Genomic regions associated with susceptibility to Barrett's esophagus and esophageal adenocarcinoma in African Americans: The cross BETRNet admixture study.
Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) are far more prevalent in European Americans than in African Americans. Hypothesizing that this racial disparity in prevalence might represent a genetic susceptibility, we used an admixture mapping approach to interrogate disease association with genomic differences between European and African ancestry. Formalin fixed paraffin embedded samples were identified from 54 African Americans with BE or EAC through review of surgical pathology databases at participating Barrett's Esophagus Translational Research Network (BETRNet) institutions. DNA was extracted from normal tissue, and genotyped on the Illumina OmniQuad SNP chip. Case-only admixture mapping analysis was performed on the data from both all 54 cases and also on a subset of 28 cases with high genotyping quality. Haplotype phases were inferred with Beagle 3.3.2, and local African and European ancestries were inferred with SABER plus. Disease association was tested by estimating and testing excess European ancestry and contrasting it to excess African ancestry. Both datasets, the 54 cases and the 28 cases, identified two admixture regions. An association of excess European ancestry on chromosome 11p reached a 5% genome-wide significance threshold, corresponding to -log10(P) = 4.28. A second peak on chromosome 8q reached -log10(P) = 2.73. The converse analysis examining excess African ancestry found no genetic regions with significant excess African ancestry associated with BE and EAC. On average, the regions on chromosomes 8q and 11p showed excess European ancestry of 15% and 20%, respectively. Chromosomal regions on 11p15 and 8q22-24 are associated with excess European ancestry in African Americans with BE and EAC. Because GWAS have not reported any variants in these two regions, low frequency and/or rare disease associated variants that confer susceptibility to developing BE and EAC may be driving the observed European ancestry association evidence.


Meanings of being old, living on one's own and suffering from incurable cancer in rural Norway.
The aim of this study was to explore and understand the lived experience of older people living alone and suffering from incurable cancer in rural Norway. Narrative interviews were conducted with five older people with incurable cancer (three women and two men, aged 71-79), receiving outpatient and life-prolonging chemotherapy and living alone in their homes in rural areas. A phenomenological hermeneutical approach was used to interpret the meaning of the lived experience. Four main themes were found: enduring by keeping hope alive, becoming aware that you are on your own, living up to expectations of being a good patient and being at risk of losing one's identity and value. Enduring this situation means struggling with terminal illness and facing death in a brave manner, and replacing former ways of living. The process of providing treatment may threaten dignity and cause additional distress. These results show a complex and comprehensive situation where physical symptoms and emotions are interwoven. Further the results describe how the ways of suffering caused by the manner in which care is delivered, suffering related to the cancer disease and existential suffering, may increase each other's impact. The social and rural context calls for special attention as the patients may lack recourses to gain sufficient care. Their comfort depends to a large extent on the health professionals' sensitivity.


A novel miR-371a-5p-mediated pathway, leading to BAG3 upregulation in cardiomyocytes in response to epinephrine, is lost in Takotsubo cardiomyopathy.
Molecular mechanisms protecting cardiomyocytes from stress-induced death, including tension stress, are essential for cardiac physiology and defects in these protective mechanisms can result in pathological alterations. Bcl2-associated athanogene 3 (BAG3) is expressed in cardiomyocytes and is a component of the chaperone-assisted autophagy pathway, essential for homeostasis of mechanically altered cells. BAG3 ablation in mice results in a lethal cardiomyopathy soon after birth and mutations of this gene have been associated with different cardiomyopathies including stress-induced Takotsubo cardiomyopathy (TTC). The pathogenic mechanism leading to TTC has not been defined, but it has been suggested that the heart can be damaged by excessive epinephrine (epi) spillover in the absence of a protective mechanism. The aim of this study was to provide more evidence for a role of BAG3 in the pathogenesis of TTC. Therefore, we sequenced BAG3 gene in 70 TTC patients and in 81 healthy donors with the absence of evaluable cardiovascular disease. Mutations and polymorphisms detected in the BAG3 gene included a frequent nucleotide change g2252c in the BAG3 3'-untranslated region (3'-UTR) of Takotsubo patients (P<0.05), resulting in loss of binding of microRNA-371a-5p (miR-371a-5p) as evidenced by dual-luciferase reporter assays and argonaute RNA-induced silencing complex catalytic component 2/pull-down assays. Moreover, we describe a novel signaling pathway in cardiomyocytes that leads to BAG3 upregulation on exposure to epi through an ERK-dependent upregulation of miR-371a-5p. In conclusion, the presence of a g2252c polymorphism in the BAG3 3'-UTR determines loss of miR-371a-5p binding and results in an altered response to epi, potentially representing a new molecular mechanism that contributes to TTC pathogenesis.


Similar genetic basis of resistance to Bt toxin Cry1Ac in Boll-selected and diet-selected strains of pink bollworm.
Genetically engineered cotton and corn plants producing insecticidal Bacillus thuringiensis (Bt) toxins kill some key insect pests. Yet, evolution of resistance by pests threatens long-term insect control by these transgenic Bt crops. We compared the genetic basis of resistance to Bt toxin Cry1Ac in two independently derived, laboratory-selected strains of a major cotton pest, the pink bollworm (Pectinophora gossypiella [Saunders]). The Arizona pooled resistant strain (AZP-R) was started with pink bollworm from 10 field populations and selected with Cry1Ac in diet. The Bt4R resistant strain was started with a long-term susceptible laboratory strain and selected first with Bt cotton bolls and later with Cry1Ac in diet. Previous work showed that AZP-R had three recessive mutations (r1, r2, and r3) in the pink bollworm cadherin gene (PgCad1) linked with resistance to Cry1Ac and Bt cotton producing Cry1Ac. Here we report that inheritance of resistance to a diagnostic concentration of Cry1Ac was recessive in Bt4R. In interstrain complementation tests for allelism, F(1) progeny from crosses between AZP-R and Bt4R were resistant to Cry1Ac, indicating a shared resistance locus in the two strains. Molecular analysis of the Bt4R cadherin gene identified a novel 15-bp deletion (r4) predicted to cause the loss of five amino acids upstream of the Cry1Ac-binding region of the cadherin protein. Four recessive mutations in PgCad1 are now implicated in resistance in five different strains, showing that mutations in cadherin are the primary mechanism of resistance to Cry1Ac in laboratory-selected strains of pink bollworm from Arizona.


No split, no tenotomy transposition procedure for complete abducens palsy.
Abducens palsy is one of the commonly encountered cranial nerve palsies in strabismus clinic. For large-angle esotropia, due to complete abducens palsies, various vertical recti transposition (VRT) procedures have been described. Hummelsheim and Jensen's procedure are especially popular among them. Risk of anterior segment ischemia and induced vertical deviation postVRT prompt to search for better procedures to correct the esotropia and also improve the abduction. Modified Nishida's procedure (no split, no tenotomy transposition) is one of the newly described procedure in this direction. We describe three cases of complete abducens nerve palsy treated by this procedure.


The archaeogenetics of Europe.
A new timescale has recently been established for human mitochondrial DNA (mtDNA) lineages, making mtDNA at present the most informative genetic marker system for studying European prehistory. Here, we review the new chronology and compare mtDNA with Y-chromosome patterns, in order to summarize what we have learnt from archaeogenetics concerning five episodes over the past 50,000 years which significantly contributed to the settlement history of Europe: the pioneer colonisation of the Upper Palaeolithic, the Late Glacial re-colonisation of the continent from southern refugia after the Last Glacial Maximum, the postglacial re-colonization of deserted areas after the Younger Dryas cold snap, the arrival of Near Easterners with an incipient Neolithic package, and the small-scale migrations along continent-wide economic exchange networks beginning with the Copper Age. The available data from uniparental genetic systems have already transformed our view of the prehistory of Europe, but our knowledge of these processes remains limited. Nevertheless, their legacy remains as sedimentary layers in the gene pool of modern Europeans, and our understanding of them will improve substantially when more mtDNAs are completely sequenced, the Y chromosome more thoroughly analysed, and haplotype blocks of the autosomal genome become amenable to phylogeographic studies.


Prediction and control of number of cells in microdroplets by stochastic modeling.
Manipulation and encapsulation of cells in microdroplets has found many applications in various fields such as clinical diagnostics, pharmaceutical research, and regenerative medicine. The control over the number of cells in individual droplets is important especially for microfluidic and bioprinting applications. There is a growing need for modeling approaches that enable control over a number of cells within individual droplets. In this study, we developed statistical models based on negative binomial regression to determine the dependence of number of cells per droplet on three main factors: cell concentration in the ejection fluid, droplet size, and cell size. These models were based on experimental data obtained by using a microdroplet generator, where the presented statistical models estimated the number of cells encapsulated in droplets. We also propose a stochastic model for the total volume of cells per droplet. The statistical and stochastic models introduced in this study are adaptable to various cell types and cell encapsulation technologies such as microfluidic and acoustic methods that require reliable control over number of cells per droplet provided that settings and interaction of the variables is similar.


NOS1AP variant associated with incidence of type 2 diabetes in calcium channel blocker users in the Atherosclerosis Risk in Communities (ARIC) study.
To validate the reported association between rs10494366 in NOS1AP (the gene encoding nitric oxide synthase-1 adaptor protein) and the incidence of type 2 diabetes in calcium channel blocker (CCB) users and to identify additional NOS1AP variants associated with type 2 diabetes risk. Data from 9 years of follow-up in 9,221 middle-aged white and 2,724 African-American adults free of diabetes at baseline from the Atherosclerosis Risk in Communities study were analysed. Nineteen NOS1AP variants were examined for associations with incident diabetes and fasting glucose levels stratified by baseline CCB use. Prevalence of CCB use at baseline was 2.7% (n = 247) in whites and 2.3% (n = 72) in African-Americans. Among white CCB users, the G allele of rs10494366 was associated with lower diabetes incidence (HR 0.57, 95% CI 0.35-0.92, p = 0.016). The association was marginally significant after adjusting for age, sex, obesity, smoking, alcohol use, physical activity, hypertension, heart rate and electrocardiographic QT interval (HR 0.63, 95% CI 0.38-1.04, p = 0.052). rs10494366 was associated with lower average fasting glucose during follow-up (p = 0.037). No other variants were associated with diabetes risk in CCB users after multiple-testing correction. No associations were observed between any NOS1AP variant and diabetes development in non-CCB users. NOS1AP variants were not associated with diabetes risk in either African-American CCB users or non-CCB users. We have independently replicated the association between rs10494366 in NOS1AP and incident diabetes among white CCB users. Further exploration of NOS1AP variants and type 2 diabetes and functional studies of NOS1AP in type 2 diabetes pathology is warranted.


Detection of hepatitis B virus infection in wild-born chimpanzees (Pan troglodytes verus): phylogenetic relationships with human and other primate genotypes.
Infection with hepatitis B virus (HBV) was detected by serological testing for HBV surface antigen and by PCR assay for HBV DNA in serum samples from two common chimpanzees (Pan troglodytes subsp. verus) born in West Africa. The complete genome sequences obtained by nucleotide sequencing of overlapping DNA fragments amplified by PCR were compared with HBV variants recovered from other primates and with human genotypes A to F. Both chimpanzee sequences were 3, 182 nucleotides in length, and the surface gene sequence predicted the existence of a, d, and w serological determinants. Neither sequence contained stop codons in the precore region. On phylogenetic analysis, the HBV variants infecting the chimpanzees clustered together with a third chimpanzee HBV isolate independently obtained from an infected captive animal (A. J. Zuckerman, A. Thornton, C. R. Howard, K. N. Tsiquaye, D. M. Jones, and M. R. Brambell, Lancet ii:652-654, 1978), with an overall sequence similarity of >94%. This provides strong evidence for a chimpanzee-specific genotype of HBV which circulates in nature. These findings add to the recent evidence for infection in the wild of other Old and New World primates (gibbon, orangutan, and woolly monkey) with species-specific variants of HBV. There is no evidence for close phylogenetic clustering of variants found so far in primates with any of the established HBV genotypes from humans. With the new evidence for the widespread distribution of HBV in primates, hypotheses for the origins of human infection are reviewed.


Human immunodeficiency virus type 1 Vpr induces apoptosis in human neuronal cells.
Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system (CNS) causes AIDS dementia complex (ADC) in certain infected individuals. Recent studies have suggested that patients with ADC have an increased incidence of neuronal apoptosis leading to neuronal dropout. Of note, a higher level of the HIV-1 accessory protein Vpr has been detected in the cerebrospinal fluid of AIDS patients with neurological disorders. Moreover, extracellular Vpr has been shown to form ion channels, leading to cell death of cultured rat hippocampal neurons. Based on these previous findings, we first investigated the apoptotic effects of the HIV-1 Vpr protein on the human neuronal precursor NT2 cell line at a range of concentrations. These studies demonstrated that apoptosis induced by both Vpr and the envelope glycoprotein, gp120, occurred in a dose-dependent manner compared to protein treatment with HIV-1 integrase, maltose binding protein (MBP), and MBP-Vpr in the undifferentiated NT2 cells. For mature, differentiated neurons, apoptosis was also induced in a dose-dependent manner by both Vpr and gp120 at concentrations ranging from 1 to 100 ng/ml, as demonstrated by both the terminal deoxynucleotidyltransferase (Tdt)-mediated dUTP-biotin nick end labeling and Annexin V assays for apoptotic cell death. In order to clarify the intracellular pathways and molecular mechanisms involved in Vpr- and gp120-induced apoptosis in the NT2 cell line and differentiated mature human neurons, we then examined the cellular lysates for caspase-8 activity in these studies. Vpr and gp120 treatments exhibited a potent increase in activation of caspase-8 in both mature neurons and undifferentiated NT2 cells. This suggests that Vpr may be exerting selective cytotoxicity in a neuronal precursor cell line and in mature human neurons through the activation of caspase-8. These data represent a characterization of Vpr-induced apoptosis in human neuronal cells, and suggest that extracellular Vpr, along with other lentiviral proteins, may increase neuronal apoptosis in the CNS. Also, identification of the intracellular activation of caspase-8 in Vpr-induced apoptosis of human neuronal cells may lead to therapeutic approaches which can be used to combat HIV-1-induced neuronal apoptosis in AIDS patients with ADC.


Formation, maintenance and consequences of the imprint at the mating-type locus in fission yeast.
Mating-type switching in the fission yeast Schizosaccharomyces pombe is initiated by a strand-specific imprint located at the mating-type (mat1) locus. We show that the imprint corresponds to a single-strand DNA break (SSB), which is site- but not sequence-specific. We identified three novel cis-acting elements, involved in the formation and stability of the SSB. One of these elements is essential for a replication fork pause next to mat1 and interacts in vivo with the Swi1 protein. Another element is essential for maintaining the SSB during cell cycle progression. These results suggest that the DNA break appears during the S-phase and is actively protected against repair. Consequently, during the following round of replication, a polar double-strand break is formed. We show that when the replication fork encounters the SSB, the leading-strand DNA polymerase is able to synthesize DNA to the edge of the SSB, creating a blunt-ended recombination intermediate.


Diagnosis of small partial-thickness rotator cuff tears using vibro-acoustography.
Vibro-acoustography is a new imaging technique based on the dynamic radiation force of ultrasound. The purpose of this study was to apply this new imaging technique to the diagnosis of small partial-thickness rotator cuff tears and to determine how small of tears could be detected with this imaging technique. Seven supraspinatus tendons excised from embalmed cadavers were used. Three different sizes of partial-thickness bursal-sided tears (1, 3, and 5 mm(3)) were created in each specimen. The intersection of two co-focused ultrasound beams of slightly different frequency was swept across the intended imaging area. The acoustic emission data were collected and used to form and display a vibro-acoustography image of the tendon. Vibro-acoustography images were read by two orthopedic surgeons. The rotator cuff tear could be detected by vibro-acoustography in all specimens. The diagnostic concordance rate was 90.5 % and the kappa coefficient value was 0.88, which resulted in a high concordance. The diagnostic concordance rate for the 1 mm tear was 71.3 %, which was low concordance (κ = 0.481), whereas that for the 3 and 5 mm tears was 100 %. We were able to detect a 3-mm tear by using vibro-acoustography. There is a possibility that this new imaging technique could become a useful imaging tool for the diagnosis of small partial-thickness rotator cuff tears.


Clients of female sex workers: a population-based survey of China.
The control of HIV and other sexually transmitted infections (STI) is a challenge in China, with female sex workers (FSW) and male clients suspected as bridge groups. This study used a 2006 national probability survey of 2,707 adult men. Among men 15-49 years old, the prevalence of FSW contacts last year was 4.2% (95% CI, 3.3-5.2) overall, with 7.2% (CI, 5.9-8.7) in urban and 1.8% (CI, 1.0-3.3) in rural areas. In urban areas, the men most at risk for FSW were high income, often traveled, engaged in business entertaining, ages 25-39, and had early sex histories. When compared to men with only wife or stable sex partner, those most likely to report STI last year also reported FSW sex of any type (aOR,13.10; CI, 5.87-29.42). Additionally, when compared to men reporting consistent condom use with FSW, men with inconsistent condom use had elevated STI (aOR, 3.71; CI, 1.18-11.66). Additional efforts are needed for high income men in urban areas, and on consistent condom use with FSW.


Permanent Contraception for Women.
Permanent contraception is a highly desired and commonly used contraceptive option for women around the world who desire never to become pregnant. Current methods of female permanent contraception require surgery. Postpartum tubal ligation and interval surgical tubal ligation are safe and effective, do not interfere with menstrual cycles, and require no ongoing cost or medical checkups. Hysteroscopic tubal occlusion offers a less invasive surgical approach, but requires an imaging study for verification of correct placement. However, not all women have access to a surgeon trained to provide permanent contraception, or they may face other prohibitive logistic or financial burdens. The development of novel permanent contraception methods that are immediately effective and/or nonsurgical could help improve access to and acceptability of permanent contraception. The expansion of permanent contraception options could help women achieve their family planning goals and reduce unintended pregnancies.


Monitoring asthma in childhood: symptoms, exacerbations and quality of life.
Monitoring asthma in children in clinical practice is primarily performed by reviewing disease activity (daytime and night-time symptoms, use of reliever medication, exacerbations requiring frequent use of reliever medication and urgent visits to the healthcare professional) and the impact of the disease on children's daily activities, including sports and play, in a clinical interview. In such an interview, most task force members also discuss adherence to maintenance therapy and the patients' (and parents') views and beliefs on the goals of treatment and the amount of treatment required to achieve those goals. Composite asthma control and quality of life measures, although potentially useful in research, have limited value in clinical practice because they have a short recall window and do not cover the entire spectrum of asthma control. Telemonitoring of children with asthma cannot replace face-to-face follow-up and monitoring because there is no evidence that it is associated with improved health outcomes.


Activating protein 1-mediated cyclooxygenase-2 expression is independent of N-terminal phosphorylation of c-Jun.
Transcriptional activation of the cyclooxygenase (COX)-2 gene is responsible for high level of prostaglandin production during inflammation and carcinogenesis. We found previously that c-Jun induction plays a crucial role in epidermal growth factor (EGF)-induced gene expression of COX-2. In this study, the functional role of c-Jun in EGF-induced transcriptional activation of COX-2 in A431 cells was investigated. We found that overexpression of c-Jun N-terminal phosphorylation site mutants had similar stimulatory effects on COX-2 promoter activity and protein expression as c-Jun wild type. TAM-67, a mutant of c-Jun that lacks the N-terminal transactivation domain of c-Jun, also enhanced COX-2 promoter activity and protein expression in cells treated with EGF. In vitro DNA affinity precipitation and reporter assays revealed that regulation of c-Jun C terminus by EGF enhanced c-Jun binding to COX-2 promoter and induced COX-2 expression. Furthermore, we demonstrated that c-Fos, which provides transactivation function in Jun/Fos heterodimer, was required for EGF-induced expression of COX-2. These results indicated that c-Jun N-terminal phosphorylation was not required for EGF-induced expression of COX-2. c-Jun, which could recruit other transcription factors such as c-Fos, was required for EGF-induced expression of COX-2 in A431 cells.


Insulin resistance in critical illness.
The purpose of this review is to describe current concepts on inflammation, immunity and insulin resistance. Metabolic and immune systems are closely involved in inflammation and significantly contribute to the pathology seen in the pediatric intensive care unit. The ability of insulin to decrease hepatic glucose production, suppress adipose tissue lipolytic rate, stimulate skeletal muscle glucose uptake, suppress protein breakdown and increase protein synthesis is critical to maintain metabolic function. Hence, a better understanding of these regulatory mechanisms and the alterations leading to dysfunction will set the basis for a better metabolic and immune support of critically ill patients. Inflammation can be elicited by infection (sepsis) through pathogen associated molecular patterns (PAMPs) or through danger associated molecular patterns (DAMPs) as a response to an insult (systemic inflammatory response syndrome; SIRS) in the absence of infection. Mitochondrial DAMPs and PAMPs share the same pattern recognition receptors. These receptors act also as nutrient sensors, and in the presence of fatty acids will induce an inflammatory cascade that affects insulin signaling with development of insulin resistance. Lipotoxicity is emerging as a significant contributor to the development of insulin resistance. Insulin resistance is an adaptive mechanism that prioritizes utilization of energy for immune response in the presence of infection or injury. A better understanding of the complex interactions between metabolism, inflammation and immunity in critically ill children will lead to appropriate metabolic and immune support of these patients.


Distribution of neuropeptide Y Leu7Pro polymorphism in patients with type 1 diabetes and diabetic nephropathy among Swedish and American populations.
The distribution of Leu7Pro polymorphism in the neuropeptide Y gene shows a geographical north to south gradient of decreasing frequency, suggesting that it may be a population-specific causal variant. This polymorphism is found to be associated with diabetic nephropathy (DN) and coronary heart disease in Finnish women with type 1 diabetes (T1D). The present study aims to evaluate the susceptibility of this polymorphism to the development of DN in two different populations. One sample set consists of 174 (females 98 and males 76) Swedish T1D patients with DN and 249 (females 132 and males 117) patients without DN. Another sample set includes 597 (females 356 and males 241) American T1D patients without DN and 577 (females 264 and males 313) patients with DN, who were descents of European Caucasians and were from the Genetics of Kidneys in Diabetes (GoKinD) Study. Genotyping of Leu7Pro polymorphism was performed by dynamic allele-specific hybridization. The C allele frequencies of Leu7Pro polymorphism in T1D patients between Swedish and American GoKinD populations were significantly different (6.3 vs 4.0%; P=0.006). Particularly, the C allele frequency in Swedish female T1D patients with DN was significantly higher in comparison with T1D patients without DN (10.2 vs 4.2%; P=0.011, OR=2.614, 95% confidence intervals: 1.249-5.467). No significant association of this polymorphism with DN was observed in Swedish male T1D patients and the patients from GoKinD. The present study provides further evidence that Leu7Pro polymorphism confers the susceptibility to the development of DN in Swedish female T1D patients.


Exploring the impact of gender inequities on the promotion of cardiovascular health of women in Pakistan.
Cardiovascular disease exerts an enormous burden on women's health. The intake of a healthy diet may reduce this burden. However, social norms and economic constraints are often factors that restrain women from paying attention to their diet. Underpinned by critical realism, this study explores how gender/sex influences decision-making regarding food consumption among women of low socioeconomic status (SES). The study was carried out at two cardiac facilities in Karachi, Pakistan, on 24 participants (male and female from different ethnic backgrounds), who had received health education. Using an interpretive descriptive approach, the study identified major barriers to a healthy diet: proscribed gender roles and lack of women's autonomy, power, male domination, and abusive behaviours. Cardiovascular risk and disease outcomes for the Pakistani women of low SES are likely to further escalate if individual and structural barriers are not reduced using multifactorial approaches.


Biochemical characterization and surfactant properties of horse allergens.
A new allergen from horse dander, Equ c 5 has been purified. Its biochemical and biophysical properties have been characterized and compared with those of Equ c 1, Equ c 2 and Equ c 4. Their molecular masses, determined by mass spectrometry, were 22 kDa for Equ c 1, 16 kDa for Equ c 2, 18.7 kDa for Equ c 4 and 16.7 kDa for Equ c 5. Their pI values were between 3.8 and 5.25. Equ c 2 and Equ c 5 are not glycosylated, while Equ c 4 contains a tri-antennary tri-sialylated N-linked glycan. Linkages of terminal N-acetylneuraminic acid to galactose were: alpha-(2-->6) in Equ c 4, and both alpha-(2-->3) and alpha-(2-->6) in Equ c 1. Oligosaccharide portions of Equ c 1 or Equ c 4 were barely involved in IgE-immunoreactivity. Partial N-terminal sequence of Equ c 4 shares a significant sequence homology with the rat submandibular gland protein A. No matching was found for two internal peptides of Equ c 5. Surfactant properties of horse allergens as well as other proteins were investigated. In contrast to Equ c 2 and Equ c 3, solutions of Equ c 1, Equ c 4 and Equ c 5 significantly lowered the surface tension. Relationship between a property such as this, involving oriented hydrophobic patches of a molecule and allergenicity, is addressed.


The combination of ribavirin and peginterferon is superior to peginterferon and placebo for children and adolescents with chronic hepatitis C.
Although randomized trials of adults infected with hepatitis C virus (HCV) have shown that ribavirin increases the efficacy of pegylated interferon (PEG), such trials have not been performed in children. We conducted a randomized controlled trial of PEG and ribavirin, compared with PEG and placebo, in children 5 to 17 years old with chronic hepatitis C. HCV RNA-positive children from 11 university medical centers were randomly assigned to receive either PEG alfa-2a (PEG-2a; 180 μg/1.73 m(2) body surface area, subcutaneously each week; n = 55) and ribavirin (15 mg/kg orally in 2 doses daily) or PEG-2a and placebo (n = 59) for 48 weeks. The primary end point was sustained virologic response (SVR; lack of detectable HCV RNA at least 24 weeks after stopping therapy). SVR was achieved in 53% of children treated with PEG-2a and ribavirin, compared with 21% of children who received PEG-2a and placebo (P < .001). Early virologic response (HCV RNA reduction >2 log(10) IU at 12 weeks) had a negative predictive value of only 0.89 in children with genotype 1, indicating that these children might benefit from 24 weeks of therapy before stopping treatment. Side effects, especially neutropenia, led to dose modification in 40% of children. Eighty-two percent of the PEG/ribavirin and 86% of the PEG/placebo group were in compliance with the year 2 follow-up visit; the durability of virologic response was 100% in both groups. The combination of PEG and ribavirin is superior to PEG and placebo as therapy for chronic hepatitis C in children and adolescents.


The PCR-Based Diagnosis of Central Nervous System Tuberculosis: Up to Date.
Central nervous system (CNS) tuberculosis, particularly tuberculous meningitis (TBM), is the severest form of Mycobacterium tuberculosis (M.Tb) infection, causing death or severe neurological defects in more than half of those affected, in spite of recent advancements in available anti-tuberculosis treatment. The definitive diagnosis of CNS tuberculosis depends upon the detection of M.Tb bacilli in the cerebrospinal fluid (CSF). At present, the diagnosis of CNS tuberculosis remains a complex issue because the most widely used conventional "gold standard" based on bacteriological detection methods, such as direct smear and culture identification, cannot rapidly detect M.Tb in CSF specimens with sufficient sensitivity in the acute phase of TBM. Recently, instead of the conventional "gold standard", the various molecular-based methods including nucleic acid amplification (NAA) assay technique, particularly polymerase chain reaction (PCR) assay, has emerged as a promising new method for the diagnosis of CNS tuberculosis because of its rapidity, sensitivity and specificity. In addition, the innovation of nested PCR assay technique is worthy of note given its contribution to improve the diagnosis of CNS tuberculosis. In this review, an overview of recent progress of the NAA methods, mainly highlighting the PCR assay technique, was presented.


Joint Maximum Likelihood Estimation for High-Dimensional Exploratory Item Factor Analysis.
Joint maximum likelihood (JML) estimation is one of the earliest approaches to fitting item response theory (IRT) models. This procedure treats both the item and person parameters as unknown but fixed model parameters and estimates them simultaneously by solving an optimization problem. However, the JML estimator is known to be asymptotically inconsistent for many IRT models, when the sample size goes to infinity and the number of items keeps fixed. Consequently, in the psychometrics literature, this estimator is less preferred to the marginal maximum likelihood (MML) estimator. In this paper, we re-investigate the JML estimator for high-dimensional exploratory item factor analysis, from both statistical and computational perspectives. In particular, we establish a notion of statistical consistency for a constrained JML estimator, under an asymptotic setting that both the numbers of items and people grow to infinity and that many responses may be missing. A parallel computing algorithm is proposed for this estimator that can scale to very large datasets. Via simulation studies, we show that when the dimensionality is high, the proposed estimator yields similar or even better results than those from the MML estimator, but can be obtained computationally much more efficiently. An illustrative real data example is provided based on the revised version of Eysenck's Personality Questionnaire (EPQ-R).


Caregiver support groups in patients with dementia: a meta-analysis.
Meta-analysis studies of specific types of support groups are limited. We conducted a review and assessment of the effectiveness of support groups for caregivers of demented patients, and examined the impact of support group characteristics. A search of multiple, electronic databases including the Cochrane Library, Medline, PUBMED, and others was conducted; studies published between 1998 and 2009 were collected. Thirty quantitative journal articles that were true and quasi-experimental controlled trials on support groups for non-professional caregivers, including mutual support, psychoeducational, and educational groups were analyzed. Outcome indicators were psychological well-being, depression, burden, and social outcomes. Support groups showed a significant positive effect on caregivers' psychological well-being (Hedge's g = -0.44, 95% CI = -0.73, -0.15), depression (Hedge's g = -0.40, 95% CI = -0.72, -0.08), burden (Hedge's g = -0.23, 95% CI = -0.33, -0.13), and social outcomes (Hedge's g = 0.40, 95% CI = 0.09, 0.71). The use of theoretical models, and length and intensity of group sessions had a significant impact on the effect sizes for psychological well-being and depression. Ratio of female participation (for psychological well-being and depression) and average age (social outcomes) were significant predictor variables. Support groups benefit caregivers and findings of this meta-analysis serve as immediate guidance for group facilitators. Future research should include additional outcome variables with our defined factors on effectiveness collected as demographic characteristic data for comparison. A more comprehensive understanding of the effectiveness of support groups is indicated to enhance outcomes for caregivers and patients.


Epidemiology of hospital-treated cricket injuries sustained by women from 2002-2003 to 2013-2014 in Victoria, Australia.
To present the first comprehensive epidemiological profile of hospital-treated injuries sustained by female cricketers from 2002-2003 to 2013-2014 in Victoria, Australia. Analysis of routinely collected hospital data (detailed case-series). A retrospective analysis of hospital-treatment data associated with cricket injuries sustained by women between 1 July 2002 and 30 June 2014, inclusive were extracted from databases held by the Victorian Injury Surveillance Unit in Australia. Over the 12-year period, 668 cases were treated in Victoria. Of these, 547 were emergency department (ED)-presentations. There were 121 hospital-admissions, of which, the length of stay was <2 days for 78.5% cases. All cases were treated and released, and no fatalities were reported. The 10-14 year age group most frequently presented to ED (19.9%) and were most commonly admitted to hospital (16.5% of the total admissions). Fractures were the most common cause of hospital-admissions (47.1%) but only accounted for 17.2% of the ED-presentations. Dislocations, sprains and strains, were the most common (36.4%) cause of ED-presentations. The head was the most commonly injured anatomical location (27.8% of ED-presentations and 28.1% of hospital-admissions), followed by the wrist and hand (27.8% ED-presentations and 17.4% hospital-admissions). These findings provide the first overview of the nature of injuries requiring hospital attendance in female cricketers, and a foundation to inform the development of targeted injury prevention programs for female cricketers.


Sorting out the trash: the spatial nature of eukaryotic protein quality control.
Failure to maintain protein homeostasis is associated with aggregation and cell death, and underies a growing list of pathologies including neurodegenerative diseases, aging, and cancer. Misfolded proteins can be toxic and interfere with normal cellular functions, particularly during proteotoxic stress. Accordingly, molecular chaperones, the ubiquitin-proteasome system (UPS) and autophagy together promote refolding or clearance of misfolded proteins. Here we discuss emerging evidence that the pathways of protein quality control (PQC) are intimately linked to cell architecture, and sequester proteins into spatially and functionally distinct PQC compartments. This sequestration serves a number of functions, including enhancing the efficiency of quality control; clearing the cellular milieu of potentially toxic species and facilitating asymmetric inheritance of damaged proteins to promote rejuvenation of daughter cells.


A Randomized, Controlled Trial of Wholistic Hybrid Derived From Eye Movement Desensitization and Reprocessing and Emotional Freedom Technique (WHEE) for Self-Treatment of Pain, Depression, and Anxiety in Chronic Pain Patients.
In this pilot study, a convenience sample of 24 chronic pain patients (17 with chronic fatigue syndrome/fibromyalgia) were randomized into WHEE treatment and wait-list control groups for 6 weeks. Assessments of depression, anxiety, and pain were completed before, during, and at 1 and 3 months after treatment. Wait-listed patients then received an identical course of WHEE and assessments. WHEE decreased anxiety ( P < .5) and depression ( P < .05) compared with the control group. The wait-list-turned-WHEE assessments demonstrated decreased pain severity ( P < .05) and depression ( P < .04) but not pain interference or anxiety. WHEE appears a promising method for pain, anxiety, and depression in patients with chronic pain, compared to standard medical care alone. Though a small pilot study, the present results suggest that further research appears warranted. An incidental finding was that a majority of patients with chronic pain had suffered psychological trauma in childhood and/or adulthood.


Coughs and colds: nurse management of upper respiratory tract infection.
Nurses in general practice are increasingly managing minor illness. This literature review examines the management of upper respiratory tract infection (URTI) as one area of patient care where nurses can make a major contribution. The challenge for nurses is to respond to the changing healthcare environment creatively and in collaboration with doctors and patients.


Neonatal screening for sickle cell disease in France.
As a result of population growth in African-Caribbean regions of overseas France, and now immigration essentially from North and sub-Saharan Africa to mainland France, neonatal screening for sickle cell disease (SCD) has been performed in France since 1985 in Guadalupe and dependencies, as a universal test. After several pilot studies, screening was gradually extended to mainland France in 1996. Since 2000, the test has been performed at national level for all newborns defined as being "at risk" for SCD based on ethnic origin. A dry blood sample is obtained by heel stick and analysed by isoelectric focusing as a first-line method, followed by either high-performance liquid chromatography or acid agar electrophoresis for confirmation, whenever a variant haemoglobin is observed on isoelectric focusing. In 2007, 28.45% of all newborns in mainland France were screened for SCD. Since 1996, a total of 3,890 newborns have been found to have SCD, and they have been followed up by reference paediatricians. Although screening for SCD at birth in France is not universal, it appears that missed babies are relatively infrequent. Despite obvious sociological problems inherent to the at-risk population, the follow-up of SCD babies is rather successful. Due to the birth prevalence of SCD in France, especially in comparison with other common genetic diseases, screening all newborns regardless of ethnic origin is an issue that is being addressed.


Comparative analysis of 3D expression patterns of transcription factor genes and digit fate maps in the developing chick wing.
Hoxd13, Tbx2, Tbx3, Sall1 and Sall3 genes are candidates for encoding antero-posterior positional values in the developing chick wing and specifying digit identity. In order to build up a detailed profile of gene expression patterns in cell lineages that give rise to each of the digits over time, we compared 3 dimensional (3D) expression patterns of these genes during wing development and related them to digit fate maps. 3D gene expression data at stages 21, 24 and 27 spanning early bud to digital plate formation, captured from in situ hybridisation whole mounts using Optical Projection Tomography (OPT) were mapped to reference wing bud models. Grafts of wing bud tissue from GFP chicken embryos were used to fate map regions of the wing bud giving rise to each digit; 3D images of the grafts were captured using OPT and mapped on to the same models. Computational analysis of the combined computerised data revealed that Tbx2 and Tbx3 are expressed in digit 3 and 4 progenitors at all stages, consistent with encoding stable antero-posterior positional values established in the early bud; Hoxd13 and Sall1 expression is more dynamic, being associated with posterior digit 3 and 4 progenitors in the early bud but later becoming associated with anterior digit 2 progenitors in the digital plate. Sox9 expression in digit condensations lies within domains of digit progenitors defined by fate mapping; digit 3 condensations express Hoxd13 and Sall1, digit 4 condensations Hoxd13, Tbx3 and to a lesser extent Tbx2. Sall3 is only transiently expressed in digit 3 progenitors at stage 24 together with Sall1 and Hoxd13; then becomes excluded from the digital plate. These dynamic patterns of expression suggest that these genes may play different roles in digit identity either together or in combination at different stages including the digit condensation stage.


Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function.
Haematopoietic stem cells (HSCs) regenerate blood cells throughout the lifespan of an organism. With age, the functional quality of HSCs declines, partly owing to the accumulation of damaged DNA. However, the factors that damage DNA and the protective mechanisms that operate in these cells are poorly understood. We have recently shown that the Fanconi anaemia DNA-repair pathway counteracts the genotoxic effects of reactive aldehydes. Mice with combined inactivation of aldehyde catabolism (through Aldh2 knockout) and the Fanconi anaemia DNA-repair pathway (Fancd2 knockout) display developmental defects, a predisposition to leukaemia, and are susceptible to the toxic effects of ethanol-an exogenous source of acetaldehyde. Here we report that aged Aldh2(-/-) Fancd2(-/-) mutant mice that do not develop leukaemia spontaneously develop aplastic anaemia, with the concomitant accumulation of damaged DNA within the haematopoietic stem and progenitor cell (HSPC) pool. Unexpectedly, we find that only HSPCs, and not more mature blood precursors, require Aldh2 for protection against acetaldehyde toxicity. Additionally, the aldehyde-oxidizing activity of HSPCs, as measured by Aldefluor stain, is due to Aldh2 and correlates with this protection. Finally, there is more than a 600-fold reduction in the HSC pool of mice deficient in both Fanconi anaemia pathway-mediated DNA repair and acetaldehyde detoxification. Therefore, the emergence of bone marrow failure in Fanconi anaemia is probably due to aldehyde-mediated genotoxicity restricted to the HSPC pool. These findings identify a new link between endogenous reactive metabolites and DNA damage in HSCs, and define the protective mechanisms that counteract this threat.


Alzheimer's disease brain: alterations in RNA levels and in a ribonuclease-inhibitor complex.
A macromolecular alteration occurs at the posttranscriptional level in the Alzheimer's disease (AD) brain. Compared with age-matched controls, total cellular RNA and polyadenylated RNA were substantially reduced in the AD cortex with many neuritic plaques and neurofibrillary tangles. RNA changes are associated with a significant increase in alkaline ribonuclease activity due to an abnormality in the ribonuclease-inhibitor complex. The decrease in protein synthesis in the AD brain, previously observed in patients severely affected with AD, and in translation systems in vitro with AD cortical messenger RNA, may be partly related to an enzyme-inhibitor alteration that affects RNA levels and activity. Decreased protein synthesis therefore may contribute to the characteristic decline in certain neurotransmitter enzymes and to the loss of neurons in the AD brain.


Reactivation of inactivated endogenous proteolytic activities in phosphoric acid-etched dentine by etch-and-rinse adhesives.
Auto-degradation of collagen matrices occurs in resin-infiltrated dentine by the slow action of host-derived matrix metalloproteinases. As phosphoric acid-etching inactivates these endogenous enzymes, it is puzzling how hybrid layers created by simplified etch-and-rinse adhesives can degrade in vivo. This study tested the null hypothesis that there are no differences in the relative proteolytic activities of mineralised dentine, acid-etched dentine, and etch-and-rinse adhesive-treated acid-etched dentine. Powdered dentine prepared from extracted human teeth was treated with 17% EDTA, 10% phosphoric acid, or with five simplified etch-and-rinse adhesives that were applied to 10% phosphoric acid-etched dentine. The gelatinolytic activity of the dentine powder was assayed using fluorescein-labelled gelatine. TEM examination of the air-dried, treated dentine powder was performed to confirm the presence of remnant mineralised dentine after acid-etching. 17% EDTA significantly reduced the relative proteolytic activity (73.2%) of the untreated mineralised dentine powder (control), while 10% phosphoric acid-etched dentine exhibited the highest reduction (98.1%). Treating the acid-etched dentine powder with any of the five simplified etch-and-rinse adhesives resulted in the reactivation of the proteolytic activity, with a significant negative linear correlation (P<0.05) between the increases in fluorescence and the corresponding pH values of the adhesives. It is concluded that simplified etch-and-rinse adhesives can reactivate endogenous enzymatic activities in dentine that are previously inactivated by phosphoric acid-etching. The amount of enzyme reactivated may even exceed the original quantity present in untreated mineralised dentine. This provides an explanation for the degradation of hybrid layers after acid-etched dentine matrices are infiltrated with these adhesives.


Active commuting to school: how far is too far?
Walking and cycling to school provide a convenient opportunity to incorporate physical activity into an adolescent's daily routine. School proximity to residential homes has been identified as an important determinant of active commuting among children. The purpose of this study is to identify if distance is a barrier to active commuting among adolescents, and if there is a criterion distance above which adolescents choose not to walk or cycle. Data was collected in 2003-05 from a cross-sectional cohort of 15-17 yr old adolescents in 61 post primary schools in Ireland. Participants self-reported distance, mode of transport to school and barriers to active commuting. Trained researchers took physical measurements of height and weight. The relation between mode of transport, gender and population density was examined. Distance was entered into a bivariate logistic regression model to predict mode choice, controlling for gender, population density socio-economic status and school clusters. Of the 4013 adolescents who participated (48.1% female, mean age 16.02 +/- 0.661), one third walked or cycled to school. A higher proportion of males than females commuted actively (41.0 vs. 33.8%, chi2 (1) = 22.21, p < 0.001, r = -0.074). Adolescents living in more densely populated areas had greater odds of active commuting than those in the most sparsely populated areas (chi2 (df = 3) = 839.64, p < 0.001). In each density category, active commuters travelled shorter distances to school. After controlling for gender and population density, a 1-mile increase in distance decreased the odds of active commuting by 71% (chi2 (df = 1) = 2591.86, p < 0.001). The majority of walkers lived within 1.5 miles and cyclists within 2.5 miles. Over 90% of adolescents who perceived distance as a barrier to active commuting lived further than 2.5 miles from school. Distance is an important perceived barrier to active commuting and a predictor of mode choice among adolescents. Distances within 2.5 miles are achievable for adolescent walkers and cyclists. Alternative strategies for increasing physical activity are required for individuals living outside of this criterion.


The utility of Stroop task switching as a marker for early-stage Alzheimer's disease.
Past studies have suggested attentional control tasks such as the Stroop task and the task-switching paradigm may be sensitive for the early detection of dementia of the Alzheimer's type (DAT). The authors of the current study combined these tasks to create a Stroop switching task. Performance was compared across young adults, older adults, and individuals diagnosed with very mild dementia. Results indicated that this task strongly discriminated individuals with healthy aging from those with early-stage DAT. In a logistic regression analysis, incongruent error rates from the Stroop switching task discriminated healthy aging from DAT better than any of the other 18 cognitive tasks given in a psychometric battery.


Low-threshold optical bistabilities in ultrathin nonlinear metamaterials.
Optical bistability typically occurs only when the optical thickness in the device or the input light power is unfavorably large. Here we show that, for a class of plasmonic metamaterials consisting of ultrathin holey metallic plates filled with nonlinear materials, the optical bistability can occur with an ultralow excitation power. We present a realistic design working at 0.2 THz and perform full-wave simulations to quantitatively study its optical bistability properties. An analytical model is developed to explain the inherent physics and provides a general design guideline for future development.


Limited proteolysis of creatine kinase. Implications for three-dimensional structure and for conformational substrates.
Proteinase K, subtilisin, pronase E, elastase, bactotrypsin, and thermolysin are all shown here to cleave native mitochondrial creatine kinase from chicken heart (Mib-CK) very specifically at a single site, either before or after Ala-323. In analogy with hen egg ovalbumin, where the same proteases all cleaved the polypeptide chain very specifically around Ala-352, Ala-323 of Mib-CK may be located in an exposed surface loop that is sensitive to protease attack. Gel permeation chromatography demonstrated that the two proteolytic fragments of Mib-CK with M(r)'s of approximately 37,000 and approximately 6000 remain associated with each other. Proteinase K cleavage did not influence the octamer to dimer ratio of Mib-CK, indicating that selective cleavage after Ala-323 has no direct effect on dimer-dimer interfaces within the octamer. However, upon addition of MgADP plus creatine and nitrate to induce a transition-state analogue complex of the enzyme, native Mib-CK dissociated much more readily into dimers than proteinase K-digested Mib-CK. Furthermore, proteinase K cleavage of Mib-CK resulted in 2-11-fold decreases in the Vmax values, as well as in 6-23-fold increases in the Km values for phosphocreatine, creatine, and MgATP, whereas the Kd values for both MgATP and creatine were unaffected. Consequently, proteinase K cleavage of Mib-CK does not affect substrate binding per se, but interferes with substrate-induced conformational changes which are essential for catalysis and which mediate the synergism in substrate binding as it is observed with the unmodified enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)


Prenatal screening of sialic acid storage disease and confirmation in cultured fibroblasts by LC-MS/MS.
Sialic acid storage disease (SASD) is an inborn error resulting from defects in the lysosomal membrane protein sialin. The SASD phenotypical spectrum ranges from a severe presentation, infantile sialic acid storage disease (ISSD) which may present as hydrops fetalis, to a relatively mild form, Salla disease. Screening for SASD is performed by determination of free sialic acid (FSA) in urine or amniotic fluid supernatant (AFS). Subsequent diagnosis of SASD is performed by quantification of FSA in cultured fibroblasts and by mutation analysis of the sialin gene, SLC17A5. We describe simple quantitative procedures to determine FSA as well as conjugated sialic acid in AFS, and FSA in cultured fibroblasts, using isotope dilution ((13)C(3)-sialic acid) and multiple reaction monitoring LC-ESI-MS/MS. The whole procedure can be performed in 2-4 h. Reference values in AFS were 0-8.2 μmol/L for 15-25 weeks of gestation and 3.2-12.0 μmol/L for 26-38 weeks of gestation. In AFS samples from five fetuses affected with ISSD FSA was 23.9-58.9 μmol/L demonstrating that this method is able to discriminate ISSD pregnancies from normal ones. The method was also validated for determination of FSA in fibroblast homogenates. FSA in SASD fibroblasts (ISSD; 20-154 nmol/mg protein, intermediate SASD; 12.9-15.1 nmol/mg, Salla disease; 5.9-7.4 nmol/mg) was clearly elevated compared to normal controls (0.3-2.2 nmol/mg). In conclusion, we report simple quantitative procedures to determine FSA in AFS and cultured fibroblasts improving both prenatal diagnostic efficacy for ISSD as well as confirmatory testing in cultured fibroblasts following initial screening in urine or AFS.


A phenomenological model of visually evoked spike trains in cat geniculate nonlagged X-cells.
The visual information that first-order cortical cells receive is contained in the visually evoked spike trains of geniculate relay cells. To address functional issues such as the ON/OFF structure of visual cortical receptive fields with modelling studies, a geniculate cell model is needed where the spatial and temporal characteristics of the visual response are described quantitatively. We propose a model simulating the spike trains produced by cat geniculate nonlagged X-cells, based on a review of the electrophysiological literature. The level of description chosen is phenomenological, fitting the dynamics and amplitude of phasic and tonic responses, center/surround antagonism, surround excitatory responses, and the statistical properties of both spontaneous and visually evoked spike trains. The model, which has been constrained so as to reproduce the responses to centered light spots of expanding size and optimal light and dark annuli, predicts responses to thin and large bars flashed in various positions of the receptive field. The switching gamma renewal process method has been introduced for modelling spontaneous and visually evoked spike trains within the same mathematical framework. The statistical structure of the spike process is assumed to be more regular during phasic than tonic visual responses. On the whole, this model generates more realistic geniculate input to cortex than the currently used retinal models.


Amphoteric water as acid and base for protic ionic liquids and their electrochemical activity when used as fuel cell electrolytes.
Amphoteric water was mixed with equimolar amounts of a super-strong acid, trifluoromethanesulfonic acid (TfOH), and a super-strong base, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU). Bulk physicochemical and electrochemical properties of the mixtures were compared with those of the best ever reported protic ionic liquid (PIL), diethylmethylammonium trifluoromethanesulfonate ([dema][TfO]), which has excellent physicochemical properties as a fuel cell electrolyte. The acidic mixture ([H3O][TfO]) behaved as a protic ionic liquid, while the basic mixture ([DBU]OH) showed incomplete proton transfer. The Walden plot indicated that [H3O][TfO] behaves as a good PIL, similar to [dema][TfO], whereas [DBU]OH behaves as a poor PIL. [H3O][TfO] showed excellent H2/O2 fuel cell performance at 80 °C; however, the performance deteriorated as the bulk water content increased, because of the retardation of the electrode kinetics due to the oxidation of Pt in the presence of bulk water. On the other hand, [DBU]OH exhibited very poor performance possibly because of the existence of neutral species in the system.


Paragangliomas: update on differential diagnostic considerations, composite tumors, and recent genetic developments.
Recent developments in molecular genetics have expanded the spectrum of disorders associated with pheochromocytomas (PCCs) and extra-adrenal paragangliomas (PGLs) and have increased the roles of pathologists in helping to guide patient care. At least 30% of these tumors are now known to be hereditary, and germline mutations of at least 10 genes are known to cause the tumors to develop. Genotype-phenotype correlations have been identified, including differences in tumor distribution, catecholamine production, and risk of metastasis, and types of tumors not previously associated with PCC/PGL are now considered in the spectrum of hereditary disease. Important new findings are that mutations of succinate dehydrogenase genes SDHA, SDHB, SDHC, SDHD, and SDHAF2 (collectively "SDHx") are responsible for a large percentage of hereditary PCC/PGL and that SDHB mutations are strongly correlated with extra-adrenal tumor location, metastasis, and poor prognosis. Further, gastrointestinal stromal tumors and renal tumors are now associated with SDHx mutations. A PCC or PGL caused by any of the hereditary susceptibility genes can present as a solitary, apparently sporadic, tumor, and substantial numbers of patients presenting with apparently sporadic tumors harbor occult germline mutations of susceptibility genes. Current roles of pathologists are differential diagnosis of primary tumors and metastases, identification of clues to occult hereditary disease, and triaging of patients for optimal genetic testing by immunohistochemical staining of tumor tissue for the loss of SDHB and SDHA protein. Diagnostic pitfalls are posed by morphological variants of PCC/PGL, unusual anatomic sites of occurrence, and coexisting neuroendocrine tumors of other types in some hereditary syndromes. These pitfalls can be avoided by judicious use of appropriate immunohistochemical stains. Aside from loss of staining for SDHB, criteria for predicting risk of metastasis are still controversial, and "malignancy" is diagnosed only after metastases have occurred. All PCCs/PGLs are considered to pose some risk of metastasis, and long-term follow-up is advised.


A behavioral database for masked form priming.
Reading involves a process of matching an orthographic input with stored representations in lexical memory. The masked priming paradigm has become a standard tool for investigating this process. Use of existing results from this paradigm can be limited by the precision of the data and the need for cross-experiment comparisons that lack normal experimental controls. Here, we present a single, large, high-precision, multicondition experiment to address these problems. Over 1,000 participants from 14 sites responded to 840 trials involving 28 different types of orthographically related primes (e.g., castfe-CASTLE) in a lexical decision task, as well as completing measures of spelling and vocabulary. The data were indeed highly sensitive to differences between conditions: After correction for multiple comparisons, prime type condition differences of 2.90 ms and above reached significance at the 5% level. This article presents the method of data collection and preliminary findings from these data, which included replications of the most widely agreed-upon differences between prime types, further evidence for systematic individual differences in susceptibility to priming, and new evidence regarding lexical properties associated with a target word's susceptibility to priming. These analyses will form a basis for the use of these data in quantitative model fitting and evaluation and for future exploration of these data that will inform and motivate new experiments.


A marine dinoflagellate, Amphidinium eilatiensis n. sp., from the benthos of a mariculture sedimentation pond in Eilat, Israel.
A species of Amphidinium bloomed in a mariculture sedimentation pond that was used to grow bivalves near the Gulf of Eilat, Israel. Its overall length averaged 13 microm, the hypocone was 11 microm, and its width was 8 microm. It has a ventral ridge. The sulcus begins at the longitudinal flagellar pore and does not project forward in the apex toward the transverse flagellar pore and left margin of the cingulum. The sulcus is a very shallow groove that projects variably about a third of the body length toward the antapex. The cingulum is a deep groove as it circles the cell from the left ventral side to the dorsal side and then becomes very shallow on the right ventral side as it arches posterior toward the longitudinal flagellar pore. Using a modified method for studying dinoflagellate chromosomes in the SEM, we observed 31 chromosomes. The plastid is dorsal and peripheral with 6 ventrally projecting peripheral digital lobes that wrap around the sides of the ventral and posterior nucleus. Amphidinium eilatiensis n. sp. is morphologically closest to Amphidinium carterae and Amphidinium rhynchocephalum, but it does not have the obvious thecal plates or polygonal units described for the former species. Instead, it has a series of spicules, bumps, and ridges on its surface. It differs from A. rhynchocephalum by two morphological characters: surface morphology and gross plastid architecture. The amplified fragments of the rDNA from A. eilatiensis n. sp. isolated from 2 separate sedimentation ponds in Eilat include the 3'- end of the SSU rDNA (about 100 nt), the whole ITS region (ITS1 + 5.8S + ITS2) and the 5'-end of the LSU rDNA (about 900 nts). The total length of the sequences ranged from 1,460 nt. (A. eilatiensis isolate #1) to 1,461 nts. (A. eilatiensis isolate #2). The latter sequences are identical, the difference in length being due to three insertions. Amphidinium eilatiensis is genetically more closely related to A. carterae than to A. klebsii, with respectively 2.36% and 6.93% of sequence divergence.


Reaction of cresyl saligenin phosphate, the organophosphorus agent implicated in aerotoxic syndrome, with human cholinesterases: mechanistic studies employing kinetics, mass spectrometry, and X-ray structure analysis.
Aerotoxic syndrome is assumed to be caused by exposure to tricresyl phosphate (TCP), an antiwear additive in jet engine lubricants and hydraulic fluid. CBDP (2-(ortho-cresyl)-4H-1,2,3-benzodioxaphosphoran-2-one) is the toxic metabolite of triortho-cresylphosphate, a component of TCP. Human butyrylcholinesterase (BChE; EC 18.104.22.168) and human acetylcholinesterase (AChE; EC 184.108.40.206) are irreversibly inhibited by CBDP. The bimolecular rate constants of inhibition (k(i)), determined under pseudo-first-order conditions, displayed a biphasic time course of inhibition with k(i) of 1.6 × 10(8) M(-1) min(-1) and 2.7 × 10(7) M(-1) min(-1) for E and E' forms of BChE. The inhibition constants for AChE were 1 to 2 orders of magnitude slower than those for BChE. CBDP-phosphorylated cholinesterases are nonreactivatable due to ultra fast aging. Mass spectrometry analysis showed an initial BChE adduct with an added mass of 170 Da from cresylphosphate, followed by dealkylation to a structure with an added mass of 80 Da. Mass spectrometry in (18)O-water showed that (18)O was incorporated only during the final aging step to form phospho-serine as the final aged BChE adduct. The crystal structure of CBDP-inhibited BChE confirmed that the phosphate adduct is the ultimate aging product. CBDP is the first organophosphorus agent that leads to a fully dealkylated phospho-serine BChE adduct.


Study on the Influence of Chirality in the Threading of Calix[6]arene Hosts with Dialkylammonium Axles.
: The influence of chirality in calixarene threading has been studied by exploiting the "superweak anion approach". In particular, the formation of chiral pseudo[2]rotaxanes bearing a classical stereogenic center in their axle and/or wheel components has been considered. Two kind of pseudo[2]rotaxane stereoadducts, the "endo-chiral" and "exo-chiral" ones, having the stereogenic center of a cationic axle inside or outside, respectively, the calix-cavity of a chiral calixarene were preferentially formed with specifically designed chiral axles by a fine exploitation of the so-called "endo-alkyl rule" and a newly defined "endo-α-methyl-benzyl rule" (threading of a hexaalkoxycalix[6]arene with a directional (α-methyl-benzyl)benzylammonium axle occurs with an endo-α-methyl-benzyl preference). The obtained pseudorotaxanes were studied in solution by 1D and 2D NMR, and in the gas-phase by means of the enantiomer-labeled (EL) mass spectrometry method, by combining enantiopure hosts with pseudoracemates of one deuterated and one unlabeled chiral axle enantiomer. In both instances, there was not a clear enantiodiscrimination in the threading process with the studied host/guest systems. Possible rationales are given to explain the scarce reciprocal influence between the guest and host chiral centers.


Imaging drug uptake by bioorthogonal stimulated Raman scattering microscopy.
Stimulated Raman scattering (SRS) microscopy in tandem with bioorthogonal Raman labelling strategies is set to revolutionise the direct visualisation of intracellular drug uptake. Rational evaluation of a series of Raman-active labels has allowed the identification of highly active labels which have minimal perturbation on the biological efficacy of the parent drug. Drug uptake has been correlated with markers of cellular composition and cell cycle status, and mapped across intracellular structures using dual-colour and multi-modal imaging. The minimal phototoxicity and low photobleaching associated with SRS microscopy has enabled real-time imaging in live cells. These studies demonstrate the potential for SRS microscopy in the drug development process.


Safety and efficacy of sucrose-formulated full-length recombinant factor VIII: experience in the standard clinical setting.
The safety of full-length sucrose-formulated recombinant factor VIII (rFVIII-FS; Kogenate FS) for up to 24 months of use was evaluated in a postmarketing observational study in Europe. Long-term safety and efficacy data were available for 212 patients with severe haemophilia A, including 13 previously untreated patients (PUPs) and 12 patients with 1-19 exposure days (EDs). Patients accumulated a mean (+/- SD) of 187 (121) EDs to rFVIII-FS and received a total of 39,627 infusions, mainly for prophylaxis and for the treatment of 4,283 spontaneous or trauma-related bleeds during an average observation time of 710 (136) days. Of these bleeding episodes, 85.4% were successfully treated with one or two infusions of rFVIII-FS. Haemostasis was also evaluated during 46 minor to major surgical procedures, and the response to infusion was "excellent" or "good" in all cases. FVIII inhibitor formation was observed in six patients (two de novo; four persistent or recurrent). The de novo cases represent 8.0% (2 of 25) of patients who reported 0-19 previous EDs at study entry. Four of the five patients who reported possible drug-related adverse effects developed inhibitors. The results of this observational study demonstrate the efficacy and safety of rFVIII-FS during normal clinical use in the treatment of patients with severe haemophilia A. Furthermore, these findings are consistent with those of previous phase III clinical studies with rFVIII-FS, particularly with regard to its efficacy and low incidence of inhibitor formation.


Fish embryo vulnerability to combined acidification and warming coincides with a low capacity for homeostatic regulation.
The vulnerability of fish embryos and larvae to environmental factors is often attributed to a lack of adult-like organ systems (gills) and thus insufficient homeostatic capacity. However, experimental data supporting this hypothesis are scarce. Here, by using Atlantic cod (Gadus morhua) as a model, the relationship between embryo vulnerability (to projected ocean acidification and warming) and homeostatic capacity was explored through parallel analyses of stage-specific mortality and in vitro activity and expression of major ion pumps (ATP-synthase, Na+/K+-ATPase, H+-ATPase) and co-transporters (NBC1, NKCC1). Immunolocalization of these transporters was used to study ionocyte morphology in newly hatched larvae. Treatment-related embryo mortality until hatching (+20% due to acidification and warming) occurred primarily during an early period (gastrulation) characterized by extremely low ion transport capacity. Thereafter, embryo mortality decreased in parallel with an exponential increase in activity and expression of all investigated ion transporters. Significant changes in transporter activity and expression in response to acidification (+15% activity) and warming (-30% expression) indicate some potential for short-term acclimatization, although this is probably associated with energetic trade-offs. Interestingly, whole-larvae enzyme activity (supported by abundant epidermal ionocytes) reached levels similar to those previously measured in gill tissue of adult cod, suggesting that early-life stages without functional gills are better equipped in terms of ion homeostasis than previously thought. This study implies that the gastrulation period represents a critical transition from inherited (maternal) defenses to active homeostatic regulation, which facilitates enhanced resilience of later stages to environmental factors.


[Twenty five years of residency training in the Netherlands].
Over the last 25 years in the Netherlands the residency training programme for psychiatry has been concerned primarily with teaching students to use practice guidelines, providing science education, promoting internationalisation and satisfying society's requirement for transparency. This has led to the transformation of the classical training programme with its paternalistic 'master-apprentice' relationship to a programme in which the required professional competencies are taught and assessed by supervisors who in the future will need to be explicitly qualified in particular areas. The dramatic increase in the number of women wanting to become psychiatrists has made it clear that the classical training programme puts a heavy burden on students who are struggling to combine private life with a heavy work-load and enthusiasm for their chosen subject. The compulsory personal therapy in the curriculum may be helpful in solving this problem.


The Natural History Museum Data Portal.
The Natural History Museum, London (NHM), generates and holds some of the largest global data sets relating to the biological and geological diversity of the natural world. A majority of these data were, until 2015, not widely accessible, and, even when published, were typically hard to find, poorly documented and in formats that impede discovery and integration. To better serve the bespoke needs of user communities outside and within the NHM, a dedicated data portal was developed to surface these data sets and provide a sustainable platform to encourage their citation and reuse. This paper describes the technical development of the data portal, from its inception to beta launch in December 2015, its first 2 years of operation, and future plans for the project. It outlines the development principles adopted for this prototypical project, which subsequently informed new digital project management methodologies at the NHM. The process of developing the data portal acted as a driver to implement policies necessary to encourage a culture of data sharing at the NHM.


Use of Arc expression as a molecular marker of increased postsynaptic 5-HT function after SSRI/5-HT1A receptor antagonist co-administration.
An increase in central postsynaptic 5-hydroxytryptamine (5-HT) function activates expression of activity-related cytoskeletal protein (Arc). Here, Arc expression was used to test whether, in rats, co-administration of a 5-HT re-uptake inhibitor (paroxetine) and a 5-HT1A receptor antagonist (WAY 100635) increases postsynaptic 5-HT function. After pre-treatment with WAY 100635 (0.3 mg/kg s.c.), paroxetine (5 mg/kg s.c.) caused a threefold increase in 5-HT in prefrontal cortex microdialysates. In situ hybridization studies found that neither paroxetine (5 mg/kg s.c.) nor WAY 1000635 (0.3 mg/kg s.c.) altered Arc mRNA abundance in any region examined. In contrast, paroxetine (5 mg/kg s.c.) increased Arc mRNA after pre-treatment with WAY 100635 (0.3 mg/kg s.c.). This increase was apparent in cortical regions (frontal, parietal and cingulate) and caudate nucleus but was absent in hippocampus (CA1). Increases in Arc mRNA were accompanied by an increase in c-fos mRNA. The increase in Arc expression induced by paroxetine/WAY 100635 was abolished by the 5-HT synthesis inhibitor, p-chlorophenylalanine (300 mg/kg i.p., daily for two days). In conclusion, paroxetine and WAY 100635 injected in combination (but not alone) caused a region-specific, 5-HT-mediated increase in Arc expression. These data provide molecular evidence that co-administration of a 5-HT re-uptake inhibitor and 5-HT1A receptor antagonist increases 5-HT function at the postsynaptic level.


Aberration compensation for optical trapping of cells within living mice.
Optical tweezers have been used to trap and manipulate microparticles within living animals. When the optical trap is constructed with an oil-immersion objective, it suffers from spherical aberration. There have been many investigations on the influence of spherical aberration when the particles are trapped in a water medium. However, the dependence of optical force on trapping depth is still ambiguous when the trapped particles are immersed in a high refractive index medium (such as biological tissue, refractive index solution) in experiments. In this paper, the microparticles are immersed in an aqueous solution of glycerol to mimic the cells within biological tissue. As the trapping laser is focused into the specimen, spherical aberration is introduced, degrading the optical trapping performance. It is similar to trapping in water; altering the effective tube length can also compensate for the spherical aberration of the optical trap in a high refractive index medium. Finally, the cells in living mice are trapped by the optical tweezers with the help of spherical aberration compensation.


Anthropometric, socioeconomic, and maternal health determinants of placental transfer of organochlorine compounds.
The aim of this study was to relate placental transfer, quantified by the cord to maternal serum concentration ratio (C/M), of five organochlorine pesticides (OCP) hexachlorobenzene (HCB), β-hexachlorocyclohexane (β-HCH), γ-hexachlorocyclohexane (γ-HCH) , p,p'-DDT, p,p'-DDE and 15 polychlorinated biphenyl (PCB) congeners (28, 52, 101, 105, 114, 118, 123(+149), 138(+163), 153, 156(+171), 157, 167, 170, 180, and 189) to anthropometric, socioeconomic, and maternal health characteristics. We included into the study 1,134 births during the period 2002-2004 from two districts in eastern Slovakia with high organochlorine concentrations relative to other areas of the world. Only concentrations >LOD were taken into account. Variables as age, weight and height of mothers, parity, ethnicity, alcohol consumption, illness during pregnancy, smoking during pregnancy, hypertension, respiratory diseases, rheumatoid arthritis and diabetes mellitus, and birth weight were related to C/M. Results of regression analyses showed that C/M was predicted by several factors studied. Positive associations were observed for gestational alcohol consumption, fewer illnesses during pregnancy, maternal age, and maternal weight. Caucasians had a greater C/M compared to Romani for wet weight data of congeners 170 and 180 and in contrast C/M for HCB was greater in Romani. Our results show that drinking mothers compared to abstaining expose their fetuses not only to alcohol but to an increased level of several PCB congeners. A straightforward explanation of associations between C/M shifts and factors studied is very difficult, however, with regard to the high lipophilicity of OCPs and PCBs, changes in their kinetics probably reflect lipid kinetics.


Artificial Intelligence-Assisted Online Social Therapy for Youth Mental Health.
Introduction: Benefits from mental health early interventions may not be sustained over time, and longer-term intervention programs may be required to maintain early clinical gains. However, due to the high intensity of face-to-face early intervention treatments, this may not be feasible. Adjunctive internet-based interventions specifically designed for youth may provide a cost-effective and engaging alternative to prevent loss of intervention benefits. However, until now online interventions have relied on human moderators to deliver therapeutic content. More sophisticated models responsive to user data are critical to inform tailored online therapy. Thus, integration of user experience with a sophisticated and cutting-edge technology to deliver content is necessary to redefine online interventions in youth mental health. This paper discusses the development of the moderated online social therapy (MOST) web application, which provides an interactive social media-based platform for recovery in mental health. We provide an overview of the system's main features and discus our current work regarding the incorporation of advanced computational and artificial intelligence methods to enhance user engagement and improve the discovery and delivery of therapy content. Methods: Our case study is the ongoing Horyzons site (5-year randomized controlled trial for youth recovering from early psychosis), which is powered by MOST. We outline the motivation underlying the project and the web application's foundational features and interface. We discuss system innovations, including the incorporation of pertinent usage patterns as well as identifying certain limitations of the system. This leads to our current motivations and focus on using computational and artificial intelligence methods to enhance user engagement, and to further improve the system with novel mechanisms for the delivery of therapy content to users. In particular, we cover our usage of natural language analysis and chatbot technologies as strategies to tailor interventions and scale up the system. Conclusions: To date, the innovative MOST system has demonstrated viability in a series of clinical research trials. Given the data-driven opportunities afforded by the software system, observed usage patterns, and the aim to deploy it on a greater scale, an important next step in its evolution is the incorporation of advanced and automated content delivery mechanisms.


Integrated dual-modality microfluidic sensor for biomarker detection using lithographic plasmonic crystal.
This paper reports an integrated dual-modality microfluidic sensor chip, consisting of a patterned periodic array of nanoposts coated with gold (Au) and graphene oxide (GO), to detect target biomarker molecules in a limited sample volume. The device generates both electrochemical and surface plasmon resonance (SPR) signals from a single sensing area of Au-GO nanoposts. The Au-GO nanoposts are functionalized with specific receptor molecules, serving as a spatially well-defined nanostructured working electrode for electrochemical sensing, as well as a nanostructured plasmonic crystal for SPR-based sensing via the excitation of surface plasmon polaritons. High sensitivity of the electrochemical measurement originates from the presence of the nanoposts on the surface of the working electrode where radial diffusion of redox species occurs. Complementarily, the SPR detection allows convenient tracking of dynamic antigen-antibody interactions, to describe the association and dissociation phases occurring at the sensor surface. The soft-lithographically formed nanoposts provide high reproducibility of the sensor response to epidermal growth factor receptor (ErbB2) molecules even at a femtomolar level. Sensitivities of the electrochemical measurements to ErbB2 are found to be 20.47 μA μM-1 cm-2 in a range from 1 fM to 0.1 μM, and those of the SPR measurements to be 1.35 nm μM-1 in a range from 10 pM to 1 nM, and 0.80 nm μM-1 in a range from 1 nM to 0.1 μM. The integrated dual-modality sensor offers higher sensitivity (through higher surface area and diffusions from nanoposts for electrochemical measurements), as well as the dynamic measurements of antigen-antibody bindings (through the SPR measurement), while operating simultaneously in a same sensing area using the same sample volume.


Comparison of stapling and hand-suture for left-sided large bowel anastomosis.
One hundred patients undergoing elective left-sided colonic or rectal resections were randomly allocated to have an anastomosis performed either with the EEA stapling gun or by hand suture using a single layer of interrupted sutures. In six patients the anastomosis could not be performed with the stapling gun. Clinical leakage occurred in two of the remaining 94 cases; both had hand-sutured anastomoses. Radiological leakage was demonstrated in 13 further cases (7 stapled, 6 sutured); there was no statistical difference in leakage rate with stapled and hand-sutured anastomoses.


Measuring air quality to protect children from secondhand smoke in cars.
Secondhand tobacco smoke (SHS) is a major, preventable contributor to acute and chronic adverse health outcomes that affect children disproportionately. The predominant source of SHS among children is domestic exposure, and while up to two thirds of U.S. households have car smoking bans, an unacceptable number of children remain vulnerable. To help promote more effective protection through legislation, health communication strategies, or behavioral interventions, data demonstrating the adverse effect of SHS on air quality in cars are needed. Secondhand tobacco smoke in a motor vehicle under actual driving conditions was monitored by measuring respirable suspended particles (RSPs) of less than 2.5 microns in diameter, and carbon monoxide. Forty-five driving trials were conducted, using teams of volunteer drivers and smokers recruited from the general community. Three smoking conditions (nonsmoking baseline, active smoking, and immediate post-smoking period, each 5 minutes) were crossed with two ventilation conditions (windows open, closed) in a 3 x 2 within-sessions factorial design. The highest mean observed RSP level was 271 mug/m(3), which is unsafe, particularly for children. Peak RSP levels were considerably higher. RSPs and carbon monoxide increased significantly from baseline after smoking, and these increases were greatest during the closed ventilation condition, compared with open ventilation. Private passenger cars are a domestic environment with the potential to yield unsafe levels of SHS contaminants. These data may assist policymakers and health advocates to promote protective strategies to ensure smoke-free domestic environments for children.


Validity of a food frequency questionnaire to assess nutritional intake among Sri Lankan adults.
Sri Lanka is undergoing nutritional transition and diet-related chronic diseases are emerging as an important health problem. Currently, no validated food frequency questionnaire (FFQ) exists to measure habitual dietary intake of Sri Lankan adults. The purpose of the study is to assess the validity of a semi-quantitative FFQ and 7-day weighed-intake dietary records (7DWR), designed to assess dietary intake among Sri Lankan adults. Dietary intake was measured using both a FFQ and 7DWR. The FFQ consisted of 8 food groups containing the main foods comprising the diet of Sri Lankan adults, a total of 85 items and 12 color photographs to identify serving size. One hundred healthy adults were randomly recruited from a community sample and administrated the FFQ followed by completion of the 7DWR. Paired sample t tests, Pearson's correlation coefficients, kappa test and Bland-Altman analysis were conducted to determine correlation and the level of agreement for energy and micronutrients. Seventy-seven participants completed both the FFQ and 7DWR. Estimated mean energy intake (SD) from FFQ (1794 ± 398 kcal) and 7DWR (1698 ± 333 kcal, p < 0.001) were significantly different due to a significant overestimation of carbohydrate (11.5 g/day, p < 0.001) and to some extent fat (5.7 g/day, ns). Significant positive correlations (p < 0.05) were found between the FFQ and 7DWR for energy (r = 0.39), carbohydrate (r = 0.47), protein (r = 0.26), fat (r = 0.17) and dietary fiber (r = 0.32). Bland-Altman graphs indicated fairly good agreement between methods with no relationship between bias and average intake of each nutrient examined. Based on these findings, the FFQ appears to be an acceptable tool for assessing the nutrient intake of Sri Lankans and will assist proper categorization of individuals by dietary intake.


Impaired social cognition in multiple sclerosis.
Multiple sclerosis (MS) is an inflammatory and neurodegenerative disorder of the CNS that is frequently associated with neuropsychiatric symptoms and decreased quality of life. Social support, which has been found to buffer the psychosocial burden of MS, critically depends on intact social cognition. Here we assess social cognition in patients with MS using a naturalistic video based test and explore if potential deficits in theory of mind (ToM) occur independently of known MS associated neuropsychiatric symptoms, such as depression and cognitive impairment. 45 outpatients with clinically definite MS and 45 age, sex and education matched healthy control subjects (HCs) underwent standardised testing using the Movie for the Assessment of Social Cognition. MS patients also completed a neuropsychological battery. MS patients showed significantly impaired ToM compared with HCs. Impairments were more pronounced in identification of emotions than in identification of thoughts or intentions. Significantly lower ToM compared with HCs was detected in MS patients during the early disease stages, with limited disability and without substantial neuropsychological deficits. These results suggest impaired social cognition in MS. Importantly, ToM impairments in this group may not simply be a consequence of the well known neuropsychological deficits. Difficulties with correctly identifying emotions, thoughts and intentions in social situations may result in interpersonal problems and could contribute to the psychosocial burden of MS.


Protein Flexibility and Synergy of HMG Domains Underlie U-Turn Bending of DNA by TFAM in Solution.
Human mitochondrial transcription factor A (TFAM) distorts DNA into a U-turn, as shown by crystallographic studies. The relevance of this U-turn is associated with transcription initiation at the mitochondrial light strand promoter (LSP). However, it has not been yet discerned whether a tight U-turn or an alternative conformation, such as a V-shape, is formed in solution. Here, single-molecule FRET experiments on freely diffusing TFAM/LSP complexes containing different DNA lengths show that a DNA U-turn is induced by progressive and cooperative binding of the two TFAM HMG-box domains and the linker between them. SAXS studies further show compaction of the protein upon complex formation. Finally, molecular dynamics simulations reveal that TFAM/LSP complexes are dynamic entities, and the HMG boxes induce the U-turn against the tendency of the DNA to adopt a straighter conformation. This tension is resolved by reversible unfolding of the linker, which is a singular mechanism that allows a flexible protein to stabilize a tight bending of DNA.


Protocols for Mechanical Cleaning of the Post Space on the Bond Strength Between Root Dentin and Cementation System.
To evaluate the effects of mechanical versus chemical cleaning protocols for cleaning the root dentin surface before cementation of fiberglass posts for their effect on the bond strength, failure mode, and dentinal penetration of the cementing agent using an etch-and-rinse adhesive system on dentin prepared to receive a fiberglass post. Forty roots of bovine teeth were endodontically treated and prepared for fiber post cementation. The specimens were randomized into 4 groups of 10: Control group (CO) - irrigation with 2.5% NaOCl; DW group- irrigation with distilled water; RB group - rotating brush for cleaning root canals, and CUI group - continuous ultrasonic irrigation. The fiberglass posts were cemented, and the specimens were immersed in distilled water for 6 months. A push-out test was performed on the cervical, middle, and apical thirds of the samples. Dentinal penetration of the cementing agent and the fracture pattern were evaluated by laser confocal microscopy. Statistical analysis was performed using analysis of variance (ANOVA) and post hoc Tukey tests (α=0.05). Results: The RB and CUI groups showed significantly higher bond strength values when compared to the Control and DW groups (p<0.05). In addition, in the control and DW groups, the apical third presented lower bond strength values when compared to middle and cervical thirds. While DW showed the highest incidence of adhesive type failure, CUI resulted in the highest dentinal penetration of the cementing agent (p<0.05). RB and CUI resulted in the highest bond strength between cementation system and root dentin. In addition, CUI favored greater dentinal penetration of fiberglass post cementing agent.


Phthalate metabolites in harbor porpoises (Phocoena phocoena) from Norwegian coastal waters.
The exposure of marine mammals to phthalates has received considerable attention due to the ubiquitous occurrence of these pollutants in the marine environment and their potential adverse health effects. The occurrence of phthalate metabolites is well established in human populations, but data is scarce for marine mammals. In this study, concentrations of 17 phthalate metabolites were determined in liver samples collected from one hundred (n = 100) by-caught harbor porpoises (Phocoena phocoena) along the coast of Norway. Overall, thirteen phthalate metabolites were detected in the samples. Monoethyl phthalate (mEP), mono-iso-butyl phthalate (mIBP), mono-n-butyl phthalate (mBP) and phthalic acid (PA) were the most abundant metabolites, accounting for detection rates ≥ 85%. The highest median concentrations were found for mIBP (30.6 ng/g wet weight [w.w.]) and mBP (25.2 ng/g w.w.) followed by PA (7.75 ng/g w.w.) and mEP (5.67 ng/g w.w.). The sum of the median phthalate metabolites concentrations that were found in the majority of samples (detection rates > 50%) indicated that concentrations were lower for porpoises collected along the coastal area of Bodø (Nordland), Lebesby (Finnmark) and Varangerfjord (as compared to other coastal areas); these areas are among the least populated coastal areas but also the most distant (>700 km) from offshore active oil and gas fields. The monomethyl phthalate metabolite (mMP) was detected in 69% of the samples, and to our knowledge, alongside with PA, this is the first report of their occurrence in marine mammals. PA, as the non-specific marker of phthalate exposures, showed a statistically significant negative association with the body mass and length of the harbor porpoises. Among the phthalate metabolites, statistically significant positive associations were found between mBP and mIBP, mMP and mEP, PA and mEP, mIBP and mono(2-ethyl-5-oxohexyl) phthalate (mEOHP), mIBP and mono(2-ethyl-5-hydroxyhexyl) phthalate (mEHHP), mBP and mEHHP, mono-n-nonyl phthalate (mNP) and PA, and between monobenzyl phthalate (mBzP) and mNP. To our knowledge, this is the first study on the biomonitoring of 17 phthalate metabolites in harbor porpoises.


Self-assessed performance improves statistical fusion of image labels.
Expert manual labeling is the gold standard for image segmentation, but this process is difficult, time-consuming, and prone to inter-individual differences. While fully automated methods have successfully targeted many anatomies, automated methods have not yet been developed for numerous essential structures (e.g., the internal structure of the spinal cord as seen on magnetic resonance imaging). Collaborative labeling is a new paradigm that offers a robust alternative that may realize both the throughput of automation and the guidance of experts. Yet, distributing manual labeling expertise across individuals and sites introduces potential human factors concerns (e.g., training, software usability) and statistical considerations (e.g., fusion of information, assessment of confidence, bias) that must be further explored. During the labeling process, it is simple to ask raters to self-assess the confidence of their labels, but this is rarely done and has not been previously quantitatively studied. Herein, the authors explore the utility of self-assessment in relation to automated assessment of rater performance in the context of statistical fusion. The authors conducted a study of 66 volumes manually labeled by 75 minimally trained human raters recruited from the university undergraduate population. Raters were given 15 min of training during which they were shown examples of correct segmentation, and the online segmentation tool was demonstrated. The volumes were labeled 2D slice-wise, and the slices were unordered. A self-assessed quality metric was produced by raters for each slice by marking a confidence bar superimposed on the slice. Volumes produced by both voting and statistical fusion algorithms were compared against a set of expert segmentations of the same volumes. Labels for 8825 distinct slices were obtained. Simple majority voting resulted in statistically poorer performance than voting weighted by self-assessed performance. Statistical fusion resulted in statistically indistinguishable performance from self-assessed weighted voting. The authors developed a new theoretical basis for using self-assessed performance in the framework of statistical fusion and demonstrated that the combined sources of information (both statistical assessment and self-assessment) yielded statistically significant improvement over the methods considered separately. The authors present the first systematic characterization of self-assessed performance in manual labeling. The authors demonstrate that self-assessment and statistical fusion yield similar, but complementary, benefits for label fusion. Finally, the authors present a new theoretical basis for combining self-assessments with statistical label fusion.