomes, ranging from quick recovery to extinction for both pest and parasitoid species. The authors discuss the implications of these results and emphasize the need to incorporate variability and uncertainty in point estimates for use in risk assessment.


Myeloperoxidase genotypes and enhanced efficacy of chemotherapy for early-stage breast cancer in SWOG-8897.
Myeloperoxidase (MPO) generates reactive oxygen species and also activates xenobiotics. In a rigorous clinical trial (Southwest Oncology Group SWOG-8897), we examined relationships between genotypes and disease-free survival (DFS) among women treated for breast cancer, as well as those who did not receive adjuvant chemotherapy. Patients were assigned to risk groups according to standard prognostic features; the low-risk group (n = 753 genotyped) received follow-up only, and the high-risk group (n = 401 genotyped) was randomly assigned to adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) or cyclophosphamide, doxorubicin, and fluorouracil (CAF), with or without tamoxifen. DNA from archived normal lymph node tissue was genotyped, and Cox proportional hazard models were used to calculate DFS associated with MPO genotypes. Among women in the treatment arm, those with MPO G alleles had more than a two-fold reduction in hazard of recurrence (adjusted hazard ratio [HR] for GA genotypes, 0.51; 95% CI, 0.21 to 0.99; HR for GG genotypes, 0.41; 95% CI, 0.21 to 0.77). Effects were greatest among women who were further randomly assigned to tamoxifen (HR for GA genotypes, 0.28; 95% CI, 0.12 to 0.69; HR for GG genotypes, 0.19; 95% CI, 0.08 to 0.45). There were no significant associations between genotypes and DFS among women in the untreated arm, and relationships between genotypes and DFS did not differ by CAF or CMF. These results, observed in two independent study populations, indicate that high-activity MPO genotypes are associated with better survival among women receiving cyclophosphamide-containing therapy, particularly when followed by tamoxifen therapy. MPO can be inhibited and/or upregulated by commonly used drugs; thus, our findings merit further investigation for optimization of therapeutics for breast cancer.


A herpes-like virus infects a non-ostreid bivalve species: virus replication in Ruditapes philippinarum larvae.
Sporadic high mortalities were reported in June 1997 among hatchery-reared larval Manila clam Ruditapes philippinarum in a French commercial hatchery. Cellular abnormalities were observed in semi-thin sections in affected animals. Transmission electron microscopy revealed the presence of herpes-like virus particles in larvae. This is the first description of a herpes-like virus infection in larval R. philippinarum, a non-ostreid bivalve species. Virus particles were similar to other herpes-like viruses described from different oyster species with respect to ultrastructure and morphogenesis. Electron microscopic examination also demonstrated cells with condensed chromatin and extensive perinuclear fragmentation of chromatin. Like viruses infecting oysters, the herpes-like virus detected in clams may induce apoptosis in infected animals.


Prevalence of glaucoma in Eastern India: The Hooghly River Glaucoma Study.
Glaucoma is the leading cause of global irreversible blindness. No recent study with adequate sample size has been carried out to estimate glaucoma prevalence in Eastern India. The aim of this study was to assess and compare the prevalence and types of glaucoma in a rural and urban East Indian population. The Hooghly River Glaucoma Study (HRGS) is a population-based cross-sectional study from West Bengal. A tertiary hospital in Kolkata was our urban study center. Our rural study area included 28 contiguous villages from the district of Hooghly surrounding the rural base hospital located at Dhobapara in village Bakulia. Individuals aged 40 years and above were included in this study. All subjects underwent a detailed ophthalmic examination at our base hospitals including applanation tonometry, ultrasound pachymetry, gonioscopy, and frequency doubling technology perimetry. Glaucoma was defined using modified International Society of Geographical and Epidemiological Ophthalmology criteria. Analysis was performed using Chi-square test and multiple logistic regression using SPSS. Totally, 14,092 individuals participated; 2.7% were detected to have glaucoma in rural arm and 3.23% in urban arm (P < 0.001). In urban population, 2.10% had primary open angle glaucoma (POAG), 0.97% had primary angle closure glaucoma (PACG), and 0.15% had secondary glaucoma. In rural population, 1.45% had POAG, 1.15% had ACG, and 0.10% had secondary glaucoma. HRGS is the largest population-based glaucoma study in India to date with glaucoma prevalence comparable to other landmark Indian studies. POAG was the most common form of glaucoma in our study population as well. PACG was more common in this region than previously thought.


Effector cells in allelic H-2 class I-incompatible skin graft rejection.
The cellular mechanisms of skin graft rejection with allelic H-2 class I differences were studied by examining the effect on graft survival of in vivo administration of anti-Lyt-2.2 mAb, anti-L3T4 mAb, or both to recipient mice. The injections of anti-Lyt-2.2 mAb and anti-L3T4 mAb caused selective depletions of Lyt-2+ cells and L3T4+ cells, respectively. Injection of anti-Lyt-2.2 mAb significantly prolonged graft survival in 7 of 12 combinations of H-2D-end difference, but did not prolong graft survival in 5 other combinations of H-2D-end difference, or in 2 combinations of H-2K-end difference. Injection of anti-L3T4 mAb did not prolong graft survival in any combinations with class I difference tested. Injection of anti-L3T4 mAb plus anti-Lyt-2.2 mAb markedly prolonged graft survival in the combinations with class I difference in which anti-Lyt-2.2 mAb had no effect and overcame the effect of anti-Lyt-2.2 mAb in those in which anti-Lyt-2.2 mAb had an effect in prolonging graft survival. These results indicated that in combinations in which anti-Lyt-2.2 mAb did not prolong graft survival, class I antigen stimulated L3T4+ effector cells when Lyt-2+ cells were blocked and Lyt-2+ effector cells when L3T4+ cells were blocked. On the other hand, in the combinations in which anti-Lyt-2.2 mAb prolong graft survival, these antigens initially caused preferential stimulation of Lyt-2+ but not L3T4+ effector cells, although delayed activation of L3T4+ effector cells occurred when Lyt-2+ cells were blocked. Furthermore, a significant correlation was found between the effect of anti-Lyt-2.2 mAb in prolonging graft survival and the failure of recipient mice to produce H-2 antibody. These results can be taken as evidence that L3T4+ effector cells are not involved in the initial phase of graft rejection in these combinations.


Epigenome-wide association study in whole blood on type 2 diabetes among sub-Saharan African individuals: findings from the RODAM study.
Type 2 diabetes (T2D) results from a complex interplay between genetics and the environment. Several epigenome-wide association studies (EWAS) have found DNA methylation loci associated with T2D in European populations. However, data from African populations are lacking. We undertook the first EWAS for T2D among sub-Saharan Africans, aiming at identifying ubiquitous and novel DNA methylation loci associated with T2D. The Illumina 450k DNA-methylation array was used on whole blood samples of 713 Ghanaian participants (256 with T2D, 457 controls) from the cross-sectional Research on Obesity and Diabetes among African Migrants (RODAM) study. Differentially methylated positions (DMPs) for T2D and HbA1c were identified through linear regression analysis adjusted for age, sex, estimated cell counts, hybridization batch, array position and body mass index (BMI). We also did a candidate analysis of previously reported EWAS loci for T2D in non-African populations, identified through a systematic literature search. Four DMPs [cg19693031 (TXNIP), cg04816311 (C7orf50), cg00574958 (CPT1A), cg07988171 (TPM4)] were associated with T2D after correction for inflation by possible systematic biases. The most strongly associated DMP-cg19693031, TXNIP (P = 2.6E-19) -showed hypomethylation in T2D cases compared with controls. Two out of the four DMPs [cg19693031 (TXNIP), cg04816311 (C7orf50)] remained associated with T2D after adjustment for BMI, and one locus [cg07988171 (TPM4)] that has not been reported previously. In this first EWAS for T2D in sub-Saharan Africans, we have identified four DMPs at epigenome-wide level, one of which is novel. These findings provide insight into the epigenetic loci that underlie the burden of T2D in sub-Saharan Africans.


Young Aboriginal people's engagement with STI testing in the Northern Territory, Australia.
Australian surveillance data document higher rates of sexually transmissible infections (STIs) among young Aboriginal people (15-29 years) in remote settings than non-Aboriginal young people. Epidemiological data indicate a substantial number of young Aboriginal people do not test for STIs. Rigorous qualitative research can enhance understanding of these findings. This paper documents socio-ecological factors influencing young Aboriginal people's engagement with clinic-based STI testing in two remote settings in the Northern Territory, Australia. In-depth interviews with 35 young Aboriginal men and women aged 16-21 years; thematic analysis examining their perceptions and personal experiences of access to clinic-based STI testing. Findings reveal individual, social and health service level influences on willingness to undertake clinic-based STI testing. Individual level barriers included limited knowledge about asymptomatic STIs, attitudinal barriers against testing for symptomatic STIs, and lack of skills to communicate about STIs with health service staff. Social influences both promoted and inhibited STI testing. In setting 1, local social networks enabled intergenerational learning about sexual health and facilitated accompanied visits to health clinics for young women. In setting 2, however, social connectedness inhibited access to STI testing services. Being seen at clinics was perceived to lead to stigmatisation among peers and fear of reputational damage due to STI-related rumours. Modalities of health service provision both enhanced and inhibited STI testing. In setting 1, outreach strategies by male health workers provided young Aboriginal men with opportunities to learn about sexual health, initiate trusting relationships with clinic staff, and gain access to clinics. In setting 2, barriers were created by the location and visibility of the clinic, appointment procedures, waiting rooms and waiting times. Where inhibitive factors at the individual, social and health service levels exist, young Aboriginal people reported more limited access to STI testing. This is the first socio-ecological analysis of factors influencing young Aboriginal people's willingness to undertake testing for STIs within clinics in Australia. Strategies to improve uptake of STI testing must tackle the overlapping social and health service factors that discourage young people from seeking sexual health support. Much can be learned from young people's lived sexual health experiences and family- and community-based health promotion practices.


Dual-Energy CT Iodine Mapping and 40-keV Monoenergetic Applications in the Diagnosis of Acute Bowel Ischemia.
Sensitivity of CT of the abdomen for detection of acute bowel ischemia (ABI) can be as low as 60%. In this study, we assessed the diagnostic performance of iodine-map and monoenergetic (40-keV) images in patients with suspected ABI. This retrospective study included 60 consecutive patients with suspected ABI who underwent a standardized imaging protocol dual-source dual-energy CT (DECT) over a 26-month period. Clinical and operative outcomes were recorded as the reference standard. Two abdominal radiologists who were unaware of clinical and surgical information independently assessed conventional CT images for ABI. After a time interval designed to reduce recall, readers reassessed conventional images with supplementary iodine-map and 40-keV postprocessed images. Quantitative ROI analysis was also performed. ABI was observed in 11 patients. For reader A, sensitivity was 63.6% (95% CI, 30.8-89.1%) when interpreting conventional images alone. Sensitivity for detection of ABI increased to 81.8% (95% CI, 48.2-97.7%) and 100% (95% CI, 71.5-100%) when iodine-map and 40-keV images were assessed, respectively. For reader B, no change in sensitivity was seen with either technique, but the number of false-positives were reduced with supplementary iodine-map and 40-keV postprocessed images. Interobserver agreement was fair with conventional images (κ = 0.29) but improved to moderate (κ = 0.45) and substantial (κ = 0.63) with iodine-map and 40-keV images, respectively. Quantitative assessment found significant differences in iodine uptake (1.01 ± 0.55 mg/mL vs 3.04 ± 1.19 mg/mL) and mean attenuation (75.2 ± 38.4 HU vs 163.5 ± 48.9 HU) between nonischemic and ischemic segments, respectively. Iodine-map and 40-keV monoenergetic images increase conspicuity of ABI, resulting in improved diagnostic accuracy compared with review of conventional CT images alone.


The perception of sexual attractiveness: sex differences in variability.
Results of three independent studies supported predictions derived from evolutionary theory: Men's assessments of sexual attractiveness are determined more by objectively assessable physical attributes; women's assessments are more influenced by perceived ability and willingness to invest (e.g., partners' social status, potential interest in them). Consequently, women's assessments of potential partners' sexual attractiveness and coital acceptability vary more than men's assessments. The proposition that polygamous women's assessments of men's sexual attractiveness vary less than those of monogamous women (because the former allegedly are more influenced by target persons' physical attributes) was also tested. In Study 1 male college students showed more agreement than females in their rankings of the sexual attractiveness of opposite-sex target persons. Target persons' flesh and bodily display enhanced this sex difference. In Study 2 men exhibited less variance than did women in their ratings of target persons' acceptability for dating and sexual relations. Women who viewed models described as having low status showed more variability than did women in the high-status condition. In Study 3 women showed more variability than men did in their ratings of 20 opposite-sex celebrities' sexual attractiveness. Studies 2 and 3 included the Sociosexual Orientation Inventory (SOI)-a measure of polygamous attitudes and behavior. Women's SOI scores did not affect the variability of their assessments in either Study 2 or 3. In Study 3 men with low SOI scores showed less variability than did men with high SOI scores. Alternative explanations of the findings are examined. Theoretical and empirical implications are discussed.


Fostering accountable health care: moving forward in medicare.
To succeed, health care reform must slow spending growth while improving quality. We propose a new approach to help achieve more integrated and efficient care by fostering local organizational accountability for quality and costs through performance measurement and "shared savings" payment reform. The approach is practical and feasible: it is voluntary for providers, builds on current referral patterns, requires no change in benefits or lock-in for beneficiaries, and offers the possibility of sustained provider incomes even as total costs are constrained. We simulate the potential expenditure impact and show that significant Medicare savings are possible.