Abdominal Multidetector Computed Tomography for Suspected Small-Bowel Obstruction: Multireader Study Comparing Radiologist Performance for Predicting Surgical Outcomes.
To compare performance of junior (JR)/senior (SR) abdominal radiologists using multidetector computed tomography (MDCT) to predict surgical intervention, bowel resection, and presence of bowel ischemia in patients with suspected small-bowel obstruction (SBO). Retrospective, institutional review board-approved, Health Insurance Portability and Accountability Act-compliant, blinded, independent review of MDCT studies for suspected SBO in 179 adults (mean age, 55.8 years; 86 men/93 women) was performed by 12 board-certified radiologists (6 JR, 6 SR). Readers rated likelihood of need for surgery, bowel ischemia, and resection. Correlation with clinical outcomes/pathology was performed. Pooled receiver operating characteristic area under the curve for surgery, ischemia, and resection were 0.802, 0.736, and 0.824 and 0.773, 0.851, and 0.751 JR/SR, respectively. Sensitivity/specificity for predicting surgery was 86.7%/65.4% and 79.6%/64.4%. No differences existed between JR/SR performance overall (P = 0.451); highest/lowest performing readers between groups (P < 0.001) and within groups (P = 0.008) varied. Junior radiologists performed as well as SR in predicting surgical outcomes on MDCT in patients with suspected SBO.


Jarosite and hematite at Meridiani Planum from Opportunity's Mossbauer Spectrometer.
Mossbauer spectra measured by the Opportunity rover revealed four mineralogical components in Meridiani Planum at Eagle crater: jarosite- and hematite-rich outcrop, hematite-rich soil, olivine-bearing basaltic soil, and a pyroxene-bearing basaltic rock (Bounce rock). Spherules, interpreted to be concretions, are hematite-rich and dispersed throughout the outcrop. Hematitic soils both within and outside Eagle crater are dominated by spherules and their fragments. Olivine-bearing basaltic soil is present throughout the region. Bounce rock is probably an impact erratic. Because jarosite is a hydroxide sulfate mineral, its presence at Meridiani Planum is mineralogical evidence for aqueous processes on Mars, probably under acid-sulfate conditions.


Internal versus external tocodynamometry during induced or augmented labour.
Uterine contractions can be registered by external tocodynamometry (ET) or, after rupture of the membranes, by internal tocodynamometry (IT). Monitoring of the frequency of contractions is important especially when intravenous oxytocin is used as excessive uterine activity (hyperstimulation or tachysystole) can cause fetal distress. During induction of labour as well as during augmentation with intravenous oxytocin, some clinicians choose to monitor frequency and strength of contractions with IT rather than with ET as an intrauterine pressure catheter measures intrauterine activity more accurately than an extra-abdominal tocodynamometry device. However, insertion of an intrauterine catheter has higher costs and also potential risks for mother and child. To assess the effectiveness of IT compared with using ET when intravenous oxytocin is used for induction or augmentation of labour. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (11 April 2012) and PubMed (1966 to 7 March 2012). We included all published randomised controlled trials with data from women in whom IT was compared with ET in induced or augmented labour with oxytocin. We excluded trials that employed quasi-randomised methods of treatment allocation. We found no unpublished or ongoing studies on this subject. Two review authors independently assessed trial eligibility and risk of bias, and independently extracted data. Data were checked for accuracy. Where necessary, we contacted study authors for additional information. Three studies involving a total of 1945 women were included. Overall, risk of bias across the three trials was mixed. No serious complications were reported in the trials and no neonatal or maternal deaths occurred. The neonatal outcome was not statistically different between groups: Apgar score less than seven at five minutes (RR 1.78, 95% CI 0.83 to 3.83; three studies, n = 1945); umbilical artery pH less than 7.15 (RR 1.31, 95% CI 0.95 to 1.79; one study, n = 1456); umbilical artery pH less than 7.16 (RR 1.23, 95% CI 0.39 to 3.92; one study, n = 239); admission to the neonatal intensive care unit (RR 0.34, 95% CI 0.07 to 1.67; two studies, n = 489); and more than 48 hours hospitalisation (RR 0.92, 95% CI 0.71 to 1.20; one study, n = 1456). The pooled risk for instrumental delivery (including caesarean section, ventouse and forceps extraction) was not statistically significantly different (RR 1.05, 95% CI 0.91 to 1.21; three studies, n = 1945). Hyperstimulation was reported in two studies (n = 489), but there was no statistically significant difference between groups (RR 1.21, 95% CI 0.78 to 1.88). This review found no differences between the two types of monitoring (internal or external tocodynamometry) for any of the maternal or neonatal outcomes. Given that this review is based on three studies (N = 1945 women) of moderate quality, there is insufficient evidence to recommend the use of one form of tocodynamometry over another for women where intravenous oxytocin was administered for induction or augmentation of labour.


Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Focused Update.
Purpose This focused update addresses the use of MammaPrint (Agendia, Irvine, CA) to guide decisions on the use of adjuvant systemic therapy. Methods ASCO uses a signals approach to facilitate guideline updates. For this focused update, the publication of the phase III randomized MINDACT (Microarray in Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy) study to evaluate the MammaPrint assay in 6,693 women with early-stage breast cancer provided a signal. An expert panel reviewed the results of the MINDACT study along with other published literature on the MammaPrint assay to assess for evidence of clinical utility. Recommendations If a patient has hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-negative breast cancer, the MammaPrint assay may be used in those with high clinical risk to inform decisions on withholding adjuvant systemic chemotherapy due to its ability to identify a good-prognosis population with potentially limited chemotherapy benefit. Women in the low clinical risk category did not benefit from chemotherapy regardless of genomic MammaPrint risk group. Therefore, the MammaPrint assay does not have clinical utility in such patients. If a patient has hormone receptor-positive, HER2-negative, node-positive breast cancer, the MammaPrint assay may be used in patients with one to three positive nodes and a high clinical risk to inform decisions on withholding adjuvant systemic chemotherapy. However, such patients should be informed that a benefit from chemotherapy cannot be excluded, particularly in patients with greater than one involved lymph node. The clinician should not use the MammaPrint assay to guide decisions on adjuvant systemic therapy in patients with hormone receptor-positive, HER2-negative, node-positive breast cancer at low clinical risk, nor any patient with HER2-positive or triple-negative breast cancer, because of the lack of definitive data in these populations. Additional information can be found at www.asco.org/breast-cancer-guidelines and www.asco.org/guidelineswiki .


Metastatic breast cancer confined to the skeletal system. An indolent disease.
The records of 86 patients with metastatic breast cancer confined to the skeletal system were retrospectively reviewed to evaluate the clinical impression that this subset of patients with metastatic breast cancer has a favorable prognosis. The median survival for this group of patients was 48 months, compared with a median survival of 17 months in patients with breast cancer metastatic to other sites (p less than 0.01). Systemic treatment with either hormonal therapy or chemotherapy was highly effective in these patients; 56 of 64 (87 percent) showed response to the first hormonal therapy received (median, 10 months; range, four to 54 months), and 43 of 46 (93 percent) showed response to initial chemotherapy (median, 11 months; range, six to 22 months). Most patients received several therapeutic modalities sequentially; sequential responses to hormonal therapy were frequent. Orthopedic complications were common (pathologic fracture in 18; epidural spinal cord compression in 13) and occurred a median of 24 months after documentation of bone metastasis. Prolonged survival was common after these complications (median, 18 months; range, two to 48 months). The presence of metastatic disease at the time of diagnosis and premenopausal status were not adverse prognostic factors. Metastases often remained localized to the skeleton; however, appearance of extraskeletal metastasis was associated with short subsequent survival (median, nine months). Metastatic breast cancer confined to the skeletal system is a common entity that can be defined clinically, is highly responsive to treatment, and is frequently associated with prolonged survival.


Becoming disabled: The association between disability onset in younger adults and subsequent changes in productive engagement, social support, financial hardship and subjective wellbeing.
Very few population-based studies have investigated the association between the onset of health conditions/impairments associated with disability and subsequent well-being. To examine the association between the onset of disability and four indicators of well-being (full-time engagement in employment or education, financial hardship, social support, subjective well-being) among a nationally representative sample of Australian adolescents and young adults. Secondary analysis of the first eight waves (2001-2008) of the survey of Household Income and Labour Dynamics in Australia. For financial hardship and subjective well-being, the majority of participants belonged to trajectory classes for which there was no evidence that the onset of disability was associated with a subsequent lowering of well-being. For participation in employment and education, the majority of participants belonged to trajectory classes for which there was evidence of a modest immediate reduction in participation rates followed by subsequent stability. For social support, the majority of participants belonged to trajectory classes for which there was evidence of a modest temporary reduction in support followed by rebound back to initial levels. Membership of classes associated with poorer outcomes was associated with a number of covariates including: male gender; younger age of disability onset; being born overseas; not living with both parents at age 14; lower proficiency in the English language; and parental education being year 12 or below. The results of our analyses illustrate the existence of clear empirically defined trajectory classes following the onset of disability across a range of indicators of well-being.


Forensic age estimation in human skeletal remains: current concepts and future directions.
Skeletal identification has a long tradition in both physical and forensic anthropology. The process generally begins with formulation of a biological profile (osteobiography); specifically, estimation of sex, age, ethnicity and stature. The present paper briefly reviews a selection of the principal methods used for one aspect of the identification process; the estimation of personal age. It is well-documented that variability in the morphological features used to assess age in the human skeleton progressively increases from birth to old age. Thus choice of method is inherently related to whether unidentified remains are those of a juvenile or an adult. This review, therefore, considers methods appropriate for age estimation in both juvenile and adult remains; the former being primarily based on developmental, and the latter degenerative, morphological features. Such a review is timely as new methods are constantly being developed, concurrent with refinements to those already well established in mainstream anthropology.


Predicting outcome after traumatic brain injury: development and international validation of prognostic scores based on admission characteristics.
Traumatic brain injury (TBI) is a leading cause of death and disability. A reliable prediction of outcome on admission is of great clinical relevance. We aimed to develop prognostic models with readily available traditional and novel predictors. Prospectively collected individual patient data were analyzed from 11 studies. We considered predictors available at admission in logistic regression models to predict mortality and unfavorable outcome according to the Glasgow Outcome Scale at 6 mo after injury. Prognostic models were developed in 8,509 patients with severe or moderate TBI, with cross-validation by omission of each of the 11 studies in turn. External validation was on 6,681 patients from the recent Medical Research Council Corticosteroid Randomisation after Significant Head Injury (MRC CRASH) trial. We found that the strongest predictors of outcome were age, motor score, pupillary reactivity, and CT characteristics, including the presence of traumatic subarachnoid hemorrhage. A prognostic model that combined age, motor score, and pupillary reactivity had an area under the receiver operating characteristic curve (AUC) between 0.66 and 0.84 at cross-validation. This performance could be improved (AUC increased by approximately 0.05) by considering CT characteristics, secondary insults (hypotension and hypoxia), and laboratory parameters (glucose and hemoglobin). External validation confirmed that the discriminative ability of the model was adequate (AUC 0.80). Outcomes were systematically worse than predicted, but less so in 1,588 patients who were from high-income countries in the CRASH trial. Prognostic models using baseline characteristics provide adequate discrimination between patients with good and poor 6 mo outcomes after TBI, especially if CT and laboratory findings are considered in addition to traditional predictors. The model predictions may support clinical practice and research, including the design and analysis of randomized controlled trials.


Weather, season, and daily stroke admissions in Hong Kong.
Previous studies examining daily temperature and stroke incidence have given conflicting results. We undertook this retrospective study of all stroke admissions in those aged 35 years old and above to Hong Kong public hospitals from 1999 through 2006 in order to better understand the effects of meteorological conditions on stroke risk in a subtropical setting. We used Poisson Generalized Additive Models with daily hemorrhagic (HS) and ischemic stroke (IS) counts separately as outcomes, and daily mean temperature, humidity, solar radiation, rainfall, air pressure, pollutants, flu consultation rates, day of week, holidays, time trend and seasonality as predictors. Lagged effects of temperature, humidity and pollutants were also considered. A total of 23,457 HS and 107,505 IS admissions were analyzed. Mean daily temperature had a strong, consistent, negative linear association with HS admissions over the range (8.2-31.8°C) observed. A 1°C lower average temperature over the same day and previous 4 days (lags 0-4) being associated with a 2.7% (95% CI: 2.0-3.4%, P < .0.0001) higher admission rate after controlling for other variables. This association was stronger among older subjects and females. Higher lag 0-4 average change in air pressure from previous day was modestly associated with higher HS risk. The association between IS and temperature was weaker and apparent only below 22°C, with a 1°C lower average temperature (lags 0-13) below this threshold being associated with a 1.6% (95% CI:1.0-2.2%, P < 0.0001) higher IS admission rate. Pollutant levels were not associated with HS or IS. Future studies should examine HS and IS risk separately.


Clustering, mobility, and triggering activity of small oligomers of immunoglobulin E on rat basophilic leukemia cells.
We have recently shown that small oligomers of IgE bound to univalent receptors for IgE on the surface of rat basophilic leukemia cells induce extensive aggregation of the receptors at 4 degrees C into patches resolvable by fluorescence microscopy and that this does not occur with monomeric IgE (Menon, A. K., D. Holowka, and B. Baird, 1984, J. Cell Biol. 98:577-583). Here we use fluorescence photobleaching recovery measurements to show that receptor oligomerization by this means is accompanied by a dramatic reduction of receptor lateral mobility, and that this immobilization occurs even when the clustering is not microscopically detectable. Furthermore, the degree of immobility induced by a particular oligomer fraction from a gel filtration column correlates positively with its ability to trigger cellular degranulation, whereas receptors labeled with monomeric IgE have no triggering activity and exhibit typical membrane protein mobility. The slow, large-scale oligomer-induced clustering appears to be a long term consequence of earlier selective interactions that result in receptor immobilization, and this highly clustered state provides a competent, noninhibitory triggering signal resulting in cellular degranulation upon warming to 37 degrees C. We conclude that even limited clustering of IgE receptors on rat basophilic leukemia cells induces interactions with other cellular components that constrain receptor mobility and eventually cause massive coalescence of the clusters. These primary selective interactions occurring at the level of receptor oligomers or small clusters of oligomers that result in immobilization may play a role in triggering cellular degranulation.


Flexible, stretchable, transparent carbon nanotube thin film loudspeakers.
We found that very thin carbon nanotube films, once fed by sound frequency electric currents, could emit loud sounds. This phenomenon could be attributed to a thermoacoustic effect. The ultra small heat capacity per unit area of carbon nanotube thin films leads to a wide frequency response range and a high sound pressure level. On the basis of this finding, we made practical carbon nanotube thin film loudspeakers, which possess the merits of nanometer thickness and are transparent, flexible, stretchable, and magnet-free. Such a single-element thin film loudspeaker can be tailored into any shape and size, freestanding or on any insulating surfaces, which could open up new applications of and approaches to manufacturing loudspeakers and other acoustic devices.


Impact of prehybridization PCR amplification on microarray detection of nitrifying bacteria in wastewater treatment plant samples.
A gel-based microarray that included a set of 26 oligonucleotide probes targeting all nitrifying bacteria at varying levels of specificity suggested the presence of targeted microorganisms when hybridized to RNA isolated from a wastewater treatment plant, but could not discriminate between perfectly matched and mismatched sequences due in part to low signal intensity. To enhance sensitivity and improve discrimination, polymerase chain reaction was used to selectively amplify the 16S rRNA genes of specific nitrifier groups. RNA transcribed from these DNA templates was hybridized to the microarray and thermal dissociation analysis was used to characterize the specificity of hybridization. Amplification with Nitrospira-specific primers resulted in the selective amplification of this target group, confirmed by both a significant increase in signal intensity and a melting profile identical to the reference RNA. In contrast, Nitrobacter was not detected in the environmental samples with probe Nbac1000 despite pre-amplification with Nitrobacter-specific primers, indicating the absence of strains containing this Nitrobacter-specific sequence. Pre-amplification using primers specific for beta-Proteobacterial ammonia-oxidizing bacteria resulted in a significant increase in signal intensity for probe Nso190, but melting profiles for probe Nso190 showed a slight deviation between amplified RNA and the reference microorganism, suggesting that the amplification products contained some sequences that varied by a single nucleotide difference in the probe target region.


"Vulnerable plaques"--ticking of the time bomb.
Atherosclerosis and its sequelae are one of the leading causes of morbidity and mortality, especially in the developed nations. Over the years, treatment protocols have changed with the changing understanding of the disease process. Inflammatory mechanisms have emerged as key players in the formation of the atherosclerotic plaque. For the majority of its life span, the plaque develops silently and only some exhibit overt clinical manifestations. The purpose of this review is to examine the inherent properties of some of these "vulnerable" or symptomatic plaques. Rupture of the plaque is related to the thickness of the fibrous cap overlying the necrotic lipid core. A thin cap is more likely to lead to rupture. Multiple factors broadly grouped as the "determinants of vulnerability" are responsible for directly or indirectly influencing the plaque dynamics. Apoptosis is considered an important underlying mechanism that contributes to plaque instability. Inflammatory reactions within the plaque trigger apoptosis by cell-cell contact and intra cellular death signaling. Once started, the apoptotic process affects all of the components that make up the plaque, including vascular smooth muscle cells, endothelial cells, and macrophages. Extensive research has identified many of the key cellular and molecular regulators that play a part in apoptosis within the atherosclerotic lesion. This information will help us to gain a better understanding of the underlying mechanisms at the cellular and molecular level and enable us to formulate better therapeutic strategies to combat this disease.


The retinal locus of fixation in simulations of progressing central scotomas.
Patients with central scotoma use a preferred retinal locus (PRL) of fixation to perform visual tasks. Some of the conditions that cause central scotoma are progressive, and as a consequence, the PRL needs to be adjusted throughout the progression. The present study investigates the peripheral locus of fixation in subjects under a simulation of progressive central scotoma. Five normally sighted subjects participated in the study. A foveally centered mask of varying size was presented to simulate the scotoma. Initially, subjects developed a peripheral locus of fixation under simulation of a 6° scotoma, which was used as a baseline. The progression was simulated in two separate conditions: a gradual progression and an abrupt progression. In the gradual progression, the diameter of the scotoma increased by a fixed amount of either 1° or 2° of visual angle, thus scotomas of 8°, 10°, and 11° of visual angle were simulated. In the abrupt progression, the diameter was adjusted individually to span the area of the visual field used by the current peripheral locus of fixation. Subjects located the peripheral locus of fixation along the same meridian under simulation of scotoma progression. Furthermore, no differences between the fixation stability of the baseline locus of fixation and the incremental progression locus of fixation were found whereas, in abrupt progression, the fixation stability decreased significantly. These results provide first insight into fixation behavior in a progressive scotoma and may contribute to the development of training tools for patients with progressive central maculopathies.


The costs and benefits of paternal care in fish: a meta-analysis.
Male-only parental care, while rare in most animals, is a widespread strategy within teleost fish. The costs and benefits to males of acting as sole carer are highly variable among fish species making it challenging to determine the selective pressures driving the evolution of male-only care to such a high prevalence. We conducted a phylogenetic meta-analysis to examine the costs and benefits of paternal care across fish species. We found no evidence that providing care negatively affects male condition. In contrast with other taxa, we also found limited evidence that male care has evolved as a strategy to improve offspring survival. Instead, we found that males already caring for a brood are preferred by females and that this preference is strongest in those species in which males work harder to care for larger broods. Thus, in fish, investment in offspring care does not constrain a male's mating success but rather augments it, suggesting that the relatively high prevalence of male-only care in fish may be in part explained by sexual selection through female preference for caring males.


Identification of neural and psychophysical predictors of headache reduction after cognitive behavioral therapy in adolescents with migraine.
Cognitive behavioral therapy (CBT) is a psychological intervention that involves development of coping strategies to reduce the experience of pain. Although CBT is a promising intervention to reduce headache days in patients with migraine, it may not be effective for all patients. Thus, there is a need to identify markers that could predict which patients will respond to CBT. We aimed to determine whether baseline brain function and amygdalar connectivity, assessed by functional magnetic resonance imaging, or pain modulation capacities, assessed by the conditioned pain modulation (CPM) response, can predict a reduction in headache days after CBT in adolescents with migraine. Patients with migraine (n = 20; age range 10-17 years) completed 8 weekly CBT sessions. The CPM response was examined in the trapezius and the leg. Headache days significantly decreased after CBT (P < 0.001). Greater functional connectivity before CBT between the right amygdala and frontal gyrus, anterior cingulate cortex, and precentral gyrus was related to greater headache reduction after CBT. Greater reduction in headache days after CBT was related with less efficient CPM response before CBT at the trapezius (r = -0.492, P = 0.028) but not at the leg. This study found that headache reduction after CBT was related to right amygdala connectivity with frontal and sensorimotor regions at baseline as well as baseline pain modulation capacities. These findings suggest that individual differences in brain function and pain modulation can be associated with clinical improvements and help with determination of CBT responsiveness.


Use of mixed-treatment-comparison methods in estimating efficacy of treatments for heavy menstrual bleeding.
A variety of pharmacological and surgical treatments have been developed for heavy menstrual bleeding (HMB), which can have negative physical, social, psychological, and economic consequences. We conducted a systematic literature review and mixed-treatment-comparison (MTC) meta-analysis of available data from randomized controlled trials (RCTs) to derive estimates of efficacy for 8 classes of treatments for HMB, to inform health-economic analysis and future studies. A systematic review identified RCTs that reported data on menstrual blood loss (MBL) at baseline and one or more follow-up times. Eight treatment classes were considered: COCs, danazol, endometrial ablation, LNG-IUS, placebo, progestogens given for less than 2 weeks out of 4 during the menstrual cycle, progestogens given for close to 3 weeks out of 4, and TXA. The primary measure of efficacy was the proportion of women who achieved MBL < 80 mL per cycle (month), as measured by the alkaline hematin method. A score less than 100 on an established pictorial blood-loss assessment chart (PBAC) was considered an acceptable substitute for MBL < 80 mL. Estimates of efficacy by treatment class and time were obtained from a Bayesian MTC model. The model also included effects for treatment class, study, and the combination of treatment class and study and an adjustment for baseline mean MBL. Several methodological challenges complicated the analysis. Some trials reported various summary statistics for MBL or PBAC, requiring estimation (with less precision) of % MBL < 80 mL or % PBAC < 100. Also, reported follow-up times varied substantially. The evidence network involved 34 RCTs, with follow-up times from 1 to 36 months. Efficacy at 3 months of follow-up (estimated as the posterior median) ranged from 87.5% for the levonorgestrel-releasing intrauterine system (LNG-IUS) to 14.2% for progestogens administered for less than 2 weeks out of 4 in the menstrual cycle. The 95% credible intervals for most estimates were quite wide, mainly because of the limited evidence for many combinations of treatment class and follow-up time and the uncertainty from estimating % MBL < 80 mL or % PBAC < 100 from summary statistics. LNG-IUS and endometrial ablation are very efficacious in treating HMB. The study yielded useful insights on using MTC in sparse evidence networks. Diversity of outcome measures and follow-up times in the HMB literature presented considerable challenges. The Bayesian credible intervals reflected the various sources of uncertainty.


Kinetics of m-xylene in man: Influence of intermittent physical exercise and changing environmental concentrations on kinetics.
Volunteer subjects were exposed to m-xylene 6 h/d over five successive days under the following types of environmental conditions: exposure type I: constant xylene concentration in air, subjects performed periodic ergometer exercise at 100 W; exposure type II: varying xylene concentration in air with peak levels coinciding with periodic ergometer exercise; and exposure type III: constant xylene concentration in air, subjects sedentary. The three types of exposure were identical in that the time-weighted averages of the xylene concentrations in the air inhaled over the whole day were about the same (in most cases 4.1 mmol/m3). Nevertheless, the daily xylene uptakes proved to be somewhat different, while the maximum rates of xylene uptake occurring in the three exposure types were markedly different. In exposure types I and II the main part of the day's xylene uptake took place during the repeated short exercise sessions and resulted, partly due to an altered distribution of organ blood flow, in a greater distribution of xylene to tissues with slow elimination characteristics (and a greater cumulation of xylene) than in exposure type III. Although relatively high pulmonary uptake rates of xylene (about 150-300 micromol/min) were estimated to have occurred over 15-min periods at a time, no signs of saturation kinetics were noted. The relative contributions of the two biotransformation pathways of m-xylene (side-chain oxidation and aromatic oxidation) were not markedly altered by the different environmental conditions, but aromatic oxidation, producing 2,4-xylenol, tended to increase slightly over the five exposure days. The blood xylene levels attained under stable near-equilibrium conditions and under conditions of greatly increased uptake appeared to be directly related to the rate of xylene uptake, whereas no such relation existed in the phase of decreasing xylene uptake.


Motor cortex microcircuit simulation based on brain activity mapping.
The deceptively simple laminar structure of neocortex belies the complexity of intra- and interlaminar connectivity. We developed a computational model based primarily on a unified set of brain activity mapping studies of mouse M1. The simulation consisted of 775 spiking neurons of 10 cell types with detailed population-to-population connectivity. Static analysis of connectivity with graph-theoretic tools revealed that the corticostriatal population showed strong centrality, suggesting that would provide a network hub. Subsequent dynamical analysis confirmed this observation, in addition to revealing network dynamics that cannot be readily predicted through analysis of the wiring diagram alone. Activation thresholds depended on the stimulated layer. Low stimulation produced transient activation, while stronger activation produced sustained oscillations where the threshold for sustained responses varied by layer: 13% in layer 2/3, 54% in layer 5A, 25% in layer 5B, and 17% in layer 6. The frequency and phase of the resulting oscillation also depended on stimulation layer. By demonstrating the effectiveness of combined static and dynamic analysis, our results show how static brain maps can be related to the results of brain activity mapping.


Quality of Life Measures in Aortic Stenosis Research: A Narrative Review.
Elderly patients with aortic stenosis (AS) not only have a reduced life expectancy but also a reduced quality of life (QoL). The benefits of an AS intervention may be considered a balance between a good QoL and a reasonably extended life. However, the different questionnaires being used to determine the QoL, were generally not developed for the specific situation of patients with AS and come with strengths and considerable weaknesses. The objective of this manuscript was to provide an overview of the available QoL instruments in AS research, describe their strengths and weaknesses, and to provide our assessment of the utility of the available scoring instruments for QoL measurements in AS. We identified and reviewed the following instruments that are used in AS research: Short Form Health Survey (SF-36/SF-12), EuroQol-5D (EQ-5D), the Illness Intrusiveness Rating Scale (IIRS), the HeartQoL, the Kansas City Cardiomyopathy Questionnaire (KCCQ), the Minnesota Living with Heart Failure Questionnaire (MLHF), the MacNew Questionnaire, and the Toronto Aortic Stenosis Quality of Life Questionnaire (TASQ). There is no standardized assessment of QoL in patients with AS. Many different questionaires are being used, but they are rarely specific for AS. There is a need for AS specific research into the QoL of patients as life prolongation may compete for an improved QoL in this elderly patient group.


Multiphosphorylated peptides: importance, synthetic strategies, and applications for studying biological mechanisms.
Unraveling the role of post-translational modification (PTM) patterns is one of the most urgent and unresolved issues facing the scientific community. Attempts to crack the phosphorylation bio-barcode led to significant findings, which suggest that many proteins cannot be regarded as a single entity but exist as several forms which differ in their phosphorylation patterns and their functions. While protein regions that do not contain PTMs can be rather simply mimicked using peptide libraries, heavily phosphorylated regions are much harder to study using the same tools. The differences between the syntheses of simple mono-, di- and tri-phosphopeptides and the synthesis of multiphosphopeptides are dramatic. While simple phosphopeptides can be synthesized using almost standard SPPS strategies, the synthesis of multiphosphopeptides is to date a major synthetic challenge. Synthesis of multiphosphopeptides requires the insertion of several phosphate groups simultaneously or sequentially into various positions on the peptide in the presence of many other potential modification sites. These groups are bulky, unstable and cannot be easily introduced when in close proximity. Moreover, since the same protein region can possess many alternative multiphosphorylation patterns, libraries comprising a large number of peptides with different degrees and positions of phosphorylation are essential. Many strategies have been developed to provide routes to enable the preparation of multiphosphopeptides. These methods are essentially different from the methods used for the preparation of simple phosphopeptides. In this review, we specifically emphasize the challenges and importance of synthesizing multiphosphopeptides and their libraries. The historical perspective and state of the art strategies are described. We demonstrate here how the different synthetic approaches attempt to address the special problems associated with the synthesis of multiphosphopeptides. The advantages and disadvantages of each strategy are discussed in order to provide a roadmap for the synthesis of such libraries. An overview of the existing strategies and some comments regarding future directions are provided. Applications of multiphosphopeptide libraries as tools to study the effect of phosphorylation patterns on the biological function of proteins are also described.


Laser heated boron doped diamond electrodes: effect of temperature on outer sphere electron transfer processes.
Thermoelectrochemical experiments can reveal significant information about electrochemical processes compared to ambient only measurements. Typical thermoelectrochemistry is performed using resistively heated wires or laser heated electrodes, both of which can suffer drawbacks associated with the electrode material employed. Boron doped diamond (BDD) is ideal for thermoelectrochemical investigations due to its extremely high thermal conductivity and diffusivity, extreme resistance to thermal ablation (can withstand laser power densities, Pd, of GW cm(-2) for nanosecond pulses) and excellent electrochemical properties (low background currents and wide potential window). In this paper we describe the use of a pulsed laser technique to heat the rear of a 1 mm diameter conducting BDD disc electrode, which drives electrochemical solution reactions at the front face. Maximum electrode temperatures of 90.0 °C were recorded experimentally and confirmed by finite element modelling (FEM). The effect of laser pulsed heating (maximum 3.8 kW cm(-2); 10 ms on and 90 ms off) on the cyclic voltammetric response of two fast (reversible) outer sphere electron transfer redox mediators (Ru(NH3)6(3+/2+) and IrCl6(2-/3-)) are investigated. In particular, we observe pulsed increases in the current, which increase with increasing Pd. The potential of the peak current is shifted positively for the Ru(NH3)6(3+/2+) couple (in accordance with a positive temperature coefficient, β, +0.68 mV K(-1)) and negatively for the IrCl6(3-/2-) couple (β = -0.48 mV K(-1)). Scanning backwards, in contrast to that observed for a macrodisc electrode in ambient solution, a cathodic peak is again observed for Ru(NH3)6(3+/2+) and an anodic peak for IrCl6(3-/2-) couple. We attribute this response to the entropy of the redox reaction and the time-dependant change in mass transport due to the induced thermal gradients at the electrode/electrolyte interface. The observed responses are in qualitative agreement with FEM simulations.


Sociodemographic, psychosocial and physical health correlates of common mental disorder symptoms among mothers in Trinidad and Tobago: Examining ethnic variations.
Historical and cultural experiences have shaped the life experiences of cultural communities in Trinidad and Tobago. Using a cultural focus, the goal of this investigation was to examine ethnic variations both in the prevalence of common mental disorder (CMD) symptoms as well as in the associations between sociodemographic, psychosocial, physical health correlates and CMDs among mothers in Trinidad and Tobago. Participants included 1002 mothers (359 African-, 353 Indo- and 290 Mixed-Ethnic Trinidadian). Mean comparisons indicated similarities in the levels of depression, somatisation and anxiety across ethnic groups. The associations between physical ill health, experiences of pain and depression and between physical ill health and somatisation were stronger for Mixed-Ethnic Trinidadian than Indo-Trinidadian mothers. The relationship between early experiences of domestic violence and depression was stronger for Indo-Trinidadian than Mixed-Ethnic Trinidadian mothers. The associations between early experiences of domestic violence and depression and between experiences of pain and somatisation were stronger for African Trinidadian than Mixed-Ethnic Trinidadian mothers. Thus beyond the direct effects, mothers belonging to specific ethnic groups indicated greater or lesser vulnerabilities to CMDs depending on their exposure to specific correlates. Results have applicability for the development of culturally sensitive interventions for mothers experiencing CMDs.


Effects of ankle fatigue on functional reflex activity during gait perturbations in young and elderly men.
There is growing evidence that aging and muscle fatigue result in impaired postural reflexes in humans. Therefore, the objective of this study was to examine the effects of ankle fatigue on functional reflex activity (FRA) during gait perturbations in young and elderly men. Twenty-eight young (27.0+/-3.1 years, n=14) and old (67.2+/-3.7 years, n=14) healthy active men participated in this study. Fatigue of the plantarflexors and dorsiflexors was induced by isokinetic contractions. Pre and post-fatigue, subjects were tested for their ability to compensate for decelerating gait perturbations while walking on a treadmill. Latency, FRA of lower extremity muscles and angular velocity of the ankle joint complex were analysed by means of surface electromyography and goniometry. After the fatigue protocol, no significant main and interaction effects were detected for the parameter latency in m. tibialis anterior (TA). For both groups, a significant pre to post-test decrease in FRA in TA (p<.001) was observed coming along with increases in antagonist coactivity (p=.013) and maximal angular velocity of the ankle joint (p=.007). However, no significant groupxtest interactions were found for the three parameters. Ankle fatigue has an impact on the ability to compensate for gait perturbations in young and elderly adults. However, no significant differences in all analysed parameters were detected between young and elderly subjects. These results may imply that age-related deteriorations in the postural control system do not specifically affect the ability to compensate for gait perturbations under fatigued condition.


Humans strategically shift decision bias by flexibly adjusting sensory evidence accumulation.
Decision bias is traditionally conceptualized as an internal reference against which sensory evidence is compared. Instead, we show that individuals implement decision bias by shifting the rate of sensory evidence accumulation toward a decision bound. Participants performed a target detection task while we recorded EEG. We experimentally manipulated participants' decision criterion for reporting targets using different stimulus-response reward contingencies, inducing either a liberal or a conservative bias. Drift diffusion modeling revealed that a liberal strategy biased sensory evidence accumulation toward target-present choices. Moreover, a liberal bias resulted in stronger midfrontal pre-stimulus 2-6 Hz (theta) power and suppression of pre-stimulus 8-12 Hz (alpha) power in posterior cortex. Alpha suppression in turn was linked to the output activity in visual cortex, as expressed through 59-100 Hz (gamma) power. These findings show that observers can intentionally control cortical excitability to strategically bias evidence accumulation toward the decision bound that maximizes reward.


Public Figure Attacks in the United States, 1995-2015.
An archival descriptive study of public figure attackers in the United States between 1995 and 2015 was undertaken. Fifty-six incidents were identified, primarily through exhaustive internet searches, composed of 58 attackers and 58 victims. A code book was developed which focused upon victims, offenders, pre-attack behaviors including direct threats, attack characteristics, post-offense and other outcomes, motivations and psychological abstracts. The average interrater agreement for coding of bivariate variables was 0.835 (intraclass correlation coefficient). The three most likely victim categories were politicians, judges, and athletes. Attackers were males, many with a psychiatric disorder, most were grandiose, and most had both a violent and nonviolent criminal history. The known motivations for the attacks were often angry and personal, the most common being dissatisfaction with a judicial or other governmental process (23%). In only one case was the primary motivation to achieve notoriety. Lethality risk during an attack was 55%. Collateral injury or death occurred in 29% of the incidents. Only 5% communicated a direct threat to the target beforehand. The term "publicly intimate figure" is introduced to describe the sociocultural blurring of public and private lives among the targets, and its possible role in some attackers' perceptions and motivations. Copyright © 2016 John Wiley & Sons, Ltd.


Robot-assisted stereoelectroencephalography in children.
OBJECTIVEThe goal in the study was to describe the clinical outcomes associated with robot-assisted stereoelectroencephalography (SEEG) in children.METHODSThe authors performed a retrospective, single-center study in consecutive children with medically refractory epilepsy who were undergoing robot-assisted SEEG. Kaplan-Meier survival analysis was used to calculate the probability of seizure freedom. Both univariate and multivariate methods were used to analyze the preoperative and operative factors associated with seizure freedom.RESULTSFifty-seven children underwent a total of 64 robot-assisted procedures. The patients' mean age was 12 years, an average of 6.4 antiepileptic drugs (AEDs) per patient had failed prior to implantation, and in 56% of the patients the disease was considered nonlesional. On average, children had 12.4 electrodes placed per implantation, with an implantation time of 9.6 minutes per electrode and a 10-day postoperative stay. SEEG analysis yielded a definable epileptogenic zone in 51 (89%) patients; 42 (74%) patients underwent surgery, half of whom were seizure free at last follow-up, 19.6 months from resection. In a multivariate generalized linear model, resective surgery, older age, and shorter SEEG-related hospital length of stay were associated with seizure freedom. In a Cox proportional hazards model including only the children who underwent resective surgery, older age was the only significant factor associated with seizure freedom. Complications related to bleeding were the major contributors to morbidity. One patient (1.5%) had a symptomatic hemorrhage resulting in a permanent neurological deficit.CONCLUSIONSThe authors report one of the largest pediatric-specific SEEG series demonstrating that the modern surgical management of medically refractory epilepsy in children can lead to seizure freedom in many patients, while also highlighting the challenges posed by this difficult patient population.


Endothelial-to-Mesenchymal Transition in Human Adipose Tissue Vasculature Alters the Particulate Secretome and Induces Endothelial Dysfunction.
Endothelial cells (EC) in obese adipose tissue (AT) are exposed to a chronic proinflammatory environment that may induce a mesenchymal-like phenotype and altered function. The objective of this study was to establish whether endothelial-to-mesenchymal transition (EndoMT) is present in human AT in obesity and to investigate the effect of such transition on endothelial function and the endothelial particulate secretome represented by extracellular vesicles (EV). Approach and Results: We identified EndoMT in obese human AT depots by immunohistochemical co-localization of CD31 or vWF and α-SMA (alpha-smooth muscle actin). We showed that AT EC exposed in vitro to TGF-β (tumor growth factor-β), TNF-α (tumor necrosis factor-α), and IFN-γ (interferon-γ) undergo EndoMT with progressive loss of endothelial markers. The phenotypic change results in failure to maintain a tight barrier in culture, increased migration, and reduced angiogenesis. EndoMT also reduced mitochondrial oxidative phosphorylation and glycolytic capacity of EC. EVs produced by EC that underwent EndoMT dramatically reduced angiogenic capacity of the recipient naïve ECs without affecting their migration or proliferation. Proteomic analysis of EV produced by EC in the proinflammatory conditions showed presence of several pro-inflammatory and immune proteins along with an enrichment in angiogenic receptors. We demonstrated the presence of EndoMT in human AT in obesity. EndoMT in vitro resulted in production of EV that transferred some of the functional and metabolic features to recipient naïve EC. This result suggests that functional and molecular features of EC that underwent EndoMT in vivo can be disseminated in a paracrine or endocrine fashion and may induce endothelial dysfunction in distant vascular beds.


Mechanisms of enhanced renal and hepatic erythropoietin synthesis by sodium-glucose cotransporter 2 inhibitors.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of major heart failure events, an action that is statistically linked to enhanced erythropoiesis, suggesting that stimulation of erythropoietin and cardioprotection are related to a shared mechanism. Four hypotheses have been proposed to explain how these drugs increase erythropoietin production: (i) renal cortical reoxygenation with rejuvenation of erythropoietin-producing cells; (ii) counterregulatory distal sodium reabsorption leading to increased tubular workload and oxygen consumption, and thus, to localized hypoxia; (iii) increased iron mobilization as a stimulus of hypoxia-inducible factor-2α (HIF-2α)-mediated erythropoietin synthesis; and (iv) direct HIF-2α activation and enhanced erythropoietin gene transcription due to increased sirtuin-1 (SIRT1) signaling. The first two hypotheses assume that the source of increased erythropoietin is the interstitial fibroblast-like cells in the deep renal cortex. However, SGLT2 inhibitors do not alter regional tissue oxygen tension in the non-diabetic kidney, and renal erythropoietin synthesis is markedly impaired in patients with anemia due to chronic kidney disease, and yet, SGLT2 inhibitors produce an unattenuated erythrocytic response in these patients. This observation raises the possibility that the liver contributes to the production of erythropoietin during SGLT2 inhibition. Hypoxia-inducible factor-2α and erythropoietin are coexpressed not only in the kidney but also in hepatocytes; the liver is a major site of production when erythropoietin stimulation is maintained for prolonged periods. The ability of SGLT2 inhibitors to improve iron mobilization by derepressing hepcidin and ferritin would be expected to increase cytosolic ferrous iron, which might stimulate HIF-2α expression in both the kidney and liver through the action of iron regulatory protein 1. Alternatively, the established ability of SGLT2 inhibitors to enhance SIRT1 might be the mechanism of enhanced erythropoietin production with these drugs. In hepatic cell lines, SIRT1 can directly activate HIF-2α by deacetylation, and additionally, through an effect of SIRT in the liver, peroxisome proliferator-activated receptor-γ coactivator-1α binds to hepatic nuclear factor 4 to promote transcription of the erythropoietin gene and synthesis of erythropoietin. Since SIRT1 up-regulation exerts direct cytoprotective effects on the heart and stimulates erythropoietin, it is well-positioned to represent the shared mechanism that links erythropoiesis to cardioprotection during SGLT2 inhibition.


Memory and visual search in naturalistic 2D and 3D environments.
The role of memory in guiding attention allocation in daily behaviors is not well understood. In experiments with two-dimensional (2D) images, there is mixed evidence about the importance of memory. Because the stimulus context in laboratory experiments and daily behaviors differs extensively, we investigated the role of memory in visual search, in both two-dimensional (2D) and three-dimensional (3D) environments. A 3D immersive virtual apartment composed of two rooms was created, and a parallel 2D visual search experiment composed of snapshots from the 3D environment was developed. Eye movements were tracked in both experiments. Repeated searches for geometric objects were performed to assess the role of spatial memory. Subsequently, subjects searched for realistic context objects to test for incidental learning. Our results show that subjects learned the room-target associations in 3D but less so in 2D. Gaze was increasingly restricted to relevant regions of the room with experience in both settings. Search for local contextual objects, however, was not facilitated by early experience. Incidental fixations to context objects do not necessarily benefit search performance. Together, these results demonstrate that memory for global aspects of the environment guides search by restricting allocation of attention to likely regions, whereas task relevance determines what is learned from the active search experience. Behaviors in 2D and 3D environments are comparable, although there is greater use of memory in 3D.


Comparison of Two- and Three-Dimensional Methods for Analysis of Trunk Kinematic Variables in the Golf Swing.
Two-dimensional methods have been used to compute trunk kinematic variables (flexion/extension, lateral bend, axial rotation) and X-factor (difference in axial rotation between trunk and pelvis) during the golf swing. Recent X-factor studies advocated three-dimensional (3D) analysis due to the errors associated with two-dimensional (2D) methods, but this has not been investigated for all trunk kinematic variables. The purpose of this study was to compare trunk kinematic variables and X-factor calculated by 2D and 3D methods to examine how different approaches influenced their profiles during the swing. Trunk kinematic variables and X-factor were calculated for golfers from vectors projected onto the global laboratory planes and from 3D segment angles. Trunk kinematic variable profiles were similar in shape; however, there were statistically significant differences in trunk flexion (-6.5 ± 3.6°) at top of backswing and trunk right-side lateral bend (8.7 ± 2.9°) at impact. Differences between 2D and 3D X-factor (approximately 16°) could largely be explained by projection errors introduced to the 2D analysis through flexion and lateral bend of the trunk and pelvis segments. The results support the need to use a 3D method for kinematic data calculation to accurately analyze the golf swing.


Cost-benefit comparisons of investments in improved water supply and cholera vaccination programs.
This paper presents the first cost-benefit comparison of improved water supply investments and cholera vaccination programs. Specifically, we compare two water supply interventions -- deep wells with public hand pumps and biosand filters (an in-house, point-of-use water treatment technology) -- with two types of cholera immunization programs with new-generation vaccines -- general community-based and targeted and school-based programs. In addition to these four stand-alone investments, we also analyze five combinations of water and vaccine interventions: (1) borehole+hand pump and community-based cholera vaccination, (2) borehole+hand pump and school-based cholera vaccination, (3) biosand filter and community-based cholera vaccination, (4) biosand filter and school-based cholera vaccination, and (5) biosand filter and borehole+hand pump. Using recent data applicable to developing country locations for parameters such as disease incidence, the effectiveness of vaccine and water supply interventions against diarrheal diseases, and the value of a statistical life, we construct cost-benefit models for evaluating these interventions. We then employ probabilistic sensitivity analysis to estimate a frequency distribution of benefit-cost ratios for all four interventions, given a wide variety of possible parameter combinations. Our results demonstrate that there are many plausible conditions in developing countries under which these interventions will be attractive, but that the two improved water supply interventions and the targeted cholera vaccination program are much more likely to yield attractive cost-benefit outcomes than a community-based vaccination program. We show that implementing community-based cholera vaccination programs after borehole+hand pump or biosand filters have already been installed will rarely be justified. This is especially true when the biosand filters are already in place, because these achieve substantial cholera risk reductions on their own. On the other hand, implementing school-based cholera vaccination programs after the installation of boreholes with hand pump is more likely to be economically attractive. Also, if policymakers were to first invest in cholera vaccinations, then subsequently investing in water interventions is still likely to yield positive economic outcomes. This is because point-of-use water treatment delivers health benefits other than reduced cholera, and deep boreholes+hand pumps often yield non-health benefits such as time savings. However, cholera vaccination programs are much cheaper than the water supply interventions on a household basis. Donors and governments with limited budgets may thus determine that cholera vaccination programs are more equitable than water supply interventions because more people can receive benefits with a given budget. Practical considerations may also favor cholera vaccination programs in the densely crowded slums of South Asian and African cities where there may be insufficient space in housing units for some point-of-use technologies, and where non-networked water supply options are limited.


Development of solvent exposure index for construction painters.
This article describes methodological approaches for reconstructing long-term occupational exposure to organic solvents among construction painters. A detailed exposure questionnaire was administered to 125 painters to develop a job exposure matrix (JEM). The questionnaire inquired about painting activities with solvent-based paints and use of protection equipment for the previous 25 years in 5-year intervals. Current and historical distributions of solvent air concentrations were assessed for the same time period based on the following information: industrial hygiene measurements, paint composition changes, and VOC emission rate changes from architectural and industrial maintenance coatings. Changes in protection factors of respirators were also assessed. A cumulative solvent exposure index was calculated for each painter through Monte Carlo simulations by combining appropriate input distributions of solvent air concentrations and protection factors of respirators with JEM. Sensitivity simulations revealed that the historical variations in solvent air concentrations had a higher impact on the cumulative solvent exposure index than changes in protection factors for respirators. Fifty-eight percent of painters were classified with a different exposure quartile when the solvent exposure index was used vs. an exposure based only on years using solvent-based paints, suggesting the need for more detailed exposure analysis than just years working when conducting epidemiologic studies for this worker population.


Adherence to dietary guidelines positively affects quality of life and functional status of older adults.
Nutritional parameters could influence self-perceived health and functional status of older adults. We prospectively determined the association between diet quality and quality of life and activities of daily living. This was an observational cohort study in which total diet scores, reflecting adherence to dietary guidelines, were determined. Dietary intakes were assessed using a food frequency questionnaire at baseline. Total diet scores were allocated for intake of selected food groups and nutrients for each participant as described in the Australian Guide to Healthy Eating. Higher scores indicated closer adherence to dietary guidelines. In Sydney, Australia, 1,305 and 895 participants (aged ≥ 55 years) with complete data were examined over 5 and 10 years, respectively. The 36-Item Short-Form Survey assesses quality of life and has eight subscales representing dimensions of health and well-being; higher scores reflect better quality of life. Functional status was determined once at the 10-year follow-up by the Older Americans Resources and Services activities of daily living scale. This scale has 14 items: seven items assess basic activities of daily living (eg, eating and walking) and seven items assess instrumental activities of daily living (eg, shopping or housework). Normalized 36-Item Short-Form Survey component scores were used in analysis of covariance to calculate multivariable adjusted mean scores. Logistic regression analysis was used to calculate adjusted odds ratios and 95% CIs to demonstrate the association between total diet score with the 5-year incidence of impaired activities of daily living. Participants in the highest vs lowest quartile of baseline total diet scores had adjusted mean scores 5.6, 4.0, 5.3, and 2.6 units higher in these 36-Item Short-Form Survey domains 5 years later: physical function (P trend=0.003), general health (P trend=0.02), vitality (P trend=0.001), and physical composite score (P trend=0.003), respectively. Participants in the highest vs lowest quartile of baseline total diet scores had 50% reduced risk of impaired instrumental activites of daily living at follow-up (multivariable-adjusted P trend=0.03). Higher diet quality was prospectively associated with better quality of life and functional ability.


The basic science of gene therapy.
The development over the past decade of methods for delivering genes to mammalian cells has stimulated great interest in the possibility of treating human disease by gene-based therapies. However, despite substantial progress, a number of key technical issues need to be resolved before gene therapy can be safely and effectively applied in the clinic. Future technological developments, particularly in the areas of gene delivery and cell transplantation, will be critical for the successful practice of gene therapy.


Effects of Trigger Point Dry Needling for Nontraumatic Shoulder Pain of Musculoskeletal Origin: A Systematic Review and Meta-Analysis.
The purpose of this study was to evaluate the effects of trigger point (TrP) dry needling alone or as an adjunct to other interventions on pain intensity and related disability in nontraumatic shoulder pain. Ten databases were searched from inception to January 2020 for randomized clinical trials in which at least 1 group received TrP dry needling for shoulder pain of musculoskeletal origin with outcomes collected on pain intensity and related disability. Data extraction including participant and therapist details, interventions, blinding strategy, blinding assessment outcomes, and results were extracted by 2 reviewers. The risk of bias (Cochrane Risk of Bias, Cochrane Guidelines), methodological quality (Physiotherapy Evidence Database score), and evidence level (Grading of Recommendations Assessment, Development, and Evaluation approach) were assessed. The search identified 551 publications with 6 trials eligible for inclusion. There was moderate-quality evidence that TrP dry needling reduces shoulder pain intensity with a small effect (mean difference = -0.49 points, 95% CI = -0.84 to -0.13; standardized mean difference = -0.25, 95% CI = -0.42 to -0.09) and low-quality evidence that TrP dry needling improves related disability with a large effect (mean difference = -9.99 points, 95% CI -15.97 to -4.01; standardized mean difference = -1.14, 95% CI -1.81 to -0.47) compared with a comparison group. The effects on pain were only found at short term. The Cochrane Risk of Bias was generally low, but the heterogenicity of the results downgraded the evidence level. Moderate- to low-quality evidence suggests positive effects of TrP dry needling for pain intensity (small effect) and pain-related disability (large effect) in nontraumatic shoulder pain of musculoskeletal origin, mostly at short term. Future clinical trials investigating long-term effects are needed. Dry needling is commonly used for the management of musculoskeletal pain. This is the first meta-analysis to examine the effects of dry needling on nontraumatic shoulder pain.


Differential effects of the rod-and-frame illusion on the timing of forearm rotations.
The current study focused on the time course of the effects of the rod-and-frame illusion (RFI) on the kinematics of targeted forearm rotations. Participants were asked to reproduce perceived rod orientations by propelling a hand-held cylinder forward while rotating it to the target orientation. Rod and frame orientations were systematically varied, and cylinder rotations were normalized to time. Average realized cylinder orientations confirmed that when the frame orientation deviated from the vertical, a reproduction error occurred in the direction opposite to the direction of the frame tilt. In contrast, the perceived orientation of the stimulus rod was exaggerated relative to the vertical (i.e., reproduction errors were in the direction of the rod tilt). Furthermore, linear regression analyses for every normalized time sample showed that the rod and frame effects start simultaneously, but they reach their maximum effect at different points in time. We discuss the implications of our findings for current views on the effects of visual illusions on motor control.


Identification of an inhibitor of the EWS-FLI1 oncogenic transcription factor by high-throughput screening.
Chromosomal translocations generating oncogenic transcription factors are the hallmark of a variety of tumors, including many sarcomas. Ewing sarcoma family of tumors (ESFTs) are characterized by the t(11;22)(q24;q12) translocation that generates the Ewing sarcoma breakpoint region 1 and Friend leukemia virus integration 1 (EWS-FLI1) fusion transcription factor responsible for the highly malignant phenotype of this tumor. Although continued expression of EWS-FLI1 is believed to be critical for ESFT cell survival, a clinically effective small-molecule inhibitor remains elusive likely because EWS-FLI1 is a transcription factor and therefore widely felt to be "undruggable." We developed a high-throughput screen to evaluate more than 50 000 compounds for inhibition of EWS-FLI1 activity in TC32 ESFT cells. We used a TC32 cell-based luciferase reporter screen using the EWS-FLI1 downstream target NR0B1 promoter and a gene signature secondary screen to sort and prioritize the compounds. We characterized the lead compound, mithramycin, based on its ability to inhibit EWS-FLI1 activity in vitro using microarray expression profiling, quantitative reverse transcription-polymerase chain reaction, and immunoblot analysis, and in vivo using immunohistochemistry. We studied the impact of this inhibition on cell viability in vitro and on tumor growth in ESFT xenograft models in vivo (n = 15-20 mice per group). All statistical tests were two-sided. Mithramycin inhibited expression of EWS-FLI1 downstream targets at the mRNA and protein levels and decreased the growth of ESFT cells at half maximal inhibitory concentrations between 10 (95% confidence interval [CI] = 8 to 13 nM) and 15 nM (95% CI = 13 to 19 nM). Mithramycin suppressed the growth of two different ESFT xenograft tumors and prolonged the survival of ESFT xenograft-bearing mice by causing a decrease in mean tumor volume. For example, in the TC32 xenograft model, on day 15 of treatment, the mean tumor volume for the mithramycin-treated mice was approximately 3% of the tumor volume observed in the control mice (mithramycin vs control: 69 vs 2388 mm(3), difference = 2319 mm(3), 95% CI = 1766 to 2872 mm(3), P < .001). Mithramycin inhibits EWS-FLI1 activity and demonstrates ESFT antitumor activity both in vitro and in vivo.


Prognosis of transient ischemic attacks in the Oxfordshire Community Stroke Project.
In a community-based study of approximately 105,000 people, 184 presented with a transient ischemic attack during the 5 years between 1981 and 1986; we believe these persons represent almost all new cases of transient ischemic attack going to a doctor during that period. During a mean follow-up of 3.7 years 49 patients died, 45 had a first-ever stroke, and 17 had a myocardial infarction. Cardiac disease accounted for 17 (35%) deaths, while stroke was the cause of death in 15 patients (31%). The average actuarial risk of death was approximately 6.3%/yr, slightly greater than that expected for similar people without transient ischemic attacks (risk ratio [observed divided by expected] = 1.4). The actuarial risk of stroke was 11.6% during the first year after a transient ischemic attack and approximately 5.9%/yr over the first 5 years. Patients who suffered a transient ischemic attack had a 13-fold excess risk of stroke during the first year and a sevenfold excess risk over the first 7 years compared with people without transient ischemic attacks. The actuarial risk of death, stroke, or myocardial infarction over the first 5 years after a transient ischemic attack was approximately 8.4%/yr. The prognosis in this community-based cohort was better than that in previous reports. The high early risk of stroke means that investigation and treatment of new cases should commence as soon as possible.


Prevalence of Sleep Disorders and their Effects on Sleep Quality in Epileptic Patients.
Epilepsy is a complex pervasive neurobehavioral and social condition accompanied by a wide range of comorbid conditions that can adversely affect the quality of life of patients. Sleep complaints are common among patients with epilepsy. The aim of this study was to assess the prevalence of subjective sleep disturbances and its effects on sleep quality in epileptic patients. In this cross-sectional study, 152 consecutive epileptic patients and 152 controls were interviewed. We used Epworth Sleepiness Scale, Insomnia Severity Index, Berlin Questionnaire and Pittsburg Sleep Quality Index to measure excessive daytime sleepiness, insomnia, obstructive sleep apnea and sleep quality. R estless leg syndrome was diagnosed using three questions. The age, gender and average total sleep time was similar in patients and control group. The frequency of excessive sleepiness scale and subjective complaint of sleep maintenance was higher in epileptic patients than control group (P<0.05). The symptoms of restless leg syndrome were reported by 32.3% of patients and 11.8% of controls (P<0.05). Daytime sleepiness, difficulty in sleep maintenance, poor sleep quality and RLS appear to be common in patients with epilepsy. Further confirmatory studies are needed using objective sleep studies to detect underlying mechanisms of sleep disorders in these patients.


Knowledge of 5-aminosalicylic acid nephrotoxicity and adherence to kidney function monitoring of patients with inflammatory bowel disease.
5-Aminosalicylic acid (5-ASA) nephrotoxicity is a rare and idiosyncratic condition in patients with inflammatory bowel disease (IBD), which may lead to end-stage kidney failure. Kidney function monitoring is recommended in clinical practice to prevent this complication. However, no data is available regarding the knowledge and adherence of patients with IBD to this monitoring. As a part of routine practice, patients with IBD under treatment or previously treated with 5-ASA were systematically interviewed about knowledge of 5-ASA nephrotoxicity and adherence to kidney function monitoring. We reported here the experience among the first 103 consecutive patients seen in a French referral center. A total of 103 patients (93.2% ulcerative colitis, 5.8% Crohn's disease, and 1% unclassified colitis) were analyzed. Among them, 70% were informed about the need for kidney function monitoring, and in most cases, information was provided by their gastroenterologist (94.4%). The adherence rate to monitoring was very high (84.7%). Monitoring consisted of serum creatinine and estimated glomerular filtration rate in most cases (97.2%), while 24-h proteinuria was less frequently used (69.4%). These tests were performed twice or ≥3 times per year by 44.4 and 41.7% of patients, respectively. One case of isolated elevation of proteinuria related to 5-ASA treatment was observed. We reported for the first time that patients with IBD are well informed and adherent to kidney function monitoring of treatment with 5-ASA. The monitoring performed by their treating physician was generally in accordance with current recommendations.


Partial Replacement of Animal Proteins with Plant Proteins for 12 Weeks Accelerates Bone Turnover Among Healthy Adults: A Randomized Clinical Trial.
Plant-based diets may reduce the risk of chronic diseases, but can also lead to low calcium and vitamin D intakes, posing a risk for bone health. We investigated whether partial replacement of animal proteins with plant-based proteins using a whole-diet approach affects bone and mineral metabolism in healthy adults in 3 groups fed diets differing in protein composition. This 12-week clinical trial was comprised of 107 women and 29 men (20-69 years old; BMI mean ± SD, 24.8 ± 3.9) randomly assigned to consume 1 of 3 diets designed to provide 17 energy percent (E%) protein: "animal" (70% animal protein, 30% plant protein of total protein intake), "50/50" (50% animal, 50% plant), and "plant" (30% animal, 70% plant) diets. We examined differences in bone formation [serum intact procollagen type I amino-terminal propeptide (S-iPINP)], bone resorption [serum collagen type 1 cross-linked C-terminal telopeptide (S-CTX)], mineral metabolism markers (primary outcomes), and nutrient intakes (secondary outcomes) by ANOVA/ANCOVA. S-CTX was significantly higher in the plant group (mean ± SEM, 0.44 ± 0.02 ng/mL) than in the other groups (P values < 0.001 for both), and differed also between the animal (mean ± SEM, 0.29 ± 0.02 ng/mL) and 50/50 groups (mean ± SEM, 0.34 ± 0.02 ng/mL; P = 0.018). S-iPINP was significantly higher in the plant group (mean ± SEM, 63.9 ± 1.91 ng/mL) than in the animal group (mean ± SEM, 55.0 ± 1.82 ng/mL; P = 0.006). In a subgroup without a history of vitamin D supplement use, plasma parathyroid hormone was significantly higher in the plant than in the animal group (P = 0.018). Vitamin D and calcium intakes were below recommended levels in the plant group (mean ± SEM, 6.2 ± 3.7 μg/d and 733 ± 164 mg/d, respectively). Partial replacement of animal proteins with plant-based proteins for 12 weeks increased the markers of bone resorption and formation among healthy adults, indicating a possible risk for bone health. This is probably caused by lower vitamin D and calcium intakes from diets containing more plant-based proteins, but it is unclear whether differences in protein intake or quality play a major role. This trial was registered at clinicaltrials.gov as NCT03206827.


Transition from IV epoprostenol to subcutaneous treprostinil in pulmonary arterial hypertension: a controlled trial.
We determined the relative efficacy of subcutaneous (SC) treprostinil in stable World Health Organization class II and III patients transitioned from IV epoprostenol. This was an 8-week, multicenter, randomized study in which patients were transitioned from IV epoprostenol to SC treprostinil or placebo over a period of up to 14 days and monitored carefully during and after the transition period for signs of deterioration. Patients with clinical deterioration were returned promptly to epoprostenol. Placebo or SC treprostinil doses were titrated in response to symptoms. Time to adjudicated clinical deterioration was compared between treatment groups, and exercise capacity, symptoms of disease, and safety were assessed throughout the study. Twenty-two patients were enrolled and completed the study. Seven of 8 patients (88%) [corrected] withdrawn to placebo had clinical deterioration, while only 1 of 14 patients (7%) [corrected] withdrawn to SC treprostinil had clinical deterioration (p = 0.00023 based on a treatment comparison of time to deterioration). Analyses of exercise capacity and symptoms strongly supported the efficacy of SC treprostinil in epoprostenol-treated patients. Adverse events consisted of painful infusion site reactions and anticipated prostacyclin side effects. SC treprostinil is effective in pulmonary arterial hypertension and prevents clinical deterioration and maintains functional status in patients transitioned from epoprostenol.


Gender, Race, and Health Insurance Status in Patients Undergoing Catheter Ablation for Atrial Fibrillation.
Catheter ablation for atrial fibrillation (AF) has emerged as a popular procedure. The purpose of this study was to examine whether there exist differences or disparities in ablation utilization across gender, socioeconomic class, insurance, or race. Using the Nationwide Inpatient Sample (2000 to 2012), we identified adults hospitalized with a principal diagnosis of AF by ICD 9 code 427.31 who had catheter ablation (ICD 9 code-37.34). We stratified patients by race, insurance status, age, gender, and hospital characteristics. A hierarchical multivariate mixed-effect model was created to identify the independent predictors of AF ablation. Among an estimated total of 3,508,122 patients (extrapolated from 20% Nationwide Inpatient Sample) hospitalized with a diagnosis of AF in the United States from the year 2000 to 2012, 102,469 patients (2.9%) underwent catheter ablations. The number of ablations was increased by 940%, from 1,439 in 2000 to 15,090 in 2012. There were significant differences according to gender, race, and health insurance status, which persisted even after adjustment for other risk factors. Female gender (0.83 [95% CI 0.79 to 0.87; p <0.001]), black (0.49 [95% CI 0.44 to 0.55; p <0.001]), and Hispanic race (0.64 [95% CI 0.56 to 0.72; p <0.001]) were associated with lower likelihoods of undergoing an AF ablation. Medicare (0.93, 0.88 to 0.98, <0.001) or Medicaid (0.67, 0.59 to 0.76, <0.001) coverage and uninsured patients (0.55, 0.49 to 0.62, <0.001) also had lower rates of AF ablation compared to patients with private insurance. In conclusion we found differences in utilization of catheter ablation for AF based on gender, race, and insurance status that persisted over time.


Characterization of nanomaterials for toxicity assessment.
A key element of any nanomaterial toxicity screening strategy is a detailed and comprehensive physicochemical characterization of the test material being studied. This is a critical factor for correlating the nanoparticle surface characteristics with any measured biological/toxicological responses, as well as to provide an adequate reference point for comparing toxicity results with the hazard-based findings of other investigators. Moreover, when hazard or risk-based evaluations are made on a particular nanomaterial (based on a variety of studies), it is important to ensure that the nanoparticle-types are identical or very similar in composition. This can only be accomplished if rigorous characterization is conducted. In the absence of an adequate assessment of the physical characteristics, it is easy to draw general conclusions on nanoparticle-types which may have similar chemical compositions but, in fact, have different sizes, shapes, crystal structures, surface coatings, and surface reactivity characteristics. The determination of nanomaterial physicochemical properties is vitally important to nanomedicinal applications in that the fate, accumulation, and transport of nanomaterials through the body over time may be predicted based on specific surface characteristics.


Reducing musculoskeletal injury and concussion risk in schoolboy rugby players with a pre-activity movement control exercise programme: a cluster randomised controlled trial.
Injury risk in youth rugby has received much attention, highlighting the importance of establishing evidence-based injury reduction strategies. To determine the efficacy of a movement control exercise programme in reducing injuries in youth rugby players and to investigate the effect of programme dose on injury measures. In a cluster-randomised controlled trial, 40 independent schools (118 teams, 3188 players aged 14-18 years) were allocated to receive either the intervention or a reference programme, both of which were to be delivered by school coaches. The intervention comprised balance training, whole-body resistance training, plyometric training, and controlled rehearsal of landing and cutting manoeuvres. Time-loss (>24 hours) injuries arising from school rugby matches were recorded by coaches and medical staff. 441 time-loss match injuries (intervention, 233; control, 208) were reported across 15 938 match exposure-hours (intervention, 9083; control, 6855). Intention-to-treat results indicated unclear effects of trial arm on overall match injury incidence (rate ratio (RR)=0.85, 90% confidence limits 0.61 to 1.17), although clear reductions were evident in the intervention arm for concussion incidence (RR=0.71, 0.48 to 1.05). When trial arm comparisons were limited to teams who had completed three or more weekly programme sessions on average, clear reductions in overall match injury incidence (RR=0.28, 0.14 to 0.51) and concussion incidence (RR=0.41, 0.17 to 0.99) were noted in the intervention group. A preventive movement control exercise programme can reduce match injury outcomes, including concussion, in schoolboy rugby players when compared with a standardised control exercise programme, although to realise the greatest effects players should complete the programme at least three times per week.


Studies of coronal lines with electronic cameras during the eclipse of 7 march 1970.
The experimental design described here allows us to study with 2-A. bandpass filters the brightness distribution of the green coronal line, the two infrared lines of Fe XIII, and the neighboring coronal continuum. For the first time, in an eclipse expedition, electrostatic cameras derived from the Lallemand type are used; full advantage was taken of their speed, especially in the near infrared spectral range, and their good photometric qualities. They permit the measurement of intensity and polarization of the lines in the corona to a height of 1.25 solar radii above the limb of the sun, with a spatial resolution >/= (10")(2).


Breast cancer subtypes as defined by the estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2) among women with invasive breast cancer in California, 1999-2004.
Breast cancer research examining either molecular profiles or biomarker subtypes has focused on the estrogen receptor negative/progesterone receptor negative/human epidermal growth factor receptor 2 negative (ER-/PR-/HER2-) and ER-/PR-/HER2+ subtypes. Less is known about the epidemiology or clinical outcome of the other subtypes. This study examines the eight combinations of ER/PR/HER2 in patients with invasive breast cancer. The 5-year relative survival and the distribution among demographic, socioeconomic, and tumor characteristics of each of the subtypes are examined. Using the California Cancer Registry, 61,309 women with primary invasive breast cancer were classified according to ER/PR/HER2 status. Five-year relative survival was computed for the eight subtypes. Bivariate analyses were used to assess the distribution of cases across all subtypes. Multivariate logistic regression was used to compute the adjusted odds of having one of the five subtypes with the best and worst survival. Survival varied from 96% (ER+/PR+/HER2-) to 76% (ER-/PR-/HER2+ and ER-/PR-/HER2-). The four subtypes with the poorest survival were all ER negative. Women who were younger than age 50, non-Hispanic black or Hispanic, of the lowest SES groups, and had stage IV tumors that were undifferentiated were overrepresented in ER-/PR-/HER2+ and triple negative (ER-/PR-/HER2-) subtypes. Asian Pacific Islanders had increased odds (OR = 1.41; 95% confidence interval [CI] = 1.26-1.57) of having the ER-/PR-/HER2+ subtype. Stage III tumors (OR = 1.25; 95% CI = 1.08-1.44) and stage IV tumors (OR = 1.58; 95% CI = 1.27-1.98) had higher odds than stage I tumors of being ER-/PR-/HER2+. Stage IV tumors (OR = 0.54; 95% CI = 0.44-0.67) strongly decreased the odds of the ER-/PR-/HER2- subtype. Poorly differentiated and undifferentiated tumors were over 20 times as likely as well-differentiated tumors of being ER-/PR-/HER2- or ER-/PR-/HER2+. There are considerable differences in survival, demographics, and tumor characteristics among the eight subtypes. We recommend reporting breast cancer as an ER/PR/HER2 subtype and precisely documenting demographic and tumor characteristics.


Unphosphorylated gelsolin is localized in regions of cell-substratum contact or attachment in Rous sarcoma virus-transformed rat cells.
Regions associated with cell-substratum contact or attachment in Rous sarcoma virus (RSV)-transformed rat fibroblasts (RR1022 cells) were identified by reflection-interference microscopy. Electron microscopy of such regions revealed the presence of discrete membrane-associated structures composed of a paracrystalline lattice of hexagons and pentagons to which actin filaments appear to be attached. Staining of actin by biotin-labeled heavy meromyosin showed that transformed cells, unlike normal fibroblasts, lack prominent actin fibers, and that, instead, much of the fluorescence is concentrated in loci corresponding to locations of transient association between the cell and the substratum. In stationary cells, such loci were found in rosette formation, predominantly in the region beneath the nucleus. In cells engaged in active movement, such as during migration into a wound, the actin-containing spots were concentrated in the region of the leading edge. A similar pattern of staining was observed with antibody to gelsolin, a 91,000-dalton Ca2+-dependent actin filament-shortening protein. Since the action of gelsolin on actin is reversible and dependent on physiologically relevant changes in calcium concentration, the localization of gelsolin, together with actin-bundling proteins such as alpha-actinin, in the regions containing many small microfilament bundles on the ventral side of cytoplasm suggests that gelsolin may be a component of the mechanism for the disassembly and assembly of actin during the dissolution and reformation of structures for cell-substratum contact during cell locomotion. Regulation of gelsolin activity was not dependent on protein phosphorylation, as shown by lack of 32P-incorporation into gelsolin in either transformed or normal fibroblasts.


Intense competition between arbuscular mycorrhizal mutualists in an in vitro root microbiome negatively affects total fungal abundance.
The root microbiome is composed of an incredibly diverse microbial community that provides services to the plant. A major question in rhizosphere research is how species in root microbiome communities interact with each other and their host. In the nutrient mutualism between host plants and arbuscular mycorrhizal fungi (AMF), competition often leads to certain species dominating host colonization, with the outcome being dependent on environmental conditions. In the past, it has been difficult to quantify the abundance of closely related species and track competitive interactions in different regions of the rhizosphere, specifically within and outside the host. Here, we used an artificial root system (in vitro root organ cultures) to investigate intraradical (within the root) and extraradical (outside the root) competitive interactions between two closely related AMF species, Rhizophagus irregularis and Glomus aggregatum, under different phosphorus availabilities. We found that competitive interactions between AMF species reduced overall fungal abundance. R. irregularis was consistently the most abundant symbiont for both intraradical and extraradical colonization. Competition was the most intense for resources within the host, where both species negatively affected each other's abundance. We found the investment ratio (i.e. extraradical abundance/intraradical abundance) shifted for both species depending on whether competitors were present or not. Phosphorus availability did not change the outcome of these interactions. Our results suggest that studies on competitive interactions should focus on intraradical colonization dynamics and consider how changes in investment ratio are mediated by fungal species interactions.


Investigation of proton dynamics and the proton transport pathway in choline dihydrogen phosphate using solid-state NMR.
Choline dihydrogen phosphate has previously been shown to be a good ionic conductor as well as an excellent host for acid doping, leading to high proton conductivities required for e.g., electrochemical devices including proton membrane fuel cells and sensors. A combination of variable-temperature (1)H solid-state NMR and 2D NMR pulse sequences, including (31)P and (13)C CODEX and (1)H BaBa, show that the proton conduction mechanism primarily involves assisted transport via a restricted three-site motion of the phosphate unit around the P-O bond that is hydrogen bonded to the choline and exchange of protons between these anions. In other words, proton transport at ambient temperatures appears to occur most favorably along the crystallographic b axis, from phosphate dimer to dimer. At elevated temperatures exchange between the protons of the hydroxyl group on the choline cation and the hydrogen-bonded dihydrogen phosphate groups also contributes to the structural diffusion of the protons in this solid state conductor.


Comparative analysis of copy number variations in ulcerative colitis associated and sporadic colorectal neoplasia.
The incidence of and mortality from colorectal cancers (CRC) can be reduced by early detection. Currently there is a lack of established markers to detect early neoplastic changes. We aimed to identify the copy number variations (CNVs) and the associated genes which could be potential markers for the detection of neoplasia in both ulcerative colitis-associated neoplasia (UC-CRN) and sporadic colorectal neoplasia (S-CRN). We employed array comparative genome hybridization (aCGH) to identify CNVs in tissue samples of UC nonprogressor, progressor and sporadic CRC. Select genes within these CNV regions as a panel of markers were validated using quantitative real time PCR (qRT-PCR) method along with the microsatellite instability (MSI) in an independent cohort of samples. Immunohistochemistry (IHC) analysis was also performed. Integrated analysis showed 10 overlapping CNV regions between UC-Progressor and S-CRN, with the 8q and 12p regions showing greater overlap. The qRT-PCR based panel of MYC, MYCN, CCND1, CCND2, EGFR and FNDC3A was successful in detecting neoplasia with an overall accuracy of 54% in S-CRN compared to that of 29% in UC neoplastic samples. IHC study showed that p53 and CCND1 were significantly overexpressed with an increasing frequency from pre-neoplastic to neoplastic stages. EGFR and AMACR were expressed only in the neoplastic conditions. CNVs that are common and unique to both UC-associated and sporadic colorectal neoplasm could be the key players driving carcinogenesis. Comparative analysis of CNVs provides testable driver aberrations but needs further evaluation in larger cohorts of samples. These markers may help in developing more effective neoplasia-detection strategies during screening and surveillance programs.


Supplementary polio immunization activities and prior use of routine immunization services in non-polio-endemic sub-Saharan Africa.
To determine participation in polio supplementary immunization activities (SIAs) in sub-Saharan Africa among users and non-users of routine immunization services and among users who were compliant or non-compliant with the routine oral poliovirus vaccine (OPV) immunization schedule. Data were obtained from household-based surveys in non-polio-endemic sub-Saharan African countries. Routine immunization service users were children (aged < 5 years) who had ever had a health card containing their vaccination history; non-users were children who had never had a health card. Users were considered compliant with the OPV routine immunization schedule if, by the SIA date, their health card reflected receipt of required OPV doses. Logistic regression measured associations between SIA participation and use of both routine immunization services and compliance with routine OPV among users. Data from 21 SIAs conducted between 1999 and 2010 in 15 different countries met inclusion criteria. Overall SIA participation ranged from 70.2% to 96.1%. It was consistently lower among infants than among children aged 1-4 years. In adjusted analyses, participation among routine immunization services users was > 85% in 12 SIAs but non-user participation was >85% in only 5 SIAs. In 18 SIAs, participation was greater among users (P < 0.01 in 16, 0.05 in 1 and < 0.10 in 1) than non-users. In 14 SIAs, adjusted analyses revealed lower participation among non-compliant users than among compliant users (P < 0.01 in 10, < 0.05 in 2 and < 0.10 in 2). Large percentages of children participated in SIAs. Prior use of routine immunization services and compliance with the routine OPV schedule showed a strong positive association with SIA participation.


Allosteric enhancement of adenosine A1 receptor binding and function by 2-amino-3-benzoylthiophenes.
Several 2-amino-3-benzoylthiophenes were found to increase the binding of [3H]N6-cyclohexyladenosine to A1 adenosine receptors in rat brain membranes. Concentration-response curves were bell-shaped, with up to 45% stimulation of binding at 10 microM followed by inhibition at higher concentrations. Because these compounds originated from a series of nonxanthine adenosine antagonists, the inhibition of binding was attributed to the presence of interfering adenosine antagonist activity. The compounds stimulated binding of several A1 agonist ligands but only inhibited binding of the A1 antagonist ligand [3H]8-cyclopentyl-1,3-dipropylxanthine, indicating that enhancement was specific for the agonist conformation of the receptor. The enhancement was also specific for the A1 receptor, because agonist binding to A2 adenosine, M2 muscarinic, alpha 2 adrenergic, and delta opiate receptors showed little or no enhancement. Uncoupling of the A1 receptor from the inhibitory guanine nucleotide-binding protein did not prevent enhancement. The enhancers slowed the dissociation of [3H]N6-cyclohexyladenosine from the A1 receptor, implying an allosteric mechanism of action. The inhibition of forskolin-stimulated cyclic AMP accumulation in FRTL-5 cells was employed as a functional index of A1 receptor activation. The enhancers caused up to 19-fold leftward shifts in the concentration-response curve for N6-cyclopentyladenosine and also caused up to 55% inhibition of cyclic AMP accumulation in the absence of agonist. The binding and functional results are consistent with a model in which the enhancers bind preferentially to the agonist conformation of the A1 receptor, thereby shifting the receptor equilibrium in favor of agonist binding. Adenosine enhancers may be useful for ischemia and other conditions involving local energy deficits. More generally, allosteric enhancers may provide a means for strengthening physiological control circuits in a variety of receptor systems.


The role of MATER in endoplasmic reticulum distribution and calcium homeostasis in mouse oocytes.
Ca(2+) oscillations are a hallmark of mammalian fertilization and play a central role in the activation of development. The calcium required for these oscillations is primarily derived from the endoplasmic reticulum (ER), which accumulates in clusters at the microvillar subcortex during oocyte maturation. The migration of the ER to the cortex during maturation is thought to play an important role in rendering the ER competent to generate the calcium transients, and the redistribution of ER is believed to be primarily mediated by microtubules and microfilaments. We have previously shown that the oocyte- and early embryo-restricted maternal effect gene Mater (Nlrp5) localizes to, and is required for, formation of the oocyte cytoplasmic lattices, a tubulin-containing structure that appears to play an important role in organelle positioning and distribution during oocyte maturation. Given these observations, we hypothesized that Mater may also be required for ER redistribution and Ca(2+) homeostasis in oocytes. To test this hypothesis, we first investigated ER localization in metaphase-II Mater(tm/tm) (hypomorph) oocytes and found ER clusters to be less abundant at the microvillar cortex when compared to wild type oocytes. To examine the potential mechanisms by which MATER mediates ER redistribution, we tested whether tubulin expression levels and localization were affected in the mutant oocytes and found that the Triton-insoluble fraction of tubulin was significantly decreased in Mater(tm/tm) oocytes. To identify potential functional defects associated with these ER abnormalities, we next set out to investigate if the pattern of Ca(2+) oscillations was altered in Mater(tm/tm) oocytes after fertilization in vitro. Intriguingly, Ca(2+) oscillations in Mater(tm/tm) oocytes exhibited a significantly lower first peak amplitude and a higher frequency when compared to wild type oocytes. We then found that the Ca(2+) oscillation defect in Mater(tm/tm) oocytes was likely caused by a reduced amount of Ca(2+) in the ER stores. Taken together, these observations support the hypothesis that MATER is required for ER distribution and Ca(2+) homeostasis in oocytes, likely due to defects in lattice-mediated ER positioning and/or redistribution.