Attribute development and level selection for a discrete choice experiment to elicit the preferences of health care providers for capitation payment mechanism in Kenya.
Stated preference elicitation methods such as discrete choice experiments (DCEs) are now widely used in the health domain. However, the "quality" of health-related DCEs has come under criticism due to the lack of rigour in conducting and reporting some aspects of the design process such as attribute and level development. Superficially selecting attributes and levels and vaguely reporting the process might result in misspecification of attributes which may, in turn, bias the study and misinform policy. To address these concerns, we meticulously conducted and report our systematic attribute development and level selection process for a DCE to elicit the preferences of health care providers for the attributes of a capitation payment mechanism in Kenya. We used a four-stage process proposed by Helter and Boehler to conduct and report the attribute development and level selection process. The process entailed raw data collection, data reduction, removing inappropriate attributes, and wording of attributes. Raw data was collected through a literature review and a qualitative study. Data was reduced to a long list of attributes which were then screened for appropriateness by a panel of experts. The resulting attributes and levels were worded and pretested in a pilot study. Revisions were made and a final list of attributes and levels decided. The literature review unearthed seven attributes of provider payment mechanisms while the qualitative study uncovered 10 capitation attributes. Then, inappropriate attributes were removed using criteria such as salience, correlation, plausibility, and capability of being traded. The resulting five attributes were worded appropriately and pretested in a pilot study with 31 respondents. The pilot study results were used to make revisions. Finally, four attributes were established for the DCE, namely, payment schedule, timeliness of payments, capitation rate per individual per year, and services to be paid by the capitation rate. By rigorously conducting and reporting the process of attribute development and level selection of our DCE,we improved transparency and helped researchers judge the quality.


Blind Trading: A Literature Review of Research Addressing the Welfare of Ball Pythons in the Exotic Pet Trade.
Extensive numbers of Ball pythons are caught, bred, traded and subsequently kept in captivity across the world as part of the exotic pet industry. Despite their widespread availability as pets, relatively little is known about the potential welfare challenges affecting them. We reviewed the literature for research focused on the health and welfare of Ball pythons in the international pet trade. From a total of 88 articles returned from the search criteria, our analysis showed that very few actually focused on trade (10%) or animal welfare (17%). Instead, the majority (64%) of articles focused on veterinary science. There was a considerable bias towards physical health, with most studies neglecting the four other domains of animal welfare (behaviour, nutrition, environment and mental health). Furthermore, very few studies considered Ball pythons prior to resulting pet ownership, during wild capture and transportation or captive breeding operations. Our review demonstrates that our current understanding of welfare for Ball pythons traded as exotic pets is limited. We recommend that future research should focus on aspects of the industry that are currently overlooked, including the potential consequences of genetic selection during captive-breeding and the conditions provided for snakes prior to and during international transportation.


High-throughput Screening in Larval Zebrafish Identifies Novel Potent Sedative-hypnotics.
WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Many general anesthetics were discovered empirically, but primary screens to find new sedative-hypnotics in drug libraries have not used animals, limiting the types of drugs discovered. The authors hypothesized that a sedative-hypnotic screening approach using zebrafish larvae responses to sensory stimuli would perform comparably to standard assays, and efficiently identify new active compounds. The authors developed a binary outcome photomotor response assay for zebrafish larvae using a computerized system that tracked individual motions of up to 96 animals simultaneously. The assay was validated against tadpole loss of righting reflexes, using sedative-hypnotics of widely varying potencies that affect various molecular targets. A total of 374 representative compounds from a larger library were screened in zebrafish larvae for hypnotic activity at 10 µM. Molecular mechanisms of hits were explored in anesthetic-sensitive ion channels using electrophysiology, or in zebrafish using a specific reversal agent. Zebrafish larvae assays required far less drug, time, and effort than tadpoles. In validation experiments, zebrafish and tadpole screening for hypnotic activity agreed 100% (n = 11; P = 0.002), and potencies were very similar (Pearson correlation, r > 0.999). Two reversible and potent sedative-hypnotics were discovered in the library subset. CMLD003237 (EC50, ~11 µM) weakly modulated γ-aminobutyric acid type A receptors and inhibited neuronal nicotinic receptors. CMLD006025 (EC50, ~13 µM) inhibited both N-methyl-D-aspartate and neuronal nicotinic receptors. Photomotor response assays in zebrafish larvae are a mechanism-independent platform for high-throughput screening to identify novel sedative-hypnotics. The variety of chemotypes producing hypnosis is likely much larger than currently known.


Origin and evolution of the octoploid strawberry genome.
Cultivated strawberry emerged from the hybridization of two wild octoploid species, both descendants from the merger of four diploid progenitor species into a single nucleus more than 1 million years ago. Here we report a near-complete chromosome-scale assembly for cultivated octoploid strawberry (Fragaria × ananassa) and uncovered the origin and evolutionary processes that shaped this complex allopolyploid. We identified the extant relatives of each diploid progenitor species and provide support for the North American origin of octoploid strawberry. We examined the dynamics among the four subgenomes in octoploid strawberry and uncovered the presence of a single dominant subgenome with significantly greater gene content, gene expression abundance, and biased exchanges between homoeologous chromosomes, as compared with the other subgenomes. Pathway analysis showed that certain metabolomic and disease-resistance traits are largely controlled by the dominant subgenome. These findings and the reference genome should serve as a powerful platform for future evolutionary studies and enable molecular breeding in strawberry.


Longitudinal Brain Development of Numerical Skills in Typically Developing Children and Children with Developmental Dyscalculia.
Developmental dyscalculia (DD) is a learning disability affecting the acquisition of numerical-arithmetical skills. Studies report persistent deficits in number processing and aberrant functional activation of the fronto-parietal numerical network in DD. However, the neural development of numerical abilities has been scarcely investigated. The present paper provides a first attempt to investigate behavioral and neural trajectories of numerical abilities longitudinally in typically developing (TD) and DD children. During a study period of 4 years, 28 children (8-11 years) were evaluated twice by means of neuropsychological tests and a numerical order fMRI paradigm. Over time, TD children improved in numerical abilities and showed a consistent and well-developed fronto-parietal network. In contrast, DD children revealed persistent deficits in number processing and arithmetic. Brain imaging results of the DD group showed an age-related activation increase in parietal regions (intraparietal sulcus), pointing to a delayed development of number processing areas. Besides, an activation increase in frontal areas was observed over time, indicating the use of compensatory mechanisms. In conclusion, results suggest a continuation in neural development of number representation in DD, whereas the neural network for simple ordinal number estimation seems to be stable or show only subtle changes in TD children over time.


Prebiological evolution and the metabolic origins of life.
The chemoton model of cells posits three subsystems: metabolism, compartmentalization, and information. A specific model for the prebiological evolution of a reproducing system with rudimentary versions of these three interdependent subsystems is presented. This is based on the initial emergence and reproduction of autocatalytic networks in hydrothermal microcompartments containing iron sulfide. The driving force for life was catalysis of the dissipation of the intrinsic redox gradient of the planet. The codependence of life on iron and phosphate provides chemical constraints on the ordering of prebiological evolution. The initial protometabolism was based on positive feedback loops associated with in situ carbon fixation in which the initial protometabolites modified the catalytic capacity and mobility of metal-based catalysts, especially iron-sulfur centers. A number of selection mechanisms, including catalytic efficiency and specificity, hydrolytic stability, and selective solubilization, are proposed as key determinants for autocatalytic reproduction exploited in protometabolic evolution. This evolutionary process led from autocatalytic networks within preexisting compartments to discrete, reproducing, mobile vesicular protocells with the capacity to use soluble sugar phosphates and hence the opportunity to develop nucleic acids. Fidelity of information transfer in the reproduction of these increasingly complex autocatalytic networks is a key selection pressure in prebiological evolution that eventually leads to the selection of nucleic acids as a digital information subsystem and hence the emergence of fully functional chemotons capable of Darwinian evolution.


Cytomorphologic findings of malignant mesothelioma in FNA biopsies and touch preps of core biopsies.
Given the lack of recent literature regarding the aspiration cytology of immunohistochemically confirmed malignant mesothelioma (MM), we were interested in reviewing the experience of our institution and establishing useful morphologic criteria. Seventeen aspiration and touch preparation specimens with a diagnosis of MM obtained between 2002-2013 were reviewed along with 20 cases of adenocarcinoma and 16 cases of squamous cell carcinoma. The utility of a number of morphologic features was evaluated. In most cases of MM, a consistent pattern emerged. Aspirates and touch preps were cellular with irregularly shaped 2 and 3 dimensional clusters. The individual cells were predominantly angulated and had dense cytoplasm with eccentric nuclei. In every case, a minority of tumor cells contained prominent microvacuoles. The chromatin pattern tended to be fine with small nucleoli. While most cases were cytologically monotonous, five cases displayed striking pleomorphism and three cases contained occasional large atypical cells. Two cases contained metachromatic background material. Features which were most useful in discriminating MM from adenocarcinoma were angulated cell shape(P = 0.0002), dense cytoplasm(P = 0.0001), and cytoplasmic microvacuoles(P = 0.0001). In our material, cases of squamous cell carcinoma were often difficult to distinguish from MM. Useful discriminatory features present in squamous cell carcinoma included ink dot nuclei(P = 0.0003), a "dirty" cystic, necrotic background (P = 0.0027) and tumor balls with peripheral spindling(P = 0.0041). Most cases of MM have a consistent appearance in core biopsy touch preps and FNAs. Distinguishing MM from adenocarcinoma and squamous cell carcinoma can be facilitated by evaluating a few key morphologic features.


[The pathophysiology of irritable bowel syndrome: inflammation and motor disorder].
Irritable bowel syndrome (IBS) is one of the most common disorders and a heterogeneous condition in view of symptoms and underlying mechanisms. Though underlying causes of pathophysiologic changes remain unclear, low grade mucosal inflammation and abnormal intestinal motility are accepted mechanisms which alter gut function and generate symptoms of IBS. First, before 1980s, abnormal colonic and rectal motor functions were regarded as the main pathophysiology of IBS, but only 25-75% of IBS patients have apparent motor abnormalities which differ from the motor functions in normal controls. So, various gastrointestinal motility tests were not indicated for the diagnosis of IBS. The high-amplitude propagating contractions of colon in IBS patients may be related to the visceral pain perception. Second, the low grade mucosal inflammation may be involved in the pathophysiology of visceral hypersensitivity. Post infectious IBS (PI-IBS) occupied 6-17% of the total IBS and some previous prospective studies reported that 7-33% of acute bacterial enteritis patients developed IBS after 6-12 months of infection. The relative risk of IBS in the gastroenteritis cohort was 11.9 and the strongest risk factor is the duration of diarrhea. After enteritis event, the increased number of immunocytes, mast cells and large amount of lymphocytes infiltration were revealed in mucosa and enteric nervous system of the gut. Beside the inflammatory cells, enterochromaffin cells, cytokines and inducible nitric oxide may be related to the pathophysiologic mechanism of PI-IBS. Lastly, the abnormalities in the gastrointestinal autonomic nervous system can induce constipation or motor disorders, but further research should elucidate it.


CO2 induced seawater acidification impacts sea urchin larval development I: elevated metabolic rates decrease scope for growth and induce developmental delay.
Anthropogenic CO(2) emissions are acidifying the world's oceans. A growing body of evidence is showing that ocean acidification impacts growth and developmental rates of marine invertebrates. Here we test the impact of elevated seawater pCO(2) (129 Pa, 1271 μatm) on early development, larval metabolic and feeding rates in a marine model organism, the sea urchin Strongylocentrotus purpuratus. Growth and development was assessed by measuring total body length, body rod length, postoral rod length and posterolateral rod length. Comparing these parameters between treatments suggests that larvae suffer from a developmental delay (by ca. 8%) rather than from the previously postulated reductions in size at comparable developmental stages. Further, we found maximum increases in respiration rates of +100% under elevated pCO(2), while body length corrected feeding rates did not differ between larvae from both treatments. Calculating scope for growth illustrates that larvae raised under high pCO(2) spent an average of 39 to 45% of the available energy for somatic growth, while control larvae could allocate between 78 and 80% of the available energy into growth processes. Our results highlight the importance of defining a standard frame of reference when comparing a given parameter between treatments, as observed differences can be easily due to comparison of different larval ages with their specific set of biological characters.


'I know you shouldn't compare to other people, but I can't do anything most people can': Age, family and occupation categorisations in men's reasoning about their anxiety in an online discussion forum.
Despite its prevalence, men's anxiety is arguably under-researched and poorly understood. The present study explores the reasoning provided by male posters to an online discussion forum about the source of their anxiety. Posts were collected from an Australian anxiety online discussion forum. This study utilises discursive psychology, informed by principles of membership categorisation analysis, to describe how age, occupation and family-related identities can be invoked within common sense reasoning about the source of male anxiety. References to various identity categories were routinely employed by male forum posters in their representations of themselves, in order to describe the source of their anxiety in terms of a contrast between how they are, and how they should be. In examining accounts of anxiety and responses to those accounts, we can trace cultural knowledge about issues regarding men, masculinity and anxiety that those accounts make relevant. Findings illustrate how men's descriptions of the source of their anxiety should be understood as culturally bound and related to expectations and obligations associated with their social context and category memberships. By enhancing understandings of how men describe the source of their anxiety, this study offers insight into improving the identification and engagement of men experiencing anxiety in health services.


A clinicopathologic study of mantle cell lymphoma in a single center study in India.
We present clinical features, histopathology and results of treatment in cases of mantle cell lymphoma (MCL) at our hospital. We had 93 cases (2.1%) of MCL out of total 4301 cases of non-Hodgkin's lymphoma (NHL) in a 4-year period. It included 68 cases (1.7%) of MCL from 3987 cases of NHL diagnosed on histopathology. Remaining 25 cases (7.9%) diagnosed solely on peripheral blood examination were excluded. Thirty-six (85%) patients had advanced-stage disease. Sixty-three were nodal and five were extranodal (all gastrointestinal tract). Common patterns were diffuse (64%), nodular (25%) and mantle zone type (11%). Sixty-two cases had lymphocytic while six had blastic morphology (all nodal). Tumor cells expressed CD20 (100%), CD43 (94%), CD5 (89%) and cyclin D1 (85%). Bone marrow was involved in 25 (59%) cases. Thirty-two patients could be treated. Median recurrence-free survival was 22.23 months. Diffuse pattern of nodal involvement had a lower overall survival.


Cell-cycle regulated transcription associates with DNA replication timing in yeast and human.
Eukaryotic DNA replication follows a specific temporal program, with some genomic regions consistently replicating earlier than others, yet what determines this program is largely unknown. Highly transcribed regions have been observed to replicate in early S-phase in all plant and animal species studied to date, but this relationship is thought to be absent from both budding yeast and fission yeast. No association between cell-cycle regulated transcription and replication timing has been reported for any species. Here I show that in budding yeast, fission yeast, and human, the genes most highly transcribed during S-phase replicate early, whereas those repressed in S-phase replicate late. Transcription during other cell-cycle phases shows either the opposite correlation with replication timing, or no relation. The relationship is strongest near late-firing origins of replication, which is not consistent with a previously proposed model—that replication timing may affect transcription—and instead suggests a potential mechanism involving the recruitment of limiting replication initiation factors during S-phase. These results suggest that S-phase transcription may be an important determinant of DNA replication timing across eukaryotes, which may explain the well-established association between transcription and replication timing.


APOBEC3A is an oral cancer prognostic biomarker in Taiwanese carriers of an APOBEC deletion polymorphism.
Oral squamous cell carcinoma is a prominent cancer worldwide, particularly in Taiwan. By integrating omics analyses in 50 matched samples, we uncover in Taiwanese patients a predominant mutation signature associated with cytidine deaminase APOBEC, which correlates with the upregulation of APOBEC3A expression in the APOBEC3 gene cluster at 22q13. APOBEC3A expression is significantly higher in tumors carrying APOBEC3B-deletion allele(s). High-level APOBEC3A expression is associated with better overall survival, especially among patients carrying APOBEC3B-deletion alleles, as examined in a second cohort (n = 188; p = 0.004). The frequency of APOBEC3B-deletion alleles is ~50% in 143 genotyped oral squamous cell carcinoma -Taiwan samples (27A3B -/-:89A3B +/-:27A3B +/+), compared to the 5.8% found in 314 OSCC-TCGA samples. We thus report a frequent APOBEC mutational profile, which relates to a APOBEC3B-deletion germline polymorphism in Taiwanese oral squamous cell carcinoma that impacts expression of APOBEC3A, and is shown to be of clinical prognostic relevance. Our finding might be recapitulated by genomic studies in other cancer types.Oral squamous cell carcinoma is a prevalent malignancy in Taiwan. Here, the authors show that OSCC in Taiwanese show a frequent deletion polymorphism in the cytidine deaminases gene cluster APOBEC3 resulting in increased expression of A3A, which is shown to be of clinical prognostic relevance.


Fused in sarcoma (FUS): an oncogene goes awry in neurodegeneration.
Fused in sarcoma (FUS) is a nuclear DNA/RNA binding protein that regulates different steps of gene expression, including transcription, splicing and mRNA transport. FUS has been implicated in neurodegeneration, since mutations in FUS cause familial amyotrophic lateral sclerosis (ALS-FUS) and lead to the cytosolic deposition of FUS in the brain and spinal cord of ALS-FUS patients. Moreover, FUS and two related proteins of the same protein family (FET family) are co-deposited in cytoplasmic inclusions in a subset of patients with frontotemporal lobar degeneration (FTLD-FUS). Cytosolic deposition of these otherwise nuclear proteins most likely causes the loss of a yet unknown essential nuclear function and/or the gain of a toxic function in the cytosol. Here we summarize what is known about the physiological functions of the FET proteins in the nucleus and cytoplasm and review the distinctive pathomechanisms that lead to the deposition of only FUS in ALS-FUS, but all three FET proteins in FTLD-FUS. We suggest that ALS-FUS is caused by a selective dysfunction of FUS, while FTLD-FUS may be caused by a dysfunction of the entire FET family. This article is part of a Special Issue entitled 'RNA and splicing regulation in neurodegeneration'.


Prediction of interacting proteins from homology-modeled complex structures using sequence and structure scores.
Protein-protein interactions support most biological processes, and it is important to find specifically interacting partner proteins among homologous proteins in order to elucidate cellular functions such as signal transduction systems. Various high-throughput experimental methods for identifying these interactions have been invented, and used to generate a huge amount of data. Because these experiments have been applied to only a few organisms, and their accuracy is believed to be limited, it would be valuable to develop computational methods for predicting protein-protein interactions from their amino acid sequences or tertiary structural information. In this study, we describe a prediction method of interacting proteins based on homology-modeled complex structures. We employed the statistical residue-residue contact energy used in a previous study, and two types of new scores, simple electrostatic energy and sequence similarity between target sequences and template structures. The validity of each protein-protein complex model was measured using their single and combined scores. We applied our method to all the protein heterodimers of Saccharomyces cerevisiae. To evaluate the prediction performance of our method, we prepared two types of protein-protein interaction dataset: a complete dataset and high confidence dataset. The complete dataset (10,325 protein dimer models) contains all the yeast protein heterodimers whose complex structures can be modeled. Among them, pairs registered in the DIP database are defined as interacting pairs, and those not registered are defined as non-interacting protein pairs. The high confidence dataset (3,219 protein dimer models) is a more reliable subset of the complete dataset extracted using the criteria of the common subcellular localization. Both datasets show that sequence similarity has a much higher discrimination power than the other structure-based scores, but that the inclusion of contact energy results in significant improvement over predictions using sequence similarity alone. These results suggest that the sequence similarity is indispensable for the prediction, whereas structure scores can play supporting roles.


Association between body mass index and colorectal neoplasia at follow-up colonoscopy: a pooling study.
A direct relation between body mass index (BMI) and risk of colorectal adenomas and cancer has been reported, but few studies have had adequate sample size for conducting stratified analyses by sex, family history, colorectal subsite, or features of metachronous lesions. Data from 8,213 participants in 7 prospective studies of metachronous colorectal adenomas were pooled to assess whether the association between BMI and metachronous neoplasia varied by these factors. A statistically significant direct association between BMI and the odds of nonadvanced adenomas (P(trend) < 0.001) was observed, while the relation for advanced adenomas was of marginal significance (P(trend) < 0.07). In sex-stratified analyses, obesity was statistically significantly associated with the odds of any metachronous lesion among men (odds ratio = 1.36, 95% confidence interval: 1.17, 1.58) but not among women (odds ratio = 1.10, 95% confidence interval: 0.89, 1.37). The associations with BMI appeared to be limited to proximal neoplasia, with statistically significant results for BMI and proximal (P(trend) < 0.001), but not distal (P(trend) < 0.85), neoplasia. Exploratory analyses indicated that BMI was significantly related to most histologic characteristics of metachronous adenomas among men but not among women. Our results provide further support for the association between BMI and metachronous colorectal adenomas, particularly among men, thereby indicating that body size may affect colorectal carcinogenesis at comparatively early stages.


Detection of HPV 16 and HPV 18 DNA in the blood of patients with cervical cancer.
Persistent infection of the uterine cervix with high-risk human papillomaviruses (HPV) is causally associated with cancer of the cervix. A few studies have reported the presence of HPV DNA in the blood of women with cervical neoplasia. The aim of this study was to determine if HPV DNA could be detected in whole blood of women with a range of cervical pathologies and with HPV 16 or 18 cervical infections and if there is a correlation between cervical lesion grade and the appearance of HPV DNA in the circulatory system. Forty-five women with histologically graded cervical cancer were confirmed to have cervical HPV 16 or 18 infections. Eleven (24.4%) of these women had detectable HPV 16 or 18 in their blood. The HPV types detected in the blood matched those detected at the cervix. No HPV 16 or 18 DNA was detected in the blood of 32 women with pre-cursor cervical lesions or normal cervical pathology but who had cervical HPV 16 or 18 infections. One of 77 women with normal cervical pathology and no cervical HPV infection was positive for HPV 16 DNA in her blood. The results indicate that HPV DNA can be detected in the blood of women with more advanced cervical carcinomas but not in the blood of women with pre-cursor cervical lesions. The results of our study indicate that the role of HPV DNA in the circulatory system appears not be of diagnostic significance and HPV DNA is only detectable in women with more advanced cervical cancers.


[Pharmacy and therapeutics committees in Brazil: lagging behind international standards].
The inadequate use of drugs leads to lack of therapeutic efficacy, adverse reactions, side effects, preventable drug interactions, increased bacterial resistance to antibiotics, and wasted resources. Changing this scenario is one of the most complex challenges facing health systems today. One approach used to rationalize the use of drugs lies in the creation of pharmacy and therapeutics committees, whose main role is to guide and assist health institutions at all levels in selecting drugs and monitoring their use, training professionals to use drugs rationally, and collecting systematized information to guide new strategies and actions. Brazil, unlike other parts of the world, does not make it compulsory to have pharmacy and therapeutics committees. Although committees for monitoring hospital infections are compulsory in that country, their action is restricted to hospitals and is not as broad as that proposed for pharmacy and therapeutics committees. Data from 2003 shows that among 250 public and private hospitals in Brazil, only 29 had pharmacy and therapeutics committees. It is essential that the need to make these committees compulsory at all levels of the Brazilian health system be discussed, and that the national Ministry of Health and other related agencies create the conditions necessary for the establishment of pharmacy and therapeutics committees, in accordance with other health policies currently in place.


Progress report on new antiepileptic drugs: A summary of the Thirteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIII).
The Thirteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIII) took place in Madrid, Spain, on June 26-29, 2016, and was attended by >200 delegates from 31 countries. The present Progress Report provides an update on experimental and clinical results for drugs presented at the Conference. Compounds for which summary data are presented include an AED approved in 2016 (brivaracetam), 12 drugs in phase I-III clinical development (adenosine, allopregnanolone, bumetanide, cannabidiol, cannabidivarin, 2-deoxy-d-glucose, everolimus, fenfluramine, huperzine A, minocycline, SAGE-217, and valnoctamide) and 6 compounds or classes of compounds for which only preclinical data are available (bumetanide derivatives, sec-butylpropylacetamide, FV-082, 1OP-2198, NAX 810-2, and SAGE-689). Overall, the results presented at the Conference show that considerable efforts are ongoing into discovery and development of AEDs with potentially improved therapeutic profiles compared with existing agents. Many of the drugs discussed in this report show innovative mechanisms of action and many have shown promising results in patients with pharmacoresistant epilepsies, including previously neglected rare and severe epilepsy syndromes.


Factors affecting the stability of blood lipid and lipoprotein levels from youth to adulthood: evidence from the Childhood Determinants of Adult Health Study.
To examine the effect of lifestyle changes on the stability of blood lipid and lipoprotein levels from youth to adulthood. Prospective cohort study. Australia. Five hundred thirty-nine young adults who underwent measurement at baseline in 1985 when aged 9, 12, or 15 years and again at follow-up between 2004 and 2006. Changes in adiposity, cardiorespiratory fitness, saturated fat intake, smoking, and socioeconomic position. Child and adult blood lipid levels. Using established cut points, we found that substantial proportions of individuals with high-risk blood lipid and lipoprotein levels at baseline no longer had high-risk levels at follow-up. Of the participants who had high-risk levels in youth, those with greater increases in adiposity or who commenced or continued smoking were more likely to maintain high-risk blood lipid and lipoprotein levels (P < .05). Participants who became high risk at follow-up had greater increases in adiposity, were less likely to improve their socioeconomic position, and tended to become less fit between surveys compared with those who maintained normal-risk levels (P ≤ .05). These effects tended to remain (P ≤ .10) after adjustment for all predictive lifestyle variables. Unhealthy lifestyle changes that occur between youth and adulthood affect whether an individual maintains, loses, or develops high-risk blood lipid and lipoprotein levels in adulthood. Interventions that promote weight control in the first instance, but also physical activity, not smoking, and improved socioeconomic position in the transition from youth to adulthood, are likely to be of benefit in preventing adult dyslipidemia.


Genetic properties influencing the evolvability of gene expression.
Identifying the properties of gene networks that influence their evolution is a fundamental research goal. However, modes of evolution cannot be inferred solely from the distribution of natural variation, because selection interacts with demography and mutation rates to shape polymorphism and divergence. We estimated the effects of naturally occurring mutations on gene expression while minimizing the effect of natural selection. We demonstrate that sensitivity of gene expression to mutations increases with both increasing trans-mutational target size and the presence of a TATA box. Genes with greater sensitivity to mutations are also more sensitive to systematic environmental perturbations and stochastic noise. These results provide a mechanistic basis for gene expression evolvability that can serve as a foundation for realistic models of regulatory evolution.


Human DNA Exonuclease TREX1 Is Also an Exoribonuclease That Acts on Single-stranded RNA.
3' repair exonuclease 1 (TREX1) is a known DNA exonuclease involved in autoimmune disorders and the antiviral response. In this work, we show that TREX1 is also a RNA exonuclease. Purified TREX1 displays robust exoribonuclease activity that degrades single-stranded, but not double-stranded, RNA. TREX1-D200N, an Aicardi-Goutieres syndrome disease-causing mutant, is defective in degrading RNA. TREX1 activity is strongly inhibited by a stretch of pyrimidine residues as is a bacterial homolog, RNase T. Kinetic measurements indicate that the apparent Km of TREX1 for RNA is higher than that for DNA. Like RNase T, human TREX1 is active in degrading native tRNA substrates. Previously reported TREX1 crystal structures have revealed that the substrate binding sites are open enough to accommodate the extra hydroxyl group in RNA, further supporting our conclusion that TREX1 acts on RNA. These findings indicate that its RNase activity needs to be taken into account when evaluating the physiological role of TREX1.


Pervasive population genomic consequences of genome duplication in Arabidopsis arenosa.
Ploidy-variable species allow direct inference of the effects of chromosome copy number on fundamental evolutionary processes. While an abundance of theoretical work suggests polyploidy should leave distinct population genomic signatures, empirical data remains sparse. We sequenced ~300 individuals from 39 populations of Arabidopsis arenosa, a naturally diploid-autotetraploid species. We find that the impacts of polyploidy on population genomic processes are subtle yet pervasive, such as reduced efficiency of purifying selection, differences in linked selection and rampant gene flow from diploids. Initial masking of deleterious mutations, faster rates of nucleotide substitution and interploidy introgression likely conspire to shape the evolutionary potential of polyploids.


Spatiotemporal dynamics of modality-specific and supramodal word processing.
The ability of written and spoken words to access the same semantic meaning provides a test case for the multimodal convergence of information from sensory to associative areas. Using anatomically constrained magnetoencephalography (aMEG), the present study investigated the stages of word comprehension in real time in the auditory and visual modalities, as subjects participated in a semantic judgment task. Activity spread from the primary sensory areas along the respective ventral processing streams and converged in anterior temporal and inferior prefrontal regions, primarily on the left at around 400 ms. Comparison of response patterns during repetition priming between the two modalities suggest that they are initiated by modality-specific memory systems, but that they are eventually elaborated mainly in supramodal areas.


Resveratrol interferes with the aggregation of membrane-bound human-IAPP: a molecular dynamics study.
Amyloid aggregation of islet amyloid polypeptide (IAPP) in pancreatic tissues is a typical feature of type 2 diabetes mellitus. Resveratrol, a natural product extensively studied for its wide range of biological effects, has been shown to inhibit IAPP aggregation. However, the mechanism by which resveratrol inhibits IAPP aggregation is still far from complete elucidation. Now, an increasing knowledge of the mechanism of amyloid toxicity shifts the target of research towards the development of compounds which can prevent amyloid-mediated membrane damage rather than merely inhibit fiber formation. In this study we used all atom molecular dynamics to investigate the interaction of resveratrol with full-length human IAPP in a negatively charged membrane environment. Our results show that the presence of resveratrol induces the formation of secondary structures (sheets and helices) by inserting in a hydrophobic pocket between the interaction surface of two IAPP molecules in aqueous solution. On the other hand, resveratrol significantly perturbs the interaction of IAPP with negatively charged membranes by anchoring specific hydrophobic regions (23FGA25 and 32VGS34) of the peptide and forming a stable 1:2 IAPP:resveratrol complex at the water/membrane interphase.


[DNA damage and repair induced by acute exposure of microwave from mobile phone on cultured human lens epithelial cells].
To investigate the effects of acute exposure of low-power 217 Hz modulated 1. 8 GHz microwave radiation on the DNA damage of human lens epithelial cells (hLECs) and repair. Cultured hLECs were exposed to 217 Hz modulated 1. 8 GHz microwave radiation at SAR (specific absorption rate) of 1. 0, 2. 0, 3. O0 and 4. 0 W/kg for 2 hours in an sXc-1800 incubator and irradiate system, the DNA single strand breaks were detected with comet assay ( single-cell gel electrophoresis) in sham-irradiated cells and irradiated cells incubated for varying periods: 0, 30 and 60 minutes after irradiation. Images of comets were digitized and analyzed using an Imagine-pro plus software, and the indexes used in this study were tail length (TL) and tail moment (TM). BrdU was added into the medium with additional one hour incubation after radiation, the cell proliferation rate was determined using a BrdU-kit. The difference of DNA-breaks between the exposure and sham exposure groups induced by 1.0 and 2.0 W/kg irradiation were not significant in each time points (P > 0.05) ; there were significant difference in both groups at the exposure dose of 3. 0 and 4. 0 W/kg immediately and at the time of 30 minutes after irradiation (P <0. 01) ; if the radiation exposure time was beyond one hour no differences were be able to detected in 3.0 W/kg group (P > 0. 05) compared with control, but the evidence of significant DNA damage still existed in 4. 0 W/kg group at the same time point. Cell proliferation rate had no significant difference when the application of SAR was < or = 3. 0 W/kg (P >0. 05) , however the cell proliferation was decreased significantly at the dose of 4. 0 W/kg irradiation ( P < 0. 01). No effective DNA damage was induced using comet assay after 2 hours irradiation of 1. 8 GHz microwave on hLECs at the dose SAR < or = 3.0 W/kg. 4.0 W/kg irradiation caused significantly DNA damage and inhibition of hLECs proliferation.


Neurophysiologic evaluation of auditory recognition memory in healthy newborn infants and infants of diabetic mothers.
We evaluated the integrity of neural pathways for auditory recognition memory in normal newborn infants (n = 32) and infants of diabetic mothers (IDMs, n = 25). IDMs are at risk for fetal metabolic abnormalities that potentially damage recognition memory pathways. We hypothesized that newborn IDMs would have recognition memory deficits that would be correlated with later cognitive development. Recognition memory was assessed with event-related potentials (ERPs). Neonatal ERPs elicited by the maternal voice were compared with those elicited by a stranger's voice. The Bayley Scales of Infant Development were administered at 1 year of age. Infants in both the control and IDM groups demonstrated recognition of the maternal voice, but their ERP patterns differed. Both groups demonstrated increased amplitude and latency for the "P2" peak elicited by the maternal voice compared with the stranger's voice. In the control group the stranger's voice also elicited a negative slow wave, which was attenuated in the IDMs. The negative slow wave correlated significantly with the 1-year Mental Developmental Index. The presence of a specific neonatal ERP pattern indicated better 1-year cognitive development in infants in the control and IDM groups. ERPs from IDMs demonstrated subtle evidence of recognition memory impairments.


Val-ala-pro-gly, an elastin-derived non-integrin ligand: smooth muscle cell adhesion and specificity.
The elastin-derived peptide val-ala-pro-gly (VAPG) may be useful as a biospecific cell adhesion ligand for smooth muscle cells. By grafting the peptide sequence into a hydrogel material, we were able to assess its effects on smooth muscle cell adhesion and spreading. These materials are photopolymerizable hydrogels based on acrylate-terminated derivatives of polyethylene glycol (PEG). Because of their high PEG content, these materials are highly resistant to protein adsorption and cell adhesion. However, PEG diacrylate derivatives can be mixed with adhesive peptide-modified PEG monoacrylate derivatives to facilitate cell adhesion. Following photopolymerization, PEG monoacrylate derivatives are grafted into the hydrogel network formed by the PEG diacrylate. This results in covalent immobilization of adhesive peptides to the hydrogel via a flexible linker chain. The resistance of PEG to protein adsorption makes it an ideal material for this model system since cell-material interactions are limited to biomolecules that are covalently incorporated into the material. In this case we were able to demonstrate that VAPG is specific for adhesion of smooth muscle cells. It also was shown that fibroblasts, endothelial cells, and platelets cannot adhere to VAPG. In addition, not only was smooth muscle cell adhesion dependent on ligand concentration, but also cell spreading increased with increasing ligand concentration.


Plasticity of the muscle proteome to exercise at altitude.
The ascent of humans to the summits of the highest peaks on Earth initiated a spurt of explorations into the physiological consequences of physical activity at altitude. The past three decades have demonstrated that the resetting of respiratory and cardiovascular control with chronic exposure to altitudes above 4000 m is accompanied by important structural-functional adjustments of skeletal muscle. The fully altitude-adapted phenotype preserves energy charge at reduced aerobic capacity through the promotion of anaerobic substrate flux and tighter metabolic control, often at the expense of muscle mass. In seeming contrast, intense physical activity at moderate hypoxia (2500 to 4000 m) modifies this response in both low and high altitude natives through metabolic compensation by elevating local aerobic capacity and possibly preventing muscle fiber atrophy. The combined use of classical morphometry and contemporary proteomic technology provides a highly resolved picture of the temporal control of hypoxia-induced muscular adaptations. The muscle proteome signature identifies mitochondrial autophagy and protein degradation as prime adaptive mechanisms to passive altitude exposure and ascent to extreme altitude. Protein measures also explain the lactate paradox by a sparing of glycolytic enzymes from general muscle wasting. Enhanced mitochondrial and angiogenic protein expression in human muscle with exercise up to 4000 m is related to the reduction in intramuscular oxygen content below 1% (8 torr), when the master regulator of hypoxia-dependent gene expression, HIF-1alpha, is stabilized. Accordingly, it is proposed here that the catabolic consequences of chronic hypoxia exposure reflect the insufficient activation of hypoxia-sensitive signaling and the suppression of energy-consuming protein translation.


Mathematical Model for Biomolecular Quantification Using Large-Area Surface-Enhanced Raman Spectroscopy Mapping.
Surface-enhanced Raman spectroscopy (SERS) based on nanostructured platforms is a promising technique for quantitative and highly sensitive detection of biomolecules in the field of analytical biochemistry. Here, we report a mathematical model to predict experimental SERS signal (or hotspot) intensity distributions of target molecules on receptor-functionalized nanopillar substrates for biomolecular quantification. We demonstrate that by utilizing only a small set of empirically determined parameters, our general theoretical framework agrees with the experimental data particularly well in the picomolar concentration regimes. This developed model may be generally used for biomolecular quantification using Raman mapping on SERS substrates with planar geometries, in which the hotspots are approximated as electromagnetic enhancement fields generated by closely spaced dimers. Lastly, we also show that the detection limit of a specific target molecule, TAMRA-labeled vasopressin, approaches the single molecule level, thus opening up an exciting new chapter in the field of SERS quantification.


Dynamics of influenza virus infection and pathology.
A key question in pandemic influenza is the relative roles of innate immunity and target cell depletion in limiting primary infection and modulating pathology. Here, we model these interactions using detailed data from equine influenza virus infection, combining viral and immune (type I interferon) kinetics with estimates of cell depletion. The resulting dynamics indicate a powerful role for innate immunity in controlling the rapid peak in virus shedding. As a corollary, cells are much less depleted than suggested by a model of human influenza based only on virus-shedding data. We then explore how differences in the influence of viral proteins on interferon kinetics can account for the observed spectrum of virus shedding, immune response, and influenza pathology. In particular, induction of high levels of interferon ("cytokine storms"), coupled with evasion of its effects, could lead to severe pathology, as hypothesized for some fatal cases of influenza.


The effect of claw horn disruption lesions and body condition score at dry-off on survivability, reproductive performance, and milk production in the subsequent lactation.
The objective of this study was to evaluate the effects of claw horn disruption lesions (CHDL; sole ulcers and white line disease) and body condition score (BCS) at dry-off on survivability, milk production, and reproductive performance during the subsequent lactation. An observational prospective cohort study was conducted on a large commercial dairy in Cayuga County, New York, from September 2008 until January 2009. A total of 573 cows enrolled at dry-off were scored for body condition and hoof trimmed; digits were visually inspected for the presence of CHDL. The BCS data were recategorized into a 3-level variable BCS group (BCSG), with cows with BCS<3 placed in BCSG 1 (n=113), cows with BCS=3 placed in BCSG 2 (n=254), and cows with BCS>3 placed in BCSG 3 (n=206). Cows in BCSG 2 were 1.35 and 1.02 times more likely to conceive than cows in BCSG 1 and 3, respectively. The cull/death hazard for BCSG 1 cows was 1.55 and 1.47 times higher than for cows in BCSG 2 and BCSG 3, respectively. Milk yield for cows in BCSG 2 (44.6 kg/d, 95% CI 43.4-45.8) was significantly greater than that for cows in BCSG 1 (41.5 kg/d, 95% CI 39.8-43.3). Cows with previous lactation days open<or=91 had 1.6 times higher odds of being classified into BCSG 1 at dry-off; cows with previous lactation mature-equivalent 305-d milk>14,054 kg had a similar 1.6 times higher odds of being classified into BCSG 1. Claw horn disruption lesions were found in 24.4% of the cows (n=140) at dry-off. Cows without CHDL were 1.4 times more likely to conceive than cows with CHDL. Additionally, lesion cows were 1.7 times more likely to die or be culled than nonlesion cows. Absence of CHDL did not have a significant effect on milk yield. These findings highlight the importance of claw health and BCS at the end of lactation on future survival and performance.


The SycN/YscB chaperone-binding domain of YopN is required for the calcium-dependent regulation of Yop secretion by Yersinia pestis.
Numerous Gram-negative bacterial pathogens employ type III secretion systems (T3SSs) to inject effector proteins into eukaryotic cells. The activation of the type III secretion (T3S) process is tightly controlled in all T3SSs. In Yersinia pestis, the secretion of effector proteins, termed Yersinia outer proteins (Yops), is regulated by the activity of the YopN/SycN/YscB/TyeA complex. YopN is a secreted protein that interacts with the SycN/YscB chaperone via an N-terminal chaperone-binding domain (CBD) and with TyeA via a C-terminal TyeA-binding domain (TBD). Efficient YopN secretion is dependent upon its N-terminal secretion signal (SS), CBD, and the SycN/YscB chaperone. In this study, we investigate the role of the YopN CBD in the regulation of Yop secretion. Analysis of YopE/YopN hybrid proteins in which the YopN SS or SS and CBD were replaced with the analogous regions of YopE indicated that the YopN CBD or SycN/YscB chaperone play a role in the regulation of Yop secretion that is independent of their established roles in YopN secretion. To further analyze the role of the YopN CBD in the regulation of Yop secretion a series of tetra-alanine substitution mutants were generated throughout the YopN CBD. A number of these mutants exhibited a defect in the regulation of Yop secretion but showed no defect in YopN secretion or in the interaction of YopN with the SycN/YscB chaperone. Finally, conditions were established that enabled YopN and TyeA to regulate Yop secretion in the absence of the SycN/YscB chaperone. Importantly, a number of the YopN CBD mutants maintained their defect in the regulation of Yop secretion even under the established SycN/YscB chaperone-independent conditions. These studies establish a role for the CBD region of YopN in the regulation of Yop secretion that is independent from its role in YopN secretion or in the binding of the SycN/YscB chaperone.


Gut Microbiota in Health, Diverticular Disease, Irritable Bowel Syndrome, and Inflammatory Bowel Diseases: Time for Microbial Marker of Gastrointestinal Disorders.
Few data exist on differences in gut microbiota composition among principal gastrointestinal (GI) diseases. We evaluated the differences in gut microbiota composition among uncomplicated diverticular disease (DD), irritable bowel syndrome (IBS) and inflammatory bowel diseases (IBD) patients. DD, IBS, and IBD patients along with healthy controls (CT) were enrolled in our Italian GI outpatient clinic. Stool samples were collected. Microbiota composition was evaluated through a metagenomic gene-targeted approach. GI pathology represented a continuous spectrum of diseases where IBD displayed one extreme, while CT displayed the other. Among Phyla, Biplot PC2/PC3 and dendogram plot showed major differences in samples from IBS and IBD. DD resembled species CT composition, but not for Bacteroides fragilis. In IBS, Dialister spp. and then Faecalibacterium prausnitzii were the most representative species. Ulcerative colitis showed a reduced concentration of Clostridium difficile and an increase of Bacteroides fragilis. In Crohn's disease, Parabacteroides distasonis was the most represented, while Faecalibacterium prausnitzii and Bacteroides fragilis were significantly reduced. Each disorder has its definite overall microbial signature, which produces a clear differentiation from the others. On the other hand, shared alterations constitute the "core dysbiosis" of GI diseases. The assessment of these microbial markers represents a parameter that may complete the diagnostic assessment.


Myosin is involved in postmitotic cell spreading.
We have investigated a role for myosin in postmitotic Potoroo tridactylis kidney (PtK2) cell spreading by inhibitor studies, time-lapse video microscopy, and immunofluorescence. We have also determined the spatial organization and polarity of actin filaments in postmitotic spreading cells. We show that butanedione monoxime (BDM), a known inhibitor of muscle myosin II, inhibits nonmuscle myosin II and myosin V adenosine triphosphatases. BDM reversibly inhibits PtK2 postmitotic cell spreading. Listeria motility is not affected by this drug. Electron microscopy studies show that some actin filaments in spreading edges are part of actin bundles that are also found in long, thin, structures that are connected to spreading edges and substrate (retraction fibers), and that 90% of this actin is oriented with barbed ends in the direction of spreading. The remaining actin in spreading edges has a more random orientation and spatial arrangement. Myosin II is associated with actin polymer in spreading cell edges, but not retraction fibers. Myosin II is excluded from lamellipodia that protrude from the cell edge at the end of spreading. We suggest that spreading involves myosin, possibly myosin II.


Postsynaptic injection of calcium-independent phospholipase A2 inhibitors selectively increases AMPA receptor-mediated synaptic transmission.
The calcium-independent form of phospholipase A2 (iPLA2), an enzyme known to generate arachidonic acid (AA), was recently identified as the predominant constitutive phospholipase in the hippocampus. The present study shows that the iPLA2 inhibitor bromoenol lactone, when introduced into hippocampal CA1 pyramidal cells through a patch pipette, generated a dose-dependent increase in the amplitude of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor-mediated excitatory postsynaptic currents (EPSCs). The iPLA2 inhibitor by itself interfered with neither paired pulse facilitation nor N-methyl-D-aspartate (NMDA) receptor-mediated EPSCs, suggesting that its influence on synaptic transmission is postsynaptic in origin and specific to the AMPA subtype of glutamate receptors. Comparable results were obtained with palmitoyl trifluoromethyl ketone, a second structurally distinct iPLA2 inhibitor. The ability of iPLA2 inhibitors to increase AMPA receptor-mediated currents was also reproduced by MK-866, an inhibitor recognized to interfere with the generation of 5-lipoxygenase by-products of AA. At the biochemical level, we found that AMPA, but not NMDA glutamate receptor subunits, were upregulated in rat brain sections pre-incubated with the iPLA2 inhibitors. Collectively, these results provide the first experimental evidence that constitutive iPLA2 and/or its metabolites play an important role in the postsynaptic modulation of neurotransmission in CA1 pyramidal cells of the hippocampus.


Not just correlative: a new pathway defines how an ALDH2 SNP contributes to atherosclerosis.
Individuals with the rs671 SNP in the gene encoding aldehyde dehydrogenase 2 (ALDH2) are at increased risk of cardiovascular disease (CVD); however, it has been unclear if this mutation contributes to CVD development. In this issue of the JCI, Zhong et al. perform an elegant set of experiments that reveal a pathway wherein the ALDH2 rs671 mutant is phosphorylated by AMPK and translocates to the nucleus where it represses the transcription of a lysosomal H+ pump subunit that is critical for lipid degradation and foam cell formation, as occurs in atherosclerosis. The discovery of this pathway may explain how subjects harboring ALDH2 rs671 are at a greater risk for numerous other disease states and thereby provide new targets for therapeutic intervention.


Exclusion of CD45 from the T-cell receptor signaling area in antigen-stimulated T lymphocytes.
T lymphocytes are activated by the engagement of their antigen receptors (TCRs) with complexes of peptide and major histocompatibility complex (MHC) molecules displayed on the cell surface of antigen-presenting cells (APCs) [1]. An unresolved question of antigen recognition by T cells is how TCR triggering actually occurs at the cell-cell contact area. We visualized T-cell-APC contact sites using confocal microscopy and three-dimensional reconstruction of z-sections. We show the rapid formation of a specialized signaling domain at the T-cell-APC contact site that is characterized by a broad and sustained area of tyrosine phosphorylation. The T-lymphocyte cell-surface molecule CD2 is rapidly recruited into this signaling domain, whereas TCRs progressively percolate from the entire T-cell surface into the phosphorylation area. Remarkably, the highly expressed phosphatase CD45 is excluded from the signaling domain. Our results indicate that physiological TCR triggering at the T-cell-APC contact site is the result of a localized alteration in the balance between cellular kinases and phosphatases. We therefore provide experimental evidence to support current models of T-cell activation based on CD45 exclusion from the TCR signaling area [2] [3] [4].


Extracorporeal life support for acute respiratory distress syndromes.
The morbidity and mortality of acute respiratory distress syndrome remain to be high. Over the last 50 years, the clinical management of these patients has undergone vast changes. Significant improvement in the care of these patients involves the development of mechanical ventilation strategies, but the benefits of these strategies remain controversial. With a growing trend of extracorporeal support for critically ill patients, we provide a historical review of extracorporeal membrane oxygenation (ECMO) including its failures and successes as well as discussing extracorporeal devices now available or nearly accessible while examining current clinical indications and trends of ECMO in respiratory failure.


Subchondral Pathology: Proceedings of the International Consensus Meeting on Cartilage Repair of the Ankle.
The evidence supporting best practice guidelines in the field of cartilage repair of the ankle are based on both low quality and low levels of evidence. Therefore, an international consensus group of experts was convened to collaboratively advance toward consensus opinions based on the best available evidence on key topics within cartilage repair of the ankle. The purpose of this article is to report the consensus statements on "Subchondral Pathology" developed at the 2017 International Consensus Meeting on Cartilage Repair of the Ankle. Seventy-five international experts in cartilage repair of the ankle representing 25 countries and 1 territory were convened and participated in a process based on the Delphi method of achieving consensus. Questions and statements were drafted within 11 working groups focusing on specific topics within cartilage repair of the ankle, after which a comprehensive literature review was performed and the available evidence for each statement was graded. Discussion and debate occurred in cases where statements were not agreed upon in unanimous fashion within the working groups. A final vote was then held, and the strength of consensus was characterized as follows: consensus, 51% to 74%; strong consensus, 75% to 99%; unanimous, 100%. A total of 9 statements on subchondral pathology reached consensus during the 2017 International Consensus Meeting on Cartilage Repair of the Ankle. No statements achieved unanimous support, but all statements reached strong consensus (greater than 75% agreement). All statements reached at least 81% agreement. This international consensus statements regarding subchondral pathology of the talus derived from leaders in the field will assist clinicians in the assessment and management of this difficult pathology.


Interlaboratory comparison of IDH mutation detection.
Isocitrate dehydrogenase (IDH) mutational testing is becoming increasingly important. For this, robust and reliable assays are needed. We tested the variation of results between six laboratories of testing for IDH mutations. Each laboratory received five unstained slides from 31 formalin-fixed paraffin-embedded (FFPE) glioma samples, and followed its own standard IDH diagnostic routine. All laboratories used immunohistochemistry (IHC) with an antibody against the most frequent IDH1 mutation (R132H) as a first step. Three laboratories then sequenced only IHC negative cases while the others sequenced all cases. Based on the overall analysis, 13 samples from 11 tumors had an R132H mutation and one tumor showed an R132G mutation. Results of IHC for IDH1 R132H mutations in all six laboratories were completely in agreement, and identified all R132H mutations. Upon sequencing the results of two laboratories deviated from those of the others. After a review of the entire diagnostic process, on repeat (blinded) testing one laboratory was completely in agreement with the overall result. A change in technique did only partially improve the results in the other laboratory. IHC for the IDH1 R132H mutation is very reliable and consistent across laboratories. IDH sequencing procedures yielded inconsistent results in 2 out of 6 laboratories. Quality assurance is pivotal before IDH testing is made part of clinical management of patients.


Molecular dynamics simulation of nonlinear spectroscopies of intermolecular motions in liquid water.
Water is the most extensively studied of liquids because of both its ubiquity and its anomalous thermodynamic and dynamic properties. The properties of water are dominated by hydrogen bonds and hydrogen bond network rearrangements. Fundamental information on the dynamics of liquid water has been provided by linear infrared (IR), Raman, and neutron-scattering experiments; molecular dynamics simulations have also provided insights. Recently developed higher-order nonlinear spectroscopies open new windows into the study of the hydrogen bond dynamics of liquid water. For example, the vibrational lifetimes of stretches and a bend, intramolecular features of water dynamics, can be accurately measured and are found to be on the femtosecond time scale at room temperature. Higher-order nonlinear spectroscopy is expressed by a multitime correlation function, whereas traditional linear spectroscopy is given by a one-time correlation function. Thus, nonlinear spectroscopy yields more detailed information on the dynamics of condensed media than linear spectroscopy. In this Account, we describe the theoretical background and methods for calculating higher order nonlinear spectroscopy; equilibrium and nonequilibrium molecular dynamics simulations, and a combination of both, are used. We also present the intermolecular dynamics of liquid water revealed by fifth-order two-dimensional (2D) Raman spectroscopy and third-order IR spectroscopy. 2D Raman spectroscopy is sensitive to couplings between modes; the calculated 2D Raman signal of liquid water shows large anharmonicity in the translational motion and strong coupling between the translational and librational motions. Third-order IR spectroscopy makes it possible to examine the time-dependent couplings. The 2D IR spectra and three-pulse photon echo peak shift show the fast frequency modulation of the librational motion. A significant effect of the translational motion on the fast frequency modulation of the librational motion is elucidated by introducing the "translation-free" molecular dynamics simulation. The isotropic pump-probe signal and the polarization anisotropy decay show fast transfer of the librational energy to the surrounding water molecules, followed by relaxation to the hot ground state. These theoretical methods do not require frequently used assumptions and can thus be called ab initio methods; together with multidimensional nonlinear spectroscopies, they provide powerful methods for examining the inter- and intramolecular details of water dynamics.


Equity theory and fair inequality: a neuroeconomic study.
The present paper reports results from, to our knowledge, the first study designed to examine the neuronal responses to income inequality in situations in which individuals have made different contributions in terms of work effort. We conducted an experiment that included a prescanning phase in which the participants earned money by working, and a neuronal scanning phase in which we examined how the brain responded when the participants evaluated different distributions of their earnings. We provide causal evidence for the relative contribution of work effort being crucial for understanding the hemodynamic response in the brain to inequality. We found a significant hemodynamic response in the striatum to deviations from the distribution of income that was proportional to work effort, but found no effect of deviations from the equal distribution of income. We also observed a striking correlation between the hemodynamic response in the striatum and the self-reported evaluation of the income distributions. Our results provide, to our knowledge, the first set of neuronal evidence for equity theory and suggest that people distinguish between fair and unfair inequalities.


The CRF1 receptor, a novel target for the treatment of depression, anxiety, and stress-related disorders.
The present review focuses on the corticotropin releasing factor type 1 (CRF(1)) receptor as a novel target for treating depression, anxiety and other stress-related disorders. An organism's stress response system is a complex network of neuronal, endocrine and autonomic pathways which has evolved to provide adaptive reactions to severe environmental and physiological stressors. The peptide CRF plays a critical role in the proper functioning of the stress response system through its actions on CRF(1) receptors located at multiple anatomical sites. Clinical data indicate that dysfunctions of the stress response system, expressed as excessive CRF activity and possible hyperstimulation of CRF(1) receptors, are present in a range of stress-related disorders, including depression, anxiety, and irritable bowel syndrome. CRF(1) dysfunction may be particularly prominent in severe forms of these disorders (e.g. melancholic or psychotic depression, comorbid conditions, chronic posttraumatic stress disorder) and/or when these disorders are accompanied by a history of exposure to early life trauma. Available clinical data support the potential therapeutic efficacy of pharmacological agents which block the CRF(1) receptor. Preclinical studies demonstrate that CRF(1) receptor antagonists are efficacious in animal models in which CRF pathways and CRF(1) receptors are hyperactivated, whereas they tend to be quiescent in states of low basal CRF activity, indicative of potentially reduced side effects in humans. Symptom diversity in animal models of stress and in human stress disorders may result from dysfunctions in different CRF(1) receptor populations and/or different functional states of the CRF(1) receptor. Small molecule, orally-active CRF(1) receptor antagonists may be a broadly useful approach for treating a range of stress-related disorders that are associated with excessive CRF(1) receptor stimulation.


Utility of cone-beam CT imaging for the determination of feeding vessels during arterial embolization for massive hemoptysis.
We aimed to evaluate the role of cone-beam computed tomography (CT) performed as an adjunct to angiography for the determination of feeding vessels responsible for bleeding during arterial embolization for massive hemoptysis. In this retrospective study, 23 patients with massive hemoptysis who underwent cone-beam CT evaluation prior to arterial embolization from December 2014 to December 2017 were included. During the angiographic session, two interventional radiologists selected the possible feeding vessels that were likely to supply the bleeding target lesions. Contrast-enhanced cone-beam CT was performed at the indefinite feeding arteries as an adjunct to angiography to determine whether the artery was a real feeding vessel, based on whether the target lesion was detected in the perfused territory of the study artery on images. Selective cone-beam CT was successfully performed in 21 patients, at 26 possible feeding vessels that were detected by selective angiography. Cone-beam CT determined the feeding vessel in 24 arteries (92.3%) in 19 patients (90.5%). As a result of cone-beam CT findings, 16 of 24 study arteries were judged as definitively not feeding vessels (66.7%) and the remaining 8 study arteries were judged as definitively feeding vessels (33.3%). In 2 of 26 study arteries cone-beam CT could not determine the feeding vessel (7.7%). Cone-beam CT performed as an adjunctive technique to angiography is sufficient to provide adequate information for confident determination of the feeding vessel, which is essential for the operators to perform accurate embolization during arterial embolization for massive hemoptysis.


Induced defenses change the chemical composition of pine seedlings and influence meal properties of the pine weevil Hylobius abietis.
The defense of conifers against phytophagous insects relies to a large extent on induced chemical defenses. However, it is not clear how induced changes in chemical composition influence the meal properties of phytophagous insects (and thus damage rates). The defense can be induced experimentally with methyl jasmonate (MeJA), which is a substance that is produced naturally when a plant is attacked. Here we used MeJA to investigate how the volatile contents of Scots pine (Pinus sylvestris L.) tissues influence the meal properties of the pine weevil (Hylobius abietis (L.)). Phloem and needles (both weevil target tissues) from MeJA-treated and control seedlings were extracted by n-hexane and analyzed by two-dimensional gas chromatography-mass spectrometry (2D GC-MS). The feeding of pine weevils on MeJA-treated and control seedlings were video-recorded to determine meal properties. Multivariate statistical analyses showed that phloem and needle contents of MeJA-treated seedlings had different volatile compositions compared to control seedlings. Levels of the pine weevil attractant (+)-α-pinene were particularly high in phloem of control seedlings with feeding damage. The antifeedant substance 2-phenylethanol occurred at higher levels in the phloem of MeJA-treated than in control seedlings. Accordingly, pine weevils fed slower and had shorter meals on MeJA-seedlings. The chemical compositions of phloem and needle tissues were clearly different in control seedlings but not in the MeJA-treated seedlings. Consequently, meal durations of mixed meals, i.e. both needles and phloem, were longer than phloem meals on control seedlings, while meal durations on MeJA seedlings did not differ between these meal contents. The meal duration influences the risk of girdling and plant death. Thus our results suggest a mechanism by which MeJA treatment may protect conifer seedlings against pine weevils.


Inverse association of esophageal eosinophilia with Helicobacter pylori based on analysis of a US pathology database.
Eosinophilic esophagitis (EoE) is of increasing prevalence and believed to result from allergic processes. Helicobacter pylori has been inversely associated with allergic diseases, but there is no known relationship between H pylori, EoE, and esophageal eosinophilia. We investigated the association between esophageal eosinophilia and H pylori infection. We performed a cross-sectional study of data, collected from a US pathology database, on 165,017 patients in the United States who underwent esophageal and gastric biopsies from 2008 through 2010. Patients with and without H pylori on gastric biopsy were compared, and odds of esophageal eosinophilia were determined. From the data analyzed, 56,301 (34.1%) had normal esophageal biopsy specimens, 5767 (3.5%) had esophageal eosinophilia, and 11,170 (6.8%) had H pylori infection. Esophageal eosinophilia was inversely associated with H pylori (odds ratio [OR], 0.77; 95% confidence interval [CI], 0.69-0.87). Compared with patients with normal esophageal biopsy specimens, odds of H pylori were reduced among patients with ≥ 15 eosinophils per high-power field (eos/hpf) (OR, 0.79; 95% CI, 0.70-0.88), ≥ 45 eos/hpf (OR, 0.75; 95% CI, 0.61-0.93), ≥ 75 eos/hpf (OR, 0.72; 95% CI, 0.50-1.03), and ≥ 90 eos/hpf (OR, 0.52; 95% CI, 0.31-0.87) (P for trend <.001). A similar dose-response trend was observed for increasing clinical suspicion for EoE and decreasing prevalence of H pylori. Additionally, severity of histologic effects of H pylori was inversely associated with esophageal eosinophilia. All trends held in multivariate analysis. In a large cross-sectional analysis, H pylori infection was inversely associated with esophageal eosinophilia. This relationship could have implications for the pathogenesis and epidemiology of EoE.


Risk assessment adjusted for gestational age in maternal serum screening for Down's syndrome.
To investigate the relation between errors in calculation of gestational age and assessment of risk of Down's syndrome and to analyse the implications for screening programmes. Retrospective analysis of dating of gestational age by menstrual history v ultrasound scan. Computer program with maternal age and concentrations of alpha fetoprotein and free beta human chorionic gonadotrophin to calculate risk for a range of expected dates of delivery. Computer simulated prospective application of new screening programme. Teaching hospitals in Nottingham. 31,561 women with singleton pregnancies with gestational age based on routine ultrasound scan. Computer simulation of 20,000 women in three age ranges (up to 37; up to 40; all). Distribution of error between gestational age based on ultrasound scan v menstrual history. Proportion of women in the population who require precise dating of pregnancy; proportion of women who require amniocentesis. With gestational age derived from ultrasound scan as reference the 95% confidence interval for gestational age by menstrual history was -27 to +9 days. A screening programme for Down's syndrome for women up to age 40 would yield a low risk (< 1:250) for this range of days in 86.0% of cases. The 14.0% of women remaining would have one or more high risk values in their report and would thus require an ultrasound scan for precise dating of the pregnancy; 30% of these--that is, 3.7% of the screened population--would be identified as high risk and require consideration for amniocentesis. Screening programmes for Down's syndrome require the facility for precise dating of pregnancy to improve the accuracy of risk assessment. This can be achieved without introducing additional scans for early dating in the whole population but by selecting only those cases (about 14%) when an error in dates is likely to affect the risk of Down's syndrome.


Huperzine A attenuates mitochondrial dysfunction in beta-amyloid-treated PC12 cells by reducing oxygen free radicals accumulation and improving mitochondrial energy metabolism.
We observed previously that huperzine A (HupA), a selective acetylcholinesterase inhibitor, can counteract neuronal apoptosis and cell damage induced by several neurotoxic substances, and that this neuroprotective action somehow involves the mitochondria. We investigated the ability of HupA to reduce mitochondrial dysfunction in neuron-like rat pheochromocytoma (PC12) cells exposed in culture to the amyloid beta-peptide fragment 25-35 (Abeta(25-35)). After exposure to 1 microM Abeta(25-35) for various periods, cells exhibited a rapid decline of ATP levels and obvious disruption of mitochondrial membrane homeostasis and integrity as determined by characteristic morphologic alterations, reduced membrane potential, and decreased activity of ion transport proteins. In addition, Abeta(25-35) treatment also led to inhibition of key enzyme activities in the electron transport chain and the tricarboxylic acid cycle, as well as an increase of intracellular reactive oxygen species (ROS). Pre-incubation with HupA for 2 hr not only attenuated these signs of cellular stress caused by Abeta, but also enhanced ATP concentration and decreased ROS accumulation in unharmed normal cells. Those results indicate that HupA protects mitochondria against Abeta-induced damages, at least in part by inhibiting oxidative stress and improving energy metabolism, and that these protective effects reduce the apoptosis of neuronal cells exposed to this toxic peptide.


Remembered Meal Satisfaction, Satiety, and Later Snack Food Intake: A Laboratory Study.
It is well established that the satiety providing effects of food can influence meal size and a disparate area of research suggests that memory regarding recent eating informs food intake. Here we examined whether remembered meal satisfaction (encompassing memory for meal liking and satiety) can be manipulated in the laboratory and whether this influences later food intake. Participants (N = 128, body mass index mean = 23.46kg/m², standard deviation = 4.70) consumed a fixed lunch and then rehearsed the satisfying or dissatisfying aspects of the meal, or a neutral experience (control), in order to manipulate memory for meal satisfaction. Three hours later participants completed a bogus taste-test to measure food intake and meal memory measures. There was no evidence that memory for general satisfaction with the meal was affected by the rehearsal condition. However, in the dissatisfying rehearsal condition, participants remembered being less satisfied with the satiety-providing effects of the lunch meal than in the satisfying and neutral rehearsal conditions. Snack food consumption did not differ across conditions and there was a small negative correlation between how satiating participants remembered their earlier meal to be and later snack food intake (r = -0.16, p = 0.07). The present study did not produce evidence that memory relating to meal satiety affects later food intake but further research is warranted.


Modeling apple surface temperature dynamics based on weather data.
The exposure of fruit surfaces to direct sunlight during the summer months can result in sunburn damage. Losses due to sunburn damage are a major economic problem when marketing fresh apples. The objective of this study was to develop and validate a model for simulating fruit surface temperature (FST) dynamics based on energy balance and measured weather data. A series of weather data (air temperature, humidity, solar radiation, and wind speed) was recorded for seven hours between 11:00-18:00 for two months at fifteen minute intervals. To validate the model, the FSTs of "Fuji" apples were monitored using an infrared camera in a natural orchard environment. The FST dynamics were measured using a series of thermal images. For the apples that were completely exposed to the sun, the RMSE of the model for estimating FST was less than 2.0 °C. A sensitivity analysis of the emissivity of the apple surface and the conductance of the fruit surface to water vapour showed that accurate estimations of the apple surface emissivity were important for the model. The validation results showed that the model was capable of accurately describing the thermal performances of apples under different solar radiation intensities. Thus, this model could be used to more accurately estimate the FST relative to estimates that only consider the air temperature. In addition, this model provides useful information for sunburn protection management.


SUMO pathway inhibition targets an aggressive pancreatic cancer subtype.
Pancreatic ductal adenocarcinoma (PDAC) still carries a dismal prognosis with an overall 5-year survival rate of 9%. Conventional combination chemotherapies are a clear advance in the treatment of PDAC; however, subtypes of the disease exist, which exhibit extensive resistance to such therapies. Genomic MYC amplifications represent a distinct subset of PDAC with an aggressive tumour biology. It is clear that hyperactivation of MYC generates dependencies that can be exploited therapeutically. The aim of the study was to find and to target MYC-associated dependencies. We analysed human PDAC gene expression datasets. Results were corroborated by the analysis of the small ubiquitin-like modifier (SUMO) pathway in a large PDAC cohort using immunohistochemistry. A SUMO inhibitor was used and characterised using human and murine two-dimensional, organoid and in vivo models of PDAC. We observed that MYC is connected to the SUMOylation machinery in PDAC. Components of the SUMO pathway characterise a PDAC subtype with a dismal prognosis and we provide evidence that hyperactivation of MYC is connected to an increased sensitivity to pharmacological SUMO inhibition. SUMO inhibitor-based therapies should be further developed for an aggressive PDAC subtype.


Structure of primary anti-(4-hydroxy-3-nitrophenyl)acetyl (NP) antibodies in normal and idiotypically suppressed C57BL/6 mice.
Eight monoclonal antibodies from the primary response of C57BL/6 mice against the hapten (4-hydroxy-3-nitrophenyl)acetyl (NP) were isolated. The antibodies carry lambda 1 light chains and have similar affinities for the immunizing hapten. Sequence analysis at the level of mRNA reveals that all antibodies express the VH gene 186.2 and all but one the DFl 16.1 gene segment. The J segment of the heavy chain is JH2 in six cases and JH4 in two. Somatic point mutations are scarcely detectable in the antibodies, but there is extensive sequence variability at the boundaries of the D gene segment, mainly at its 5' end. However, seven of eight antibodies express tyrosine in position 99 of the heavy chain, encoded either by the 5' codon of DFl 16.1 or by presumed N sequences. In the former case, the tyrosine is the first of a stretch of three (positions 99-101). In the latter, a similar stretch (positions 99, 101, 102) is interrupted by aspartic acid, asparagine or cysteine in position 100. These variations profoundly affect idiotypic specificity. Six of the eight monoclonal antibodies came from mice neonatally suppressed by an anti-idiotope antibody whose target idiotope is regularly expressed in primary anti-NP responses and depends upon a non-germ-line-encoded aspartic acid in position 100 of the heavy chain. The sequence data show that the mice circumvent suppression by expressing antibodies which lack this aspartic acid but are otherwise structurally very similar to anti-NP antibodies from normal animals. Since suppression in the animals is partly controlled by regulatory T cells, we conclude that these T cells are highly restricted in their specificity in that they preferentially see a determinant which also depends upon the aspartic acid in position 100. The data suggest that the VH to D boundary serves as a target of idiotypic selection.


Local chemistry of the surfactant's head groups determines protein stability in reverse micelles.
When comparing protein folding in vitro and in vivo significant differences have been found. This has been attributed to crowding and confinement effects. Using a combination of GHz- and THz-dielectric relaxation spectroscopy and MD simulations, we studied hydration dynamics and reviewed protein stability data inside sodium bis(2-ethylhexyl)sulfosuccinate (AOT) and cetyltrimethylammonium bromide (CTAB) reverse micelles which are model systems for confinement. We find that water inside anionic AOT and cationic CTAB reverse micelles is characterized by a strong dielectric depolarization giving rise to a very low relative permittivity compared to an unconfined solution. Despite differences in the hydration dynamics of the surfactant's head groups, simulations using the two-phase thermodynamics method predict a similar reduction in water entropy for both reverse micelle systems compared to bulk water. When we compare the stability data of proteins in these reverse micelles we find that in contrast to our initial expectation, protein stability correlates rather with the local chemistry of the hydrated head groups than with the excluded volume effect or the low global permittivity.


Aneurysmal bone cyst of the cuboid.
Aneurysmal bone cysts are a rare entity encountered in podiatric medicine. The frequency of aneurysmal bone cysts distal to the ankle joint is low. The authors present a literature review of the etiologies and possible treatments of an aneurysmal bone cyst. An unusual case of an aneurysmal bone cyst in the cuboid is also presented. Only one other documented case of an aneurysmal bone cyst in the cuboid has been reported since 1967.


Three-dimensional characterization of cell clusters using synchrotron-radiation-based micro-computed tomography.
Micro-computed tomography with the highly intense, monochromatic X rays produced by the synchrotron is a superior method to nondestructively measure the local absorption in three-dimensional space. Because biological tissues and cells consist mainly of water as the surrounding medium, higher absorbing agents have to be incorporated into the structures of interest. Even without X-ray optics such as refractive lens, one can uncover the stain distribution with the spatial resolution of about 1 mum. Incorporating the stain at selected cell compartments, for example, binding to the RNA/DNA, their density distribution becomes quantified. In this communication, we demonstrate that tomograms obtained at the beamlines BW2 and W2 (HASYLAB at DESY, Hamburg, Germany) and 4S (SLS, Villigen, Switzerland) clearly show that the RNA/DNA-stained HEK 293 cell clusters have a core of high density and a peripheral part of lower density, which correlate with results of optical microscopy. The inner part of the clusters is associated with nonvital cells as the result of insufficient oxygen and nutrition supply. This necrotic part is surrounded by (6 +/- 1) layers of vital cells.


Ultrathin inorganic molecular nanowire based on polyoxometalates.
The development of metal oxide-based molecular wires is important for fundamental research and potential practical applications. However, examples of these materials are rare. Here we report an all-inorganic transition metal oxide molecular wire prepared by disassembly of larger crystals. The wires are comprised of molybdenum(VI) with either tellurium(IV) or selenium(IV): {(NH4)2[XMo6O21]}n (X=tellurium(IV) or selenium(IV)). The ultrathin molecular nanowires with widths of 1.2 nm grow to micrometre-scale crystals and are characterized by single-crystal X-ray analysis, Rietveld analysis, scanning electron microscopy, X-ray photoelectron spectroscopy, ultraviolet-visible spectroscopy, thermal analysis and elemental analysis. The crystals can be disassembled into individual molecular wires through cation exchange and subsequent ultrasound treatment, as visualized by atomic force microscopy and transmission electron microscopy. The ultrathin molecular wire-based material exhibits high activity as an acid catalyst, and the band gap of the molecular wire-based crystal is tunable by heat treatment.


Catheter related infection in hemodialysis patients.
To determine the frequency of hemodialysis (HD) catheter related infection, causative microorganisms and predisposing factors contributing to these infections at our center, we conducted a prospective study in 2007 involving 57 (45.6% males) patients in whom a temporary catheter was inserted for HD. The patients were followed for one month to document any episodes of hemodialysis catheter related infection (HCRI). There were 11 (19.3%) patients who developed HCRI proven by blood culture; 5 patients were infected with more than one organism. Staphylococcus Coagulase negative and Staphylococcus aureus (S. aureus) remain the most common pathogens. All the organisms were sensitive to antibiotics administered empirically, however, 3 patients developed multiple resistant S. aureus (MRSA). All the infected patients experienced previous episodes of HCRI, which formed a risk factor in addition to low albumin when compared to the non-infected group (P=0.024 and P= 0.001, respectively). We conclude that the rate of HCRI and the causative organisms found in our study is comparable to previous reports. We still need to adopt measures to minimize the use of temporary vascular accesses by creation of fistulas in a timely fashion.


Characterization of chronic vocal fold scarring in a rabbit model.
The purpose of the current study was to assess the histologic and rheologic properties of the scarred vocal fold lamina propria during a chronic phase of wound repair in a rabbit model. Eighteen rabbit larynges were scarred using a procedure that involved stripping the vocal fold lamina propria down to the thyroarytenoid muscle, using 3-mm microforceps. The approximate dimension of injury to the vocal fold was 3 x 1.5 x 0.5 mm [length x width x depth]. At 6 months postoperatively, histologic analysis of the scarred and control lamina propria in eight of these rabbits was completed for collagen, procollagen, elastin, and hyaluronic acid. Compared with control samples, scarred tissue samples revealed fragmented and disorganized elastin fibers. Additionally, collagen was significantly increased, organized, and formed thick bundles in the scarred vocal fold lamina propria. Measurements of the viscoelastic shear properties of the scarred and control lamina propria in the remaining 10 rabbits revealed increased elastic shear modulus (G') in 8 of 10 scarred samples and increased dynamic viscosity (eta') in 9 of 10 scarred samples. Although rheologic differences were not statistically significant, they revealed that on average, scarred samples were stiffer and more viscous than the normal controls. Histologic data are interpreted as indicating that by 6 months postinjury, the scarred rabbit vocal fold has reached a mature phase of wound repair, characterized by an increased, organized, and thick bundle collagen matrix. Rheologic data are interpreted as providing support for the potential role of increased, thick bundle collagen, and a disorganized elastin network on shear stiffness and dynamic viscosity in the chronic vocal fold scar. Based on these results, a 6-month postoperative time frame is proposed for future studies of chronic vocal fold scarring using the rabbit animal model.


Ultra-high-speed phase-sensitive optical coherence reflectometer with a stretched pulse supercontinuum source.
We demonstrate an ultra-high-speed phase-sensitive time-wavelength-domain optical coherence reflectometer with a stretched pulse supercontinuum source. A pulsed fiber laser operating at 10 MHz repetition rate was used to generate a pulsed supercontinuum of 30 ps pulse duration by using a nonlinear optical fiber. The supercontinuum pulses are stretched into 70 ns pulses with a highly dispersive fiber. With this stretched pulse source, we have built a phase-sensitive optical coherence reflectometer that measures the spectral interferogram of reflected light. By using the linear relation between the wavelength and the temporal position in a linearly chirped pulse, ultra-high-speed spectrum measurement can be obtained with this method in the time domain. We have demonstrated ultra-high-speed two-dimensional surface profiling for a standard image target and high-speed single-point monitoring for a fixed point under vibrational motion. It is shown that the measurement speed for the position of a single point can be as fast as 2.5 MHz, while the position accuracy can be better than 4.49 nm.


Alveolar rhabdomyosarcomas in conditional Pax3:Fkhr mice: cooperativity of Ink4a/ARF and Trp53 loss of function.
Alveolar rhabdomyosarcoma is an aggressive childhood muscle cancer for which outcomes are poor when the disease is advanced. Although well-developed mouse models exist for embryonal and pleomorphic rhabdomyosarcomas, neither a spontaneous nor a transgenic mouse model of alveolar rhabdomyosarcoma has yet been reported. We report the first mouse model of alveolar rhabdomyosarcoma using a conditional Pax3:Fkhr knock-in allele whose activation in late embryogenesis and postnatally is targeted to terminally differentiating Myf6-expressing skeletal muscle. In these mice, alveolar rhabdomyosarcomas occur but at low frequency, and Fkhr haploinsufficiency does not appear to accelerate tumorigenesis. However, Pax3:Fkhr homozygosity with accompanying Ink4a/ARF or Trp53 pathway disruption, by means of conditional Trp53 or Ink4a/ARF loss of function, substantially increases the frequencies of tumor formation. These results of successful tumor generation postnatally from a target pool of differentiating myofibers are in sharp contrast to the birth defects and lack of tumors for mice with prenatal and postnatal satellite cell triggering of Pax3:Fkhr. Furthermore, these murine alveolar rhabdomyosarcomas have an immunohistochemical profile similar to human alveolar rhabdomyosarcoma, suggesting that this conditional mouse model will be relevant to study of the disease and will be useful for preclinical therapeutic testing.


Exfoliation of one-dimensional TiO5 chain in K2TiO3.
Potassium titanate, K2TiO3, with a chain structure of TiO5 polyhedra was exfoliated in an aqueous nitric acid solution of pH ≤ 1 and Tyndall scattering due to the colloid formed by the exfoliation was observed. The colloidal particle size measured by dynamic light scattering was approximately 300 nm. The stripe pattern observed by transmission electron microscopy for the aggregated grains after their drying suggested that the TiO5 chains were exfoliated in acid solution. X-ray absorption showed that the coordination polyhedron around Ti(4+) changed from a square pyramid in K2TiO3 powder to a distorted octahedron formed with the additional hydronium ions in the acidic solution.


All-oral combination of ledipasvir, vedroprevir, tegobuvir, and ribavirin in treatment-naïve patients with genotype 1 HCV infection.
This phase II trial assessed the efficacy and safety of a combination regimen of the nonstructural protein (NS)5A inhibitor ledipasvir (LDV), NS3 protease inhibitor vedroprevir (VDV), non-nucleoside NS5B inhibitor tegobuvir (TGV), and ribavirin (RBV) in treatment-naïve patients with chronic hepatitis C virus (HCV) genotype 1 without cirrhosis. Patients were randomized 1:2 to LDV 30 mg once daily (QD; Arm 1; n = 46) or LDV 90 mg QD (Arm 2; n = 94); patients in both arms also received VDV 200 mg QD, TGV 30 mg twice-daily, and RBV 1,000-1,200 mg/day. Patients in Arm 2 with vRVR, defined as HCV RNA below the lower limit of quantification (LLOQ) from treatment weeks 2 to 10, were randomized 1:1 to stop treatment at 12 weeks or continue for 24 weeks. Sustained virologic response 12 weeks after treatment (SVR12) was higher in patients receiving 90 mg of LDV for 24 weeks (63%), compared with LDV 90 mg for 12 weeks (54%) and LDV 30 mg for 24 weeks (48%). In patients with very rapid virologic response (vRVR) in Arm 2, SVR12 was achieved by 68% and 81% of patients treated for 12 and 24 weeks, respectively. Virologic breakthrough was more common in patients with HCV genotype 1a and was associated with resistance-associated variants for all three direct-acting antiviral agents (DAAs); however, in all but 1 patient who relapsed, resistance-associated variants directed against only one or two of the DAAs were detected. The most common adverse events were fatigue, headache, nausea, rash, and diarrhea. In patients with HCV genotype 1, an interferon-free regimen containing LDV/VDV/TGV/RBV was well tolerated and led to SVR12 in up to 63% of patients. LDV 90 mg is currently being investigated in combination with the nucleotide polymerase inhibitor, sofosbuvir.


Sedation-associated hiccups in adults undergoing gastrointestinal endoscopy and colonoscopy.
To investigate whether the incidence of hiccups in patients undergoing esophagogastroduodenoscopy (EGD) or same-day bidirectional endoscopy (EGD and colonoscopy; BDE) with sedation is different from those without sedation in terms of quantity, duration and typical onset time. Consecutive patients scheduled for elective EGD or same-day BDE at the gastrointestinal endoscopy unit or the health examination center were allocated to two groups: EGD without sedation (Group A) and BDE with sedation (Group B). The use of sedation was based on the patients' request. Anesthesiologists participated in this study by administrating sedative drugs as usual. A single experienced gastroenterologist performed both the EGD and the colonoscopic examinations for all the patients. The incidence, duration and onset time of hiccups were measured in both groups. In addition, the association between clinical variables and hiccups were analyzed. A total of 435 patients were enrolled in the study. The incidences of hiccups in the patients with and without sedation were significantly different (20.5% and 5.1%, respectively). The use of sedation for patients undergoing endoscopy was still significantly associated with an increased risk of hiccups (adjusted odds ratio: 8.79, P < 0.001) after adjustment. The incidence of hiccups in males under sedation was high (67.4%). The sedated patients who received 2 mg midazolam developed hiccups more frequently compared to those receiving 1 mg midazolam (P = 0.0028). The patients with the diagnosis of gastroesophageal reflux disease (GERD) were prone to develop hiccups (P = 0.018). Male patients undergoing EGD or BDE with sedation are significantly more likely to suffer from hiccups compared to those without sedation. Midazolam was significantly associated with an increased risk of hiccups. Furthermore, patients with GERD are prone to develop hiccups.