Development and survival of Ascaris suum eggs in deep litter of pigs.
SUMMARY Indoor transmission of Ascaris suum partly depends on the physico-chemical conditions in bedding material. Temperature, pH, aqueous ammonia, moisture, occurrence and development of A. suum eggs were therefore compared in different areas (resting, intermediate and latrine) of two deep litter pens on an organic farm in four seasons. There was some variation, but mean ammonia levels were generally very low (1·0-2·6 mm) and pH levels were moderate (8·04-8·88) in all three areas. Relatively, resting areas were characterized by overall moderate moisture (36%) and moderately high temperature (35·7 °C) levels. The area contained few eggs (50 eggs g-1 DM) of which 17% were viable, and though only 4% were larvated and 0·7% appeared infective, it was more than in the other areas. Intermediate areas had moderate moisture (43%) and high temperature (43·6 °C) levels. There were many eggs (523 eggs g-1 DM), but overall viability was very low (5%) and few eggs were larvated (0·004%) or even infective (0·002%). Latrines typically had high moisture (79%) and moderate temperature (30 °C) levels. The concentration of eggs was very high (1444 egg g-1 DM) and though 32% were viable, none had developed larval stages. The large majority of A. suum eggs appear to die and only few become infective while in the deep litter. However, a large fraction of eggs may remain viable for some time and could thus contaminate agricultural land and develop to infectivity, if the manure is not composted appropriately.


Revised vertebral count in the "longest-necked vertebrate" Elasmosaurus platyurus Cope 1868, and clarification of the cervical-dorsal transition in Plesiosauria.
Elasmosaurid plesiosaurians are renowned for their immensely long necks, and indeed, possessed the highest number of cervical vertebrae for any known vertebrate. Historically, the largest count has been attributed to the iconic Elasmosaurus platyurus from the Late Cretaceous of Kansas, but estimates for the total neck series in this taxon have varied between published reports. Accurately determining the number of vertebral centra vis-à-vis the maximum length of the neck in plesiosaurians has significant implications for phylogenetic character designations, as well as the inconsistent terminology applied to some osteological structures. With these issues in mind, we reassessed the holotype of E. platyurus as a model for standardizing the debated cervical-dorsal transition in plesiosaurians, and during this procedure, documented a "lost" cervical centrum. Our revision also advocates retention of the term "pectorals" to describe the usually three or more distinctive vertebrae close to the cranial margin of the forelimb girdle that bear a functional rib facet transected by the neurocentral suture, and thus conjointly formed by both the parapophysis on the centrum body and diapophysis from the neural arch (irrespective of rib length). This morphology is unambiguously distinguishable from standard cervicals, in which the functional rib facet is borne exclusively on the centrum, and dorsals in which the rib articulation is situated above the neurocentral suture and functionally borne only by the transverse process of the neural arch. Given these easily distinguishable definitions, the maximum number of neck vertebrae preserved in E. platyurus is 72; this is only three vertebrae shorter than the recently described Albertonectes, which together with E. platyurus constitute the "longest necked" animals ever to have lived.


International Society of Human and Animal Mycology (ISHAM)-ITS reference DNA barcoding database--the quality controlled standard tool for routine identification of human and animal pathogenic fungi.
Human and animal fungal pathogens are a growing threat worldwide leading to emerging infections and creating new risks for established ones. There is a growing need for a rapid and accurate identification of pathogens to enable early diagnosis and targeted antifungal therapy. Morphological and biochemical identification methods are time-consuming and require trained experts. Alternatively, molecular methods, such as DNA barcoding, a powerful and easy tool for rapid monophasic identification, offer a practical approach for species identification and less demanding in terms of taxonomical expertise. However, its wide-spread use is still limited by a lack of quality-controlled reference databases and the evolving recognition and definition of new fungal species/complexes. An international consortium of medical mycology laboratories was formed aiming to establish a quality controlled ITS database under the umbrella of the ISHAM working group on "DNA barcoding of human and animal pathogenic fungi." A new database, containing 2800 ITS sequences representing 421 fungal species, providing the medical community with a freely accessible tool at http://www.isham.org/ and http://its.mycologylab.org/ to rapidly and reliably identify most agents of mycoses, was established. The generated sequences included in the new database were used to evaluate the variation and overall utility of the ITS region for the identification of pathogenic fungi at intra-and interspecies level. The average intraspecies variation ranged from 0 to 2.25%. This highlighted selected pathogenic fungal species, such as the dermatophytes and emerging yeast, for which additional molecular methods/genetic markers are required for their reliable identification from clinical and veterinary specimens.


Gene and chromosomal alterations in sporadic breast cancer: correlation with histopathological features and implications for genesis and progression.
A number of gene and chromosome alterations have been identified in sporadic breast carcinomas, and their clinical implications have been investigated. Changes in proto-oncogenes and tumor-suppressor genes, e.g., HER2, p53, and E-cadherin, and various numerical and structural chromosome alterations are strongly correlated with histological type and grade in breast carcinomas. The amount of information on these alterations has been dramatically increased by the introduction of high-throughput molecular cytogenetic approaches. In the near future, breast cancers will be classified into specific groups according to their profile of gene and chromosome alterations, allowing more effective personalized therapies targeting the associated molecular pathways.


Phenotype evaluation and genomewide linkage study of clinical variables in schizophrenia.
Genetic factors are likely to influence clinical variation in schizophrenia, but it is unclear which variables are most suitable as phenotypes and which molecular genetic loci are involved. We evaluated clinical variable phenotypes and applied suitable phenotypes in genome-wide covariate linkage analysis. We ascertained 170 affected relative pairs (168 sibling-pairs and two avuncular pairs) with DSM-IV schizophrenia or schizoaffective disorder from the United Kingdom. We defined psychotic symptom dimensions, age at onset (AAO), and illness course using the OPCRIT checklist. We evaluated phenotypes using within sibling-pair correlations and applied suitable phenotypes in multipoint covariate linkage analysis based on 372 microsatellite markers at ∼10 cM intervals. The statistical significance of linkage results was assessed by simulation. The positive and disorganized symptom dimensions, AAO, and illness course qualified as suitable phenotypes. There were no genome-wide significant linkage results. There was suggestive evidence of linkage for the positive dimension on chromosomes 2q32, 10q26, and 20q12; the disorganized dimension on 8p21 and 17q21; and illness course on 2q33 and 22q11. The linkage peak for disorganization on 17q21 remained suggestive after correction for multiple testing. To our knowledge, this is the first study to integrate phenotype evaluation and genome-wide covariate linkage analysis for symptom dimensions and illness history variables in sibling-pairs with schizophrenia. The significant within-pair correlations strengthen the evidence that some clinical variables within schizophrenia are suitable phenotypes for molecular genetic investigations. At present there are no genome-wide significant linkage results for these phenotypes, but a number of suggestive findings warrant further investigation.


Parametrisation of the free energy of ATP binding to wild-type and mutant Kir6.2 potassium channels.
ATP-sensitive K(+) (K(ATP)) channels, comprised of pore-forming Kir6.x and regulatory SURx subunits, play important roles in many cellular functions; because of their sensitivity to inhibition by intracellular ATP, K(ATP) channels provide a link between cell metabolism and membrane electrical activity. We constructed structural homology models of Kir6.2 and a series of Kir6.2 channels carrying mutations within the putative ATP-binding site. Computational docking was carried out to determine the conformation of ATP in its binding site. The Linear Interaction Energy (LIE) method was used to estimate the free-energy of ATP binding to wild-type and mutant Kir6.2 channels. Comparisons of the theoretical binding free energies for ATP with those determined from mutational experiments enabled the identification of the most probable conformation of ATP bound to the Kir6.2 channel. A set of LIE parameters was defined that may enable prediction of the effects of additional Kir6.2 mutations within the ATP binding site on the affinity for ATP.


Behavioral inhibition moderates the association between overvaluation of shape and weight and noncompensatory purging in eating disorders.
The cognitive-behavioral therapy (CBT) model of eating disorders suggests that compensatory purging behaviors (e.g., self-induced vomiting, inappropriate laxative use) are primarily driven by binge eating. However, many individuals endorse purging in the absence of binge eating (i.e., noncompensatory purging [NCP]). Research is needed to understand why some individuals purge in the absence of objective or subjective binge-eating episodes. Given the importance of overvaluation of shape/weight in the CBT model, and the existing evidence linking temperamental characteristics like behavioral inhibition (i.e., the tendency to withdraw in response to threat cues) with purging in general, we tested whether behavioral inhibition moderated the relationship between overvaluation of shape/weight and NCP in a sample of individuals in a residential eating disorder treatment center (N = 143). Overvaluation was more strongly related to NCP in individuals with high (relative to low) levels of behavioral inhibition. Among individuals low in behavioral inhibition, overvaluation predicted engagement in NCP to a much weaker extent. For those high (relative to low) in behavioral inhibition, both emotional avoidance and overvaluation may be important targets in the treatment of NCP, particularly in the absence of binge eating.


Rational Choice and Developmental Influences on Recidivism Among Adolescent Felony Offenders.
Recent case law and social science both have claimed that the developmental limitations of adolescents affect their capacity for control and decision making with respect to crime, diminishing their culpability and reducing their exposure to punishment. Social science has focused on two concurrent adolescent developmental influences: the internalization of legal rules and norms that regulate social and antisocial behaviors, and the development of rationality to frame behavioral choices and decisions. The interaction of these two developmental processes, and the identification of one domain of socialization and development as the primary source of motivation or restraint in adolescence, is the focus of this article. Accordingly, we combine rational choice and legal socialization frameworks into an integrated, developmental model of criminality. We test this framework in a large sample of adolescent felony offenders who have been interviewed at six-month intervals for two years. Using hierarchical and growth curve models, we show that both legal socialization and rational choice factors influence patterns of criminal offending over time. When punishment risks and costs are salient, crime rates are lower over time. We show that procedural justice is a significant antecedent of legal socialization, but not of rational choice. We also show that both mental health and developmental maturity moderate the effects of perceived crime risks and costs on criminal offending.


Endoscopic sphincterotomy for common bile duct calculi in patients with gall bladder in situ considered unfit for surgery.
Endoscopic sphincterotomy (ES) was attempted in 106 patients with common bile duct (CBD) calculi and gall bladders present, who were considered unfit for surgery on the grounds of age and frailty alone (35%) and/or the presence of major medical problems (65%). Endoscopic sphincterotomy was successful in 105 patients (99%). Early ES related complications occurred in 21 patients (19.8%). Twelve hospital deaths occurred (11.3%), although this was due to biliary causes in only five (4.7%) and one of these was moribund on admission. Complications were more frequent in those in whom initial ES did not clear the common bile duct (30.4%) compared with those in whom this was (11.7%; p = 0.0164). The mortality was also greater in patients in whom there was no ERCP proof of CBD clearance (p = 0.01) unless operated upon. Twelve patients developed gall bladder complications (11.3%) including five with empyema (4.7%). Analysis of clinical, haematological, and biochemical factors together with ERCP findings showed that the only factor which had any value in predicting gall bladder complications was pre-existing cholangitis. The present series was compared with another using ES as a definitive procedure, and with a surgical series. Although there were significant differences in outcome, differences with respect to medical risk factors and the incidence of complications of CBD stones (jaundice, cholangitis, and acute pancreatitis) were striking. Further analysis of these factors may allow a clearer definition of patients most likely to benefit from either ES or surgery.


Growth of limb muscle is dependent on skeletal-derived Indian hedgehog.
During embryogenesis, muscle and bone develop in close temporal and spatial proximity. We show that Indian Hedgehog, a bone-derived signaling molecule, participates in growth of skeletal muscle. In Ihh(-/-) embryos, skeletal muscle development appears abnormal at embryonic day 14.5 and at later ages through embryonic day 20.5, dramatic losses of hindlimb muscle occur. To further examine the role of Ihh in myogenesis, we manipulated Ihh expression in the developing chick hindlimb. Reduction of Ihh in chicken embryo hindlimbs reduced skeletal muscle mass similar to that seen in Ihh(-/-) mouse embryos. The reduction in muscle mass appears to be a direct effect of Ihh since ectopic expression of Ihh by RCAS retroviral infection of chicken embryo hindlimbs restores muscle mass. These effects are independent of bone length, and occur when Shh is not expressed, suggesting Ihh acts directly on fetal myoblasts to regulate secondary myogenesis. Loss of muscle mass in Ihh null mouse embryos is accompanied by a dramatic increase in myoblast apoptosis by a loss of p21 protein. Our data suggest that Ihh promotes fetal myoblast survival during their differentiation into secondary myofibers by maintaining p21 protein levels.


Specific processing of meiosis-related transcript is linked to final maturation in human oocytes.
Human meiosis in oocytes entails an intricate regulation of the transcriptome to support late oocyte growth and early embryo development, both crucial to reproductive success. Currently, little is known about the co- and post-transcriptional mRNA processing mechanisms regulating the last meiotic phases, which contribute to transcriptome complexity and influence translation rates. We analyzed gene expression changes, splicing and pre-mRNA processing in an RNA sequencing set of 40 human oocytes at different meiotic maturation stages, matured both in vivo and in vitro. We found abundant untranslated region (UTR) processing, mostly at the 3' end, of meiosis-related genes between the germinal vesicle (GV) and metaphase II (MII) stages, supported by the differential expression of spliceosome and pre-mRNA processing related genes. Importantly, we found very few differences among GV oocytes across several durations of IVM, as long as they did not reach MII, suggesting an association of RNA processing and successful meiosis transit. Changes in protein isoforms are minor, although specific and consistent for genes involved in chromosome organization and spindle assembly. In conclusion, we reveal a dynamic transcript remodeling during human female meiosis, and show how pre-mRNA processing, specifically 3'UTR shortening, drives a selective translational regulation of transcripts necessary to reach final meiotic maturation.


Job satisfaction and retention of midwives in rural Nigeria.
Nigeria is one of the 57 countries with a critical shortage of human resources for health, especially in remote rural areas and in northern states. The National Midwifery Service Scheme (MSS) is one approach introduced by the Government of Nigeria to address the health workforce shortage in rural areas. Since 2009, unemployed, retired and newly graduated midwives are deployed to primary health care (PHC) facilities in rural areas of Nigeria. These midwives form the mainstay of the health system at the primary health care level especially as it relates to the provision of skilled attendance at birth. This study followed up and explored the job satisfaction and retention of the MSS midwives in three Northern states of Nigeria. this was a descriptive study. Data were collected using a mixed method approach which included a job satisfaction survey, focus group discussions (FGDs) and exit interviews to explore job satisfaction and retention factors. All 119 MSS midwives deployed by the National Primary Health Care Development Agency between 2010 and 2012 to the 51 Partnership for Reviving Routine Immunisation- Maternal and Child Health (PRRINN-MNCH) programme targeted PHC facilities were included in the study. MSS midwives were very satisfied with from the feeling of caring for women and children in the community (4.56), with the chance to help and care for others (Mean 4.50), the feeling of worthwhile accomplishment from doing the job (Mean 4.44) and the degree of respect and fair treatment they received from more senior staff and/or supervisor (Mean 4.39). MSS midwives were least satisfied with the lack of existence of a (established) career ladder (Mean 2.5), availability of promotional opportunities within the scheme (Mean 2.66), safety of accommodation (Mean 3.18), and with 'the degree to which they were fairly paid for what they contribute to the health facility' (Mean 3.41). When asked about future career plans, 38% (n=33) of the MSS midwives planned to leave the scheme within two years, of which 16 (18%) wanted to leave within one year. However, 39% of the midwives (n=34) indicated that they would be happy to continue working even after the scheme has ended. Of these 34 participants, 18 would like to continue working in the same facility where they are now whereas the remaining 16 would like to continue working in the north but not in the facility where they are working currently. Eight themes on job satisfaction and retention emerged from the FGDs conducted with current midwives, whereas six themes emerged from the exit interviews from midwives who have left the scheme. the MSS programme is a short-term solution to increase SBA coverage in rural Nigeria. MSS midwives were dissatisfied with the short term contract, lack of career structure, irregular payment, poor working condition, inadequate supervision and poor accommodation being offered by the programme, which all contribute to poor retention of MSS midwives. IMPLICATIONS FOR POLICY AND PRACTICE: midwives׳ job satisfaction and retention are critical to improving the health of mothers and their newborn. Poor job satisfaction and retention therefore requires improvements in financial and non-financial incentives, health systems, supportive supervision, ensuring job security and a career structure for midwives working in rural health facilities. Initiating effective strategies to motivate and increase the retention of rural health workers is important for Nigeria to achieve the Millennium/Sustainable Development Goals.


Spatial organization and correlations of cell nuclei in brain tumors.
Accepting the hypothesis that cancers are self-organizing, opportunistic systems, it is crucial to understand the collective behavior of cancer cells in their tumorous heterogeneous environment. In the present paper, we ask the following basic question: Is this self-organization of tumor evolution reflected in the manner in which malignant cells are spatially distributed in their heterogeneous environment? We employ a variety of nontrivial statistical microstructural descriptors that arise in the theory of heterogeneous media to characterize the spatial distributions of the nuclei of both benign brain white matter cells and brain glioma cells as obtained from histological images. These descriptors, which include the pair correlation function, structure factor and various nearest neighbor functions, quantify how pairs of cell nuclei are correlated in space in various ways. We map the centroids of the cell nuclei into point distributions to show that while commonly used local spatial statistics (e.g., cell areas and number of neighboring cells) cannot clearly distinguish spatial correlations in distributions of normal and abnormal cell nuclei, their salient structural features are captured very well by the aforementioned microstructural descriptors. We show that the tumorous cells pack more densely than normal cells and exhibit stronger effective repulsions between any pair of cells. Moreover, we demonstrate that brain gliomas are organized in a collective way rather than randomly on intermediate and large length scales. The existence of nontrivial spatial correlations between the abnormal cells strongly supports the view that cancer is not an unorganized collection of malignant cells but rather a complex emergent integrated system.


Neural decoding with visual attention using sequential Monte Carlo for leaky integrate-and-fire neurons.
How the brain makes sense of a complicated environment is an important question, and a first step is to be able to reconstruct the stimulus that give rise to an observed brain response. Neural coding relates neurobiological observations to external stimuli using computational methods. Encoding refers to how a stimulus affects the neuronal output, and entails constructing a neural model and parameter estimation. Decoding refers to reconstruction of the stimulus that led to a given neuronal output. Existing decoding methods rarely explain neuronal responses to complicated stimuli in a principled way. Here we perform neural decoding for a mixture of multiple stimuli using the leaky integrate-and-fire model describing neural spike trains, under the visual attention hypothesis of probability mixing in which the neuron only attends to a single stimulus at any given time. We assume either a parallel or serial processing visual search mechanism when decoding multiple simultaneous neurons. We consider one or multiple stochastic stimuli following Ornstein-Uhlenbeck processes, and dynamic neuronal attention that switches following discrete Markov processes. To decode stimuli in such situations, we develop various sequential Monte Carlo particle methods in different settings. The likelihood of the observed spike trains is obtained through the first-passage time probabilities obtained by solving the Fokker-Planck equations. We show that the stochastic stimuli can be successfully decoded by sequential Monte Carlo, and different particle methods perform differently considering the number of observed spike trains, the number of stimuli, model complexity, etc. The proposed novel decoding methods, which analyze the neural data through psychological visual attention theories, provide new perspectives to understand the brain.


Comparison of the Performance of APACHE II, SOFA, and mNUTRIC Scoring Systems in Critically Ill Patients: A 2-year Cross-sectional Study.
Different severity scores are being used to assess outcomes in intensive care unit, but variable data had been reported so far per their performance. Main objective of this study is to compare performance of acute physiology and chronic health evaluation II (APACHE II), sequential organ failure assessment (SOFA), and modified nutrition risk in critically ill (mNUTRIC) scoring systems regarding the outcomes in the form of morbidity and mortality in medical intensive care unit (MICU) at rural tertiary-care health center. In this cross-sectional study, 1,990 patients older than 18 years admitted in the ICU were enrolled. Age, gender, diagnosis, intubation, comorbidities, APACHE II, SOFA scores, m NUTRIC score, MICU stays in days, and need of mechanical ventilation were noted. When we compared different score with mortality, APACHE-II was having sensitivity of 89.9% and specificity of 97.6%; SOFA had 90.1% sensitivity and 96.6% specificity; while mNUTRIC score had 97.2% sensitivity and 74.0% specificity. APACHE-II score had sensitivity of 93.4%, SOFA had 90.5%, and mNUTRIC score 92.3% with low specificity of 76.5% in predicting requirement of mechanical ventilation. mNUTRIC score and ICU length of stay showed moderate positive correlation (p value = <0.001). All the three scores were comparable in sensitivity and specificity in predicting outcomes in the form of mortality, need of mechanical ventilation, and length of ICU stays. mNUTRIC score was more sensitive than others, and as it was based on nutritional status, hence more weightage should be given on this score. Kumar S, Gattani SC, Baheti AH, Dubey A. Comparison of the Performance of APACHE II, SOFA, and mNUTRIC Scoring Systems in Critically Ill Patients: A 2-year Cross-sectional Study. Indian J Crit Care Med 2020;24(11):1057-1061.


A new method for wideband characterization of resonator-based sensing platforms.
A new approach to the electronic instrumentation for extracting data from resonator-based sensing devices (e.g., microelectromechanical, piezoelectric, electrochemical, and acoustic) is suggested and demonstrated here. Traditionally, oscillator-based circuitry is employed to monitor shift in the resonance frequency of the resonator. These circuits give a single point measurement at the frequency where the oscillation criterion is met. However, the resonator response itself is broadband and contains much more information than a single point measurement. Here, we present a method for the broadband characterization of a resonator using white noise as an excitation signal. The resonator is used in a two-port filter configuration, and the resonator output is subjected to frequency spectrum analysis. The result is a wideband spectral map analogous to the magnitude of the S21 parameters of a conventional filter. Compared to other sources for broadband excitation (e.g., frequency chirp, multisine, or narrow time domain pulse), the white noise source requires no design of the input signal and is readily available for very wide bandwidths (1 MHz-3 GHz). Moreover, it offers simplicity in circuit design as it does not require precise impedance matching; whereas such requirements are very strict for oscillator-based circuit systems, and can be difficult to fulfill. This results in a measurement system that does not require calibration, which is a significant advantage over oscillator circuits. Simulation results are first presented for verification of the proposed system, followed by measurement results with a prototype implementation. A 434 MHz surface acoustic wave (SAW) resonator and a 5 MHz quartz crystal microbalance (QCM) are measured using the proposed method, and the results are compared to measurements taken by a conventional bench-top network analyzer. Maximum relative differences in the measured resonance frequencies of the SAW and QCM resonators are 0.0004% and 0.002%, respectively. The ability to track a changing sensor response is demonstrated by inducing temperature variations and measuring resonance frequency simultaneously using the proposed technique in parallel with a network analyzer. The relative difference between the two measurements is about 5.53 ppm, highlighting the impressive accuracy of the proposed system. Using commercially available digital signal processors (DSPs), we believe that this technique can be implemented as a system-on-a-chip solution resulting in a very low cost, easy to use, portable, and customizable sensing system. In addition, given the simplicity of the signal and circuit design, and its immunity to other common interface concerns (injection locking, oscillator interference, and drift, etc.), this method is better suited to accommodating array-based systems.


A study on the implementation fidelity of the performance-based financing policy in Burkina Faso after 12 months.
Performance-based financing (PBF) in the health sector has recently gained momentum in low- and middle-income countries (LMICs) as one of the ways forward for achieving Universal Health Coverage. The major principle underlying PBF is that health centers are remunerated based on the quantity and quality of services they provide. PBF has been operating in Burkina Faso since 2011, and as a pilot project since 2014 in 15 health districts randomly assigned into four different models, before an eventual scale-up. Despite the need for expeditious documentation of the impact of PBF, caution is advised to avoid adopting hasty conclusions. Above all, it is crucial to understand why and how an impact is produced or not. Our implementation fidelity study approached this inquiry by comparing, after 12 months of operation, the activities implemented against what was planned initially and will make it possible later to establish links with the policy's impacts. Our study compared, in 21 health centers from three health districts, the implementation of activities that were core to the process in terms of content, coverage, and temporality. Data were collected through document analysis, as well as from individual interviews and focus groups with key informants. In the first year of implementation, solid foundations were put in place for the intervention. Even so, implementation deficiencies and delays were observed with respect to certain performance auditing procedures, as well as in payments of PBF subsidies, which compromised the incentive-based rationale to some extent. Over next months, efforts should be made to adjust the intervention more closely to context and to the original planning.


The anti-motion sickness mechanism of ginger. A comparative study with placebo and dimenhydrinate.
A controlled, double-blind study was carried out to determine whether nystagmus response to optokinetic or vestibular stimuli might be altered by some agent contained in powdered ginger root (Zingiber officinale). For comparative purposes, the test subjects were examined after medication with ginger root, placebo and with dimenhydrinate. Eye movements were recorded using standard ENG equipment and evaluation was performed by automatic nystagmus analysis. It could be demonstrated that the effect of ginger root did not differ from that found at baseline, or with placebo, i.e. it had no influence on the experimentally induced nystagmus. Dimenhydrinate, on the other hand, was found to cause a reduction in the nystagmus response to caloric, rotatory and optokinetic stimuli. From the present study it can be concluded that neither the vestibular nor the oculomotor system, both of which are of decisive importance in the occurrence of motion sickness, are influenced by ginger. A CNS mechanism, which is characteristic of the conventional anti-motion sickness drugs, can thus be excluded as regards ginger root. It is more likely that any reduction of motion-sickness symptoms derives from the influence of the ginger root agents on the gastric system.


Endovascular treatment of intracranial dural arteriovenous fistulas.
Endovascular treatment options for dural arteriovenous fistulas (DAVFs) have vastly expanded and become progressively safer in the last several years. Angiographic imaging systems have improved, catheter technology has advanced, and liquid embolic and coil options have increased. As a likely result, an increasing proportion of DAVFs are treated via an endovascular approach. In addition to allowing physicians to appreciate and treat lesions better, varied approaches have been developed. The "plug and push" technique and the new availability of dimethyl sulfoxide--compatible dual lumen balloons have allowed safer and more thorough transarterial treatments. Transvenous treatment has proved to be a valuable technique for some lesions. Hybrid approaches with surgical assisted access to vascular structures have been successfully used to treat more challenging fistulas.


Sleeping parathyroid tumor: rapid hyperfunction after removal of the dominant tumor.
Due to frequent multiplicity of tumors in multiple endocrine neoplasia type 1, it may be difficult to decide when to stop a parathyroid exploration. A fall of intraoperative serum PTH by a certain percentage during parathyroid surgery is often used as one criterion for ending the operation. We report two patients with primary hyperparathyroidism due to multiple endocrine neoplasia type 1 who had their first parathyroidectomy at the National Institutes of Health. In both cases, two and a half glands were removed, an extensive search was done for an occult parathyroid tumor, and intraoperative PTH decreased markedly to the lower limits of normal, suggesting a successful operation. Despite this, both patients became hypercalcemic within 3 d after the operation and showed persistent primary hyperparathyroidism. Detailed findings suggest the following course: chronic hypercalcemia had caused near total suppression of PTH secretion by an undiscovered parathyroid tumor (sleeping parathyroid tumor). When the hypercalcemia decreased after surgery due to the removal of the dominant parathyroid tumor(s), the abnormal yet previously suppressed tumor rapidly began to oversecrete PTH and thus caused postoperative hypercalcemia. Even a fall of the intraoperative PTH to the lower limits of the normal range cannot guarantee that removal of all parathyroid tumors has been complete in cases with multiple tumors. These findings likely reflect strikingly differing PTH secretory functions among distinct tumors in the same patient, with hypercalcemia at least from a dominant tumor suppressing PTH secretion by one or more other parathyroid tumors.


Emergence of Multiple EGFR Extracellular Mutations during Cetuximab Treatment in Colorectal Cancer.
Patients with colorectal cancer who respond to the anti-EGFR antibody cetuximab often develop resistance within several months of initiating therapy. To design new lines of treatment, the molecular landscape of resistant tumors must be ascertained. We investigated the role of mutations in the EGFR signaling axis on the acquisition of resistance to cetuximab in patients and cellular models. Tissue samples were obtained from 37 patients with colorectal cancer who became refractory to cetuximab. Colorectal cancer cells sensitive to cetuximab were treated until resistant derivatives emerged. Mutational profiling of biopsies and cell lines was performed. Structural modeling and functional analyses were performed to causally associate the alleles to resistance. The genetic profile of tumor specimens obtained after cetuximab treatment revealed the emergence of a complex pattern of mutations in EGFR, KRAS, NRAS, BRAF, and PIK3CA genes, including two novel EGFR ectodomain mutations (R451C and K467T). Mutational profiling of cetuximab-resistant cells recapitulated the molecular landscape observed in clinical samples and revealed three additional EGFR alleles: S464L, G465R, and I491M. Structurally, these mutations are located in the cetuximab-binding region, except for the R451C mutant. Functionally, EGFR ectodomain mutations prevent binding to cetuximab but a subset is permissive for interaction with panitumumab. Colorectal tumors evade EGFR blockade by constitutive activation of downstream signaling effectors and through mutations affecting receptor-antibody binding. Both mechanisms of resistance may occur concomitantly. Our data have implications for designing additional lines of therapy for patients with colorectal cancer who relapse upon treatment with anti-EGFR antibodies.


Moorrees-like mesh diagram for Romanian patients - a pilot study.
In 1976, Coenraad F.A. Moorrees completed a series of facial mesh diagrams to ease the orthodontic diagnosis and treatment of North-American patients. Subsequently, the system was adapted by different authors to other races and populations. The objective of this study is to provide a system of Moorrees-like mesh diagrams for the Romanian population, Caucasian race, which would help orthodontists, surgeons and prosthetists. 40 patients were introduced in the study, 20 males and 20 females, with ages between 12-33 years, permanent dentition and slight dental-maxillary abnormalities, class I and II Angle. For each patient, a lateral cephalometric radiograph was taken, with CRANEX 3D, head straight, maximum intercuspation. On tracing paper were drawn 35 anthropometric points and 3 planes, Frankfurt plane, as the horizontal landmark, a perpendicular line through nasion as the vertical landmark and the occlusal plane. From each point we measured the distance in millimeters to the horizontal landmark and to the vertical landmark, respectively. The obtained values were introduced into 40 tables, using Microsoft Office Excel 2007 and 3 arithmetic means were calculated, for males, for females and a general one, for children under 12 years old. The arithmetic means were transferred on millimetric paper and tracing paper, joining the obtained points and completing the templates. Three different Moorrees-like mesh diagrams were obtained, one for male, one for female and a mixt one for children under 12 years, Romanian patients, Caucasian race, respectively. Mesh diagram comes in the support of a better perspective of the anatomical elements of the face and the facial growth, being a useful tool in predicting treatment. Computer based programs with Moorrees-like diagrams adapted to Romanian patients may be the object of further studies.


Characterization of murine lung interstitial macrophages in comparison with alveolar macrophages in vitro.
The present study was performed to characterize the immunologic potential of interstitial macrophages (INT) in comparison with alveolar macrophages (AL). The data showed that AL, compared with INT, have a more efficient phagocytic potential. In addition, they have a strong microbicidal activity and secrete large amounts of reactive oxygen radicals, nitric oxides, TNF, and IFN on appropriate stimulation. They also exert strong tumoricidal and parasiticidal activities. In contrast, INT are more efficient in releasing immunoregulatory cytokines such as IL-1 and IL-6. As determined by Ab staining, INT express more MHC class II molecules and are more effective in functioning as accessory cells for mitogen-stimulated lymphocyte proliferation compared with AL. Thus, AL appear to be particularly effective as nonspecific first line defense cells against infectious agents, whereas INT are equipped to cooperate with interstitial lymphocytes in inducing a specific immune reaction.


Protein phosphatase 1 regulates the cytoplasmic dynein-driven formation of endoplasmic reticulum networks in vitro.
Interphase Xenopus egg extracts form extensive tubular membrane networks in vitro. These networks are identified here as endoplasmic reticulum by the presence of ER resident proteins, as shown by immunofluorescence, and by the presence of single ribosomes and polysomes, as shown by electron microscopy. The effect of phosphorylation on ER movement in interphase was tested using the phosphatase inhibitor, okadaic acid. Okadaic acid treatment resulted in an increase of up to 27-fold in the number of ER tubules moving and in the extent of ER networks formed compared to control extracts. This activation was blocked by the broad-specificity kinase inhibitor 6-dimethylaminopurine. Okadaic acid had no effect, however, on the direction of ER tubule movement, which occurred towards the minus end of microtubules, and was sensitive to low concentrations of vanadate. Inhibition of phosphatases also had no effect on the speed or duration of ER tubule extensions, and did not stimulate the activity of soluble cytoplasmic dynein. The sensitivity of ER movement to okadaic acid closely matched that of protein phosphatase 1. Although the amount of ER motility was greatly increased by inhibiting protein phosphatase 1 (PP1), the amount of cytoplasmic dynein associated with the membrane was not altered. The data support a model in which phosphorylation regulates ER movement by controlling the activity of cytoplasmic dynein bound to the ER membrane.


The origins and diversity of bat songs.
Singing plays an important role in the social lives of several disparate bat species, but just how significant the behavior may be among bats generally is unknown. Recent discoveries suggest singing by bats might be surprisingly more diverse and widespread than anticipated, but if true then two questions must be addressed: firstly why has singing been so rarely documented among bats, and secondly do bats sing for the same reasons as songbirds? We address the first question by reviewing how sampling bias and technical constraints may have produced a myopic view of bat social communication. To address the second question, we review evidence from 50 years of batsong literature supporting the supposition that bat singing is linked to the same constellation of ecological variables that favored birdsong, including territoriality, polygyny, metabolic constraints, migratory behaviors and especially powered flight. We propose that bats sing like birds because they fly like birds; flight is energetically expensive and singing reduces time spent flying. Factoring in the singular importance of acoustic communication for echolocating bats, it seems likely that singing may prove to be relatively common among certain groups of bats once it becomes clear when and where to look for it.


Associations of environmental factors with elderly health and mortality in China.
We examined the effects of community socioeconomic conditions, air pollution, and the physical environment on elderly health and survival in China. We analyzed data from a nationally representative sample of 15 973 elderly residents of 866 counties and cities with multilevel logistic regression models in which individuals were nested within each county or city. After control for individual-level factors, communities' gross domestic product per capita, adult labor force participation rate, and illiteracy rate were significantly associated with physical, mental, and overall health and mortality among the elderly in China. We also found that air pollution increased the odds of disability in activities of daily living (ADLs), cognitive impairment, and health deficits; more rainfall was protective, reducing the odds of ADL disability and cognitive impairment; low seasonal temperatures increased the odds of ADL disability and mortality; high seasonal temperatures increased the odds of cognitive impairment and deficits; and living in hilly areas decreased the odds of ADL disability and health deficits. Efforts to reduce pollution and improve socioeconomic conditions could significantly improve elderly health and survival.


Efavirenz or nevirapine in three-drug combination therapy with two nucleoside or nucleotide-reverse transcriptase inhibitors for initial treatment of HIV infection in antiretroviral-naïve individuals.
The advent of highly active antiretroviral therapy (ART) has reduced the morbidity and mortality due to HIV infection. The World Health Organization (WHO) ART guidelines focus on three classes of antiretroviral drugs, namely nucleoside or nucleotide reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors. Two of the most common medications given as first-line treatment are the NNRTIs, efavirenz (EFV) and nevirapine (NVP). It is unclear which NNRTI is more efficacious for initial therapy. This systematic review was first published in 2010. To determine which non-nucleoside reverse transcriptase inhibitor, either EFV or NVP, is more effective in suppressing viral load when given in combination with two nucleoside reverse transcriptase inhibitors as part of initial antiretroviral therapy for HIV infection in adults and children. We attempted to identify all relevant studies, regardless of language or publication status, in electronic databases and conference proceedings up to 12 August 2016. We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov to 12 August 2016. We searched LILACS (Latin American and Caribbean Health Sciences Literature) and the Web of Science from 1996 to 12 August 2016. We checked the National Library of Medicine (NLM) Gateway from 1996 to 2009, as it was no longer available after 2009. We included all randomized controlled trials (RCTs) that compared EFV to NVP in people with HIV without prior exposure to ART, irrespective of the dosage or NRTI's given in combination.The primary outcome of interest was virological success. Other primary outcomes included mortality, clinical progression to AIDS, severe adverse events, and discontinuation of therapy for any reason. Secondary outcomes were change in CD4 count, treatment failure, development of ART drug resistance, and prevention of sexual transmission of HIV. Two review authors assessed each reference for inclusion using exclusion criteria that we had established a priori. Two review authors independently extracted data from each included trial using a standardized data extraction form. We analysed data on an intention-to-treat basis. We performed subgroup analyses for concurrent treatment for tuberculosis and dosage of NVP. We followed standard Cochrane methodological procedures. Twelve RCTs, which included 3278 participants, met our inclusion criteria. None of these trials included children. The length of follow-up time, study settings, and NRTI combination drugs varied greatly. In five included trials, participants were receiving concurrent treatment for tuberculosis.There was little or no difference between EFV and NVP in virological success (RR 1.04, 95% CI 0.99 to 1.09; 10 trials, 2438 participants; high quality evidence), probably little or no difference in mortality (RR 0.84, 95% CI 0.59 to 1.19; 8 trials, 2317 participants; moderate quality evidence) and progression to AIDS (RR 1.23, 95% CI 0.72 to 2.11; 5 trials, 2005 participants; moderate quality evidence). We are uncertain whether there is a difference in all severe adverse events (RR 0.91, 95% CI 0.71 to 1.18; 8 trials, 2329 participants; very low quality evidence). There is probably little or no difference in discontinuation rate (RR 0.93, 95% CI 0.69 to 1.25; 9 trials, 2384 participants; moderate quality evidence) and change in CD4 count (MD -3.03; 95% CI -17.41 to 11.35; 9 trials, 1829 participants; moderate quality evidence). There may be little or no difference in treatment failure (RR 0.97, 95% CI 0.76 to 1.24; 5 trials, 737 participants; low quality evidence). Development of drug resistance is probably slightly less in the EFV arms (RR 0.76, 95% CI 0.60 to 0.95; 4 trials, 988 participants; moderate quality evidence). No studies were found that looked at sexual transmission of HIV.When we examined the adverse events individually, EFV probably is associated with more people with impaired mental function (7 per 1000) compared to NVP (2 per 1000; RR 4.46, 95% CI 1.65 to 12.03; 6 trials, 2049 participants; moderate quality evidence) but fewer people with elevated transaminases (RR 0.52, 95% CI 0.35 to 0.78; 3 trials, 1299 participants; high quality evidence), fewer people with neutropenia (RR 0.48, 95% CI 0.28 to 0.82; 3 trials, 1799 participants; high quality evidence), and probably fewer people withrash (229 per 100 with NVP versus 133 per 1000 with EFV; RR 0.58, 95% CI 0.34 to 1.00; 7 trials, 2277 participants; moderate quality evidence). We found that there may be little or no difference in gastrointestinal adverse events (RR 0.76, 95% CI 0.48 to 1.21; 6 trials, 2049 participants; low quality evidence), pyrexia (RR 0.65, 95% CI 0.15 to 2.73; 3 trials, 1799 participants; low quality evidence), raised alkaline phosphatase (RR 0.65, 95% CI 0.17 to 2.50; 1 trial, 1007 participants; low quality evidence), raised amylase (RR 1.40, 95% CI 0.72 to 2.73; 2 trials, 1071 participants; low quality evidence) and raised triglycerides (RR 1.10, 95% CI 0.39 to 3.13; 2 trials, 1071 participants; low quality evidence). There was probably little or no difference in serum glutamic oxaloacetic transaminase (SGOT; MD 3.3, 95% CI -2.06 to 8.66; 1 trial, 135 participants; moderate quality evidence), serum glutamic- pyruvic transaminase (SGPT; MD 5.7, 95% CI -4.23 to 15.63; 1 trial, 135 participants; moderate quality evidence) and raised cholesterol (RR 6.03, 95% CI 0.75 to 48.78; 1 trial, 64 participants; moderate quality evidence).Our subgroup analyses revealed that NVP slightly increases mortality when given once daily (RR 0.34, 95% CI 0.13 to 0.90; 3 trials, 678 participants; high quality evidence). There were little or no differences in the primary outcomes for patients who were concurrently receiving treatment for tuberculosis. Both drugs have similar benefits in initial treatment of HIV infection when combined with two NRTIs. The adverse events encountered affect different systems, with EFV more likely to cause central nervous system adverse events and NVP more likely to raise transaminases, cause neutropenia and rash.


Presenilin proteins undergo heterogeneous endoproteolysis between Thr291 and Ala299 and occur as stable N- and C-terminal fragments in normal and Alzheimer brain tissue.
Humans inheriting missense mutations in the presenilin (PS)1 and -2 genes undergo progressive cerebral deposition of the amyloid beta-protein at an early age and develop a clinically and pathologically severe form of familial Alzheimer's disease (FAD). Because PS1 mutations cause the most aggressive known form of AD, it is important to elucidate the structure and function of this multitransmembrane protein in the brain. Using a panel of region-specific PS antibodies, we characterized the presenilin polypeptides in mammalian tissues, including brains of normal, AD, and PS1-linked FAD subjects, and in transfected and nontransfected cell lines. Very little full-length PS1 or -2 was detected in brain and untransfected cells; instead the protein occurred as a heterogeneous array of stable N- and C-terminal proteolytic fragments that differed subtly among cell types and mammalian tissues. Sequencing of the major C-terminal fragment from PS1-transfected human 293 cells showed that the principal endoproteolytic cleavage occurs at and near Met298 in the proximal portion of the large hydrophilic loop. Full-length PS1 in these cells is quickly turned over (T1/2 approximately 60 min), in part to the two major fragments. The sizes and amounts of the PS fragments were not significantly altered in four FAD brains with the Cys410Tyr PS1 missense mutation. Our results indicate that presenilins are rapidly processed to N- and C-terminal fragments in both neural and nonneural cells and that interference with this processing is not an obligatory feature of FAD-causing mutations.


Musculoskeletal Disorders Associated With Quality of Life and Body Composition in Urban and Rural Public School Teachers.
Introduction: Teachers have been reported to be a labor group with high rates of musculoskeletal disorders (MSDs), stress, and strong deterioration of quality of life (QoL). However, little information exists about the association between MSD, QoL, and body composition in rural and urban teachers. Objective: The aim was to study the association of MSD with QoL perception and body composition of urban and rural teachers. Participants and Methods: Participants are comprised a representative sample of urban and rural public schoolteachers from the Valparaiso Region, Chile. MSDs were evaluated with the Standardized Nordic Questionnaire for Musculoskeletal Symptoms validated for the Chilean population. QoL perception was evaluated with the 36-Item Short-Form Survey (SF-36). Body composition was measured via bioimpedance. A logistic regression model was used to evaluate the association between MSD, QoL, and body composition, adjusted for age and gender. Results: A total of 88.9% (urban 90%; rural 87%) of teachers felt pain in some body area, 71.2% of them with limitations; 39% of teachers presented body fat obesity, with the highest rate in rural women. The body area with the greatest MSD prevalence was the neck and shoulders (68.6%). Significant differences were observed between teachers with >p75 of MSD (over six pain regions) and those with ≤p75 (six or fewer painful regions; p < 0.05) on six QoL scales and on physical health components (PCSs) and mental health (MCS) in urban teachers. However, rural teachers presented no differences. The association between teachers with >p75 MSD and low QoL perception was significant (p < 0.05) in PCS and MCS. Furthermore, the regression model presents a significant association between rural areas and low PCS perception. Conclusions: Urban and rural teachers present high rates of MSD and obesity. Teachers with higher rates of MSD have their mental and physical QoL affected, making workplace intervention in MSD necessary to prevent teacher health deterioration.


The structure-electrochemical property relationship of quinone electrodes for lithium-ion batteries.
Quinones are promising electrode materials for lithium-ion batteries (LIBs), but their structure-electrochemical property relationship remains unclear. The aim of this study is to unravel the structural influence on the electrochemical properties of different quinones in LIBs. Through density functional theory calculations, redox potentials of 20 parent quinone isomers were examined, which revealed an increasing order of redox potentials as para-quinones < discrete-quinones < ortho-quinones. Two new methods were introduced to calculate and design organic electrode materials rationally. One is the vertical electron affinity in consideration of solvation effect, which was used to estimate the number of electron accommodation for quinones during lithiation. The other is a new index denoted as ΔA2Li used in para- and ortho-quinones, which was introduced to reveal the relationship between aromaticity and redox potential, establishing the theoretical basis for the design of analogous high-voltage organic electrode materials of LIBs.


Maternal age-based prenatal screening for chromosomal disorders: attitudes of women and health care providers toward changes.
To explore views of women and health care providers (HCPs) about the changing recommendations regarding maternal age-based prenatal screening. Mixed-methods design. Ontario. A sample of women who had given birth within the previous 2 years and who had attended a family medicine centre, midwifery practice, or baby and mother wellness program (n = 42); and a random sample of family physicians (n = 1600), and all Ontario obstetricians (n = 694) and midwives (n = 334) who provided prenatal care. We used focus groups (FGs) to explore women's views. Content analysis was used to uncover themes and delineate meaning. To explore HCPs' views, we conducted a cross-sectional self-completion survey. All FG participants (42 women in 6 FGs) expressed the importance of individual choice of prenatal screening modality, regardless of age. They described their perception that society considers women older than 35 to be at high obstetric risk and raised concerns that change in the maternal age-related screening policy would require education. The HCP survey response rate was 40%. Results showed 24% of HCPs agreed that women of any age should be eligible for invasive diagnostic testing regardless of prenatal screening results; 15% agreed that the age for diagnostic testing should be increased to 40 years, 14% agreed that diagnostic testing should be reserved for women with positive prenatal screening results, and 45% agreed that prenatal screening should remain unchanged. Maternity care organizations have recommended that maternal age-based prenatal screening is no longer appropriate. Informed choice is of paramount importance to women and should be part of any change. Health care providers need to be engaged in and educated about any change to screening guidelines to offer women informed choices.


False positive molecular diagnosis of Leber's hereditary optic neuropathy.
The most common pathogenic mitochondrial DNA (mtDNA) mutation associated with Leber's hereditary optic neuropathy (LHON) is at the 11,778 nucleotide (nt) position and is usually detected by loss of an Sfa NI restriction site. However, Sfa NI restriction site includes five nucleotides. Substitution of any of the five nucleotides leads to loss of the cutting site and causes a false-positive result. We investigated the false-positive diagnosis of LHON by loss of the Sfa NI restriction site using Sfa NI restriction site analysis and single-strand conformation polymorphism (SSCP) analysis. Mae III restriction analysis for double confirmation of the Sfa NI restriction site and direct sequencing for final confirmation of SSCP analysis were performed. The sensitivity of Sfa NI test was 100% and the specificity of the Sfa NI test was 97%. The false-positive rate of Sfa NI test was 3%. SSCP analysis showed 100% sensitivity. Direct sequencing showed 32 patients had a mutation at nt 11,778 of mtDNA and one patient had a silent mutation at nt 11,782 of mtDNA. These results suggest that restriction enzyme digestion analysis requires double confirmation to avoid a false-positive diagnosis and that DNA sequencing is needed for the confirmation of the mutation detected by SSCP.


L3MBTL2 protein acts in concert with PcG protein-mediated monoubiquitination of H2A to establish a repressive chromatin structure.
We have identified human MBT domain-containing protein L3MBTL2 as an integral component of a protein complex that we termed Polycomb repressive complex 1 (PRC1)-like 4 (PRC1L4), given the copresence of PcG proteins RING1, RING2, and PCGF6/MBLR. PRC1L4 also contained E2F6 and CBX3/HP1γ, known to function in transcriptional repression. PRC1L4-mediated repression necessitated L3MBTL2 that compacted chromatin in a histone modification-independent manner. Genome-wide location analyses identified several hundred genes simultaneously bound by L3MBTL2 and E2F6, preferentially around transcriptional start sites that exhibited little overlap with those targeted by other E2Fs or by L3MBTL1, another MBT domain-containing protein that interacts with RB1. L3MBTL2-specific RNAi resulted in increased expression of target genes that exhibited a significant reduction in H2A lysine 119 monoubiquitination. Our findings highlight a PcG/MBT collaboration that attains repressive chromatin without entailing histone lysine methylation marks.


Unmixing dynamic PET images with variable specific binding kinetics.
To analyze dynamic positron emission tomography (PET) images, various generic multivariate data analysis techniques have been considered in the literature, such as principal component analysis (PCA), independent component analysis (ICA), factor analysis and nonnegative matrix factorization (NMF). Nevertheless, these conventional approaches neglect any possible nonlinear variations in the time activity curves describing the kinetic behavior of tissues with specific binding, which limits their ability to recover a reliable, understandable and interpretable description of the data. This paper proposes an alternative analysis paradigm that accounts for spatial fluctuations in the exchange rate of the tracer between a free compartment and a specifically bound ligand compartment. The method relies on the concept of linear unmixing, usually applied on the hyperspectral domain, which combines NMF with a sum-to-one constraint that ensures an exhaustive description of the mixtures. The spatial variability of the signature corresponding to the specific binding tissue is explicitly modeled through a perturbed component. The performance of the method is assessed on both synthetic and real data and is shown to compete favorably when compared to other conventional analysis methods.


Direction tuning of human motion detection determined from a population model.
Mass responses that are obtained using electrophysiological or psychophysical techniques are inadequate to characterize motion detectors at the single-unit level. Therefore, we have modelled a population of motion detectors and fitted their mass response to motion-onset EEG data. By examining a single unit of the modelled population we could assess the range of directions and the level of adaptation an individual motion detector responded to. Stimuli were patterns of randomly distributed dots. After subjects had adapted to either a non-moving pattern or to motion in one fixed direction, the pattern moved in one of seven possible test directions. The population model assumed elementary motion detectors with a Gaussian angle-selectivity profile. The population response was calculated as the sum of all adaptation-weighted individual responses to the test direction. In all subjects, we observed sizeable effects of adaptation on test directions close to the adapted direction and small amounts of direction-independent adaptation for all test directions. The model fit explained 75% (Oz) and 94% (lateral derivation) of the total variance and revealed a motion detector bandwidth (full width at half maximum) of 72 degrees (Oz) and 62 degrees (lateral derivation). The maximal adaptation depth was estimated as 72% (Oz) and 66% (lateral derivation). Estimates inferred from the population model representing human motion detectors were found to be close to those obtained by single-cell data from non-human primates.


Terahertz field control of in-plane orbital order in La(0.5)Sr(1.5)MnO4.
In-plane anisotropic ground states are ubiquitous in correlated solids such as pnictides, cuprates and manganites. They can arise from doping Mott insulators and compete with phases such as superconductivity; however, their origins are debated. Strong coupling between lattice, charge, orbital and spin degrees of freedom results in simultaneous ordering of multiple parameters, masking the mechanism that drives the transition. Here we demonstrate that the orbital domains in a manganite can be oriented by the polarization of a pulsed THz light field. Through the application of a Hubbard model, we show that domain control can be achieved by enhancing the local Coulomb interactions, which drive domain reorientation. Our results highlight the key role played by the Coulomb interaction in the control and manipulation of orbital order in the manganites and demonstrate a new way to use THz to understand and manipulate anisotropic phases in a potentially broad range of correlated materials.


Slow-Pull Using a Fanning Technique Is More Useful Than the Standard Suction Technique in EUS-Guided Fine Needle Aspiration in Pancreatic Masses.
Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is useful for obtaining pancreatic mass samples. The combination of modified techniques (i.e., slow-pull technique and fanning technique) may improve the quality of the sample obtained by EUS-FNA. We investigated the effectiveness of a combined slow-pull fanning technique in EUS-FNA for pancreatic mass. This prospective comparative study investigated EUS-FNA performed for pancreatic solid masses between August 2015 and July 2016. Pairwise specimens were alternately obtained using the following two techniques for targeted pancreatic lesions: standard suction or slow-pull with fanning. We compared the specimen quality, blood contamination, and diagnostic accuracy of these techniques. Forty-eight consecutive patients were included (29 men; mean age, 68.1±11.9 years), and 96 pancreatic mass specimens were obtained. The slow-pull with fanning technique had a significantly superior diagnostic accuracy than the suction technique (88% vs 71%, p=0.044). Furthermore, blood contamination was significantly reduced using the slow-pull with fanning technique (ratio of no or slight contamination, 77% vs 56%, p=0.041). No difference was observed in the acquisition of adequate cellularity between the groups. In the subgroup analysis, the tumor size and sampling technique were related to the EUS-FNA diagnostic accuracy. The slow-pull with needle fanning technique showed a good diagnostic yield for EUS-FNA for pancreatic mass. This technique can be useful for performing EUS-guided sampling for diagnosing pancreatic disease.


Diminished error-related brain activity as a promising endophenotype for substance-use disorders: evidence from high-risk offspring.
One of the core features of individuals with a substance-use disorder (SUD) is the reduced ability to successfully process errors and monitor performance, as reflected by diminished error-related negativities (ERN). However, whether these error-related brain abnormalities are caused by chronic substance use or rather predates it remains unclear. The present study elucidated whether hypoactive performance monitoring represents an endophenotypic vulnerability marker for SUD by using a high-risk paradigm. We assessed the behavioral components of error-processing, as well as the amplitude of the ERN in the event-related brain potential (ERP) during performance of the Eriksen Flanker Task among high-risk adolescents of parents with a SUD (HR; n = 28) and normal-risk controls (NR; n = 40). Results revealed that HR offspring were characterized by a higher prevalence of internalizing symptoms and more frequent cannabis use, the latter having a significant influence on the ERN. Interestingly, risk group uniquely predicted the negativity amplitude in response to error trials above and beyond confounding variables. Moreover, we found evidence of smaller ERN amplitudes in (cannabis use-naïve) HR offspring, reflecting impaired early processing of error information and suboptimal performance monitoring, whereas no robust group differences were found for overall behavioral performance. This effect was independent of an overall reduction in brain activity. Taken together, although we cannot rule out alternative explanations, the results of our study may provide evidence for the idea that diminished error-processing represents a promising endophenotype for SUD that may indicate a vulnerability to the disorder.


Posttraumatic balance disorders.
Head trauma is being more frequently recognized as a causative agent in balance disorders. Most of the published literature examining traumatic brain injury (TBI) after head trauma has focused on short-term prognostic indicators and neurocognitive disorders. Few data are available to guide those individuals who see patients with balance disorders secondary to TBI. Our group has previously examined balance disorders after mild head trauma. In this study, we study all classes of head trauma. We provide a classification system that is useful in the diagnosis and management of balance disorders after head trauma and we examine treatment outcomes. As dizziness is one of the most common outcomes of TBI, it is essential that those who study and treat dizziness be familiar with this subject.


Scribble and E-cadherin cooperate to control symmetric daughter cell positioning by multiple mechanisms.
The fate of the two daughter cells is intimately connected to their positioning, which is in turn regulated by cell junction remodelling and orientation of the mitotic spindle. How multiple cues are integrated to dictate the ultimate positioning of daughters is not clear. Here, we identify novel mechanisms of regulation of daughter positioning in single MCF10A cells. The polarity protein, Scribble cooperates with E-cadherin for sequential roles in daughter positioning. First Scribble stabilises E-cadherin at the mitotic cortex as well as the retraction fibres, to mediate spindle orientation. Second, Scribble re-locates to the junction between the two daughters to allow a new E-cadherin-based-interface to form between them, influencing the width of the nascent daughter-daughter junction and subsequent cell positioning. Thus, E-cadherin and Scribble dynamically relocate to different intracellular sites during cell division to orient the mitotic spindle and control placement of the daughter cells after cell division. This article has an associated First Person interview with the first author of the paper.


Prospective Randomized Clinical Trial Investigating the Effect of the Reamer-Irrigator-Aspirator on the Volume of Embolic Load and Respiratory Function During Intramedullary Nailing of Femoral Shaft Fractures.
We sought to determine whether the use of the Reamer-Irrigator-Aspirator (RIA) device resulted in a decreased amount of fat emboli compared with standard reaming (SR) when performing intramedullary (IM) nailing of femoral shaft fractures. Prospective randomized clinical trial. Multi-centered trial, level I trauma centers. All eligible patients who presented to participating institutions with an isolated femoral shaft fracture amenable to fixation with antegrade IM nailing. Thirty-one patients were enrolled: nine were excluded because of technical difficulties with the transesophageal echocardiogram (TEE) recording. Therefore, the study comprised 22 patients: 11 patients randomized to the SR group and eleven patients randomized to the RIA group. Antegrade IM nailing of a femoral shaft fracture with standard reamers or the RIA device. All patients were monitored intraoperatively with a continuous TEE to assess embolic events in the right atrium. A radial arterial line was used to monitor blood gases and potential systemic effects of emboli. Duration, size, and severity of emboli as measured by TEE. The operative procedure was divided into 6 distinct stages: preoperative, reduction, guidewire passage, reaming, nail insertion, and postoperative. There was no significant difference in emboli between the RIA and SR groups preoperatively, during fracture reduction, guidewire insertion, or postoperatively. Measured with a standardized scoring system, there was a modest reduction in total emboli score in the RIA group during reaming (SR 5.30 [SD; 1.81] vs. RIA 4.05 [SD; 2.19], P = 0.005) and during nail insertion (SR 5.09 [SD; 1.74] vs. RIA 4.25 [SD; 1.89], P = 0.03). We were unable to correlate this reduction with any improvement in physiologic parameters (mean arterial pressure, end-tidal CO2, O2 saturation, pH, paO2, and paCO2). This study showed a modest reduction of embolic debris during the reaming and nail insertion segments of the operative procedure. We were unable to correlate this with any change in physiologic parameters. Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.


A potential role for extracellular nitric oxide generation in cGMP-independent inhibition of human platelet aggregation: biochemical and pharmacological considerations.
1. Nitric oxide (NO) is a potent inhibitor of platelet activation, that inhibits the agonist-induced increase in cytosolic Ca2+ concentration through both cGMP-dependent and independent pathways. However, the NO-related (NOx) species responsible for cGMP-independent signalling in platelets is unclear. We tested the hypothesis that extracellular NO, but not NO+ or peroxynitrite, generated in the extracellular compartment is responsible for cGMP-independent inhibition of platelet activation via inhibition of Ca2+ signalling. 2. Concentration-response curves for diethylamine diazeniumdiolate (DEA/NO; a spontaneous NO generator), S-nitroso-N-valerylpenicillamine (SNVP; an S-nitrosothiol) and 3-morpholinosydnonomine (SIN-1; a peroxynitrite generator) were generated in platelet-rich plasma (PRP) and washed platelets (WP) in the presence and absence of a supramaximal concentration of the soluble guanylate cyclase inhibitor, ODQ (20 microM). All three NOx donors displayed cGMP-independent inhibition of platelet aggregation in PRP, but only DEA/NO exhibited cGMP-independent inhibition of aggregation in WP. 3. Analysis of NO generation using an isolated NO-electrode revealed that cGMP-independent effects coincided with the generation of substantial levels of extracellular NO (>40 nM) from the NOx donors. 4. Reconstitution of WP with plasma factors indicated that the copper-containing plasma protein, caeruloplasmin (CP), catalysed the release of NO from SNVP, while Cu/Zn superoxide dismutase (SOD) unmasked NO generated from SIN-1. The increased generation of extracellular NO correlated with a switch to cGMP-independent effects with both NOx donors. 5. Analysis of Fura-2 loaded WP revealed that only DEA/NO inhibited Ca2+ signalling in platelets via a cGMP-independent mechanism. However, preincubation of SNVP and SIN-1 with CP and SOD, respectively, induced cGMP-independent inhibition of intraplatelet Ca2+ trafficking by the NOx donors. 6. Taken together, our data suggest that extracellular NO (>40 nM) is required for cGMP-independent inhibition of platelet activation. Plasma constituents may play an important pharmacological role in activating cGMP-independent signalling by S-nitrosothiols or peroxynitrite generators.


Neuronal function and dysfunction of Drosophila dTDP.
TDP-43 is an RNA- and DNA-binding protein well conserved in animals including the mammals, Drosophila, and C. elegans. In mammals, the multi-function TDP-43 encoded by the TARDBP gene is a signature protein of the ubiquitin-positive inclusions (UBIs) in the diseased neuronal/glial cells of a range of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-U). We have studied the function and dysfunction of the Drosophila ortholog of the mammalian TARDBP gene, dTDP, by genetic, behavioral, molecular, and cytological analyses. It was found that depletion of dTDP expression caused locomotion defect accompanied with an increase of the number of boutons at the neuromuscular junctions (NMJ). These phenotypes could be rescued by overexpression of Drosophila dTDP in the motor neurons. In contrast, overexpression of dTDP in the motor neurons also resulted in reduced larval and adult locomotor activities, but this was accompanied by a decrease of the number of boutons and axon branches at NMJ. Significantly, constitutive overexpression of dTDP in the mushroom bodies caused smaller axonal lobes as well as severe learning deficiency. On the other hand, constitutive mushroom body-specific knockdown of dTDP expression did not affect the structure of the mushroom bodies, but it impaired the learning ability of the flies, albeit moderately. Overexpression of dTDP also led to the formation of cytosolic dTDP (+) aggregates. These data together demonstrate the neuronal functions of dTDP, and by implication the mammalian TDP-43, in learning and locomotion. The effects of mis-expression of dTDP on Drosophila NMJ suggest that eukaryotic TDP-43 guards against over development of the synapses. The conservation of the regulatory pathways of functions and dysfunctions of Drosophila dTDP and mammalian TDP-43 also shows the feasibility of using the flies as a model system for studying the normal TDP-43 function and TDP-43 proteinopathies in the vertebrates including human.


Isolation and Characterization of Antibacterial Compounds from Aspergillus fumigatus: An Endophytic Fungus from a Mangrove Plant of the Sundarbans.
The Sundarbans, a UNESCO world heritage site, is one of the largest mangrove forests in one stretch. Mangrove plants from this forest are little studied for their endophytic fungi. In this study, we isolated fourteen endophytic fungi from the plants Ceriops decandra and Avicennia officinalis collected from the Sundarbans. Five of them were identified as Aspergillus sp. and one as Penicillium sp. by macroscopic and microscopic observation. Antibacterial activity of the crude extracts obtained from these endophytes was determined against Staphylococcus aureus, Micrococcus luteus, Escherichia coli, and Pseudomonas aeruginosa using resazurin-based microtiter assay. The isolated endophytes showed varying degrees of antibacterial activity with MICs ranging between 5 and 0.078 mg/mL. Molecular identification of the most active endophyte revealed its identity as Aspergillus fumigatus obtained from the leaves of C. decandra. Acute toxicity study of the ethyl acetate extract of A. fumigatus in mice revealed no mortality even at the highest dose of 2000 mg/kg bodyweight, though some opposing results are found in the subacute toxicity study. The extract was subjected to silica gel and Sephadex column chromatography resulting in the isolation of three pure compounds. LC-MS analysis of these pure compounds revealed their identity as fumigaclavine C, azaspirofuran B, and fraxetin. This is the first report of fraxetin from A. fumigatus. All three identified compounds were previously reported for their antibacterial activity against different strains of both Gram-positive and Gram-negative bacteria. Therefore, the observed antibacterial activity of the ethyl acetate (EtOAc) extract of A. fumigatus could be due to the presence of these compounds. These results support the notion of investigating fungal endophytes from the Sundarbans for new antimicrobial compounds.


Climate cooling and clade competition likely drove the decline of lamniform sharks.
Understanding heterogeneity in species richness between closely related clades is a key research question in ecology and evolutionary biology. Multiple hypotheses have been proposed to interpret such diversity contrasts across the tree of life, with most studies focusing on speciation rates to explain clades' evolutionary radiations, while often neglecting extinction rates. Here we study a notorious biological model as exemplified by the sister relationships between mackerel sharks (Lamniformes, 15 extant species) and ground sharks (Carcharhiniformes, ∼290 extant species). Using a comprehensive fossil dataset, we found that the diversity dynamics of lamniforms waxed and waned following repeated cycles of radiation phases and declining phases. Radiation phases peaked up to 3 times the current diversity in the early Late Cretaceous. In the last 20 million years, the group declined to its present-day diversity. Along with a higher extinction risk for young species, we further show that this declining pattern is likely attributed to a combination of abiotic and biotic factors, with a cooling-driven extinction (negative correlation between temperature and extinction) and clade competition with some ground sharks. Competition from multiple clades successively drove the demise and replacement of mackerel sharks due to a failure to originate facing the rise of ground sharks, particularly since the Eocene. These effects came from ecologically similar carcharhiniform species inhibiting diversification of medium- and large-sized lamniforms. These results imply that the interplay between abiotic and biotic drivers had a substantial role in extinction and speciation, respectively, which determines the sequential rise and decline of marine apex predators.


Physiology and pathophysiology of potassium homeostasis.
Total body potassium content and proper distribution of potassium across the cell membrane is of critical importance for normal cellular function. Potassium homeostasis is maintained by several different methods. In the kidney, total body potassium content is achieved by alterations in renal excretion of potassium in response to variations in intake. Insulin and beta-adrenergic tone play critical roles in maintaining the internal distribution of potassium under normal conditions. Despite homeostatic pathways designed to maintain potassium levels within the normal range, disorders of altered potassium homeostasis are common. The clinical approach to designing effective treatments relies on understanding the pathophysiology and regulatory influences which govern the internal distribution and external balance of potassium. Here we provide an overview of the key regulatory aspects of normal potassium physiology. This review is designed to provide an overview of potassium homeostasis as well as provide references of seminal papers to guide the reader into a more in depth discussion of the importance of potassium balance. This review is designed to be a resource for educators and well-informed clinicians who are teaching trainees about the importance of potassium balance.


Multiplexed imaging by means of optically generated Kronecker products: 1. The basic concept.
Atechnique for multiplexed imaging is described. By using mask combinations, this technique requires far fewer encoding masks to generate the same number of masking operations than do more traditional approaches. It is also theoretically capable of higher optical throughput efficiencies. The method is readily adaptable to new image geometries and to applications in multispectral imaging.


Climate related sea-level variations over the past two millennia.
We present new sea-level reconstructions for the past 2100 y based on salt-marsh sedimentary sequences from the US Atlantic coast. The data from North Carolina reveal four phases of persistent sea-level change after correction for glacial isostatic adjustment. Sea level was stable from at least BC 100 until AD 950. Sea level then increased for 400 y at a rate of 0.6 mm/y, followed by a further period of stable, or slightly falling, sea level that persisted until the late 19th century. Since then, sea level has risen at an average rate of 2.1 mm/y, representing the steepest century-scale increase of the past two millennia. This rate was initiated between AD 1865 and 1892. Using an extended semiempirical modeling approach, we show that these sea-level changes are consistent with global temperature for at least the past millennium.


The TrxG Complex Mediates Cytokine Induced De Novo Enhancer Formation in Islets.
To better understand how β-cells respond to proinflammatory cytokines we mapped the locations of histone 3 lysine 4 monomethylation (H3K4me1), a post-translational histone modification enriched at active and poised cis-regulatory regions, in IFNγ, Il-1β, and TNFα treated pancreatic islets. We identified 96,721 putative cis-regulatory loci, of which 3,590 were generated de novo, 3,204 had increased H3K4me1, and 5,354 had decreased H3K4me1 in IFNγ, Il-1β, and TNFα exposed islets. Roughly 10% of the de novo and increased regions were enriched for the repressive histone modification histone 3 lysine 27 trimethylation (H3K27me3) in untreated cells, and these were frequently associated with chemokine genes. We show that IFNγ, Il-1β, and TNFα exposure overcomes this repression and induces chemokine gene activation in as little as three hours, and that this expression persists for days in absence of continued IFNγ, Il-1β, and TNFα exposure. We implicate trithorax group (TrxG) complexes as likely players in the conversion of these repressed loci to an active state. To block the activity of these complexes, we suppressed Wdr5, a core component of the TrxG complexes, and used the H3K27me3 demethylase inhibitor GSK-J4. We show that GSK-J4 is particularly effective in blunting IFNγ, Il-1β, and TNFα-induced chemokine gene expression in β-cells; however, it induced significant islet-cell apoptosis and β-cell dysfunction. Wdr5 suppression also reduced IFNγ, Il-1β, and TNFα induced chemokine gene expression in β-cells without affecting islet-cell survival or β-cell function after 48hrs, but did begin to increase islet-cell apoptosis and β-cell dysfunction after four days of treatment. Taken together these data suggest that the TrxG complex is potentially a viable target for preventing cytokine induced chemokine gene expression in β-cells.


Expected Fitness Gains of Randomized Search Heuristics for the Traveling Salesperson Problem.
Randomized search heuristics are frequently applied to NP-hard combinatorial optimization problems. The runtime analysis of randomized search heuristics has contributed tremendously to our theoretical understanding. Recently, randomized search heuristics have been examined regarding their achievable progress within a fixed-time budget. We follow this approach and present a fixed-budget analysis for an NP-hard combinatorial optimization problem. We consider the well-known Traveling Salesperson Problem (TSP) and analyze the fitness increase that randomized search heuristics are able to achieve within a given fixed-time budget. In particular, we analyze Manhattan and Euclidean TSP instances and Randomized Local Search (RLS), (1+1) EA and (1+[Formula: see text]) EA algorithms for the TSP in a smoothed complexity setting, and derive the lower bounds of the expected fitness gain for a specified number of generations.


T-tube management of late esophageal perforation.
Esophageal perforation is a serious condition with a high mortality rate. Management strategy of such a patient depends on the extent of perforation and the time interval between perforation and diagnosis. The use of a T tube to treat delayed esophageal perforation with complete resolution and no need for future definitive surgery has been less frequently described. We adapted this principle in successful management of a 73 year old patient with four days history of fever, shortness of breath, chest pain and radiological evidence of perforation.


A monomeric red fluorescent protein with low cytotoxicity.
Multicolour labelling with fluorescent proteins is frequently used to differentially highlight specific structures in living systems. Labelling with fusion proteins is particularly demanding and is still problematic with the currently available palette of fluorescent proteins that emit in the red range due to unsuitable subcellular localization, protein-induced toxicity and low levels of labelling efficiency. Here we report a new monomeric red fluorescent protein, called FusionRed, which demonstrates both high efficiency in fusions and low toxicity in living cells and tissues.


Platinum(0)-mediated C-O bond activation of ethers via an SN2 mechanism.
A computational study of the C(methyl)-O bond activation of fluorinated aryl methyl ethers by a platinum(0) complex Pt(PCyp3)2 (Cyp = cyclopentyl) (N. A. Jasim, R. N. Perutz, B. Procacci and A. C. Whitwood, Chem. Commun., 2014, 50, 3914) demonstrates that the reaction proceeds via an SN2 mechanism. Nucleophilic attack of Pt(0) generates an ion pair consisting of a T-shaped platinum cation with an agostic interaction with a cyclopentyl group and a fluoroaryloxy anion. This ion-pair is converted to a 4-coordinate Pt(ii) product trans-[PtMe(OArF)(PCyp3)2]. Structure-reactivity correlations are fully consistent with this mechanism. The Gibbs energy of activation is calculated to be substantially higher for aryl methyl ethers without fluorine substituents and higher still for alkyl methyl ethers. These conclusions are in accord with the experimental results. Further support was obtained in an experimental study of the reaction of Pt(PCy3)2 with 2,3,5,6-tetrafluoro-4-allyloxypyridine yielding the salt of the Pt(η3-allyl) cation and the tetrafluoropyridinolate anion [Pt(PCy3)2(η3-allyl)][OC5NF4]. The calculated activation energy for this reaction is significantly lower than that for fluorinated aryl methyl ethers.


When the forest dies: the response of forest soil fungi to a bark beetle-induced tree dieback.
Coniferous forests cover extensive areas of the boreal and temperate zones. Owing to their primary production and C storage, they have an important role in the global carbon balance. Forest disturbances such as forest fires, windthrows or insect pest outbreaks have a substantial effect on the functioning of these ecosystems. Recent decades have seen an increase in the areas affected by disturbances in both North America and Europe, with indications that this increase is due to both local human activity and global climate change. Here we examine the structural and functional response of the litter and soil microbial community in a Picea abies forest to tree dieback following an invasion of the bark beetle Ips typographus, with a specific focus on the fungal community. The insect-induced disturbance rapidly and profoundly changed vegetation and nutrient availability by killing spruce trees so that the readily available root exudates were replaced by more recalcitrant, polymeric plant biomass components. Owing to the dramatic decrease in photosynthesis, the rate of decomposition processes in the ecosystem decreased as soon as the one-time litter input had been processed. The fungal community showed profound changes, including a decrease in biomass (2.5-fold in the litter and 12-fold in the soil) together with the disappearance of fungi symbiotic with tree roots and a relative increase in saprotrophic taxa. Within the latter group, successive changes reflected the changing availability of needle litter and woody debris. Bacterial biomass appeared to be either unaffected or increased after the disturbance, resulting in a substantial increase in the bacterial/fungal biomass ratio.


Dietary inflammatory index and risk of colorectal cancer in the Iowa Women's Health Study.
Colorectal cancer, the third most common cancer in the United States, has a natural history that usually encompasses several decades. Dietary components have been implicated in the etiology of colorectal cancer, perhaps through their effect on inflammation. We examined the ability of the dietary inflammatory index (DII) to predict colorectal cancer in the Iowa Women's Health Study. The DII was computed based on dietary intake assessed by a 121-item food frequency questionnaire in this cohort of 34,703 women, ages 55 to 69 years, free of any self-reported prior malignancy at enrollment in 1986. Incident colorectal cancer cases were identified through linkage with the State Health Registry of Iowa (a Surveillance, Epidemiology, and End Results program member). Cox proportional hazards regression was used to estimate HRs. Through the end of 2010, 1,636 incident colorectal cancers were identified, including 1,329 colon and 325 rectal cancers. Multivariable analysis, adjusting for body mass index, smoking status, pack-years of smoking, hormone replacement therapy, education, diabetes, and total energy intake, revealed positive associations between higher DII and colorectal cancer risk [HR for DIIcontinuous: 1.07 per unit increase in DII (corresponding to 0.5 SD unit increase); 95% confidence interval (CI), 1.01-1.13; HR for DIIquintiles: Q5 vs. Q1 = 1.20; 95% CI, 1.01-1.43]. HRs for DII were similar for colon cancer and rectal cancer, though not statistically significant for rectal cancer. These results indicate that a proinflammatory diet, as indicated by higher DII scores, was associated with higher risk of developing colorectal cancer. Proinflammatory diets are associated with increased risk of colorectal cancer.


A phase II clinical trial of 6-mercaptopurine (6MP) and methotrexate in patients with BRCA defective tumours: a study protocol.
BRCA1 and BRCA2 genes are critical in homologous recombination DNA repair and have been implicated in familial breast and ovarian cancer tumorigenesis. Tumour cells with these mutations demonstrate increased sensitivity to cisplatin and poly (ADP-ribose) polymerase (PARP) inhibitors. 6MP was identified in a screen for novel drugs and found to selectively kill BRCA-defective cells in a xenograft model as effectively as the PARP inhibitor AGO14699, even after these cells had acquired resistance to a PARP inhibitor or cisplatin. Exploiting the genetic basis of these tumours enables us to develop a more tailored approach to therapy for patients with BRCA mutated cancers. This multi-centre phase II single arm trial was designed to investigate the activity and safety of 6-mercaptopurine (6MP) 55 mg/m² per day, and methotrexate 15 mg/m² per week in patients with advanced breast or ovarian cancer, ECOG PS 0-2, progressing after ≥ one prior regimen and known to bear a BRCA1/2 germ line mutation. Accrual was planned in two stages, with treatment continuing until progression or unacceptable toxicity; in the first, if less than 3/30 evaluable patients respond at 8 weeks after commencing treatment, the trial will be stopped for futility; if not, then accrual would proceed to a second stage, in which if more than 9/65 evaluable patients are found to respond at 8 weeks, the treatment will be regarded as potentially effective and a phase III trial considered subject to satisfactory safety and tolerability. The primary outcome is objective response at 8 weeks, defined by RECISTS v1.1 as complete response, partial response or stable disease. Secondary outcomes include safety, progression- free and overall survival, and quality of life. This study aims to investigate whether 6MP might be an effective treatment for BRCA deficient tumours even after the development of resistance to PARP inhibitors or platinum drugs. The study has surpassed the first stage analysis criteria of more than 3 out of 30 evaluable patients responding at 8 weeks, and is currently in the second stage of recruitment. NCT01432145 http://www.ClinicalTrials.gov.


The effect of covalently linked RGD peptide on the conformation of polysaccharides in aqueous solutions.
Covalently modified polysaccharides are routinely used in tissue engineering due to their tailored biofunctionality. Understanding the effect of single-chain level modification on the solution conformation of the single chain, and more importantly on the self-assembly and aggregation of the ensemble of chains is expected to improve our ability to control network topology and the properties of the resulting gels. Attaching an RGD peptide to a polysaccharide backbone is a common procedure used to promote cell adhesion in hydrogel scaffolds. Recently it has been shown that the spatial presentation of the RGD sequences affects the cell behavior; thus, understanding the effects of grafted RGD on the conformational properties of the solvated polysaccharide chains is a prerequisite for rational design of polysaccharide-peptide based biomaterials. Here we investigate the effect of covalently linked G4RGDS on the conformational state of the individual chain and chain assemblies of alginate, chitosan, and hyaluronic acid (HA) in aqueous solutions. Two peptide fractions were studied using small-angle X-ray scattering (SAXS) and rheology. In all cases, upon peptide conjugation structural differences were observed. Analysis of the scattering data shows evidence of clustering for a higher fraction of bound peptide. Moreover for all three polysaccharides the typical shear thinning behavior of the natural polysaccharide solutions is replaced by a Newtonian fluid behavior for the lower fraction conjugated peptide while a more pronounced shear thinning behavior is observed for the higher fraction. These results indicate that the fraction of the bounded peptide, determines the behavior of a polysaccharide-peptide conjugates in solution, regardless of the specific nature of the polysaccharide.


Quality of life and technology: impact on children and families with diabetes.
Ensuring quality of life (QOL) while maintaining glycemic control within targets is an important challenge in type 1 and type 2 diabetes treatment. For children with diabetes, QOL includes enjoying meals, feeling safe in school, and perceiving positive, supportive relationships with parents, siblings, and friends. Yet many treatment-related and psychosocial barriers can interfere with a child's QOL and their ability to manage diabetes effectively. Diabetes management also imposes considerable lifestyle demands that are difficult and often frustrating for children to negotiate at a young age. Recent advances in diabetes medications and technologies have improved glycemic control in children with diabetes. Two widely used technologies are the insulin pump and continuous glucose monitoring (CGM) system. These technologies provide patients with more flexibility in their daily life and information about glucose fluctuations. Several studies report improvements in glycemic control in children with type 1 diabetes using the insulin pump or sensor-augmented pump therapy. Importantly, these technologies may impact QOL for children and families with diabetes, although they are rarely used or studied in the treatment of children with type 2 diabetes. Further, emerging closed loop and web- and phone-based technologies have great potential for supporting diabetes self-management and perhaps QOL. A deeper understanding and appreciation of the impact of diabetes technology on children's and parents' QOL is critical for both the medical and psychological care of diabetes. Thus, the purpose of this review is to discuss the impact of new diabetes technologies on QOL in children, adolescents and families with type 1 diabetes.