A crossover randomized trial of transcutaneous electrical nerve stimulation and oxybutynin in patients with detrusor instability.
Management of idiopathic detrusor instability is difficult in most patients mainly due to the lack of a complete understanding of the pathophysiology. Oxybutynin and transcutaneous electrical nerve stimulation have been used but to our knowledge no direct comparisons have been made. Patients with frequency, urgency, urge incontinence and proved detrusor instability were studied with urodynamics, quality of life instruments, and frequency and volume charts. Patients were randomized to transcutaneous electrical nerve stimulation or oxybutynin. After 6 weeks of treatment, they were reassessed and after a washout of 2 weeks, they were started on the second arm of treatment and reassessed 6 weeks later. A total of 13 male and 30 female patients were studied. Functional capacity had increased and number of voids daily had decreased significantly compared with before treatment in both arms (p <0.005). There were significant improvements in symptom specific quality of life measures but no changes were found on the global Short Form 36 (SF-36) quality of life questionnaire. The volume to first desire to void and first unstable contraction had increased significantly with oxybutynin but not with transcutaneous electrical nerve stimulation. Of 23 patients 7 were stabilized with treatment, including 2 with oxybutynin only, 2 with either nerve stimulation or oxybutynin and the remaining 3 with only nerve stimulation. Total bladder capacity did not change significantly with either treatment but patients noticed side effects more commonly with oxybutynin. Both treatments clearly improved subjective parameters. However, only oxybutynin showed significant improvements in objective urodynamic parameters. Transcutaneous electrical nerve stimulation can be used in patients who cannot take oxybutynin. Further studies are needed to show the long-term efficacy and cost analyses of nerve stimulation.


Deterrence and Risk Preferences in Sequential Attacker-Defender Games with Continuous Efforts.
Most attacker-defender games consider players as risk neutral, whereas in reality attackers and defenders may be risk seeking or risk averse. This article studies the impact of players' risk preferences on their equilibrium behavior and its effect on the notion of deterrence. In particular, we study the effects of risk preferences in a single-period, sequential game where a defender has a continuous range of investment levels that could be strategically chosen to potentially deter an attack. This article presents analytic results related to the effect of attacker and defender risk preferences on the optimal defense effort level and their impact on the deterrence level. Numerical illustrations and some discussion of the effect of risk preferences on deterrence and the utility of using such a model are provided, as well as sensitivity analysis of continuous attack investment levels and uncertainty in the defender's beliefs about the attacker's risk preference. A key contribution of this article is the identification of specific scenarios in which the defender using a model that takes into account risk preferences would be better off than a defender using a traditional risk-neutral model. This study provides insights that could be used by policy analysts and decisionmakers involved in investment decisions in security and safety.


Increased frequency of late-senescent T cells lacking CD127 in chronic hepatitis C disease.
Hepatitis C virus (HCV) causes persistent disease in ~85% of infected individuals, where the viral replication appears to be tightly controlled by HCV-specific CD8+ T cells. Accumulation of senescent T cells during infection results in considerable loss of functional HCV-specific immune responses. We characterized the distinct T-cell phenotypes based on the expression of costimulatory molecules CD28 and CD27, senescence markers PD-1 and CD57, chronic immune activation markers CD38 and HLA-DR, and survival marker CD127 (IL-7R) by flow cytometry following activation of T cells using HCV peptides and phytohemagglutinin. HCV-specific CD4+ and CD8+ T cells from chronic HCV (CHC) patients showed increased expression of PD-1. Furthermore, virus-specific CD4+ T cells of CHC-infected subjects displayed relatively increased expression of HLA-DR and CD38 relative to HCV-specific CD8+ T cells. The CD4+ and CD8+ T cells from HCV-infected individuals showed significant increase of late-differentiated T cells suggestive of immunosenescence. In addition, we found that the plasma viral loads positively correlated with the levels of CD57 and PD-1 expressed on T cells. Chronic HCV infection results in increased turnover of late-senescent T cells that lack survival potentials, possibly contributing to viral persistence. Our findings challenge the prominence of senescent T-cell phenotypes in clinical hepatitis C infection.


Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population.
The aim of this study was to estimate the contribution of deleterious mutations in the RAD51B, RAD51C, and RAD51D genes to invasive epithelial ovarian cancer (EOC) in the population and in a screening trial of individuals at high risk of ovarian cancer. The coding sequence and splice site boundaries of the three RAD51 genes were sequenced and analyzed in germline DNA from a case-control study of 3,429 patients with invasive EOC and 2,772 controls as well as in 2,000 unaffected women who were BRCA1/BRCA2 negative from the United Kingdom Familial Ovarian Cancer Screening Study (UK_FOCSS) after quality-control analysis. In the case-control study, we identified predicted deleterious mutations in 28 EOC cases (0.82%) compared with three controls (0.11%; P < .001). Mutations in EOC cases were more frequent in RAD51C (14 occurrences, 0.41%) and RAD51D (12 occurrences, 0.35%) than in RAD51B (two occurrences, 0.06%). RAD51C mutations were associated with an odds ratio of 5.2 (95% CI, 1.1 to 24; P = .035), and RAD51D mutations conferred an odds ratio of 12 (95% CI, 1.5 to 90; P = .019). We identified 13 RAD51 mutations (0.65%) in unaffected UK_FOCSS participants (RAD51C, n = 7; RAD51D, n = 5; and RAD51B, n = 1), which was a significantly greater rate than in controls (P < .001); furthermore, RAD51 mutation carriers were more likely than noncarriers to have a family history of ovarian cancer (P < .001). These results confirm that RAD51C and RAD51D are moderate ovarian cancer susceptibility genes and suggest that they confer levels of risk of EOC that may warrant their use alongside BRCA1 and BRCA2 in routine clinical genetic testing.


Reducing risk for cardiovascular disease in uninsured women: combined results from two WISEWOMAN projects.
to evaluate the effectiveness of a cardiovascular disease (CVD) risk factor reduction program for financially disadvantaged women. The program included cholesterol and blood pressure assessments and tailored physical activity and nutrition interventions. Women who attended selected National Breast and Cervical Cancer Early Detection Program sites in North Carolina and Massachusetts received either enhanced physical activity and nutrition interventions (EI) or minimum interventions (MI). The effectiveness of EI was assessed by pooling data from the North Carolina and Massachusetts projects after 1 year, and a mixed models analysis of covariance was used to compare changes in CVD risk factors across groups. The blood pressure, total cholesterol, and high-density lipoprotein cholesterol profiles of both groups improved, body weight was maintained, and smoking declined. The 10-year estimated coronary heart disease death rate (per 1,000 women) at baseline was 64.8 for the El group and 61.9 for the MI group. The rate declined by 3.5 deaths per 1,000 for the EI and 0.7 per 1,000 for the MI. Although the decline was statistically significant for the EI group, the difference between groups was not significant. Further lifestyle intervention research targeting financially disadvantaged women is needed.


Binary partition tree as an efficient representation for image processing, segmentation, and information retrieval.
This paper discusses the interest of binary partition trees as a region-oriented image representation. Binary partition trees concentrate in a compact and structured representation a set of meaningful regions that can be extracted from an image. They offer a multiscale representation of the image and define a translation invariant 2-connectivity rule among regions. As shown in this paper, this representation can be used for a large number of processing goals such as filtering, segmentation, information retrieval and visual browsing. Furthermore, the processing of the tree representation leads to very efficient algorithms. Finally, for some applications, it may be interesting to compute the binary partition tree once and to store it for subsequent use for various applications. In this context, the paper shows that the amount of bits necessary to encode a binary partition tree remains moderate.


Experimental evaluation of the effects of Ankaferd Blood Stopper and collagenated heterologous bone graft on bone healing in sinus floor augmentation.
The aim of this study was to evaluate the effect of collagenated heterologous bone graft (CHBG) and Ankaferd Blood Stopper (ABS), a plant extract, on bone healing after sinus floor augmentation. Thirty-six New Zealand rabbits were used. Bilateral sinus augmentation was performed, and 72 bone defects were created. The maxillary sinuses were grafted with four different biomaterials: blood clot (control group), CHBG (Apatos Mix, OsteoBiol, Tecnoss) (graft group), ABS (ABS group), and ABS + CHBG (ABS+graft group). The rabbits were sacrificed at 1, 4, and 8 weeks after surgery. Histochemical and immunohistochemical examinations were performed on all samples. Staining with hematoxylin-eosin and Masson trichrome was performed, and bone marker activity was evaluated. Lymphocyte infiltration was high at the first week in all groups and decreased from 1 to 8 weeks. All materials were biocompatible. Osteoclast numbers increased in the control group from 1 to 8 weeks and decreased in the other groups. There was no new bone formation in week 1 in all groups. New bone formation increased in all groups from 1 to 8 weeks, and at the fourth week, new bone formation was greater in the ABS and ABS+graft groups than in the other groups. There were osteoclasts around the bone graft materials, but degeneration of the graft was seen only in the ABS+graft group at week 8. ABS accelerates bone healing in sinus augmentation procedures and can be used alone or with CHBG. CHBG has osteoconductive properties, and ABS can accelerate bone graft degeneration.


Effect of an exercise intervention on gestational diabetes mellitus: a randomized controlled trial.
To examine the effect of an individually tailored, motivationally matched prenatal exercise intervention on gestational diabetes mellitus (GDM) and other measures of glucose intolerance among ethnically diverse prenatal care patients at increased risk for GDM. The Behaviors Affecting Baby and You study randomized eligible women at a mean (standard deviation) of 18.2 (4.1) weeks of gestation to a 12-week individually tailored, motivationally matched exercise intervention or a comparison health and wellness intervention. The goal of the exercise intervention was to achieve the American College of Obstetricians and Gynecologists' guidelines for physical activity during pregnancy. Diagnosis of GDM, impaired glucose tolerance, abnormal glucose screen, and screening glucose values (mg/dL) were abstracted from medical records. A sample size of 352 women (176 per group) was planned to have 80% power to detect reductions in risk of 35% or larger. From July 2007 to December 2012, a total of 251 (86.5%) women completed the intervention; n=124 and 127 in the exercise and comparison interventions, respectively. Based on an intention-to-treat analysis, no statistically significant differences between the intervention groups were observed; the relative odds of GDM in the exercise group was 0.61 (95% confidence interval [CI] 0.28-1.32) as compared with the health and wellness comparison group. Odds ratios for impaired glucose tolerance and abnormal glucose screen were 0.68 (95% CI 0.35-1.34) and 0.86 (95% CI 0.51-1.47), respectively. The intervention had no effect on birth outcomes. In this randomized trial among ethnically diverse pregnant women at increased risk for GDM, we found that a prenatal exercise intervention implemented in the second trimester did not result in a statistically significant reduction in relative odds for GDM, impaired glucose tolerance, or abnormal glucose screen. I.


Development and Validation of an Ultradeep Next-Generation Sequencing Assay for Testing of Plasma Cell-Free DNA from Patients with Advanced Cancer.
Purpose: Tumor-derived cell-free DNA (cfDNA) in plasma can be used for molecular testing and provide an attractive alternative to tumor tissue. Commonly used PCR-based technologies can test for limited number of alterations at the time. Therefore, novel ultrasensitive technologies capable of testing for a broad spectrum of molecular alterations are needed to further personalized cancer therapy.Experimental Design: We developed a highly sensitive ultradeep next-generation sequencing (NGS) assay using reagents from TruSeqNano library preparation and NexteraRapid Capture target enrichment kits to generate plasma cfDNA sequencing libraries for mutational analysis in 61 cancer-related genes using common bioinformatics tools. The results were retrospectively compared with molecular testing of archival primary or metastatic tumor tissue obtained at different points of clinical care.Results: In a study of 55 patients with advanced cancer, the ultradeep NGS assay detected 82% (complete detection) to 87% (complete and partial detection) of the aberrations identified in discordantly collected corresponding archival tumor tissue. Patients with a low variant allele frequency (VAF) of mutant cfDNA survived longer than those with a high VAF did (P = 0.018). In patients undergoing systemic therapy, radiological response was positively associated with changes in cfDNA VAF (P = 0.02), and compared with unchanged/increased mutant cfDNA VAF, decreased cfDNA VAF was associated with longer time to treatment failure (TTF; P = 0.03).Conclusions: Ultradeep NGS assay has good sensitivity compared with conventional clinical mutation testing of archival specimens. A high VAF in mutant cfDNA corresponded with shorter survival. Changes in VAF of mutated cfDNA were associated with TTF. Clin Cancer Res; 23(18); 5648-56. ©2017 AACR.


Ecological and microbiological diversity of chigger mites, including vectors of scrub typhus, on small mammals across stratified habitats in Thailand.
Scrub typhus, caused by a bacterial pathogen (Orientia spp.), is a potentially life-threatening febrile illness widely distributed in the Asia-Pacific region and is emerging elsewhere. The infection is transmitted by the larval stage of trombiculid mites ("chiggers") that often exhibit low host specificity. Here, we present an analysis of chigger ecology for 38 species sampled from 11 provinces of Thailand and microbiomes for eight widespread species. In total, > 16,000 individual chiggers were collected from 1574 small mammal specimens belonging to 18 species across four horizontally-stratified habitat types. Chigger species richness was positively associated with higher latitudes, dry seasonal conditions, and host maturity; but negatively associated with increased human land use. Human scrub typhus incidence was found to be positively correlated with chigger species richness. The bacterial microbiome of chiggers was highly diverse, with Sphingobium, Mycobacterium, Neisseriaceae and various Bacillales representing the most abundant taxa. Only Leptotrombidium deliense was found to be infected with Orientia and another potential pathogen, Borrelia spp., was frequently detected in pools of this species. β-diversity, but not α-diversity, was significantly different between chigger species and geographic regions, although not between habitat types. Our study identified several key environmental and host-derived correlates of chigger species richness across Thailand, which in turn impacted on human scrub typhus incidence. Moreover, this first extensive field survey of the chigger microbiome revealed species- and province-level variation in microbial β-diversity across the country, providing a framework for future studies on interactions between pathogens and other symbionts in these understudied vectors.


Impaired left amygdala resting state functional connectivity in subthreshold depression individuals.
Subthreshold depression (StD) affects people who experience clinically relevant depressive symptoms, which does not meet the diagnostic criteria for major depressive disorder (MDD). StD represents an ideal model for understanding the pathophysiological mechanisms of depression. Impaired emotion processing is a core feature of depression; careful investigation is required to better understand the neural correlates of emotion processing in depressed populations. In the current study, we explored whether the resting-state functional connectivity of the amygdala, a hub that taps a wide range of brain areas involved in emotion processing, is altered in individuals with StD when compared with healthy controls. Resting-state imaging data was collected from 59 individuals with StD and 59 age- and gender-matched controls. We found that the resting-state functional connectivity of the left amygdala with the cognitive control network and the left insula was significantly lower in people with StD than that in healthy controls. Such association was not observed in the right amygdala. Furthermore, functional connectivity strength between the left amygdala and the left precuneus was positively associated with depressive symptoms in individuals with StD. Our findings are in line with those reported in subjects with MDD, which may assist in further elucidating the pathophysiological mechanisms of depression, and contribute to the development of tailored treatments for individuals with StD who are at high risk of developing MDD.


The active form of DNA polymerase V is UmuD'(2)C-RecA-ATP.
DNA-damage-induced SOS mutations arise when Escherichia coli DNA polymerase (pol) V, activated by a RecA nucleoprotein filament (RecA*), catalyses translesion DNA synthesis. Here we address two longstanding enigmatic aspects of SOS mutagenesis, the molecular composition of mutagenically active pol V and the role of RecA*. We show that RecA* transfers a single RecA-ATP stoichiometrically from its DNA 3'-end to free pol V (UmuD'(2)C) to form an active mutasome (pol V Mut) with the composition UmuD'(2)C-RecA-ATP. Pol V Mut catalyses TLS in the absence of RecA* and deactivates rapidly upon dissociation from DNA. Deactivation occurs more slowly in the absence of DNA synthesis, while retaining RecA-ATP in the complex. Reactivation of pol V Mut is triggered by replacement of RecA-ATP from RecA*. Thus, the principal role of RecA* in SOS mutagenesis is to transfer RecA-ATP to pol V, and thus generate active mutasomal complex for translesion synthesis.


beta2-adrenoceptor gene polymorphisms and blood pressure variations in East Anglian Caucasians.
The amino-terminal polymorphisms, Arg16Gly and Gln27Glu, of the beta2-adrenergic receptor (beta2AR) have been shown to affect regulation of the receptor expression by an agonist in cell culture studies. The Arg16Gly polymorphism has also been recently shown to be associated with essential hypertension. We therefore evaluated whether the amino-terminal polymorphisms of beta2AR are associated with hypertension in a Caucasian population. We performed an association study in 298 hypertensive patients and an equal number of age-matched normotensive controls from the East Anglian region, with blood pressure assessed categorically and quantitatively. We also examined the influence of the amino-terminal polymorphisms on blood pressure response to beta-blockade in 144 of the patients randomly assigned to this class of drug. Genotyping of the Arg16Gly polymorphism was undertaken by a newly designed mismatched polymerase chain reaction (PCR) and digestion with Nde I, whereas the Gln27Glu polymorphism was genotyped by PCR followed by Fnu4H I cleavage. We found no differences in the genotype or allele frequencies of the beta2AR polymorphisms between hypertensive and normotensive participants. There was also no association between the beta2AR genotypes and variations in either basal blood pressure or the blood pressure response to a beta-blocker. These findings suggest that the amino-terminal polymorphisms of the beta2AR gene are unlikely to constitute major susceptibility for essential hypertension in the East Anglian population.


Multilevel modeling of household contextual determinants of tuberculin skin test positivity among contacts of infectious tuberculosis patients, Umerkot, Pakistan.
This cross-sectional study sought to identify household contextual determinants that might be associated with Mycobacterium tuberculosis infection as assessed by tuberculin skin test (TST) positivity among familial contacts of index patients of infectious pulmonary tuberculosis (TB) while controlling for the effects of individual-level factors. We analyzed data on TST results on 359 household contacts of 77 index cases of acid-fast bacilli (AFB) sputum smear-positive pulmonary TB using multilevel logistic regression analysis with characteristics of household contacts at the first level and that of households at the second level. The prevalence of M. tuberculosis infection as assessed by TST positivity among household contacts of index TB patients was 49.9% (179/359). After taking into account the individual-level risk factors, household-level contextual determinants significantly associated with contact's TST positivity were gender of index TB patient (adjusted odds ratio [OR] = 2.2; 95% confidence interval [CI]: 1.3-3.9%) and density of AFB sputum smear (adjusted OR = 3.2; 95% CI: 1.9-5.5%). Household variances in multilevel models indicated significant inter-household heterogeneity in TST positivity among contacts. This study provided the evidence for substantive effects of household-level contextual variables on the TST positivity among contacts of index TB patients. Thus, both individual-level and household-level characteristics need to be taken into account while prioritizing contacts for investigations to improve TB control and prevention in resource-constrained countries such as Pakistan.


mTORC2 can associate with ribosomes to promote cotranslational phosphorylation and stability of nascent Akt polypeptide.
The mechanisms that couple translation and protein processing are poorly understood in higher eukaryotes. Although mammalian target of rapamycin (mTOR) complex 1 (mTORC1) controls translation initiation, the function of mTORC2 in protein synthesis remains to be defined. In this study, we find that mTORC2 can colocalize with actively translating ribosomes and can stably interact with rpL23a, a large ribosomal subunit protein present at the tunnel exit. Exclusively during translation of Akt, mTORC2 mediates phosphorylation of the nascent polypeptide at the turn motif (TM) site, Thr450, to avoid cotranslational Akt ubiquitination. Constitutive TM phosphorylation occurs because the TM site is accessible, whereas the hydrophobic motif (Ser473) site is concealed in the ribosomal tunnel. Thus, mTORC2 can function cotranslationally by phosphorylating residues in nascent chains that are critical to attain proper conformation. Our findings reveal that mTOR links protein production with quality control.


High mutability in male hybrids of Drosophila melanogaster.
The frequencies of sex-linked lethal mutations arising in hybrid male offspring from crosses and in nonhybrid controls were determined. The hybrids were produced by crossing representative strains of the P-M system of hybrid dysgenesis in all possible combinations. Males from the cross of P males x M females had a mutation rate about 15 times higher than that of nonhybrid males from the P strain. Genetically identical males from the reciprocal cross had a mutation rate 3 to 4 times that of the nonhybrids. For crosses involving a Q strain, a significant increase in the mutation rate was detected in males produced by matings of Q males with M females. No increase was observed in genetically identical males from the reciprocal mating. Crosses between P and Q strains gave male hybrids with mutation rates not different from those of nonhybrids. Many of the lethals that occurred in hybrids from the cross of P males x M females appeared to be unstable; fewer lethals that arose in hybrids from the cross of Q males x M females were unstable. The relationship between P and Q strains is discussed with respect to a model of mutation induction in dysgenic hybrids.


Peripheral Neuropathy and Nerve Dysfunction in Individuals at High Risk for Type 2 Diabetes: The PROMISE Cohort.
Emerging evidence suggests that peripheral neuropathy begins in the early stages of diabetes pathogenesis. Our objective was to describe the prevalence of peripheral neuropathy and nerve dysfunction according to glucose tolerance and metabolic syndrome status and examine how these conditions are associated with neurological changes in individuals at risk for type 2 diabetes. We studied 467 individuals in the longitudinal PROMISE (Prospective Metabolism and Islet Cell Evaluation) cohort. Peripheral neuropathy was defined by Michigan Neuropathy Screening Instrument (MNSI) scores (>2), and the severity of nerve dysfunction was measured objectively by vibration perception thresholds (VPTs) using a neurothesiometer. Metabolic syndrome was defined using the International Diabetes Federation/American Heart Association harmonized criteria. The prevalence of peripheral neuropathy was 29%, 49%, and 50% for normal glycemia, prediabetes, and new-onset diabetes, respectively (P < 0.001 for trend). The mean VPT was 6.5 V for normal glycemia, 7.9 V for prediabetes, and 7.6 V for new-onset diabetes (P = 0.024 for trend). Prediabetes was associated with higher MNSI scores (P = 0.01) and VPTs (P = 0.004) versus normal glycemia, independent of known risk factors. Additionally, progression of glucose intolerance over 3 years predicted a higher risk of peripheral neuropathy (P = 0.007) and nerve dysfunction (P = 0.002). Metabolic syndrome was not independently associated with MNSI scores or VPTs. In individuals with multiple risk factors for diabetes, prediabetes was associated with similar risks of peripheral neuropathy and severity of nerve dysfunction as new-onset diabetes. Prediabetes, but not metabolic syndrome, was independently associated with both the presence of peripheral neuropathy and the severity of nerve dysfunction.


Worry or craving? A selective review of evidence for food-related attention biases in obese individuals, eating-disorder patients, restrained eaters and healthy samples.
Living in an 'obesogenic' environment poses a serious challenge for weight maintenance. However, many people are able to maintain a healthy weight indicating that not everybody is equally susceptible to the temptations of this food environment. The way in which someone perceives and reacts to food cues, that is, cognitive processes, could underlie differences in susceptibility. An attention bias for food could be such a cognitive factor that contributes to overeating. However, an attention bias for food has also been implicated with restrained eating and eating-disorder symptomatology. The primary aim of the present review was to determine whether an attention bias for food is specifically related to obesity while also reviewing evidence for attention biases in eating-disorder patients, restrained eaters and healthy-weight individuals. Another aim was to systematically examine how selective attention for food relates (causally) to eating behaviour. Current empirical evidence on attention bias for food within obese samples, eating-disorder patients, and, even though to a lesser extent, in restrained eaters is contradictory. However, present experimental studies provide relatively consistent evidence that an attention bias for food contributes to subsequent food intake. This review highlights the need to distinguish not only between different (temporal) attention bias components, but also to take different motivations (craving v. worry) and their impact on attentional processing into account. Overall, the current state of research suggests that biased attention could be one important cognitive mechanism by which the food environment tempts us into overeating.


B-cell lymphoma/leukemia 10 promotes oral cancer progression through STAT1/ATF4/S100P signaling pathway.
B-cell lymphoma/leukemia 10 (BCL10) is an apoptotic regulatory protein related to advanced TNM stage and disease recurrence in oral squamous cell carcinoma (OSCC). However, the regulatory mechanism of BCL10 in OSCC progression is still unknown. Here, we showed that knockdown of endogenous BCL10 could significantly reduce cell migration and invasion abilities, retard cell proliferation by G0/G1 phase accumulation and inhibit tumorigenicity in vivo. In molecular level, we identified S100P as a crucial downstream effector of BCL10-inhibited OSCC progression by high-throughput microarray analysis. S100P messenger RNA and protein expression levels were significantly diminished in silenced-BCL10 clones, and transfected S100P expression plasmids restored migration, invasion, proliferation abilities and tumorigenicity in shBCL10 transfectants. Furthermore, we provided evidence that BCL10 regulated S100P expression through signal transducers and activators of transcription 1 (STAT1) and activating transcription factor 4 (ATF4). Knockdown of BCL10 decreased S100P promoter activity, but showed no effect in truncated STAT1/ATF4 S100P promoter. In addition, we also found that the P50/P65 signaling pathway was involved in BCL10-enhanced OSCC progression. Restored S100P in silenced-BCL10 clones could markedly reverse P65 activation via outside-in signaling. Taken together, we discovered a novel axis of BCL10-regulated OSCC progression via STAT1/ATF4/S100P/P65 signaling, which could predict the prognosis of OSCC and will be beneficial for developing therapeutic strategy against advanced OSCC.


Inequality and mental healthcare utilisation among first-year university students in South Africa.
Addressing inequalities in mental healthcare utilisation among university students is important for socio-political transformation, particularly in countries with a history of educational exclusion. As part of the WHO World Mental Health International College Student Initiative, we investigated inequalities in mental healthcare utilisation among first-year students at two historically "White" universities in South Africa. Data were collected via a web-based survey from first-year university students (n = 1402) to assess 12-month mental healthcare utilisation, common mental disorders, and suicidality. Multivariate logistic regression models were used to estimate associations between sociodemographic variables and mental healthcare utilisation, controlling for common mental disorders and suicidality. A total of 18.1% of students utilised mental healthcare in the past 12 months, with only 28.9% of students with mental disorders receiving treatment (ranging from 28.1% for ADHD to 64.3% for bipolar spectrum disorder). Of those receiving treatment, 52.0% used psychotropic medication, 47.3% received psychotherapy, and 5.4% consulted a traditional healer. Treatment rates for suicidal ideation, plan and attempt were 25.4%, 41.6% and 52.9%, respectively. In multivariate regression models that control for the main effects of mental health variables and all possible joint effects of sociodemographic variables, the likelihood of treatment was lower among males (aOR = 0.57) and Black students (aOR = 0.52). An interaction was observed between sexual orientation and first generation status; among second-generation students, the odds of treatment were higher for students reporting an atypical sexual orientation (aOR = 1.55), while among students with atypical sexual orientations, the likelihood of mental healthcare utilisation was lower for first-generation students (aOR = 0.29). Odds of treatment were significantly elevated among students with major depressive disorder (aOR = 1.88), generalised anxiety disorder (aOR = 2.34), bipolar spectrum disorder (aOR = 4.07), drug use disorder (aOR = 3.45), suicidal ideation (without plan or attempt) (aOR = 2.00), suicide plan (without attempt) (aOR = 3.64) and suicide attempt (aOR = 4.57). Likelihood of treatment increased with level of suicidality, but not number of mental disorders. We found very low mental healthcare treatment utilisation among first-year university students in South Africa, with enduring disparities among historically marginalised groups. Campus-based interventions are needed to promote mental healthcare utilisation by first-year students in South Africa, especially among male and Black students and first-generation students with atypical sexual orientations.


Effect of acute resistance exercise on carotid artery stiffness and cerebral blood flow pulsatility.
Arterial stiffness is associated with cerebral flow pulsatility. Arterial stiffness increases following acute resistance exercise (RE). Whether this acute RE-induced vascular stiffening affects cerebral pulsatility remains unknown. To investigate the effects of acute RE on common carotid artery (CCA) stiffness and cerebral blood flow velocity (CBFv) pulsatility. Eighteen healthy men (22 ± 1 yr; 23.7 ± 0.5 kg·m(-2)) underwent acute RE (5 sets, 5-RM bench press, 5 sets 10-RM bicep curls with 90 s rest intervals) or a time control condition (seated rest) in a randomized order. CCA stiffness (β-stiffness, Elastic Modulus (Ep)) and hemodynamics (pulsatility index, forward wave intensity, and reflected wave intensity) were assessed using a combination of Doppler ultrasound, wave intensity analysis and applanation tonometry at baseline and 3 times post-RE. CBFv pulsatility index was measured with transcranial Doppler at the middle cerebral artery (MCA). CCA β-stiffness, Ep and CCA pulse pressure significantly increased post-RE and remained elevated throughout post-testing (p < 0.05). No changes in MCA or CCA pulsatility index were observed (p > 0.05). There were significant increases in forward wave intensity post-RE (p < 0.05) but not reflected wave intensity (p > 0.05). Although acute RE increases CCA stiffness and pressure pulsatility, it does not affect CCA or MCA flow pulsatility. Increases in pressure pulsatility may be due to increased forward wave intensity and not pressure from wave reflections.


Progression of chronic kidney disease and the risk of tuberculosis: an observational cohort study.
<sec id="st1"> <title>BACKGROUND</title> Little is known about tuberculosis (TB) risk in the earlier stages of chronic kidney disease (CKD). </sec> <sec id="st2"> <title>OBJECTIVE</title> To investigate the relationship between CKD at all stages and the risk of incident TB. </sec> <sec id="st3"> <title>METHODS</title> We conducted a cohort study using 100 058 participants of a community-based health screening programme in northern Taiwan, 2005-2008. Renal function was ascertained at baseline using serum creatinine level and the urine dipstick test. The occurrence of active TB was ascertained using the National Tuberculosis Registry. Cox proportional hazards regression was used to estimate the association between CKD and TB. </sec> <sec id="st4"> <title>RESULTS</title> During a median follow-up of 7.5 years, TB incidence was 472. In the Cox regression analyses, individuals with Stage 1-4 CKD had a 25% increase in TB hazard than those without disease (adjusted hazard ratio [aHR] 1.25, 95%CI 1.02-1.54). A positive correlation between CKD stage and TB was observed (P = 0.02 for trend). TB risk increased by 5.1% with every 10 ml/min/1.73 m² decrease in the estimated glomerular filtration rate (aHR 1.05, 95%CI 0.99-1.12). </sec> <sec id="st5"> <title>CONCLUSIONS</title> Our results suggested an increased risk of TB in early-stage CKD. TB prevention efforts should consider individuals with earlier stages of CKD. </sec>.


Alteration of synaptic activity-regulating genes underlying functional improvement by long-term exposure to an enriched environment in the adult brain.
Housing animals in an enriched environment (EE) enhances behavioral function. However, the mechanism underlying this EE-mediated functional improvement and the resultant changes in gene expression have yet to be elucidated. We attempted to investigate the underlying mechanisms associated with long-term exposure to an EE by evaluating gene expression patterns. We housed 6-week-old CD-1 (ICR) mice in standard cages or an EE comprising a running wheel, novel objects, and social interaction for 2 months. Motor and cognitive performances were evaluated using the rotarod test and passive avoidance test, and gene expression profile was investigated in the cerebral hemispheres using microarray and gene set enrichment analysis (GSEA). In behavioral assessment, an EE significantly enhanced rotarod performance and short-term working memory. Microarray analysis revealed that genes associated with neuronal activity were significantly altered by an EE. GSEA showed that genes involved in synaptic transmission and postsynaptic signal transduction were globally upregulated, whereas those associated with reuptake by presynaptic neurotransmitter transporters were downregulated. In particular, both microarray and GSEA demonstrated that EE exposure increased opioid signaling, acetylcholine release cycle, and postsynaptic neurotransmitter receptors but decreased Na+ / Cl- -dependent neurotransmitter transporters, including dopamine transporter Slc6a3 in the brain. Western blotting confirmed that SLC6A3, DARPP32 (PPP1R1B), and P2RY12 were largely altered in a region-specific manner. An EE enhanced motor and cognitive function through the alteration of synaptic activity-regulating genes, improving the efficient use of neurotransmitters and synaptic plasticity by the upregulation of genes associated with postsynaptic receptor activity and downregulation of presynaptic reuptake by neurotransmitter transporters.


DNA sequence recognition by the indolocarbazole antitumor antibiotic AT2433-B1 and its diastereoisomer.
The antibiotic AT2433-B1 belongs to a therapeutically important class of antitumor agents. This natural product contains an indolocarbazole aglycone connected to a unique disaccharide consisting of a methoxyglucose and an amino sugar subunit, 2,4-dideoxy-4-methylamino-L-xylose. The configuration of the amino sugar distinguishes AT2433-B1 from its diastereoisomer iso-AT2433-B1. Here we have investigated the interaction of these two disaccharide indolocarbazole derivatives with different DNA sequences by means of DNase I footprinting and surface plasmon resonance (SPR). Accurate binding measurements performed at 4 and 25 degrees C using the BIAcore SPR method revealed that AT2433-B1 binds considerably more tightly to a hairpin oligomer containing a [CG](4) block than to an oligomer with a central [AT](4) tract. The kinetic analysis shows that the antibiotic dissociates much more slowly from the GC sequence compared to the AT one. Preferential binding of AT2433-B1 to GC-rich sequences in DNA was independently confirmed by DNase I footprinting experiments performed with a 117 bp DNA restriction fragment. The specific binding sequence 5'-AACGCCAG identified from the footprints was then converted into a biotin-labeled DNA hairpin duplex and compound interactions with this specific sequence were characterized by high resolution BIAcore SPR experiments. Such a combined approach provided a detailed understanding of the molecular basis of DNA recognition. The discovery that the glycosyl antibiotic AT2433-B1 preferentially recognizes defined sequences offers novel opportunities for the future design of sequence-specific DNA-reading small molecules.


Limitations of the use of environmental tracers to infer groundwater age.
Apparent ages obtained from the measured concentrations of environmental tracers have the potential to inform recharge rates, flow rates, and assist in the calibration of groundwater models. A number of studies have investigated sources of error in the relationships between the apparent ages, and the age assumed by models to relate this quantity to an aquifer property (e.g., recharge). These studies have also provided a number of techniques for correcting the known biases of apparent ages. In this paper, we review some of the concepts of age bias. We then demonstrate this bias through the use on four numerical examples, and assess the accuracy of correction methods in overcoming this bias. We examine this for CFCs, SF6, 3H/3He, 39Ar, and 14C. We demonstrate that in our four simple steady-state aquifer examples, bias occurs for a wide range of environmental tracers and flow configurations. When applying correction methods, we found that the values obtained are limited by the model assumptions. Models accounting for exchange with aquitards represent whole mobile zones and not discrete well screens. Mean transit times (comparable to mean ages) obtained from lumped parameter models deviate from actual values as the assumed distribution varies from the actual distribution. Methods that use multiple tracer ages are limited to ranges where both tracers report apparent ages. Our findings suggest that the incorporation of environmental tracer data into the understanding of groundwater systems requires approaches such as the direct use of concentrations, or the simulation of full age distributions.


Diversity, occurrence and conservation of sharks in the southern South China Sea.
Sharks constitute a vital sector of marine and estuarine nekton and are of great commercial importance all over the world. International concern over the fate of shark fisheries has grown recently. However, information concerning the species diversity, geographic distribution and life histories of sharks in the Indo-Pacific region is highly limited. Comprehensive research on the species composition, distribution and seasonal occurrence of sharks in the southern South China Sea (SSCS) was conducted for four years. A total of 4742 sharks belonging to 10 families and 28 species were recorded from 6 fishing ports in SSCS. The families recorded included Squalidae, Heterodontidae, Orectolobidae, Hemiscylliidae, Alopiidae, Scyliorhinidae, Triakidae, Hemigaleidae, Carcharhinidae and Sphyrnidae. Seventeen of 28 shark species were landed at various developmental stages from in the ranges of or even less than the length at birth and from newborn juveniles to fully-mature. The results suggest that these sharks were born just before fishing and landing, and reproductive-stage sharks were also fished and landed. In total, 15 species, four species and one species in 28 shark species were categorized as Near Threatened, Vulnerable and Endangered species, respectively, on the IUCN Red List. Sharks are not targeted by fisheries practices in the SSCS, but are caught as bycatch throughout the year in various developmental stages. Thus, current fisheries practices in the SSCS area might lead to further decline to critical levels and lead to extinction of some of species in the future. These results suggest that the need for gear selectivity of the commercial fishing gears in order to reduce mortality and to conserve shark stocks.


A retinoic acid-dependent network in the foregut controls formation of the mouse lung primordium.
The developmental abnormalities associated with disruption of signaling by retinoic acid (RA), the biologically active form of vitamin A, have been known for decades from studies in animal models and humans. These include defects in the respiratory system, such as lung hypoplasia and agenesis. However, the molecular events controlled by RA that lead to formation of the lung primordium from the primitive foregut remain unclear. Here, we present evidence that endogenous RA acts as a major regulatory signal integrating Wnt and Tgfbeta pathways in the control of Fgf10 expression during induction of the mouse primordial lung. We demonstrated that activation of Wnt signaling required for lung formation was dependent on local repression of its antagonist, Dickkopf homolog 1 (Dkk1), by endogenous RA. Moreover, we showed that simultaneously activating Wnt and repressing Tgfbeta allowed induction of both lung buds in RA-deficient foreguts. The data in this study suggest that disruption of Wnt/Tgfbeta/Fgf10 interactions represents the molecular basis for the classically reported failure to form lung buds in vitamin A deficiency.


"To Err Is Human" but Disclosure Must be Taught: A Simulation-Based Assessment Study.
Although error disclosure is critical in promoting safety and patient-centered care, physicians are inconsistently trained in its practice, and few objective methods to assess competence exist. We used an immersive simulation scenario to determine whether providers with varying levels of clinical experience adhere to the disclosure safe practice guidelines when exposed to a serious adverse event simulation scenario. This was a prospective cohort study with medical students, junior emergency medicine (EM) residents (PGY 1-2), senior EM residents (PGY 3-4), and attending EM physicians participating in a simulated case in which a scripted medication overdose resulted in an adverse event. Each scenario was videotaped and scored by two expert raters based on a 6-component, 21-point disclosure assessment instrument. There were 12 participants in each study group (N = 48). There was good interrater reliability (κ = 0.70). Total scores improved significantly as the level of training increased: medical student = 10.3 (2.7), PGY 1-2 = 12.3 (6.2), PGY 3-4 = 13.7 (3.2), and attending physicians = 12.8 (3.7) (P = 0.03). Seventy-five percent of participants did not address preventing recurrence of the error. Fifty-six percent offered no apology or only offered it with prompting from the patient; only 23% offered an apology with the initial disclosure. We demonstrated suboptimal adherence to best practices guidelines for error disclosure when providers are assessed in an immersive simulation setting. Despite a correlation in performance of medical error disclosure with increased physician experience, this study suggests that healthcare providers may need additional training to comply with safe practice guidelines for disclosure of unanticipated adverse events.


Loss of Extreme Long-Range Enhancers in Human Neural Crest Drives a Craniofacial Disorder.
Non-coding mutations at the far end of a large gene desert surrounding the SOX9 gene result in a human craniofacial disorder called Pierre Robin sequence (PRS). Leveraging a human stem cell differentiation model, we identify two clusters of enhancers within the PRS-associated region that regulate SOX9 expression during a restricted window of facial progenitor development at distances up to 1.45 Mb. Enhancers within the 1.45 Mb cluster exhibit highly synergistic activity that is dependent on the Coordinator motif. Using mouse models, we demonstrate that PRS phenotypic specificity arises from the convergence of two mechanisms: confinement of Sox9 dosage perturbation to developing facial structures through context-specific enhancer activity and heightened sensitivity of the lower jaw to Sox9 expression reduction. Overall, we characterize the longest-range human enhancers involved in congenital malformations, directly demonstrate that PRS is an enhanceropathy, and illustrate how small changes in gene expression can lead to morphological variation.


Telemetric analysis of haemodynamic regulation during voluntary exercise training in mouse models.
Regular physical exercise reduces the risk of cardiovascular disease and improves outcome in patients with cardiovascular diseases. The dynamic changes in blood pressure and heart rate with acute exercise are independently predictive of prognosis. Quantification of the haemodynamic response to exercise training in genetically modified mouse models may provide insight into the molecular mechanisms underlying the beneficial effects of exercise. We describe, for the first time, the use of radiotelemetry to provide continuous blood pressure monitoring in C57BL/6J mice during a programme of voluntary wheel exercise with continuous simultaneous recording and analysis of wheel rotations and beat-by-beat haemodynamic parameters. We define distinct haemodynamic profiles at rest, during normal cage activity and during episodes of voluntary wheel running. We show that whilst cage activity is associated with significant rises both in blood pressure and in heart rate, voluntary wheel running leads to a further substantial rise in heart rate with only a small increment in blood pressure. With 5 weeks of chronic exercise training, resting heart rate progressively falls, but heart rate during episodes of wheel running initially increases. In contrast, there are minimal changes in blood pressure in response to chronic exercise training. Finally, we have quantified the acute changes in heart rate at the onset of and recovery from individual episodes of wheel running, revealing that changes in heart rate are extremely rapid and that the peak rate of change of heart rate increases with chronic exercise training. The results of this study have important implications for the use of genetically modified mouse models to investigate the beneficial haemodynamic effects of chronic exercise on blood pressure and cardiovascular diseases.


Altered functional connectivity in seizure onset zones revealed by fMRI intrinsic connectivity.
The purpose of this study was to investigate functional connectivity (FC) changes in epileptogenic networks in intractable partial epilepsy obtained from resting-state fMRI by using intrinsic connectivity contrast (ICC), a voxel-based network measure of degree that reflects the number of connections to each voxel. We measured differences between intrahemispheric- and interhemispheric-ICC (ICCintra-inter) that could reveal localized connectivity abnormalities in epileptogenic zones while more global network changes would be eliminated when subtracting these values. The ICCintra-inter map was compared with the seizure onset zone (SOZ) based on intracranial EEG (icEEG) recordings in 29 patients with at least 1 year of postsurgical follow-up. Two independent reviewers blindly interpreted the icEEG and fMRI data, and the concordance rates were compared for various clinical factors. Concordance between the icEEG SOZ and ICCintra-inter map was observed in 72.4% (21/29) of the patients, which was higher in patients with good surgical outcome, especially in those patients with temporal lobe epilepsy (TLE) or lateral temporal seizure localization. Concordance was also better in the extratemporal lobe epilepsy than the TLE group. In 85.7% (18/21) of the cases, the ICCintra-inter values were negative in the SOZ, indicating decreased FC within the epileptic hemisphere relative to between hemispheres. Assessing alterations in FC using fMRI-ICC map can help localize the SOZ, which has potential as a noninvasive presurgical diagnostic tool to improve surgical outcome. In addition, the method reveals that, in focal epilepsy, both intrahemispheric- and interhemispheric-FC may be altered, in the presence of both regional as well as global network abnormalities.


[Binding-peptide motifs of HLA class II molecules susceptible to autoimmune diseases].
Recent advances in knowledge of crystal structures of MHC class II molecules has advanced understanding of the molecular basis for interactions between peptides and HLA class II molecules. Polymorphism of HLA class II molecules influences structures of peptides bound to HLA class II molecules. To elucidate mechanisms for statistical association between particular HLA class II alleles and susceptibility to autoimmune diseases, it is important to identify self peptides presented by disease-susceptible HLA class II molecules and triggering disease-causative autoreactive T cells. In this study, we tried to identify self-peptides triggering autoimmune diseases including rheumatoid arthritis, insulin autoimmune syndrome, insulin dependent diabetes mellitus and infant-onset myasthenia gravis. Susceptibility to all of these diseases in the Japanese population are known to be strongly associated with particular HLA-DR-DQ haplotypes unique to Asians, and clinical features of some of these diseases are different between Caucasians and Asians including Japanese. We investigated differences in binding-peptide motifs between disease susceptible and non-susceptible HLA class II molecules and predicted candidates of autoimmune self-peptides carrying binding-motifs to disease-susceptible HLA class II molecules. Indeed the major epitope for insulin-autoreactive CD4+ T cell was successfully identified by this strategy. We also found heterogeneity in immunogenetic background between Western type and Asian type of multiple sclerosis. Our data indicated that our strategy is useful to identify autoimmune self-peptides, and it is suggested that not only disease-susceptible HLA class II but also self-peptides causing diseases are different between Caucasians and Asians. These differences may well correlate to different clinical manifestations of diseases between the two ethnic groups.


Cerebrovascular neurosurgery in evolution: the endovascular paradigm.
Endovascular technique represents an important, minimally invasive approach to treating cerebrovascular disease. In this article, we discuss the origins of endovascular neurosurgery as a discipline in the context of important technical milestones, evidence-based medicine, and future cerebrovascular neurosurgical training. Cerebrovascular neurosurgery has seen a steady, convergent evolution toward the surgeon capable of seamless incorporation of open and endovascular approaches to any complex vascular disease affecting the central nervous system. Neurosurgery must assume the leadership role in the multidisciplinary neurovascular team.


Prognostic Characteristics of MACC1 Expression in Epithelial Ovarian Cancer.
Recent studies have shown that overexpression of metastasis-associated in colon cancer 1 (MACC1) is significantly associated with adverse prognoses of patients with different kinds of cancer. However, the exact survival effect of MACC1 on epithelial ovarian cancer (EOC) patients has not yet been established. Thus, the objective of this study was to explore the prognostic role of MACC1 mRNA in EOC by using Kaplan-Meier (KM) plotter and ONCOMINE database. Our results indicated that MACC1 mRNA high expression was significantly associated with unfavorable overall survival (hazard ratio (HR) = 1.51 (95% confidence interval (CI): 1.21 - 1.88), P = 0.00025) and progression-free survival (HR = 1.53 (95% CI: 1.24 - 1.89), P = 5.8e-05) in EOC patients. We also found that the expression of MACC1 mRNA in EOC was 2.5 times higher than that in normal surface ovarian epithelium, which was statistically significant (P = 2.86e-7). Our results suggest that MACC1 expression might be a biomarker for poor prognosis in individual EOC patients.


Denitrifying Bacteria Active in Woodchip Bioreactors at Low-Temperature Conditions.
Woodchip bioreactor technology removes nitrate from agricultural subsurface drainage by using denitrifying microorganisms. Although woodchip bioreactors have demonstrated success in many field locations, low water temperature can significantly limit bioreactor efficiency and performance. To improve bioreactor performance, it is important to identify the microbes responsible for nitrate removal at low temperature conditions. Therefore, in this study, we identified and characterized denitrifiers active at low-temperature conditions by using culture-independent and -dependent approaches. By comparative 16S rRNA (gene) analysis and culture isolation technique, Pseudomonas spp., Polaromonas spp., and Cellulomonas spp. were identified as being important bacteria responsible for denitrification in woodchip bioreactor microcosms at relatively low temperature conditions (15°C). Genome analysis of Cellulomonas sp. strain WB94 confirmed the presence of nitrite reductase gene nirK. Transcription levels of this nirK were significantly higher in the denitrifying microcosms than in the non-denitrifying microcosms. Strain WB94 was also capable of degrading cellulose and other complex polysaccharides. Taken together, our results suggest that Cellulomonas sp. denitrifiers could degrade woodchips to provide carbon source and electron donors to themselves and other denitrifiers in woodchip bioreactors at low-temperature conditions. By inoculating these denitrifiers (i.e., bioaugmentation), it might be possible to increase the nitrate removal rate of woodchip bioreactors at low-temperature conditions.


'Cross-adaptation': habituation to short repeated cold-water immersions affects the response to acute hypoxia in humans.
Adaptation to an environmental stressor is usually studied in isolation, yet these stressors are often encountered in combination in the field, an example being cold and hypoxia at altitude. There has been a paucity of research in this area, although work with rodents indicates that habituation to repeated short cold exposures has a cross-adaptive effect during hypoxia. The present study tested the hypothesis that cross-adaptation is also possible with humans. Thirty-two male volunteers were exposed to 10 min bouts of normoxic and hypoxic (FIO2 0.12) rest and exercise (100 W on a recumbent cycle ergometer). These were repeated after a 96 h interval, during which participants completed six, 5 min immersions in either cold (12°C, CW) or thermoneutral water (35°C, TW). Venous blood samples were taken immediately after each bout, for determination of catecholamine concentrations. A three-lead ECG was recorded throughout and the final 5 min of each bout was analysed for heart rate variability using fast fourier transformations (and displayed as log transformed data (ln)). In comparison with the first hypoxic exercise exposure, the second exposure of the CW group resulted in an increased ln high frequency (ln HF) power (P < 0.001) and reduced adrenaline (P < 0.001) and noradrenaline concentrations (P < 0.001). Adrenaline and noradrenaline concentrations were lower in the CW group during the second hypoxic exercise compared to the TW group (P = 0.042 and P = 0.003), but ln HF was not. When separated into hypoxic sensitive and hypoxic insensitive subgroups, ln HF was higher in the hypoxic sensitive CW group during the second hypoxic exercise than in any of the other subgroups. Cold habituation reduced the sympathetic response (indicated by the reduced catecholamine concentrations) and elevated the parasympathetic activity (increased ln HF power) to hypoxic exercise. These data suggest a generic autonomic cross-adaptive effect between cold habituation and exposure to acute hypoxia in humans.


The effects of visuospatial attention measured across visual cortex using source-imaged, steady-state EEG.
How does attention alter neural responses? Decades of electrophysiological measurements in non-human primates as well as human EEG and fMRI studies have shown that spatial attention modulates firing rates across the visual cortex, but the computations that drive this process are still unclear. Further, while it is well known that attention affects perception, we have only a limited understanding of the link between attentionally driven changes in neural firing rates and subject performance. Here we used a novel human neuroimaging method to measure the effect of spatial attention on neural responses in V1, hMT+, hV4, and the intraparietal sulcus (IPS). Attention altered signals in different ways across the visual cortex: areas V1, hMT+, and IPS exhibited primarily response gain changes while hV4 showed contrast gain modulation. Signals in V1, hMT+, and IPS correlated with contrast detection performance suggesting that behavior can be predicted by population-level signals as early as striate cortex.


Impact of a transfer center on interhospital referrals and transfers to a tertiary care center.
The partnership of faculty physicians and senior clinical hospital administrators in the decision to accept interhospital transfers has not been fully studied. Transfers to academic medical centers on the basis of economics have been of particular concern. To evaluate the impact of joint decision making on transfer acceptance, and to evaluate the basis for decisions to transfer patients to an academic medical center. This was a database study of requested adult interhospital transfers, excluding psychiatric transfers, occurring between January 1, 2003, and December 31, 2003, by using data from a computerized patient-tracking system. Where possible, comparisons with the prior calendar year (i.e., prior to implementation of the administrative review process) were made. Incidence of refusal to accept requested transfers and payer mix of transfer patients were the main outcomes of interest. More than 90% of the adult patients were transferred for conditions that required tertiary care or met Emergency Medical Treatment and Labor Act (EMTALA) requirements. The patient conditions that did not meet tertiary care needs included obstetric patients who did not have prenatal care, patients who had hand and facial trauma, and patients who weighed more than 300 pounds. The payer mix of transfer patients remained stable when using the administrator and physician team to determine acceptance of transfers. During the evaluation period, approximately 91,500 patients statewide lost some level of Medicaid coverage. The value of an administrator and physician team as partners in the interhospital transfer process was demonstrated. Active management of interhospital transfers supports transfer of patients who require tertiary care or who meet EMTALA criteria, thus conserving limited bed capacity and ensuring financial equity, while caring for the uninsured and underinsured patients throughout the state.


UNC-45A is preferentially expressed in epithelial cells and binds to and co-localizes with interphase MTs.
UNC-45A is an ubiquitously expressed protein highly conserved throughout evolution. Most of what we currently know about UNC-45A pertains to its role as a regulator of the actomyosin system. However, emerging studies from both our and other laboratories support a role of UNC-45A outside of actomyosin regulation. This includes studies showing that UNC-45A: regulates gene transcription, co-localizes and biochemically co-fractionates with gamma tubulin and regulates centrosomal positioning, is found in the same subcellular fractions where MT-associated proteins are, and is a mitotic spindle-associated protein with MT-destabilizing activity in absence of the actomyosin system. Here, we extended our previous findings and show that UNC45A is variably expressed across a spectrum of cell lines with the highest level being found in HeLa cells and in ovarian cancer cells inherently paclitaxel-resistant. Furthermore, we show that UNC-45A is preferentially expressed in epithelial cells, localizes to mitotic spindles in clinical tumor specimens of cancer and co-localizes and co-fractionates with MTs in interphase cells independent of actin or myosin. In sum, we report alteration of UNC45A localization in the setting of chemotherapeutic treatment of cells with paclitaxel, and localization of UNC45A to MTs both in vitro and in vivo. These findings will be important to ongoing and future studies in the field that further identify the important role of UNC45A in cancer and other cellular processes.


Isolation and partial characterisation of acid phosphatase isozymes from dormant oilseed of Corylus avellana L.
The acid phosphatase (orthophosphoric-monoester phosphohydrolase, EC 184.108.40.206) complement from dormant hazel (Corylus avellana L.) seeds was found to exhibit significant electrophoretic heterogeneity partially attributable to the presence of distinct molecular forms. In axiferous tissue, total acid phosphatase activity increased in a biphasic fashion during chilling, a treatment necessary to alleviate seed dormancy. Three acid phosphatase isozymes were isolated from cotyledons of dormant hazel seeds by successive ammonium sulphate precipitation, size-exclusion, Concanavalin A affinity, cation- and anion-exchange chromatographies resulting in 75-, 389- and 191-fold purification (APase1, APase2, APase3, respectively). The three glycosylated isoforms were isolated to catalytic homogeneity as determined by electrophoretic, kinetic and heat-inactivation studies. The native acid phosphatase complement of hazel seeds had an apparent Mr of 81.5 +/- 3.5 kDa as estimated by size-exclusion chromatography, while the determined pI values were 5.1 (APase1), 6.9 (APase2) and 7.3 (APase3). The optimum pH for p-nitrophenyl phosphate hydrolysis was pH 3 (APase1), pH 5.6 (APase2) and pH 6 (APase3). The hazel isozymes hydrolysed a variety of phosphorylated substrates in a non-specific manner, exhibiting low Km and the highest specificity constant (Vmax/ Km) for pyrophosphate. They were not primary phytases since they could not initiate phytic acid hydrolysis, while APase2 and APase3 had significant phospho-tyrosine phosphatase activity. Inorganic phosphate was a competitive inhibitor, while activity was significantly impaired in the presence of vanadate and fluoride.


Pathogenesis of myositis in children.
There is increasing evidence for involvement of innate immune mechanisms in the pathogenesis of idiopathic inflammatory myopathies. This review focuses on recent advances in understanding these mechanisms in juvenile dermatomyositis, the most common form of childhood inflammatory myopathy. Type I interferon activity in juvenile dermatomyositis has been demonstrated by both global gene expression profiling and immunohistochemical analysis of affected tissues. Most recently, expression of interferon-inducible genes in peripheral blood cells has shown promise as a biomarker for disease activity. The possible pathogenic actions of type I interferons include induction and maintenance of major histocompatibility complex class I expression in affected myofibers, and promotion of local pro-inflammatory cytokine and chemokine production. The cellular source of type I interferons is not clearly defined, though plasmacytoid dendritic cells that constitute a significant component of the inflammatory cell infiltrate are obvious candidates. These cells likely contribute to pathogenesis not only via type I interferon production, but also by regulating other infiltrating inflammatory cells. Type I interferons and plasmacytoid dendritic cells appear to make important contributions to the pathogenesis of juvenile dermatomyositis. Understanding the role of the innate immune system in childhood myositis may lead to novel treatment strategies.


Assumptions, conjectures, and other miracles: The application of evaluative thinking to theory of change models in community development.
Unexamined and unjustified assumptions are the Achilles' heel of development programs. In this paper, we describe an evaluation capacity building (ECB) approach designed to help community development practitioners work more effectively with assumptions through the intentional infusion of evaluative thinking (ET) into the program planning, monitoring, and evaluation process. We focus specifically on one component of our ET promotion approach involving the creation and analysis of theory of change (ToC) models. We describe our recent efforts to pilot this ET ECB approach with Catholic Relief Services (CRS) in Ethiopia and Zambia. The use of ToC models, plus the addition of ET, is a way to encourage individual and organizational learning and adaptive management that supports more reflective and responsive programming.


Determination of the optical constants (n and k) of inhomogeneous thin films with linear index profiles.
A new method for the determination of optical constants of absorbing inhomogeneous thin films is proposed. It requires measurements at normal incidence of the reflectance and transmittance of the film. In an inhomogeneous thin film, the optical constants vary along the thickness of the film. It has been reported in the literature that only the spatial integral value of the absorption index needs to be considered if its value is small. Therefore, in the proposed method, the mean value of the absorption index was used. The validity of this assumption was tested. On the other hand, the variation in the refractive index along the thickness of the film was taken into account. The method is discussed along with the nature of the solutions obtained and the effects of various parameters and assumptions. The method is applied successfully to inhomogeneous thin films of zirconium oxide.


Persistence of yellow fever vaccine-induced antibodies after solid organ transplantation.
Immunization using live attenuated vaccines represents a contra-indication after solid organ transplantation (SOT): consequently, transplant candidates planning to travel in countries where yellow fever is endemic should be vaccinated prior to transplantation. The persistence of yellow fever vaccine-induced antibodies after transplantation has not been studied yet. We measured yellow-fever neutralizing antibodies in 53 SOT recipients vaccinated prior to transplantation (including 29 kidney recipients and 18 liver recipients). All but one (98%) had protective titers of antibodies after a median duration of 3 years (min.: 0.8, max.: 21) after transplantation. The median antibody level was 40 U/L (interquartile range: 40-80). For the 46 patients with a known or estimated date of vaccination, yellow-fever antibodies were still detectable after a median time of 13 years (range: 2-32 years) post-immunization. Our data suggest there is long-term persistence of antibodies to yellow fever in SOT recipients who have been vaccinated prior to transplantation.


Ultrasound is safe... right?: resident and maternal-fetal medicine fellow knowledge regarding obstetric ultrasound safety.
This study was created to assess the knowledge levels of postgraduate year 4 obstetrics and gynecology residents and maternal-fetal medicine fellows in the United States regarding the safety of obstetric ultrasound and the use of the output display standard. An electronic survey was submitted to each Accreditation Council for Graduate Medical Education-accredited obstetrics and gynecology residency and each maternal-fetal medicine fellowship program in the United States over 2 academic years from 2008 to 2010. A total of 165 surveys were completed (67 by postgraduate year 4 obstetrics and gynecology residents and 92 by maternal-fetal medicine fellows). In total, 13.4% of residents and 20.9% of maternal-fetal medicine fellows knew how to find or use the output display standard, and 10.9% of residents and 22.7% of fellows reported use of the output display standard during their ultrasound examinations. Overall, 37% to 46% of residents and fellows reported no limitations to the use of obstetric ultrasound and 22% to 39% reported no limitations to the use of Doppler ultrasound in the first, second, and third trimesters. Maternal-fetal medicine fellow knowledge of ultrasound safety generally improved with each year of training; however, only 34.8% of third-year fellows reported use of the output display standard. Currently, obstetrics and gynecology resident knowledge of obstetric ultrasound safety is low. Maternal-fetal medicine fellow knowledge is stronger overall; however, few are using the output display standard routinely in their last year of fellowship training. This study provides evidence of the need for improved education on the subject of obstetric ultrasound safety.


Microclimates Might Limit Indirect Spillover of the Bat Borne Zoonotic Hendra Virus.
Infectious diseases are transmitted when susceptible hosts are exposed to pathogen particles that can replicate within them. Among factors that limit transmission, the environment is particularly important for indirectly transmitted parasites. To try and assess a pathogens' ability to be transmitted through the environment and mitigate risk, we need to quantify its decay where transmission occurs in space such as the microclimate harbouring the pathogen. Hendra virus, a Henipavirus from Australian Pteropid bats, spills-over to horses and humans, causing high mortality. While a vaccine is available, its limited uptake has reduced opportunities for adequate risk management to humans, hence the need to develop synergistic preventive measures, like disrupting its transmission pathways. Transmission likely occurs shortly after virus excretion in paddocks; however, no survival estimates to date have used real environmental conditions. Here, we recorded microclimate conditions and fitted models that predict temperatures and potential evaporation, which we used to simulate virus survival with a temperature-survival model and modification based on evaporation. Predicted survival was lower than previously estimated and likely to be even lower according to potential evaporation. Our results indicate that transmission should occur shortly after the virus is excreted, in a relatively direct way. When potential evaporation is low, and survival is more similar to temperature dependent estimates, transmission might be indirect because the virus can wait several hours until contact is made. We recommend restricting horses' access to trees during night time and reducing grass under trees to reduce virus survival.


Retrospective survey of museum specimens reveals historically widespread presence of Batrachochytrium dendrobatidis in China.
Chytridiomycosis, caused by the chytrid fungus Batrachochytrium dendrobatidis (Bd), has been implicated in amphibian population declines worldwide. However, no amphibian declines or extinctions associated with Bd have been reported in Asia. To investigate the history of this pathogen in China, we examined 1,007 museum-preserved amphibian specimens of 80 species collected between 1933 and 2009. Bd was detected in 60 individuals (6.0%), with the earliest case of Bd infection occurring in one specimen of Bufo gargarizans and two Fejervarya limnocharis, all collected in 1933 from Chongqing, southwest China. Although mainly detected in non-threatened native amphibians, Bd was also found in four endangered species. We report the first evidence of Bd for Taiwan and the first detection of Bd in the critically endangered Chinese giant salamander (Andrias davidianus). Bd appears to have been present at a low rate of infection since at least the 1930s in China, and no significant differences in prevalence were detected between decades or provinces, suggesting that a historical steady endemic relationship between Bd and Chinese amphibians has occurred. Our results add new insights on the global emergence of Bd and suggest that this pathogen has been more widely distributed in the last century than previously believed.


A randomized pilot study on single-port versus conventional laparoscopic rectal surgery: effects on postoperative pain and the stress response to surgery.
Potential benefits of single-port laparoscopic surgery may include improved cosmetic results, less postoperative pain, surgical trauma and faster recovery. Results of randomized prospective studies with a focus on single-port rectal surgery have not yet been presented. The aim of the present study was to compare single-port and conventional laparoscopic surgery for rectal cancer in terms of short-term outcomes including postoperative pain and trauma-induced changes in certain bioactive substances. Patients with non-metastasized rectal cancer were prospectively randomized to single-port (n = 20) or conventional laparoscopic rectal surgery (n = 20). Postoperative pain was assessed at rest, at coughing and during mobilization, with a numeric pain ranking score and was recorded at 6 h after the operation and subsequently every morning daily for 4 days. Levels of C-reactive protein (CRP), interleukin-6 (IL-6) and tissue inhibitor of metalloproteinases-1 (TIMP-1) were determined. Blood samples were collected preoperatively (baseline), and 6, 24, 48, 72 and 96 h after skin incision. Pain scores were significantly reduced in the single-port group on postoperative days 2, 3 and 4 during coughing and mobilization. In addition, the patients in the single-port group suffered significantly less pain at rest at 6 h after surgery and on postoperative days 1, 3 and 4. The levels of the three markers increased significantly after surgery. The increase was similar between groups for plasma IL-6 and TIMP-1 at all time points, while the CRP levels were significantly lower in the single-port group at 6 (p < 0.001) and 24 h (p < 0.05) after skin incision. Abdominal incisions lengths were significantly shorter in the single-port group (p = 0.001). There was no significant difference between groups in operating time and blood loss, morbidity or mortality rate. The short-term oncological outcome in the two groups was similar. Single-port rectal surgery may reduce postoperative pain. Although CRP levels were lower at some time points, results of the present randomized, pilot study suggest that the trauma-induced inflammatory response of single-port operations may be similar to the trauma-induced inflammatory response of conventional laparoscopic surgery.


Deceased donor kidney transplantation from donors with acute renal failure due to rhabdomyolysis.
With the current shortage of solid organs for transplant, the transplant community continues to look for ways to increase the number of organ donors, including extending the criteria for donation. In rhabdomyolysis, the byproducts of skeletal muscle breakdown leak into the circulation resulting in acute renal failure in up to 30% of patients. In nonbrain dead patients, this condition is reversible and most patients recover full renal function. Seven potential donors had rhabdomyolysis with acute renal failure as evidenced by the presence of urine hemoglobin, plasma creatinine kinase levels of greater than five times the normal and elevated creatinine. One donor required dialysis. At our institution, 10 kidneys were transplanted from the seven donors. Two grafts had immediate function, five grafts experienced slow graft function and three grafts had delayed graft function requiring hemodialysis. At a mean of 8.7 months posttransplant (2.4-25.2 months), all patients have good graft function, are off dialysis and have a mean creatinine of 1.3 (0.7-1.8). In conclusion, our experience suggests that rhabdomyolysis with acute renal failure should not be a contraindication for donation, although recipients may experience slow or delayed graft function.


Multilocus sequence typing supports the hypothesis that cow- and human-associated Salmonella isolates represent distinct and overlapping populations.
A collection of 179 human and 156 bovine clinical Salmonella isolates obtained from across New York state over the course of 1 year was characterized using serotyping and a multilocus sequence typing (MLST) scheme based on the sequencing of three genes (fimA, manB, and mdh). The 335 isolates were differentiated into 52 serotypes and 72 sequence types (STs). Analyses of bovine isolates collected on different farms over time indicated that specific subtypes can persist over time on a given farm; in particular, a number of farms showed evidence for the persistence of a specific Salmonella enterica serotype Newport sequence type. Serotypes and STs were not randomly distributed among human and bovine isolates, and selected serotypes and STs were associated exclusively with either human or bovine sources. A number of common STs were geographically widespread. For example, ST6, which includes isolates representing serotype Typhimurium as well as the emerging serotype 4,5,12:i:-, was found among human and bovine isolates in a number of counties in New York state. Phylogenetic analyses supported the possibility that serotype 4,5,12:i:- is closely related to Salmonella serotype Typhimurium. Salmonella serotype Newport was found to represent two distinct evolutionary lineages that differ in their frequencies among human and bovine isolates. A number of Salmonella isolates carried two copies of manB (33 isolates) or showed small deletion events in fimA (nine isolates); these duplication and deletion events may provide mechanisms for the rapid diversification of Salmonella surface molecules. We conclude that the combined use of an economical three-gene MLST scheme and serotyping can provide considerable new insights into the evolution and transmission of Salmonella.


Sexual risk taking, sexually transmitted infections and HIV prevalence among four "high-risk" occupational groups of Indonesian men.
This article reports new surveillance data on the prevalence of sexual risk taking, HIV and other sexually transmitted infections (STI) among four occupational groups of Indonesian men thought to be at elevated risk of infection. Behavioural survey data were collected from 3008 men in 11 cities, among whom 2158 men were tested for HIV and syphilis and 1950 for gonorrhoea and chlamydia. Risk factors for STI were assessed using multivariable logistic regression. Thirty-six per cent of men had sex with a female sex worker (FSW) in the previous year and 20% with non-marital female partners. Consistent condom use was low with both sex workers (17%) and other non-marital partners (13%). HIV prevalence was 2% in Papua and less than 1% elsewhere, but was for the first time detectable in a non-core transmitter male population outside of Papua. STI rates were high for a non-core transmitter group, especially syphilis. Truck drivers were the most at risk. Multivariable analyses revealed exposure to FSW and inconsistent condom use, along with geographical location (Papua vs non-Papua) and unobserved factors associated with certain occupational groups, to be key risk factors for STI infection. The results confirm that men in the four occupational groups are reasonable proxies for "high-risk men" for surveillance purposes in Indonesia. Although HIV prevalence was low, the extent of sexual risk taking and the moderately high levels of STI among these men, along with rising HIV rates among FSW, indicate the potential for HIV/AIDS transmission in Indonesia to accelerate.


Relation of total sugars, fructose and sucrose with incident type 2 diabetes: a systematic review and meta-analysis of prospective cohort studies.
Sugar-sweetened beverages are associated with type 2 diabetes. To assess whether this association holds for the fructose-containing sugars they contain, we conducted a systematic review and meta-analysis of prospective cohort studies. We searched MEDLINE, Embase, CINAHL and the Cochrane Library (through June 2016). We included prospective cohort studies that assessed the relation of fructose-containing sugars with incident type 2 diabetes. Two independent reviewers extracted relevant data and assessed risk of bias. We pooled risk ratios (RRs) using random effects meta-analyses. The overall quality of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Fiffeen prospective cohort studies (251 261 unique participants, 16 416 cases) met the eligibility criteria, comparing the highest intake (median 137, 35.2 and 78 g/d) with the lowest intake (median 65, 9.7 and 25.8 g/d) of total sugars, fructose and sucrose, respectively. Although there was no association of total sugars (RR 0.91, 95% confidence interval [CI] 0.76-1.09) or fructose (RR 1.04, 95% CI 0.84-1.29) with type 2 diabetes, sucrose was associated with a decreased risk of type 2 diabetes (RR 0.89, 95% CI 0.80-0.98). Our confidence in the estimates was limited by evidence of serious inconsistency between studies for total sugars and fructose, and serious imprecision in the pooled estimates for all 3 sugar categories. Current evidence does not allow us to conclude that fructose-containing sugars independent of food form are associated with increased risk of type 2 diabetes. Further research is likely to affect our estimates. ClinicalTrials.gov, no. NCT01608620.


Designing and implementing a communications strategy: lessons learnt from HIV and Sexual and Reproductive Health Research Programme Consortia.
In recent years there has been increasing recognition of the importance of strategic research communication. Health research organisations need to be able to communicate their research effectively to increase the probability that the findings influence policy and practice, and benefit those in greatest need. Many research funders are making communications a requirement of research funding. This paper reflects on the experience in developing and implementing communications strategies of several Research Programme Consortia funded by the Department for International Development.Different research topics will require different communications approaches in order to be effective. This is reflected in the diversity of strategies employed by different research programmes. Strategic research communications designed to influence policy and practice require different skills and expertise from those required for carrying out research and writing it up for publication in academic journals. Therefore researchers involved in communicating research should be supported in this work. One of the ways in which research programme consortia have sought to do this is through convening workshops to develop the communications skills of researchers from partner organisations. These have proven invaluable. Another way of providing ongoing support to those involved in communicating research is through a Communications Community of Practice. Where this has been used it has proven a good way to support researchers both with ideas and resources, but also a strong sense of belonging to a community that shares a common concern with communication. Developing strong partnerships with research users, other research organisations, knowledge intermediaries and other stakeholders is vital for effective communication.Embracing the challenges and opportunities presented by communicating research to influence policy practice is vital if research is to have maximum possible impact, and demonstrate its worth at a time when funding for health and development activities is at risk. Sharing lessons learnt in this process between research programmes is important to support this work.


How exposure to environmental tobacco smoke, outdoor air pollutants, and increased pollen burdens influences the incidence of asthma.
Asthma is a multifactorial airway disease that arises from a relatively common genetic background interphased with exposures to allergens and airborne irritants. The rapid rise in asthma over the past three decades in Western societies has been attributed to numerous diverse factors, including increased awareness of the disease, altered lifestyle and activity patterns, and ill-defined changes in environmental exposures. It is well accepted that persons with asthma are more sensitive than persons without asthma to air pollutants such as cigarette smoke, traffic emissions, and photochemical smog components. It has also been demonstrated that exposure to a mix of allergens and irritants can at times promote the development phase (induction) of the disease. Experimental evidence suggests that complex organic molecules from diesel exhaust may act as allergic adjuvants through the production of oxidative stress in airway cells. It also seems that climate change is increasing the abundance of aeroallergens such as pollen, which may result in greater incidence or severity of allergic diseases. In this review we illustrate how environmental tobacco smoke, outdoor air pollution, and climate change may act as environmental risk factors for the development of asthma and provide mechanistic explanations for how some of these effects can occur.


2La chromosomal inversion enhances thermal tolerance of Anopheles gambiae larvae.
The mosquito Anopheles gambiae is broadly distributed throughout sub-Saharan Africa and this contributes to making it the most efficient vector of malaria on the continent. The pervasiveness of this species is hypothesized to originate in local adaptations facilitated by inversion polymorphisms. One inversion, named 2La, is strongly associated with aridity clines in West and Central Africa: while 2La is fixed in arid savannas, the 2L+a arrangement is predominantly found in the rainforest. Ability to survive high temperature exposure is an essential component of aridity tolerance, particularly in immature stages that are restricted to shallow puddles. Toward deciphering the role of the 2La inversion in local adaptation, the present investigation focused on variation in larval and pupal thermo-tolerance in two populations dissimilar solely in 2La arrangement. A laboratory colony of A. gambiae that is polymorphic for 2La but standard for all other known inversions was used to create 2 homokaryotypic populations (2L+a and 2La). The survival of 4th instar larvae and pupae from both populations was then tested following exposure to thermal stress with and without prior heat hardening. Larvae responded identically to a 40 degrees C heat stress, with about 50% of larvae dying after 1.5-2 h and few larvae surviving a 3 h stress. When heat hardened prior to the thermal stress, thermo-tolerance of both larval populations increased, with 2La 24 h survival significantly exceeding that of 2L+a. Pupae were generally more thermo-tolerant than larvae, although 2La pupae were less so than 2L+a. Heat hardening had no positive effect on pupal thermo-tolerance. The increased thermo-tolerance observed in 2La larvae following heat hardening suggests higher responsiveness (i.e., thermal sensitivity) of the inverted karyotype. By responding more drastically to the heat shock, 2La larvae are better equipped to resist the potentially lethal temperatures that occur in arid habitats. The lower survival of 2La pupae compared with 2L+a may reflect the cost of this sensitivity, whereby the thermal resistance mechanisms prevent successful completion of metamorphosis. The costs and benefits of thermal resistance are discussed in light of the climates characterizing either end of the 2La frequency cline.


Long-term efficacy of imepitoin in the treatment of naive dogs affected by idiopathic epilepsy.
The purpose of this study was to evaluate the long-term (12 months) efficacy and tolerability of imepitoin as first-choice treatment in 56 dogs suffering from idiopathic epilepsy and identify possible factors affecting the outcome. Primary treatment success (PTS) was defined as the achievement of a seizure-free interval three times longer than the pretreatment interictal interval (at least three months). Secondary treatment success (STS) was achieved by a decrease in seizure frequency ≥50 per cent compared with the pretreatment frequency. In the long-term follow-up, PTS was recorded in 14 (25 per cent) dogs and responder-dogs (PTS+STS) were 30 (54 per cent) showing significant reduction in the monthly average number of seizures (P<0.001). Median seizure frequency per month was 1.69 pretreatment and 0.3 at 12-month follow-up. Dogs with cluster seizures were significantly reduced (P=0.02). PTS at three and six months was associated with PTS (P=0.006 and <0.001, respectively) and with the status of responder dogs (P=0.002) at 12-month follow-up. Dogs aged >36 months at the start of imepitoin treatment had a positive association to become responder dogs (P<0.001) and achieve PTS (P=0.004). 16 dogs (29 per cent) discontinued imepitoin due to its inefficacy. The receiver operator curve highlighted ≥19 mg/kg twice a day as the most effective minimal dosage. Mild and transient side effects were observed in 16 dogs (29 per cent).


Affective reactivity to daily stressors and long-term risk of reporting a chronic physical health condition.
Daily stressors, such as an argument with a spouse or an impending deadline, are associated with short-term changes in physical health symptoms. Whether these minor hassles have long-term physical health ramifications, however, is largely unknown. The current study examined whether exposure and reactivity to daily stressors is associated with long-term risk of reporting a chronic physical health condition. Participants (N = 435) from the National Study of Daily Experiences completed a series of daily diary interviews between 1995 and 1996 and again 10 years later. Greater affective (i.e., emotional) reactivity to daily stressors at time 1 was associated with an increased risk of reporting a chronic physical health condition at time 2. Results indicate that how people respond to the daily stressors in their lives is predictive of future chronic health conditions.


Inter and intra-specific diversity of parasites that cause lymphatic filariasis.
Lymphatic filariasis is caused by three closely related nematode parasites: Wuchereria bancrofti, Brugia malayi and Brugia timori. These species have many ecological variants that differ in several aspects of their biology such as mosquito vector species, host range, periodicity, and morphology. Although the genome of B. malayi (the first genome sequenced from a parasitic nematode) has been available for more than five years, very little is known about genetic variability among the lymphatic dwelling filariae. The genetic diversity among these worms is not only interesting from a biological perspective, but it may have important practical implications for the Global Program to Eliminate Lymphatic Filariasis, as the parasites may respond differently to diagnostic tests and/or medical interventions. Therefore, better information on their genetic variability is urgently needed. With improved methods for nucleic acid extraction and recent advances in sequencing chemistry and instrumentation, this gap can be filled relatively inexpensively. Improved information on filarial genetic diversity may increase the chances of success for lymphatic filariasis elimination programs.


Diabetes in primary care: prospective associations between depression, nonadherence and glycemic control.
Findings are inconsistent regarding the degree to which depression may exert a negative impact on glycemic control in patients with type 2 diabetes. We therefore aimed to examine the longitudinal relationship between depression, behavioral factors, and glycemic control. In a prospective component of a nationally representative sample, 866 patients with type 2 diabetes aged >or=18 years completed a standardized assessment including a laboratory screening, questionnaires, and diagnostic measures. Subsequent to baseline (t(0)), patients were tracked over a period of 12 months (t(1)). Depression was assessed according to DSM-IV and ICD-10 criteria. Glycemic control was determined by levels of glycosylated hemoglobin (HbA(1c)); a level of >or=7% was judged as unsatisfactory. Regression analyses were performed to analyze the prospective relationship between depression, medication adherence, diabetes-related health behavior, and HbA(1c). Patients with depression at t(0) revealed increased rates of medication nonadherence (adjusted OR: 2.67; CI: 1.38-5.15) at t(1). Depression (adjusted regression coefficient: beta = 0.96; p = 0.001) and subthreshold depression (beta = 1.01; p < 0.001) at t(0) also predicted increased problems with diabetes-related health behavior at t(1). Adjusted ORs for poor glycemic control (HbA(1c) >or=7%) at t(1) were also increased for patients with baseline depression (2.01; CI: 1.10-3.69). However, problems with medication adherence as well as problems with diabetes-related health behavior at t(0) did not predict poor glycemic control at t(1). In a prospective representative study of patients with type 2 diabetes, baseline depression predicted problems with medication adherence, problems with health-related behaviors, and unsatisfactory glycemic control at follow-up.


Decline in respiratory symptoms in service workers five months after a public smoking ban.
To evaluate the effect of a total ban on smoking indoors in restaurants and other hospitality business premises in Norway, on respiratory symptoms among workers in the industry. Phone interviews with 1525 employees in the hospitality business were conducted immediately before the enacting of the law. In a follow-up study five months later, 906 of the workers from the baseline sample participated. Questions were asked on demographic variables, passive smoking exposure, personal smoking, attitudes towards the law, and five respiratory symptoms. Change in symptom prevalence was analysed with McNemar's test and with analysis of variance (ANOVA) for repeated measures. The prevalence of all five symptoms declined after the ban; for morning cough from 20.6% to 16.2% (p < 0.01); for daytime cough from 23.2% to 20.9%; for phlegm cough from 15.3% to 11.8% (p < 0.05); for dyspnoea from 19.2% to 13.0% (p < 0.01); and for wheezing from 9.0% to 7.8%. ANOVA showed that the largest decline in symptom prevalence was seen among workers who themselves gave up smoking, and subjects with a positive attitude towards the law before it took effect. A significant decrease in respiratory symptoms among service industry workers was found five months after the enacting of a public smoking ban.


From predicting mosquito habitat to malaria seasons using remotely sensed data: practice, problems and perspectives.
Remote sensing techniques are becoming increasingly important for identifying mosquito habitats, investigating malaria epidemiology and assisting malaria control. Here, Simon Hay, Bob Snow and David Rogers review the development of these techniques, from aerial photographic identification of mosquito larval habitats on the local scale through to the space-based survey of malaria risk over continental areas using increasingly sophisticated airborne and satellite-sensor technology. They indicate that previous constraints to uptake are becoming less relevant and suggest how future delays in the use of remotely sensed data in malaria control might be avoided.