Twin concordance for attention deficit hyperactivity disorder: a comparison of teachers' and mothers' reports.
The present study examined probandwise concordance rates for attention deficit hyperactivity disorder (ADHD) in a community sample of 194 monozygotic and 94 dizygotic male twins, ages 11-12 years. DSM-III and DSM-III-R diagnoses of ADHD were based on rating scale reports from the twins' teachers and structured interview reports obtained from their mothers. Model-fitting analyses were used to estimate genetic and environmental effects on ADHD. Concordance rates for ADHD were greater for monozygotic than dizygotic twins according to both mothers' and teachers' reports; this finding indicates the importance of genetic factors in the etiology of this syndrome. Fifteen percent of subjects received an ADHD diagnosis by teachers' ratings, compared with 6% by mothers' reports. Three percent of subjects met criteria for ADHD in both school and home settings. Teachers' ratings yielded moderate monozygotic and dizygotic concordance rates, in contrast to mothers' reports, which indicated a high monozygotic and a zero dizygotic concordance for ADHD. A model that included additive genetic and nonshared environmental factors provided the best fit to these ADHD data. ADHD, as defined by DSM criteria, appears to be a genetically influenced disorder whether diagnoses are based on teachers' or mothers' reports. However, the extent of this genetic influence seems to vary by informant source. These findings suggest that obtaining diagnostic data from either teachers' or mothers' reports alone may provide an incomplete characterization of ADHD.


Motor responses of rat hypertrophic intestine following chronic obstruction.
The present work aims at investigating the changes in motor responsiveness of rat intestine hypertrophied by chronic mechanical obstruction. Motor responses to pharmacological agents and electrical field stimulation (EFS) were studied in hypertrophic ileal segments excised from rats subjected to experimental stenosis (n = 20) and compared with responses of control tissues from sham-operated animals (n = 20). Spontaneous motility and contractile responses to exogenous agents (KCl, acetylcholine and substance P) and EFS (10-s trains every minute, 120 mA, 0.5 ms, 1-10 Hz) were increased in hypertrophic longitudinal segments; however, normalization of motor responses to tissue wet weight revealed a remarkable reduction of contractile efficiency in hypertrophied tissues coupled with a loss of sensitivity to nitric oxide-mediated relaxation. Furthermore, EFS under non-adrenergic non-cholinergic (NANC) conditions unveiled a major role of the cholinergic component over the peptidergic one in the neurogenic contraction of hypertrophic intestine. On the whole, hypertrophic intestinal growth emerges as a dynamic process entailing adaptation of smooth muscle and neuronal structures to the increased functional load imposed by lumen obstruction.


The Human OligoGenome Resource: a database of oligonucleotide capture probes for resequencing target regions across the human genome.
Recent exponential growth in the throughput of next-generation DNA sequencing platforms has dramatically spurred the use of accessible and scalable targeted resequencing approaches. This includes candidate region diagnostic resequencing and novel variant validation from whole genome or exome sequencing analysis. We have previously demonstrated that selective genomic circularization is a robust in-solution approach for capturing and resequencing thousands of target human genome loci such as exons and regulatory sequences. To facilitate the design and production of customized capture assays for any given region in the human genome, we developed the Human OligoGenome Resource (http://oligogenome.stanford.edu/). This online database contains over 21 million capture oligonucleotide sequences. It enables one to create customized and highly multiplexed resequencing assays of target regions across the human genome and is not restricted to coding regions. In total, this resource provides 92.1% in silico coverage of the human genome. The online server allows researchers to download a complete repository of oligonucleotide probes and design customized capture assays to target multiple regions throughout the human genome. The website has query tools for selecting and evaluating capture oligonucleotides from specified genomic regions.


Understanding farmers' intention and behavior regarding water conservation in the Middle-East and North Africa: a case study in Iran.
There is a high risk of serious water shortages in Middle-East and North African countries. To decrease this threat water conservation strategies are gaining overall importance and one main focus is now on farmer's behavior. Among other dimensions it is assumed that normative issues play an important role in predicting environmental oriented intentions and actual actions. To empirically test the possible interactions the Theory of Planned Behavior was used, revised and expanded for the specific case on water management issues and applied to Iranian farmers. The results could not validate the TPB framework which emphasizes the importance of perceived behavioral control for intention and actual behavior and findings are much more in line with the Theory of Reasoned Action. Normative inclinations as well as perception of risk are found to be important for intention as well as actual water conservation behavior. Additionally, the importance and linkages of the dimensions are found to be different between sub-groups of farmers, especially between traditional water management farmers and those who already using advanced water management strategies. This raises the question if one-fits-all behavioral models are adequate for practical studies where sub-groups may very much differ in their actions. Still, our study suggests that in the context of water conservation, normative inclination is a key dimension and it may be useful to consider the role of positive, self-rewarding feelings for farmers when setting up policy measures in the region.


A brief intervention is sufficient for many adolescents seeking help from low threshold adolescent psychiatric services.
There has been a considerable increase in the need for psychiatric services for adolescents. Primary health care practitioners have a major role in detecting, screening and helping these adolescents. An intervention entitled SCREEN is described in this article. The SCREEN intervention was developed to help practitioners to detect and screen adolescent needs, to care for adolescents at the primary health care level and to facilitate the referral of adolescents to secondary care services in collaboration between primary and secondary health care. Secondly, the article presents the background and clinical characteristics of youths seeking help from the SCREEN services, and compares the background factors and clinical characteristics of those patients referred and not referred to secondary care services. The SCREEN intervention consisted of 1 to 5 sessions, including assessment by a semi-structured anamnesis interview, the structured Global Assessment Scale, and by a structured priority rating scale, as well as a brief intervention for each adolescent's chosen problem. Parents took part in the assessment in 39% of cases involving girls and 50% involving boys. During 34 months, 2071 adolescents (69% females) entered the intervention and 70% completed it. The mean age was 17.1 years for boys and 17.3 years for girls. For 69% of adolescents, this was the first contact with psychiatric services. The most common reasons for seeking services were depressive symptoms (31%). Self-harming behaviour had occurred in 25% of girls and 16% of boys. The intervention was sufficient for 37% of those who completed it. Psychosocial functioning improved during the intervention. Factors associated with referral for further treatment were female gender, anxiety as the main complaint, previous psychiatric treatment, self-harming behaviour, a previous need for child welfare services, poor psychosocial functioning and a high score in the priority rating scale. A brief intervention carried out by a team including professionals from both primary and secondary level services was sufficient for a considerable proportion of adolescents seeking help for their psychiatric problems. Referral practices and counselling in special level services can be standardized. In the future, it will be important to develop and assess psychiatric services for adolescents using randomised controlled trials.


The shoulders of professional beach volleyball players: high prevalence of infraspinatus muscle atrophy.
Beach volleyball is an Olympic overhead sport. It is not well known which clinical and imaging findings are normal and which are associated with symptoms. There are typical clinical and imaging findings in the hitting shoulders of fully competitive professional beach volleyball players, as compared with their nonhitting shoulders. Cross-sectional study; Level of evidence, 3. During the Beach Volleyball Grand Slam Tournament in Klagenfurt, Austria, 84 professional players (54 men, 30 women) underwent a questionnaire-based interview and a complete physical examination, including scoring and sonography of both shoulders. Twenty-nine players had shoulder MRIs. The mean age of the athletes was 28 years. Atrophy of the infraspinatus muscle was found in 30% of the hitting shoulders, and it was not typically recognized by the players. The absolute Constant score was significantly lower in the hitting shoulder (87 versus 93 points, P < .0001). Average external rotation strength was decreased in the hitting shoulder (8.2 versus 9.5 kg, P < .0001). There were more abnormalities on the sonography of the hitting shoulder (1.7 versus 0.4, P < .0001) and in the same shoulders on MRI than on sonography (P = .0231). Compression of the suprascapular nerve was not observed. Pain in the hitting shoulder was present in 63% of the players, without clear correlations to the investigated clinical and imaging parameters. The prevalence of infraspinatus muscle atrophy in professional beach volleyball players is 30%. The typical, fully competitive player has subjectively unrecognized decreased strength of external rotation and frequent unspecific shoulder pain. Therefore, abnormal clinical and imaging findings in the beach volleyball player should be interpreted with care.


Type IV procollagen missense mutations associated with defects of the eye, vascular stability, the brain, kidney function and embryonic or postnatal viability in the mouse, Mus musculus: an extension of the Col4a1 allelic series and the identification of the first two Col4a2 mutant alleles.
The basement membrane is important for proper tissue development, stability, and physiology. Major components of the basement membrane include laminins and type IV collagens. The type IV procollagens Col4a1 and Col4a2 form the heterotrimer [alpha1(IV)]2[alpha2(IV)], which is ubiquitously expressed in basement membranes during early developmental stages. We present the genetic, molecular, and phenotypic characterization of nine Col4a1 and three Col4a2 missense mutations recovered in random mutagenesis experiments in the mouse. Heterozygous carriers express defects in the eye, the brain, kidney function, vascular stability, and viability. Homozygotes do not survive beyond the second trimester. Ten mutations result in amino acid substitutions at nine conserved Gly sites within the collagenous domain, one mutation is in the carboxy-terminal noncollagenous domain, and one mutation is in the signal peptide sequence and is predicted to disrupt the signal peptide cleavage site. Patients with COL4A2 mutations have still not been identified. We suggest that the spontaneous intraorbital hemorrhages observed in the mouse are a clinically relevant phenotype with a relatively high predictive value to identify carriers of COL4A1 or COL4A2 mutations.


Contingent National Belonging: The Perceived Fit and Acceptance of Culturally Different Peers Predicts Minority Adolescents' Own Belonging.
Prevailing definitions of national identities in Europe equate belonging to the nation with "fitting in" culturally and leave immigrant minorities who are culturally different from the majority group struggling to belong. The present study focuses on an under-researched minority perspective on the intersubjective cultural contents of the national identity. We propose that minorities' national belonging is contingent on their perception that minority peers who deviate from the majority culture are accepted as real nationals. Our study aims to establish (a) minority perceptions of the national fit and acceptance of culturally different peers, and to test (b) the consequences of perceived fit and acceptance for minority adolescents' own national belonging, and (c) its affordances by the local peer context. Drawing on a large random sample of 1,489 Moroccan and Turkish minority youth (aged 12-18) and their peers across 312 classes in 63 Belgian schools, we varied cultural difference from the majority in three vignettes describing imaginary acculturating peers. Minority participants rated to what extent they saw each peer as a real national (perceived fit) and whether other nationals would accept this peer (perceived acceptance). As a measure of their own national belonging, they indicated their national self-identification. Additionally, the multi-level design included classroom contextual measures of majority peer presence and peer acculturation norms (peer norm of heritage culture maintenance). As expected, minority youth who perceived better national fit of culturally different peers, self-identified more strongly as nationals than those who perceived worse fit. This association was not explained by their own acculturation attitudes. In line with the contextual affordance of national fit, only in classes with majority peers, minority youth perceived higher national fit and acceptance of culturally different peers when peer norms supported the maintenance of a distinct heritage culture. We conclude that the national belonging of minority youth is contingent on the peer context through the perceived fit and acceptance of culturally different peers.


American Pancreatic Association Practice Guidelines in Chronic Pancreatitis: evidence-based report on diagnostic guidelines.
The diagnosis of chronic pancreatitis remains challenging in early stages of the disease. This report defines the diagnostic criteria useful in the assessment of patients with suspected and established chronic pancreatitis. All current diagnostic procedures are reviewed, and evidence-based statements are provided about their utility and limitations. Diagnostic criteria for chronic pancreatitis are classified as definitive, probable, or insufficient evidence. A diagnostic (STEP-wise; survey, tomography, endoscopy, and pancreas function testing) algorithm is proposed that proceeds from a noninvasive to a more invasive approach. This algorithm maximizes specificity (low false-positive rate) in subjects with chronic abdominal pain and equivocal imaging changes. Furthermore, a nomenclature is suggested to further characterize patients with established chronic pancreatitis based on TIGAR-O (toxic, idiopathic, genetic, autoimmune, recurrent, and obstructive) etiology, gland morphology (Cambridge criteria), and physiologic state (exocrine, endocrine function) for uniformity across future multicenter research collaborations. This guideline will serve as a baseline manuscript that will be modified as new evidence becomes available and our knowledge of chronic pancreatitis improves.


Inferring the Effects of Cancer Treatment: Divergent Results From Early Breast Cancer Trialists' Collaborative Group Meta-Analyses of Randomized Trials and Observational Data From SEER Registries.
To compare the effect of breast cancer radiotherapy as estimated from observational data with findings from randomized trials. Rate ratios were obtained for selected end points among 13,932 women randomly assigned to receive radiotherapy or not in trials contributing to recent meta-analyses by the Early Breast Cancer Trialists' Collaborative Group. Estimates of the same quantities were derived for 393,840 women registered with breast cancer in the US SEER registries between 1973 and 2008. In the randomized trials, radiotherapy after breast-conserving surgery reduced mortality from both breast cancer (rate ratio, 0.82; 95% CI, 0.75 to 0.90) and all causes (rate ratio, 0.92; 95% CI, 0.86 to 0.99). Reductions of similar magnitude were seen in the trials of radiotherapy after mastectomy in node-positive disease (rate ratios, breast cancer 0.84; 95% CI, 0.76 to 0.94; all causes, 0.89; 95% CI, 0.81 to 0.97). In the observational data, radiotherapy after breast-conserving surgery was associated with much larger mortality reductions (rate ratios, breast cancer, 0.64; 95% CI, 0.62 to 0.66; all causes, 0.63; 95% CI, 0.62 to 0.65), whereas radiotherapy after mastectomy in node-positive disease was associated with substantial increases in mortality (rate ratios, breast cancer, 1.34; 95% CI, 1.31 to 1.37; all causes, 1.23; 95% CI, 1.22 to 1.25). Detailed adjustment of the observational data for potential confounders did not reduce the divergence from the randomized data. This study of mortality after radiotherapy for breast cancer found strikingly divergent results between the Early Breast Cancer Trialists' Collaborative Group meta-analyses of randomized data and the SEER observational data, even when efforts had been made to remove confounding and selection biases. Nonrandomized comparisons are liable to provide misleading estimates of treatment effects. Therefore, they need careful justification every time they are used.


MeCP2 and Rett syndrome: reversibility and potential avenues for therapy.
Mutations in the X-linked gene MECP2 (methyl CpG-binding protein 2) are the primary cause of the neurodevelopmental disorder RTT (Rett syndrome), and are also implicated in other neurological conditions. The expression product of this gene, MeCP2, is a widely expressed nuclear protein, especially abundant in mature neurons of the CNS (central nervous system). The major recognized consequences of MECP2 mutation occur in the CNS, but there is growing awareness of peripheral effects contributing to the full RTT phenotype. MeCP2 is classically considered to act as a DNA methylation-dependent transcriptional repressor, but may have additional roles in regulating gene expression and chromatin structure. Knocking out Mecp2 function in mice recapitulates many of the overt neurological features seen in RTT patients, and the characteristic postnatally delayed onset of symptoms is accompanied by aberrant neuronal morphology and deficits in synaptic physiology. Evidence that reactivation of endogenous Mecp2 in mutant mice, even at adult stages, can reverse aspects of RTT-like pathology and result in apparently functionally mature neurons has provided renewed hope for patients, but has also provoked discussion about traditional boundaries between neurodevelopmental disorders and those involving dysfunction at later stages. In the present paper we review the neurobiology of MeCP2 and consider the various genetic (including gene therapy), pharmacological and environmental interventions that have been, and could be, developed to attempt phenotypic rescue in RTT. Such approaches are already providing valuable insights into the potential tractability of RTT and related conditions, and are useful pointers for the development of future therapeutic strategies.


Preexisting Neuropsychiatric Conditions and Associated Risk of Severe COVID-19 Infection and Other Acute Respiratory Infections.
Evidence indicates that preexisting neuropsychiatric conditions confer increased risks of severe outcomes from COVID-19 infection. It is unclear how this increased risk compares with risks associated with other severe acute respiratory infections (SARIs). To determine whether preexisting diagnosis of and/or treatment for a neuropsychiatric condition is associated with severe outcomes from COVID-19 infection and other SARIs and whether any observed association is similar between the 2 outcomes. Prepandemic (2015-2020) and contemporary (2020-2021) longitudinal cohorts were derived from the QResearch database of English primary care records. Adjusted hazard ratios (HRs) with 99% CIs were estimated in April 2022 using flexible parametric survival models clustered by primary care clinic. This study included a population-based sample, including all adults in the database who had been registered with a primary care clinic for at least 1 year. Analysis of routinely collected primary care electronic medical records was performed. Diagnosis of and/or medication for anxiety, mood, or psychotic disorders and diagnosis of dementia, depression, schizophrenia, or bipolar disorder. COVID-19-related mortality, or hospital or intensive care unit admission; SARI-related mortality, or hospital or intensive care unit admission. The prepandemic cohort comprised 11 134 789 adults (223 569 SARI cases [2.0%]) with a median (IQR) age of 42 (29-58) years, of which 5 644 525 (50.7%) were female. The contemporary cohort comprised 8 388 956 adults (58 203 severe COVID-19 cases [0.7%]) with a median (IQR) age of 48 (34-63) years, of which 4 207 192 were male (50.2%). Diagnosis and/or treatment for neuropsychiatric conditions other than dementia was associated with an increased likelihood of a severe outcome from SARI (anxiety diagnosis: HR, 1.16; 99% CI, 1.13-1.18; psychotic disorder diagnosis and treatment: HR, 2.56; 99% CI, 2.40-2.72) and COVID-19 (anxiety diagnosis: HR, 1.16; 99% CI, 1.12-1.20; psychotic disorder treatment: HR, 2.37; 99% CI, 2.20-2.55). The effect estimate for severe outcome with dementia was higher for those with COVID-19 than SARI (HR, 2.85; 99% CI, 2.71-3.00 vs HR, 2.13; 99% CI, 2.07-2.19). In this longitudinal cohort study, UK patients with preexisting neuropsychiatric conditions and treatments were associated with similarly increased risks of severe outcome from COVID-19 infection and SARIs, except for dementia.


Bivalirudin infusion to reduce ventricular infarction: the open-label, randomised Bivalirudin Infusion for Ventricular InfArction Limitation (BIVAL) study.
The aim of the study was to investigate whether bivalirudin versus unfractionated heparin (UFH) reduces infarct size (IS) for primary percutaneous coronary intervention (PPCI) in large acute myocardial infarction (AMI). This multicentre open-label trial randomised 78 patients undergoing PPCI for large AMI to bivalirudin or UFH. The primary endpoint was IS, assessed by cardiac magnetic resonance (CMR) five days after PPCI. Secondary endpoints included index of microcirculatory resistance (IMR), CMR-assessed microvascular obstruction (MVO) and ejection fraction, and biomarkers for thrombin activity and cell injury. No difference was observed in mean IS at five days (25.0±19.7 g for bivalirudin vs. 27.1±20.7 g for UFH; p=0.75). Early MVO was numerically lower with bivalirudin (5.3±5.8 g vs. 7.7±6.3 g; p=0.17), with no significant difference in ejection fraction at 90 days (54.6±12.0% vs. 49.1±12.1%; p=0.11). In the biomarkers, thrombin-antithrombin complexes were reduced by 4.8 ug/L over the first day for bivalirudin versus an increase of 1.9 ug/L in the heparin arm (p=0.0003). Acute IMR was lower (43.5±21.6 vs. 68.7±35.8 mmHg×s, respectively; p=0.014). In a planned interim analysis, an approximate 11% reduction in IS was observed with bivalirudin; the trial was discontinued for futility. This study did not achieve its primary endpoint of significant infarct size reduction in PPCI by prolonged bivalirudin infusion compared to UFH, even though complete thrombin inhibition was achieved in the acute phase, with a lower myocardial microcirculation resistance at the end of the procedure.


Fossils, molecules and embryos: new perspectives on the Cambrian explosion.
The Cambrian explosion is named for the geologically sudden appearance of numerous metazoan body plans (many of living phyla) between about 530 and 520 million years ago, only 1.7% of the duration of the fossil record of animals. Earlier indications of metazoans are found in the Neoproterozic; minute trails suggesting bilaterian activity date from about 600 million years ago. Larger and more elaborate fossil burrows appear near 543 million years ago, the beginning of the Cambrian Period. Evidence of metazoan activity in both trace and body fossils then increased during the 13 million years leading to the explosion. All living phyla may have originated by the end of the explosion. Molecular divergences among lineages leading to phyla record speciation events that have been earlier than the origins of the new body plans, which can arise many tens of millions of years after an initial branching. Various attempts to date those branchings by using molecular clocks have disagreed widely. While the timing of the evolution of the developmental systems of living metazoan body plans is still uncertain, the distribution of Hox and other developmental control genes among metazoans indicates that an extensive patterning system was in place prior to the Cambrian. However, it is likely that much genomic repatterning occurred during the Early Cambrian, involving both key control genes and regulators within their downstream cascades, as novel body plans evolved.


Marginal stability in jammed packings: quasicontacts and weak contacts.
Maximally random jammed (MRJ) sphere packing is a prototypical example of a system naturally poised at the margin between underconstraint and overconstraint. This marginal stability has traditionally been understood in terms of isostaticity, the equality of the number of mechanical contacts and the number of degrees of freedom. Quasicontacts, pairs of spheres on the verge of coming in contact, are irrelevant for static stability, but they come into play when considering dynamic stability, as does the distribution of contact forces. We show that the effects of marginal dynamic stability, as manifested in the distributions of quasicontacts and weak contacts, are consequential and nontrivial. We study these ideas first in the context of MRJ packing of d-dimensional spheres, where we show that the abundance of quasicontacts grows at a faster rate than that of contacts. We reexamine a calculation of Jin et al. [Phys. Rev. E 82, 051126 (2010)], where quasicontacts were originally neglected, and we explore the effect of their inclusion in the calculation. This analysis yields an estimate of the asymptotic behavior of the packing density in high dimensions. We argue that this estimate should be reinterpreted as a lower bound. The latter part of the paper is devoted to Bravais lattice packings that possess the minimum number of contacts to maintain mechanical stability. We show that quasicontacts play an even more important role in these packings. We also show that jammed lattices are a useful setting for studying the Edwards ensemble, which weights each mechanically stable configuration equally and does not account for dynamics. This ansatz fails to predict the power-law distribution of near-zero contact forces, P(f)∼f(θ).


Iron III isomaltose induced hypersensitivity reaction.
Iron isomaltose is considered as safe form of iron with no test dose recommended. Here, we are describing the case of a patient who experienced allergic reaction with this formulation of iron. A 35-year-old South Asian woman experienced allergic reaction, she had mild wheeze on examination of chest. She was given intranasal oxygen at 2 L/min. She was given intravenous acetaminophen 1 g for pain relief, 45.4 mg intravenous chlorphenaramine and intravenous 100 mg hydrocortisone. Within half an hour, all her symptoms improved and her hypoxia resolved. Her chest wheezing also disappeared. Iron isomaltose, although relatively safe, can cause allergic reaction. Intravenous iron can cause allergic reaction therefore it should be administered at the facility where trained staff is present so that necessary treatment can be given in case of hypersensitivity reaction.


Cross-comparative analysis of evacuation behavior after earthquakes using mobile phone data.
Despite the importance of predicting evacuation mobility dynamics after large scale disasters for effective first response and disaster relief, our general understanding of evacuation behavior remains limited because of the lack of empirical evidence on the evacuation movement of individuals across multiple disaster instances. Here we investigate the GPS trajectories of a total of more than 1 million anonymized mobile phone users whose positions were tracked for a period of 2 months before and after four of the major earthquakes that occurred in Japan. Through a cross comparative analysis between the four disaster instances, we find that in contrast to the assumed complexity of evacuation decision making mechanisms in crisis situations, an individual's evacuation probability is strongly dependent on the seismic intensity that they experience. In fact, we show that the evacuation probabilities in all earthquakes collapse into a similar pattern, with a critical threshold at around seismic intensity 5.5. This indicates that despite the diversity in the earthquakes profiles and urban characteristics, evacuation behavior is similarly dependent on seismic intensity. Moreover, we found that probability density functions of the distances that individuals evacuate are not dependent on seismic intensities that individuals experience. These insights from empirical analysis on evacuation from multiple earthquake instances using large scale mobility data contributes to a deeper understanding of how people react to earthquakes, and can potentially assist decision makers to simulate and predict the number of evacuees in urban areas with little computational time and cost. This can be achieved by utilizing only the information on population density distribution and seismic intensity distribution, which can be observed instantaneously after the shock.


Effects of supplemental vitamin D and calcium on oxidative DNA damage marker in normal colorectal mucosa: a randomized clinical trial.
The exact antineoplastic effects of calcium and vitamin D(3) in the human colon are unclear. Animal and in vitro studies show that these two agents reduce oxidative stress; however, these findings have never been investigated in humans. To address this, we conducted a pilot, randomized, double-blind, placebo-controlled, 2 x 2 factorial clinical trial to test the effects of calcium and vitamin D(3) on a marker of oxidative DNA damage, 8-hydroxy-2'-deoxyguanosine (8-OH-dG), in the normal colorectal mucosa. Patients (N = 92) with at least one pathology-confirmed colorectal adenoma were treated with 2 g/d calcium and/or 800 IU/d vitamin D(3) versus placebo over 6 months. Overall labeling and colorectal crypt distribution of 8-OH-dG in biopsies of normal-appearing rectal mucosa were detected by standardized automated immunohistochemistry and quantified by image analysis. After 6 months of treatment, 8-OH-dG labeling along the full lengths of colorectal crypts decreased by 22% (P = 0.15) and 25% (P = 0.10) in the calcium and vitamin D(3) groups, respectively, but not in the calcium plus vitamin D(3) group. The estimated treatment effects were strongest among participants with higher baseline colon crypt vitamin D receptor expression (P = 0.05). Overall, these preliminary results indicate that calcium and vitamin D(3) may decrease oxidative DNA damage in the normal human colorectal mucosa, support the hypothesis that 8-OH-dG labeling in colorectal crypts is a treatable oxidative DNA damage biomarker of risk for colorectal neoplasms, and provide support for further investigation of calcium and vitamin D(3) as chemopreventive agents against colorectal neoplasms.


White matter plasticity in the cerebellum of elite basketball athletes.
Recent neuroimaging studies indicate that learning a novel motor skill induces plastic changes in the brain structures of both gray matter (GM) and white matter (WM) that are associated with a specific practice. We previously reported an increased volume of vermian lobules VI-VII (declive, folium, and tuber) in elite basketball athletes who require coordination for dribbling and shooting a ball, which awakened the central role of the cerebellum in motor coordination. However, the precise factor contributing to the increased volume was not determined. In the present study, we compared the volumes of the GM and WM in the sub-regions of the cerebellar vermis based on manual voxel analysis with the ImageJ program. We found significantly larger WM volumes of vermian lobules VI-VII (declive, folium, and tuber) in elite basketball athletes in response to long-term intensive motor learning. We suggest that the larger WM volumes of this region in elite basketball athletes represent a motor learning-induced plastic change, and that the WM of this region likely plays a critical role in coordination. This finding will contribute to gaining a deeper understanding of motor learning-evoked WM plasticity.


Crizotinib-resistant NPM-ALK mutants confer differential sensitivity to unrelated Alk inhibitors.
The dual ALK/MET inhibitor crizotinib was recently approved for the treatment of metastatic and late-stage ALK+ NSCLC, and is currently in clinical trial for other ALK-related diseases. As predicted after other tyrosine kinase inhibitors' clinical experience, the first mutations that confer resistance to crizotinib have been described in patients with non-small cell lung cancer (NSCLC) and in one patient inflammatory myofibroblastic tumor (IMT). Here, we focused our attention on the anaplastic large cell lymphoma (ALCL), where the oncogenic fusion protein NPM-ALK, responsible for 70% to 80% of cases, represents an ideal crizotinib target. We selected and characterized 2 human NPM-ALK+ ALCL cell lines, KARPAS-299 and SUP-M2, able to survive and proliferate at different crizotinib concentrations. Sequencing of ALK kinase domain revealed that a single mutation became predominant at high crizotinib doses in each cell line, namely L1196Q and I1171N in Karpas-299 and SUP-M2 cells, respectively. These mutations also conferred resistance to crizotinib in Ba/F3 cells expressing human NPM-ALK. The resistant cell populations, as well as mutated Ba/F3 cells, were characterized for sensitivity to two additional ALK inhibitors: the dual ALK/EGFR inhibitor AP26113 and NVP-TAE684. While L1196Q-positive cell lines were sensitive to both inhibitors, cells carrying I1171N substitution showed cross-resistance to all ALK inhibitors tested. This study provides potentially relevant information for the management of patients with ALCL that may relapse after crizotinib treatment.


J1-M267 Y lineage marks climate-driven pre-historical human displacements.
The present day distribution of Y chromosomes bearing the haplogroup J1 M267(*)G variant has been associated with different episodes of human demographic history, the main one being the diffusion of Islam since the Early Middle Ages. To better understand the modes and timing of J1 dispersals, we reconstructed the genealogical relationships among 282 M267(*)G chromosomes from 29 populations typed at 20 YSTRs and 6 SNPs. Phylogenetic analyses depicted a new genetic background consistent with climate-driven demographic dynamics occurring during two key phases of human pre-history: (1) the spatial expansion of hunter gatherers in response to the end of the late Pleistocene cooling phases and (2) the displacement of groups of foragers/herders following the mid-Holocene rainfall retreats across the Sahara and Arabia. Furthermore, J1 STR motifs previously used to trace Arab or Jewish ancestries were shown unsuitable as diagnostic markers for ethnicity.


Exploration of Deaf People's Health Information Sources and Techniques for Information Delivery in Cape Town: A Qualitative Study for the Design and Development of a Mobile Health App.
Many cultural and linguistic Deaf people in South Africa face disparity when accessing health information because of social and language barriers. The number of certified South African Sign Language interpreters (SASLIs) is also insufficient to meet the demand of the Deaf population in the country. Our research team, in collaboration with the Deaf communities in Cape Town, devised a mobile health app called SignSupport to bridge the communication gaps in health care contexts. We consequently plan to extend our work with a Health Knowledge Transfer System (HKTS) to provide Deaf people with accessible, understandable, and accurate health information. We conducted an explorative study to prepare the groundwork for the design and development of the system. To investigate the current modes of health information distributed to Deaf people in Cape Town, identify the health information sources Deaf people prefer and their reasons, and define effective techniques for delivering understandable information to generate the groundwork for the mobile health app development with and for Deaf people. A qualitative methodology using semistructured interviews with sensitizing tools was used in a community-based codesign setting. A total of 23 Deaf people and 10 health professionals participated in this study. Inductive and deductive coding was used for the analysis. Deaf people currently have access to 4 modes of health information distribution through: Deaf and other relevant organizations, hearing health professionals, personal interactions, and the mass media. Their preferred and accessible sources are those delivering information in signed language and with communication techniques that match Deaf people's communication needs. Accessible and accurate health information can be delivered to Deaf people by 3 effective techniques: using signed language including its dialects, through health drama with its combined techniques, and accompanying the information with pictures in combination with simple text descriptions. We can apply the knowledge gained from this exploration to build the groundwork of the mobile health information system. We see an opportunity to design an HKTS to assist the information delivery during the patient-health professional interactions in primary health care settings. Deaf people want to understand the information relevant to their diagnosed disease and its self-management. The 3 identified effective techniques will be applied to deliver health information through the mobile health app.


Effects of rat cytomegalovirus on the nervous system of the early rat embryo.
The purpose of the study was to investigate the impact of rat cytomegalovirus (RCMV) infection on the development of the nervous system in rat embryos, and to evaluate the involvement of Wnt signaling pathway key molecules and the downstream gene neurogenin 1 (Ngn1) in RCMV infected neural stem cells (NSCs). Infection and control groups were established, each containing 20 pregnant Wistar rats. Rats in the infection group were inoculated with RCMV by intraperitoneal injection on the first day of pregnancy. Rat E20 embryos were taken to evaluate the teratogenic rate. NSCs were isolated from E13 embryos, and maintained in vitro. We found: 1) Poor fetal development was found in the infection group with low survival and high malformation rates. 2) The proliferation and differentiation of NSCs were affected. In the infection group, NSCs proliferated more slowly and had a lower neurosphere formation rate than the control. The differentiation ratio from NSCs to neurons and glial cells was significantly different from that of the control, showed by immunofluorescence staining. 3) Ngn1 mRNA expression and the nuclear β-catenin protein level were significantly lower than the control on day 2 when NSCs differentiated. 4) The Morris water maze test was performed on 4-week pups, and the infected rats were found worse in learning and memory ability. In a summary, RCMV infection caused abnormalities in the rat embryonic nervous system, significantly inhibited NSC proliferation and differentiation, and inhibited the expression of key molecules in the Wnt/β-catenin signaling pathway so as to affect NSCs differentiation. This may be an important mechanism by which RCMV causes embryonic nervous system abnormalities.


Direct oral anticoagulants for treatment of deep vein thrombosis: overview of systematic reviews.
A number of limitations of standard therapy with warfarin for deep vein thrombosis (DVT) have been established. This overview of systematic reviews presents the baseline results for efficacy and safety of the new direct oral anticoagulants (DOACs) thrombin inhibitors, and activated factor X (Xa) inhibitors in patients with DVT. Searches were run on PubMed and the Cochrane Database of Systematic Reviews. Twenty-three studies were retrieved, and one systematic review was judged eligible. This review scored maximum according to AMSTAR criteria and included 7,596 patients for analysis of thrombin inhibitors and 16,356 patients for analysis of factor Xa inhibitors. The results of the meta-analysis indicate that DOACs are similar for DVT treatment when compared to standard treatment with warfarin. The incidence of major bleeding is somewhat lower in patients treated with factor Xa inhibitors and similar to standard therapy when treated with direct thrombin inhibitors.


Posttraumatic stress symptoms mediate the relationship between adverse childhood experiences, avoidant personality traits and resilience.
Background and Objectives: It is widely recognized that posttraumatic stress (PTS) symptoms, resulting from adverse childhood experiences (ACEs), have a myriad of detrimental effects on the wellbeing of sufferers. Yet the extent to which PTS symptoms mediate positive and negative outcomes is less well-known. This study, therefore, explored whether PTS symptoms indirectly explain avoidant personality disorder (AVPD) traits and resilience following multiple ACEs. Design: A correlational design using mediation analyses was conducted. Method: One-hundred and seventy-seven participants (68.4% female; aged 18-73 years) completed an online survey measuring experiences of childhood adversity, AVPD traits, resilience, and PTS symptoms. Results: The pathway from ACEs to AVPD mediated by PTS symptoms was both positive and significant. The indirect relationship from ACEs to resilience was also significantly and negatively mediated by PTS symptoms. Of the PTS dimensions, avoidance and hyperarousal mediated the relationship between the number of ACEs and AVPD traits, while intrusions mediated the association between the number of ACEs and resilience. Conclusions: These findings indicate that PTS symptoms can have both detrimental and adaptive effects on psychological wellbeing. Treatment and management of PTS symptoms is, therefore, key to the improvement of overall psychological functioning following ACEs.


Pleural fluid cytology samples in cases of suspected lung cancer: An experience from a tertiary care centre.
Pleural effusion is present in some patients with lung carcinoma. This study was undertaken to evaluate the role of pleural fluid cytology in suspected cases of lung carcinoma. In this prospective study, 86 cases of suspected primary lung carcinoma associated with pleural effusion were included. Cytomorphology of conventional smears was combined with LBC smears and a cytomorphological diagnosis was offered. An immunopanel of CK7, CK5/6, p63, TTF1, calretinin, and CD56 was applied on cell blocks. Additional immunochemical markers were performed based on clinical details and cytomorphology, wherever indicated. The mean age of the patients was 56.8 years. The female to male ratio was 2.1:1. Lung nodule/mass could be detected in 70.9% cases by CECT chest. Cytomorphology was evaluated in all the 86 cases and IHC was used to refine the cytomorphological diagnosis. After IHC along with clinico-radiological details, 61/86 (71%) cases were confirmed as metastasis from lung primary, 5/86 (5.8%) were diagnosed as metastatic adenocarcinoma of extrapulmonary origin, and 6/86 (7%) were metastatic SCC. A diagnosis of adenosquamous carcinoma was suspected in five cases. Other cases included small cell carcinoma (n = 2), large cell carcinoma (n = 2), large cell neuroendocrine carcinoma (n = 3), and mesothelioma (n = 1). One case remained "uncategorized" even after IHC. Immunohistochemistry (IHC) performed on the pleural fluid sample can accurately diagnose and subtype primary lung carcinoma even in cases where radiology failed to identify a definite lung lesion. IHC can further help in delineating primary site in tumors of extrapulmonary origin. © 2017 Wiley Periodicals, Inc. Diagn. Cytopathol. 2017;45:195-201. © 2016 Wiley Periodicals, Inc.


Calcium regulation of mitochondria motility and morphology.
In the Fifties, electron microscopy studies on neuronal cells showed that mitochondria typically cluster at synaptic terminals, thereby introducing the concept that proper mitochondria trafficking and partitioning inside the cell could provide functional support to the execution of key physiological processes. Today, the notion that a central event in the life of every eukaryotic cell is to configure, maintain, and reorganize the mitochondrial network at sites of high energy demand in response to environmental and cellular cues is well established, and the challenge ahead is to define the underlying molecular mechanisms and regulatory pathways. Recent pioneering studies have further contributed to place mitochondria at the center of the cell biology by showing that the machinery governing remodeling of mitochondria shape and structure regulates the functional output of the organelle as the powerhouse of the cell, the gateway to programmed cell death, and the platform for Ca(2+) signaling. Thus, a raising issue is to identify the cues integrating mitochondria trafficking and dynamics into cell physiology and metabolism. Given the versatile function of calcium as a second messenger and of the role of mitochondria as a major calcium store, evidences are emerging linking Ca(2+) transients to the modulation of mitochondrial activities. This review focuses on calcium as a switch controlling mitochondria motility and morphology in steady state, stressed, and pathological conditions.


Bacterial dynamics in spring water of alpine karst aquifers indicates the presence of stable autochthonous microbial endokarst communities.
Spring water of two alpine karst aquifers differing in hydrogeology but of nearby catchments were investigated for their bacterial population dynamics. Dolomite karst aquifer spring 1 (DKAS 1) represents a dolomitic-limestone karst aquifer spring showing high average water residence time and relative constant flow. Limestone karst aquifer spring 2 (LKAS 2) constitutes a typical limestone karst aquifer spring with a dynamic hydrological regime and discharge. Dolomite karst aquifer spring 1 yielded constantly lower cell counts and biomasses (median of 15 x 10(6) cells l(-1) and 0.22 microg C l(-1)) as the LKAS 2 (median of 63 x 10(6) cells l(-1) and 1.1 microg C l(-1)) and distribution of morphotypes and mean cell volumes was also different between the considered systems, indicating the influence of hydrogeology on microbial spring water quality. Molecular bacterial V3 16S-rDNA profiles revealed remarkable constancy within each spring water throughout the investigation period. Time course analysis of a flood event in LKAS 2 further supported the trend of the temporal constancy of the microbial community. Except for one case, retrieval of partial and full length 16S rDNA gene sequences from the relative constant DKAS 1 revealed similarities to presently known sequences between 80% to 96%, supporting the discreteness of the microbial populations. The gathered results provide first evidence for the presence of autochthonous microbial endokarst communities (AMEC). Recovery of AMEC may be considered of relevance for the understanding of alpine karst aquifer biogeochemistry and ecology, which is of interest as many alpine and mountainous karst springs are important water resources throughout the world.


Enhanced macrophage degradation of biologically modified low density lipoprotein.
Low density lipoprotein (LDL) conditioned by incubation in the presence of rabbit aortic or human umbilical vein endothelial cells (endothelial cell-modified LDL) was degraded by macrophages three to five times more rapidly than LDL incubated in the absence of cells (control LDL). This enhanced degradation occurred mostly via a high affinity, saturable pathway related to the pathway for macrophage uptake of acetylated LDL. Conditioning LDL with cultured aortic smooth muscle cells had a qualitatively similar but smaller effect; conditioning with fibroblasts had no effect. Conditioning very low density lipoproteins or high density lipoproteins with endothelial cells did not affect subsequent metabolism of these lipoproteins by macrophages. Endothelial cell-modified LDL, while degraded more rapidly than control LDL by macrophages, was degraded more slowly by cultured smooth muscle cells and by human skin fibroblasts. Degradation of endothelial cell-modified LDL by macrophages was accompanied by stimulation of cholesterol esterification, inhibition of cholesterol synthesis, and a net increment in total cellular cholesterol content. Thus, a biologically generated modification of LDL is described that markedly alters cholesterol metabolism of macrophages and, consequently, may play a role in foam cell formation during atherogenesis.


Lack of defective expression of the ATM gene in sporadic breast cancer tissues and cell lines.
Homozygous mutations of the gene mutated in ataxia telangiectasia (ATM) causes the AT syndrome, a pleiotropic phenotype that includes an increased risk of cancer. Most of the known mutations at the ATM gene lead to truncations which are usually associated with instability of mRNA and protein. A decrease or loss of ATM protein expression is associated with specific lymphoid malignancies in AT and non-AT patients. ATM is located within a region in chromosome 11q22-23 that is frequently undergoing loss of heterozygosity in sporadic breast cancer. Epidemiological studies estimated a 4-fold increase in breast cancer risk in heterozygous women. However, direct mutational analysis failed to clearly support a role for mutant ATM alleles in breast carcinogenesis. If ATM does have a suppressor role in this tissue, one would expect deficient ATM expression. We therefore tested the hypothesis that the expression of the ATM gene is reduced in sporadic breast cancer. We determined ATM transcript levels using competitive RT-PCR on 89 randomly selected sporadic breast cancer samples and 29 normal breast tissues. Of these, 11 were matched normal/cancer pairs. We also evaluated 7 breast cancer cell lines. Deficiency in ATM expression was not observed. Of the 11 matched pairs, 7 tumors expressed mildly higher levels, 3 tumors expressed the same amount and only 1 tumor expressed <50% of the normal match. In addition, 3 cancers with tumor-associated LOH of the ATM gene expressed higher mRNA levels in the tumors than in their normal tissue matches, suggesting that no correlation exists between tumors with LOH and decreased ATM expression. In summary, our results do not support a suppressor role for ATM in the development of sporadic breast cancer.


Pentadecapeptide BPC 157 enhances the growth hormone receptor expression in tendon fibroblasts.
BPC 157, a pentadecapeptide derived from human gastric juice, has been demonstrated to promote the healing of different tissues, including skin, muscle, bone, ligament and tendon in many animal studies. However, the underlying mechanism has not been fully clarified. The present study aimed to explore the effect of BPC 157 on tendon fibroblasts isolated from Achilles tendon of male Sprague-Dawley rat. From the result of cDNA microarray analysis, growth hormone receptor was revealed as one of the most abundantly up-regulated genes in tendon fibroblasts by BPC 157. BPC 157 dose- and time-dependently increased the expression of growth hormone receptor in tendon fibroblasts at both the mRNA and protein levels as measured by RT/real-time PCR and Western blot, respectively. The addition of growth hormone to BPC 157-treated tendon fibroblasts dose- and time-dependently increased the cell proliferation as determined by MTT assay and PCNA expression by RT/real-time PCR. Janus kinase 2, the downstream signal pathway of growth hormone receptor, was activated time-dependently by stimulating the BPC 157-treated tendon fibroblasts with growth hormone. In conclusion, the BPC 157-induced increase of growth hormone receptor in tendon fibroblasts may potentiate the proliferation-promoting effect of growth hormone and contribute to the healing of tendon.


Consensus proposals for classification of the family Hepeviridae.
The family Hepeviridae consists of positive-stranded RNA viruses that infect a wide range of mammalian species, as well as chickens and trout. A subset of these viruses infects humans and can cause a self-limiting acute hepatitis that may become chronic in immunosuppressed individuals. Current published descriptions of the taxonomical divisions within the family Hepeviridae are contradictory in relation to the assignment of species and genotypes. Through analysis of existing sequence information, we propose a taxonomic scheme in which the family is divided into the genera Orthohepevirus (all mammalian and avian hepatitis E virus (HEV) isolates) and Piscihepevirus (cutthroat trout virus). Species within the genus Orthohepevirus are designated Orthohepevirus A (isolates from human, pig, wild boar, deer, mongoose, rabbit and camel), Orthohepevirus B (isolates from chicken), Orthohepevirus C (isolates from rat, greater bandicoot, Asian musk shrew, ferret and mink) and Orthohepevirus D (isolates from bat). Proposals are also made for the designation of genotypes within the human and rat HEVs. This hierarchical system is congruent with hepevirus phylogeny, and the three classification levels (genus, species and genotype) are consistent with, and reflect discontinuities in the ranges of pairwise distances between amino acid sequences. Adoption of this system would include the avoidance of host names in taxonomic identifiers and provide a logical framework for the assignment of novel variants.


Self-reported tinnitus and noise sensitivity among adolescents in Sweden.
It seems to be a common opinion among researchers within the field of audiology that the prevalence of tinnitus will increase as a consequence of environmental factors, for example exposure to loud noise. Young people are exposed to loud sounds, more than any other age group, especially during leisure time activities, i.e. at pop concerts, discotheques and gyms. A crucial factor for the prevention of hearing impairments and hearing-related symptoms in the young population is the use of hearing protection. The focus of the present study is use of hearing protection and self-reported hearing-related symptoms, such as tinnitus and noise sensitivity in a young population of high-school students (N=1285), aged 13 to 19 years. The results show that the prevalence of permanent tinnitus and noise sensitivity, reported in the total group, was 8.7% and 17.1% respectively. Permanent tinnitus was not significantly related to level of socio-economic status, but age-related differences in the prevalence rates of experienced tinnitus and noise sensitivity were found to be significant. Older students reported such symptoms to a greater extent than younger students did. Those who reported tinnitus and other hearing-related symptoms protected their hearing to the highest extent and were the ones most worried.


Oral tolerance in humans. T cell but not B cell tolerance after antigen feeding.
The purpose of this study was to investigate whether oral tolerance, defined as Ag-specific immunologic unresponsiveness after Ag feeding, could be induced in humans after prolonged Ag ingestion. Eight adult volunteers ingested a total dose of 0.5 g of keyhole limpet hemocyanin (KLH) followed by subcutaneous immunization with KLH. Eight controls received only the subcutaneous immunization. In the group fed KLH, there was a significant reduction in KLH-specific T cell proliferation (p = 0.04) and delayed skin test responses (p = 0.07) to KLH. KLH ingestion alone did not induce significant levels of Abs in either serum or secretions. However, after the subsequent subcutaneous immunization, the number of circulating IgG and IgM anti-KLH-producing cells, the titers of serum IgG, IgA, and IgM anti-KLH Abs, and the titers of IgA anti-KLH Abs in saliva and intestinal secretions were significantly greater in the KLH-fed group than in the nonfed group. We conclude that KLH feeding induced systemic T cell tolerance, but B cell priming, at both systemic and mucosal sites. These studies support the concept of using Ag feeding as a treatment for certain immune-mediated diseases.


Synthetic studies toward polytwistane hydrocarbon nanorods.
A synthetic strategy toward the intriguing hydrocarbon nanorod polytwistane is outlined. Our approach aims toward the polymerization of acetylene starting from precursors that would provide a helical bias for the formation of polytwistane. Both transition-metal-catalyzed and radical polymerizations were investigated. Two potential initiator molecules were synthesized that could be used for either approach. Although the intended regioselectivities were not observed, unusual organopalladium complexes and numerous compounds with novel carbon skeletons were obtained.


Correlation between the reproductive potential and the pyrethroid resistance in an Indian strain of filarial vector, Culex quinquefasciatus Say (Diptera: Culicidae).
The laboratory studies were conducted to uncover the correlation between the levels of pyrethroid resistance and the reproductive potential of parent (SS) and resistant strains of Culex quinquefasciatus (RR) originating from Delhi, India and selected with deltamethrin (RDL) or the combination of deltamethrin and PBO (1:5) (RDP) at the larval stage and selected with deltamethrin at the adult stage (RDA). The reproductive potential was evaluated in terms of fecundity, fertility, egg hatchability and longevity of gonotrophic cycles. The RR strains exhibited 68-74% reduced duration of the gonotrophic cycles when compared with that of SS strain. The considerable decrease in the egg production, ranging from 45.4% to 61.6%, observed in the selected strains as compared to the SS strain, indicates the possible positive correlation between the levels of deltamethrin resistance and the reproduction disadvantage. This correlation was further confirmed by 24.6% to 53.6% decrease in the hatchability of eggs of the selected strains with respect to that of the parent strain. A worth-mentioning observation of the reduced reproductive fitness in RDP strains suggests the effectiveness of synergized deltamethrin selections in reducing the frequency of resistant individuals. The reproductive disadvantage in adult-selected strains possessing negligible resistance to deltamethrin implicates the efficacy of deltamethrin as an adulticide rather than as a larvicide against Cx. quinquefasciatus. The results suggest that the reduced reproductive fitness of resistant genotypes in the population can eliminate heterozygotes and resistant homozygotes by implementing different resistance-management strategies against Cx. quinquefasciatus.


Ethyl acetate extract from Inula helenium L. inhibits the proliferation of pancreatic cancer cells by regulating the STAT3/AKT pathway.
Sesquiterpene lactones are bioactive compounds that have been identified as responsible for the anticancer activity of the medicinal herb, Inula helenium L. (IHL). However, the mechanisms of action involved in the anti‑pancreatic cancer activity of IHL have yet to be elucidated. The present study used an optimized extraction strategy to obtain sesquiterpene lactones from IHL (the resulting product termed ethyl acetate extract of IHL; EEIHL), and examined the potential mechanisms involved in the anti‑pancreatic cancer activity of EEIHL. Ethanol and ethyl acetate were used to extract sesquiterpene lactones from IHL to give the final product EEIHL. Cell Counting Kit‑8, colony formation and Annexin V/propidium iodide assays were used to detect the anti‑proliferative activity of EEIHL. Cell migration was determined with a wound healing assay. mRNA and protein expression levels were analyzed by reverse transcription‑quantitative polymerase chain reaction and western blot analyses, respectively. It was identified that low concentrations of EEIHL caused CFPAC‑1 cell cycle arrest in the G0/G1 phase, whereas high concentrations of EEIHL induced mitochondria‑dependent apoptosis. In addition, EEIHL could inhibit the phosphorylation of the signal transducer and activator of transcription (STAT)3/AKT pathway, potentially resulting in impeded cell mobility. In conclusion, EEIHL could activate mitochondrial‑dependent apoptosis and inhibit cell migration through the STAT3/AKT pathway in CFPAC-1 cells.


Detection and quantitation of N'-nitrosonornicotine in human toenails by liquid chromatography-electrospray ionization-tandem mass spectrometry.
Specific biomarkers of tobacco carcinogen uptake are critical for investigations of the role of tobacco smoke exposure in human cancers. Two new biomarkers of human exposure to tobacco-specific carcinogens have been recently developed by our research group: urinary N'-nitrosonornicotine (NNN) and toenail 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). In this study, we report the presence of NNN in human toenails. Toenails of 17 smokers were analyzed for total NNN. Mean total NNN level in these samples was 4.63 +/- 6.48 fmol/mg toenail and correlated with previously reported total NNAL (r = 0.96; P < 0.0001), total nicotine (r = 0.48; P < 0.05), and total cotinine (r = 0.87; P < 0.0001). An interesting finding was that amounts of NNN in smokers' toenails were generally higher than those of total NNAL. The ratio of toenail NNN to NNAL averaged 2.8, whereas the previously reported ratio between these biomarkers in smokers' urine was 0.1. NNN was also found in toenail samples from 12 nonsmokers, averaging 0.35 +/- 0.16 fmol/mg and positively correlating with toenail cotinine (r = 0.58; P = 0.05). The results of this study show the feasibility of quantifying NNN in human toenails, providing a potentially useful new biomarker of tobacco carcinogen exposure.


Mucosal immunity modulated by integrative meditation in a dose-dependent fashion.
Prior research had shown that an additional training session immediately after acute stress increased release of salivary secretory immunoglobin A (sIgA) in a group trained with 5-day Integrative Body-Mind Training (IBMT) in comparison to a control group given the same amount of relaxation training. However, 5 days of training did not influence the basal secretion of sIgA. The current study seeks to extend this finding and determine whether increasing amounts of IBMT will increase the basal sIgA level, suggesting further improvements in mucosal immune function. Thirty-five (35) Chinese undergraduates were randomly assigned either to an experimental group receiving 4 weeks of IBMT or a relaxation control. Salivary sIgA levels at baseline before training and three stages (i.e., rest, stress, and additional 20-minute practice) after 2 and 4 weeks training were assessed. The basal sIgA levels increased significantly in the experimental subjects but not in controls after 4 weeks of training. An additional IBMT practice session immediately after acute stress produced significantly higher sIgA release for the IBMT-trained group in comparison with controls at week 2 and 4. This effect was larger at week 4 than week 2. These results indicate that the IBMT produces a change in the basal immune system and larger acute effects as the dose of training increases.


Experimental and theoretical insights into the oxodiperoxomolybdenum-catalysed sulphide oxidation using hydrogen peroxide in ionic liquids.
The oxidation of organic sulphides with aqueous hydrogen peroxide in ionic liquids (ILs) catalysed by oxodiperoxomolybdenum complexes was investigated. The selective formation of several sulfones was achieved using the 1 : 3 ratio of sulphide : H2O2 in [C4mim][PF6] (C4mim = 1-butyl-3-methylimidazolium) in a reaction catalysed by the [Mo(O)(O2)2(H2O)n] complex. Conversely, sulfoxides were produced with good selectivities using a 1 : 1 ratio in the same solvent in a 1 h reaction with [Mo(O)(O2)2(Mepz)2] (Mepz = methylpyrazol). The use of [C4mim][PF6] as the solvent was advantageous for two reasons: (i) the improved performance of the H2O2-IL combination; (ii) recycling of the catalyst/IL mixture without a significant diminution of conversion or selectivity. A DFT analysis using the [Mo(O)(O2)2(L)] catalysts (L = Mepz, a; 3,5-dimethylpyrazole, dmpz, b; and H2O, c) indicated that a Sharpless-type outer-sphere mechanism is more probable than a Thiel-type one. The highest barrier of the catalytic profile was the oxo-transfer step, in which the nucleophilic attack of sulphide onto the peroxide ligand occurred with formation of dioxoperoxo species. In order to yield the sulfoxide and the starting catalyst, the oxidation of the resulting dioxoperoxo species with H2O2 was found to be the most favourable pathway. Subsequently, the sulfoxide to sulfone oxidation was performed through a similar mechanism involving the [Mo(O)(O2)2(L)] catalyst. The comparable energies found for the successive two oxo-transfer steps were in agreement with the experimental formation of sulfone in both the reaction with an excess of the oxidant and the stoichiometric reaction in the absence of the oxidant. In the latter case, diphenylsulfone was isolated as the major product in the 1 : 1 combination of diphenylsulphide and [Mo(O)(O2)2(Mepz)2] in the ionic liquid [C4mim][PF6]. Also, the compounds [HMepz]4[Mo8O26(Mepz)2]·2H2O, 1, [Hdmpz]4[Mo8O26(dmpz)2]·2dmpz, , and [Hpz]4[Mo8O22(O2)4(pz)2]·3H2O, 3, were obtained by treating in water, stoichiometrically, dimethylsulfoxide and the corresponding [Mo(O)(O2)2(L)2] complex (L = Mepz; 3,5-dimethylpyrazole, dmpz; pyrazol, pz). The crystal structures of octanuclear compounds 1-3 were indirect proof of the formation of the theoretically proposed intermediates.


Learning to Be Gendered: Gender Socialization in Early Adolescence Among Urban Poor in Delhi, India, and Shanghai, China.
The purpose of the study is to understand the gender socialization process in early adolescence. The study was located in two disadvantaged urban communities in Delhi, India and Shanghai, China and was part of the multicountry (15) Global Early Adolescent Study. Qualitative methodologies were used with boys and girls aged 11-13 years, including 16 group-based timeline exercises and 65 narrative interviews. In addition, 58 parents of participating adolescents were interviewed. Interviews were recorded, transcribed, translated, and uploaded into Atlas.ti for coding and thematic analysis. Boys and girls growing up in the same community were directed onto different pathways during their transition from early to late adolescence. Adolescents and parents in both sites identified mothers as the primary actor, socializing adolescents into how to dress and behave and what gender roles to play, although fathers were also mentioned as influential. Opposite-sex interactions were restricted, and violations enforced by physical violence. In Delhi, gender roles and mobility were more strictly enforced for girls than boys. Restrictions on opposite-sex interactions were rigid for both boys and girls in Delhi and Shanghai. Sanctions, including beating, for violating norms about boy-girl relationships were more punitive than those related to dress and demeanor, especially in Delhi. Education and career expectations were notably more equitable in Shanghai. Parents teach their children to adhere to inequitable gender norms in both Delhi and Shanghai. However, education and career expectations for boys and girls in the two sites differed. Although gender norms varied by site according to the particular cultural and historical context, similar patterns of gender inequity reflect the underlying patriarchal system in both settings. The tendency of parents to pass on the norms they grew up with is evident, yet these results illustrate the social construction of gender through children's interaction with the social ecology, including evolving political and economic systems. Efforts to bend gender norms toward greater equality can build on these results by empowering children and parents to reflect critically on inequitable gender norms and roles and by mobilizing economic and social support at key turning points in adolescents' lives.


Spinal L-type calcium channel blockade abolishes opioid-induced sensory hypersensitivity and antinociceptive tolerance.
Recent studies have suggested that prolonged exposure to morphine results in the development of paradoxical, abnormal enhanced pain. It has also been suggested that this enhanced pain state may be interpreted as antinociceptive tolerance. Although the precise mechanisms that drive opioid-induced abnormal pain are not well known, considerable evidence suggests that this state may be supported by enhanced, stimulus-evoked excitatory transmission. We hypothesized that blockade of L-type calcium channels, which are critical for excitatory neurotransmitter release, would alter the development of opioid-induced hyperalgesia and antinociceptive tolerance. Male, Swiss-Webster mice received twice-daily intrathecal injections of morphine (10 microg) alone or in combination with amlodipine (10 microg) for 8 days. Mice receiving repeated morphine injections developed enhanced responses to tactile and thermal stimuli. These hypersensitivities were prevented by the coadministration of the putative selective L-type calcium channel blocker amlodipine. Moreover, mice receiving morphine for 8 days demonstrated a significant rightward shift of the morphine antinociceptive dose-response curve, indicative of antinociceptive tolerance, whereas those that also received amlodipine along with morphine did not demonstrate tolerance. These results suggest that blockade of the L-type calcium channels with amlodipine prevented opioid-induced hyperalgesia and the expression of antinociceptive tolerance to spinal morphine, presumably by reducing stimulus-induced excitatory neurotransmitter release.


Verification of computed tomographic estimates of cochlear implant array position: a micro-CT and histologic analysis.
To determine the efficacy of clinical computed tomographic (CT) imaging to verify postoperative electrode array placement in cochlear implant (CI) patients. Nine fresh cadaver heads underwent clinical CT scanning, followed by bilateral CI insertion and postoperative clinical CT scanning. Temporal bones were removed, trimmed, and scanned using micro-CT. Specimens were then dehydrated, embedded in either methyl methacrylate or LR White resin, and sectioned with a diamond wafering saw. Histology sections were examined by 3 blinded observers to determine the position of individual electrodes relative to soft tissue structures within the cochlea. Electrodes were judged to be within the scala tympani, scala vestibuli, or in an intermediate position between scalae. The position of the array could be estimated accurately from clinical CT scans in all specimens using micro-CT and histology as a criterion standard. Verification using micro-CT yielded 97% agreement, and histologic analysis revealed 95% agreement with clinical CT results. A composite, 3-dimensional image derived from a patient's preoperative and postoperative CT images using a clinical scanner accurately estimates the position of the electrode array as determined by micro-CT imaging and histologic analyses. Information obtained using the CT method provides valuable insight into numerous variables of interest to patient performance such as surgical technique, array design, and processor programming and troubleshooting.


Passive immunization of newborn rhesus macaques prevents oral simian immunodeficiency virus infection.
To determine if passively acquired antiviral antibodies modulate virus transmission and disease progression in human pediatric AIDS, the potential of pre- and postexposure passive immunization with hyperimmune serum to prevent oral simian immunodeficiency virus (SIV) infection or disease progression in newborn rhesus macaques was tested. Untreated neonates became infected after oral SIV inoculation and had high viremia, and most animals developed fatal AIDS within 3 months. In contrast, SIV hyperimmune serum given subcutaneously prior to oral SIV inoculation protected 6 newborns against infection. When this SIV hyperimmune serum was given to 3 newborns 3 weeks after oral SIV inoculation, viremia was not reduced, and all 3 infants died within 3 months of age due to AIDS and immune-complex disease. These results suggest that passively acquired antihuman immunodeficiency virus (HIV) IgG may decrease perinatal HIV transmission. However, anti-HIV IgG may not impart therapeutic benefit to infants with established HIV infection.


The MerR-like protein BldC binds DNA direct repeats as cooperative multimers to regulate Streptomyces development.
Streptomycetes are notable for their complex life cycle and production of most clinically important antibiotics. A key factor that controls entry into development and the onset of antibiotic production is the 68-residue protein, BldC. BldC is a putative DNA-binding protein related to MerR regulators, but lacks coiled-coil dimerization and effector-binding domains characteristic of classical MerR proteins. Hence, the molecular function of the protein has been unclear. Here we show that BldC is indeed a DNA-binding protein and controls a regulon that includes other key developmental regulators. Intriguingly, BldC DNA-binding sites vary significantly in length. Our BldC-DNA structures explain this DNA-binding capability by revealing that BldC utilizes a DNA-binding mode distinct from MerR and other known regulators, involving asymmetric head-to-tail oligomerization on DNA direct repeats that results in dramatic DNA distortion. Notably, BldC-like proteins radiate throughout eubacteria, establishing BldC as the founding member of a new structural family of regulators.


An index of orthodontic treatment complexity.
The aim of the present study was to develop an index specifically for the measurement of treatment complexity. Input factors were directly related to complexity, and the output was a score measuring the degree of treatment complexity. The sample comprised 120 sets of dental casts, 30 for each of the four main malocclusion classes. Sixteen orthodontists graded the study casts for perceived treatment complexity on a six-point scale and then listed, in order of importance, up to three occlusal features which they felt contributed to complexity from a pre-determined list. Multiple regression analysis was used to derive weightings for each occlusal feature, which would reflect the relevant treatment complexity. In order to obtain an overall treatment complexity score for each case, weightings were then multiplied by the corresponding occlusal feature scores and summed. The relationship between treatment complexity scores and perceived complexity was examined using Spearman's ranked correlation coefficient. The regression equation explained 49.5 per cent of the variance in treatment complexity of the whole sample. Regression analysis on the basis of malocclusion produced R (2) values of 90.7 per cent for Class I, 42.6 per cent for Class II division 1, 62.3 per cent for Class II division 2, and 79.5 per cent for Class III malocclusions. The index of orthodontic treatment complexity (IOTC) scores showed a moderate but highly significant association with the orthodontists' perceived complexity assessments (rho = 0.42, P = 0.000). The proposed IOTC shows sufficient promise to warrant further development.


Bub1, Sgo1, and Mps1 mediate a distinct pathway for chromosome biorientation in budding yeast.
The conserved mitotic kinase Bub1 performs multiple functions that are only partially characterized. Besides its role in the spindle assembly checkpoint and chromosome alignment, Bub1 is crucial for the kinetochore recruitment of multiple proteins, among them Sgo1. Both Bub1 and Sgo1 are dispensable for growth of haploid and diploid budding yeast, but they become essential in cells with higher ploidy. We find that overexpression of SGO1 partially corrects the chromosome segregation defect of bub1Δ haploid cells and restores viability to bub1Δ tetraploid cells. Using an unbiased high-copy suppressor screen, we identified two members of the chromosomal passenger complex (CPC), BIR1 (survivin) and SLI15 (INCENP, inner centromere protein), as suppressors of the growth defect of both bub1Δ and sgo1Δ tetraploids, suggesting that these mutants die due to defects in chromosome biorientation. Overexpression of BIR1 or SLI15 also complements the benomyl sensitivity of haploid bub1Δ and sgo1Δ cells. Mutants lacking SGO1 fail to biorient sister chromatids attached to the same spindle pole (syntelic attachment) after nocodazole treatment. Moreover, the sgo1Δ cells accumulate syntelic attachments in unperturbed mitoses, a defect that is partially corrected by BIR1 or SLI15 overexpression. We show that in budding yeast neither Bub1 nor Sgo1 is required for CPC localization or affects Aurora B activity. Instead we identify Sgo1 as a possible partner of Mps1, a mitotic kinase suggested to have an Aurora B-independent function in establishment of biorientation. We found that Sgo1 overexpression rescues defects caused by metaphase inactivation of Mps1 and that Mps1 is required for Sgo1 localization to the kinetochore. We propose that Bub1, Sgo1, and Mps1 facilitate chromosome biorientation independently of the Aurora B-mediated pathway at the budding yeast kinetochore and that both pathways are required for the efficient turnover of syntelic attachments.


Update on Antiepileptic Drugs 2019.
This article is an update from the article on antiepileptic drug (AED) therapy published in the last Continuum issue on epilepsy and is intended to cover the vast majority of agents currently available to the neurologist in the management of patients with epilepsy. Treatment of epilepsy starts with AED monotherapy. Knowledge of the spectrum of efficacy, clinical pharmacology, and modes of use for individual AEDs is essential for optimal treatment for epilepsy. This article addresses AEDs individually, focusing on key pharmacokinetic characteristics, indications, and modes of use. Since the previous version of this article was published, three new AEDs, brivaracetam, cannabidiol, and stiripentol, have been approved by the US Food and Drug Administration (FDA), and ezogabine was removed from the market because of decreased use as a result of bluish skin pigmentation and concern over potential retinal toxicity.Older AEDs are effective but have tolerability and pharmacokinetic disadvantages. Several newer AEDs have undergone comparative trials demonstrating efficacy equal to and tolerability at least equal to or better than older AEDs as first-line therapy. The list includes lamotrigine, oxcarbazepine, levetiracetam, topiramate, zonisamide, and lacosamide. Pregabalin was found to be less effective than lamotrigine. Lacosamide, pregabalin, and eslicarbazepine have undergone successful trials of conversion to monotherapy. Other newer AEDs with a variety of mechanisms of action are suitable for adjunctive therapy. Most recently, the FDA adopted a policy that a drug's efficacy as adjunctive therapy in adults can be extrapolated to efficacy in monotherapy. In addition, efficacy in adults can be extrapolated for efficacy in children 4 years of age and older. Both extrapolations require data demonstrating that an AED has equivalent pharmacokinetics between its original approved use and its extrapolated use. In addition, the safety of the drug in pediatric patients has to be demonstrated in clinical studies that can be open label. Rational AED combinations should avoid AEDs with unfavorable pharmacokinetic interactions or pharmacodynamic interactions related to mechanism of action. Knowledge of AED pharmacokinetics, efficacy, and tolerability profiles facilitates the choice of appropriate AED therapy for patients with epilepsy.


Skin nitric oxide and its metabolites are increased in nonburned skin after thermal injuries.
Local and systemic inflammation can lead to progression of burn wounds, converting second- to third-degree wounds or extending the burn to adjacent areas. Previous studies have suggested that the skin is an important site of production of nitric oxide (NO), synthesized by inducible nitric oxide synthase (iNOS) activation after injury. NO increases in burned wounds, but its formation in noninjured skin has not been investigated. We hypothesized that after severe burns, NO and cytotoxic peroxynitrite would increase in noninjured skin. We also tested the hypothesis that BBS-2, a specific inhibitor of iNOS, would impair NO formation after burn. Thirteen female sheep were randomized into burn injury and smoke inhalation (n = 5, group 1), burn and smoke treated with BBS-2 (n = 3, group 2), and sham (saline treatment, no injury) (n = 5, group 3). All the animals, including the sham-injury group, were mechanically ventilated for 48 h. Samples of nonburned skin and plasma were collected from each animal, and levels of NO and its metabolites were evaluated using a NO chemiluminescent detector. Nitrotyrosine and iNOS expression were determined in the skin by Immunoperoxidase staining, and scoring of masked slides (epidermis, hair follicles, vessels, glands, and stroma) was performed. Skin NO and metabolites significantly increased in the burn and smoke injury group, and this was inhibited by BBS-2. Nitrotyrosine expression also increased significantly in the skin of burned animals. BBS-2 prevented the increase of NOx but not the increase of nitrotyrosine expression in skin. Plasma levels of NO increased in burned animals when compared with sham, but this increase was not significant. The increase of NO and its metabolites after burn in noninjured skin is followed by a significant increase in peroxynitrite, a potent cytotoxic mediator.


Inflammatory root resorption in primary molars: prevalence and associated factors.
This study aimed at determining the prevalence of inflammatory root resorption and associated factors in 1068 primary mandibular molars in 453 children 3 to 12 years of age. Age, dental history and medical history were recorded using a questionnaire administered to the children's parents/caregivers. Previously trained and calibrated examiners assessed radiographic images of the primary molars by direct observation, with the aid of a viewing box. Root resorption (physiological or inflammatory), dental crown status (healthy, carious with no pulp involvement, carious with pulp involvement and evidence of restoration), and pulpotomy or pulpectomy were determined. Data analysis involved descriptive statistics, the chi-square test and a multiple logistic regression (p < 0.05). The prevalence of inflammatory root resorption was 16.2% (n = 173). The male gender (OR: 1.4; 95% CI), the 3-to-7-years age bracket (OR: 1.5; 95% CI), an unhealthy dental crown (OR: 8.7; 95% CI), caries with pulp involvement (OR: 7.4; 95% CI), pulpotomy (OR: 3.1; 95% CI), and pulpectomy (OR: 5.4; 95% CI) were risk factors for the occurrence of inflammatory root resorption in primary molars. In conclusion, the prevalence of inflammatory root resorption in the present sample was 16.2%. Gender, age, an unhealthy tooth, caries with pulp involvement, pulpotomy, pulpectomy, and the absence of a restoration were associated with a higher occurrence of inflammatory root resorption in primary molars.


Provider Attitudes and Practice Patterns for Direct-Acting Antiviral Therapy for Patients With Hepatocellular Carcinoma.
Direct-acting antivirals (DAAs) are effective against hepatitis C virus and sustained virologic response is associated with reduced incidence of hepatocellular carcinoma (HCC). However, there is controversy over the use of DAAs in patients with active or treated HCC and uncertainty about optimal management of these patients. We aimed to characterize attitudes and practice patterns of hepatology practitioners in the United States regarding the use of DAAs in patients with HCC. We conducted a survey of hepatology providers at 47 tertiary care centers in 25 states. Surveys were sent to 476 providers and we received 279 responses (58.6%). Provider beliefs about risk of HCC recurrence after DAA therapy varied: 48% responded that DAAs reduce risk, 36% responded that DAAs do not change risk, and 16% responded that DAAs increase risk of HCC recurrence. However, most providers believed DAAs to be beneficial to and reduce mortality of patients with complete response to HCC treatment. Accordingly, nearly all providers (94.9%) reported recommending DAA therapy to patients with early-stage HCC who received curative treatment. However, fewer providers recommended DAA therapy for patients with intermediate (72.9%) or advanced (57.5%) HCC undergoing palliative therapies. Timing of DAA initiation varied among providers based on HCC treatment modality: 49.1% of providers reported they would initiate DAA therapy within 3 months of surgical resection whereas 45.9% and 5.0% would delay DAA initiation for 3-12 months and >1 year post-surgery, respectively. For patients undergoing transarterial chemoembolization (TACE), 42.0% of providers would provide DAAs within 3 months of the procedure, 46.7% would delay DAAs until 3-12 months afterward, and 11.3% would delay DAAs more than 1 year after TACE. Based on a survey sent to hepatology providers, there is variation in provider attitudes and practice patterns regarding use and timing of DAAs for patients with HCC. Further studies are needed to characterize the risks and benefits of DAA therapy in this patient population.


Sacred disease of our times: failure of the infectious disease model of spongiform encephalopathy.
Public health and agricultural policy attempts to keep bovine spongiform encephalopathy out of North America using infectious disease containment policies. Inconsistencies of the infectious disease model as it applies to the spongiform encephalopathies may result in failure of these policies. Review of historical, political and scientific literature to determine the appropriate disease model of spongiform encephalopathy. Spongiform encephalopathy has always occurred sporadically in man and other animals. Hippocrates may have described it in goats and cattle. Transmission of spongiform encephalopathy between individuals is too uncommon for it to be usefully considered an infection. Spongiform encephalopathy is a somatic disorder whose dissemination within a host or transmission between individuals is more like cancer than infectious disease. Spongiform encephalopathy transmission within a species is facilitated in comparison to transmission between species so that cannibalism may amplify the prevalence of the disease. Agricultural policy should be directed toward an absolute prohibition on occult cannibalism and away from surveillance, quarantine and slaughter, the principal measures of infectious disease containment used to control bovine spongiform encephalopathy.


Transmembrane domain modulates sorting of membrane proteins in Toxoplasma gondii.
Overlapping mechanisms that function simultaneously in the intracellular sorting of mammalian membrane proteins often confound delineation of individual sorting pathways. By analyzing sorting in the evolutionarily simpler organism Toxoplasma gondii, we demonstrate a role for transmembrane domain (TMD) length in modulating the signal-dependent segregation of membrane proteins to distinct intracellular organelles. The dense granule localization of the single pass transmembrane protein GRA4 could be completely rerouted to the Golgi and cell surface simply by replacement of its TMD with that from either vesicular stomatitis virus G or the low density lipoprotein (LDL) receptor. Mutational and biochemical analyses suggested that this effect was not caused by any specific sequence motif or strength of membrane association of the GRA4 TMD. Instead, a property imparted by the vesicular stomatitis virus G or LDL receptor TMDs, both of which are longer than the GRA4 TMD, appeared to be a decisive factor. Indeed, shortening the LDL receptor TMD to a length similar to that of GRA4 resulted in dense granule localization, whereas lengthening the GRA4 TMD resulted in rerouting to the Golgi. From these data, we conclude that although the TMD may not necessarily be a sole determinant in membrane protein sorting, its properties can markedly modulate the utilization of more conventional signal-mediated sorting pathways.


Can we always ignore ship-generated food waste?
Considerable quantities of food waste can be generated at a rapid rate in ships, particularly those with large numbers of people onboard. By virtue of the amounts involved and its nature, food waste is potentially the most difficult to manage component of a ship's garbage stream, however, in most sea areas it may be dealt with by the simple expedient of direct discharge to sea. As a consequence, only minimal attention is paid to food waste management by many ship and port operators and advisory bodies, and there is a paucity of information in the available literature. The determination that management of ships' food waste is inconsequential is, however, incorrect in many circumstances. Disposal to sea is not always possible due to restrictions imposed by MARPOL 73/78 and other marine pollution control instruments. Effective management of food waste can be critical for ships that operate in areas where disposal is restricted or totally prohibited.


High power dissipative soliton in an Erbium-doped fiber laser mode-locked with a high modulation depth saturable absorber mirror.
We report on a passively mode-locked erbium-doped fiber laser, using a high nonlinear modulation depth saturable absorber mirror, in a Fabry-Perot cavity. A segment of dispersion compensation fiber is added inside the cavity in order to build a high-positive dispersion regime. The setup produced highly chirped pulses with an energy of 1.8 nJ at a repetition rate of 33.5 MHz. Numerical simulations accurately reflect our experimental results and show that pulse-shaping in this laser could be interpreted as producing 'dissipative solitons'.


Susceptibility to disease varies with ontogeny and immunocompetence in a threatened amphibian.
Ontogenetic changes in disease susceptibility have been demonstrated in many vertebrate taxa, as immature immune systems and limited prior exposure to pathogens can place less developed juveniles at a greater disease risk. By causing the disease chytridiomycosis, Batrachochytrium dendrobatidis (Bd) infection has led to the decline of many amphibian species. Despite increasing knowledge on how Bd varies in its effects among species, little is known on the interaction between susceptibility and development within host species. We compared the ontogenetic susceptibility of post-metamorphic green and golden bell frogs Litoria aurea to chytridiomycosis by simultaneously measuring three host-pathogen responses as indicators of the development of the fungus-infection load, survival rate, and host immunocompetence-following Bd exposure in three life stages (recently metamorphosed juveniles, subadults, adults) over 95 days. Frogs exposed to Bd as recently metamorphosed juveniles acquired higher infection loads and experienced lower immune function and lower survivorship than subadults and adults, indicating an ontogenetic decline in chytridiomycosis susceptibility. By corresponding with an intrinsic developmental maturation in immunocompetence seen in uninfected frogs, we suggest these developmental changes in host susceptibility in L. aurea may be immune mediated. Consequently, the physiological relationship between ontogeny and immunity may affect host population structure and demography through variation in life stage survival, and understanding this can shape management targets for effective amphibian conservation.


The importance of interaction in the implementation of information technology in health care: a symbolic interactionism study on the meaning of accessibility.
A challenge when groups from different disciplines work together in implementing health information technology (HIT) in a health-care context is that words often have different meanings depending upon work practices, and definition of situations. Accessibility is a word commonly associated with HIT implementation. This study aimed to investigate different meanings of accessibility when implementing HIT in everyday work practice in a health-care context. It focused on the perspective of nurses to highlight another view of the complex relationship between HIT and information in a health-care context. This is a qualitative study influenced by institutional ethnographic. District nurses and student nurses were interviewed. The results indicate that when implementing HIT accessibility depends on working routines, social structures and patient relationship. The findings of the study suggest that interaction needs to take on a more important role when implementing HIT because people act upon words from the interpreted meaning of them. Symbolic interactionism is proposed as a way to set a mutual stage to facilitate an overall understanding of the importance of the meaning of words. There is a need for making place and space for negotiation of the meaning of words when implementing HIT in everyday work practice.


[Do online ratings reflect structural differences in healthcare? The example of German physician-rating websites].
Previous surveys have shown that patient satisfaction varies with the regional supply of physicians. Online ratings on physician-rating websites represent a relatively new instrument to display patient satisfaction results. The aim of this study was (1) to assess the current state of online ratings for two medical disciplines (dermatologists and ear, nose and throat (ENT) specialists), and (2) to analyze online derived patient satisfaction results according to the physician density in Germany. We collected online ratings for 420 dermatologists and 450 ear, nose, and throat (ENT) specialists on twelve German physician-rating websites. We analyzed the online ratings according to the physician density (low, medium, high physician density). For this purpose, we collected secondary data from both physician-rating websites and the regional associations of statutory health insurance physicians. Data analysis was performed using Median tests and Chi-square tests. In total, 10,239 online ratings for dermatologists and 8,168 online ratings for ENT specialists were analyzed. Almost all dermatologists (99.3 %) and ENT specialists (98.9 %) were listed on one of the physician-rating websites. A total of 93.5 % of all listed dermatologists and 96.9 % of ENT-specialists were rated on at least one of the physician-rating websites. Significant differences were found in the distribution (i.e., percentage of listed or rated physicians) of the ratings according to the regional physician density on only one physician-rating website (p<0.001). Furthermore, online ratings were shown to be better in regions with a higher physician density on two physician-rating website. On jameda.de, for example, dermatologist ratings were better in regions with a higher physician density compared to regions with a lower number of physicians (average rating: 2.16 vs. 2.67; p<0.001). Online ratings of dermatologists and ENT specialists hardly differ in terms of regional physician density. Physician-rating websites thus do not appear to be appropriate to mirror differences in the health service delivery structure. Our findings thus do not confirm the results from previously published studies.


Force-dependent isomerization kinetics of a highly conserved proline switch modulates the mechanosensing region of filamin.
Proline switches, controlled by cis-trans isomerization, have emerged as a particularly effective regulatory mechanism in a wide range of biological processes. In this study, we use single-molecule mechanical measurements to develop a full kinetic and energetic description of a highly conserved proline switch in the force-sensing domain 20 of human filamin and how prolyl isomerization modulates the force-sensing mechanism. Proline isomerization toggles domain 20 between two conformations. A stable cis conformation with slow unfolding, favoring the autoinhibited closed conformation of filamin's force-sensing domain pair 20-21, and a less stable, uninhibited conformation promoted by the trans form. The data provide detailed insight into the folding mechanisms that underpin the functionality of this binary switch and elucidate its remarkable efficiency in modulating force-sensing, thus combining two previously unconnected regulatory mechanisms, proline switches and mechanosensing.


8-plex quantitation of changes in cerebrospinal fluid protein expression in subjects undergoing intravenous immunoglobulin treatment for Alzheimer's disease.
An 8-plex version of an isobaric reagent for the quantitation of proteins using shotgun methods is presented. The 8-plex version of the reagent relies on amine-labeling chemistry of peptides similar to 4-plex reagents. MS/MS reporter ions at 113, 114, 115, 116, 117, 118, 119, and 121 m/z are used to quantify protein expression. This technology which was first applied to a test mixture consisting of eight proteins and resulted in accurate quantitation, has the potential to increase throughput of analysis for quantitative shotgun proteomics experiments when compared to 2- and 4-plex methods. The technology was subsequently applied to a longitudinal study of cerebrospinal fluid (CSF) proteins from subjects undergoing intravenous Ig treatment for Alzheimer's disease. Results from this study identify a number of protein expression changes that occur in CSF after 3 and 6 months of treatment compared to a baseline and compared to a drug washout period. A visualization tool was developed for this dataset and is presented. The tool can aid in the identification of key peptides and measurements. One conclusion aided by the visualization tool is that there are differences in considering peptide-based observations versus protein-based observations from quantitative shotgun proteomics studies.