Cardiac rate normalization in chronic atrial fibrillation: comparison of long-term efficacy of treatment with amiodarone versus AV node ablation and permanent His-bundle pacing.
Chronic atrial fibrillation (AF) is a common arrhythmia with significant morbidity and mortality. AF has been the subject of considerable attention and intensive clinical research in recent years. Current opinion on the management of AF favors the restoration and maintenance of normal ventricular rhythm. This has several potential benefits, including the alleviation of arrhythmia-associated symptoms and hemodynamic improvements. Maintenance of frequents normalization of ventricular rhythm (NVR) can be achieved with antiarrhythmic drug therapy or with AV node radiofrequency ablation (RFA) and permanent ventricular pacing. Recent interest has focused on the use of class III antiarrhythmic agents, such as amiodarone hydrochloride. This investigation compared amiodarone to AV node RFA and permanent pacing of the His-bundle area in maintaining NVR in patients with resistant chronic AF. After 12 months of treatment with amiodarone (200 to 400 mg/d) 30 % of patients remained in NVR, 30 % were in transitional phase of improvement, and 40 % showed negative effect. Only a few patients in this group developed ocular or hepatic side effects. On one year follow-up was achieved in 100 % of cases without any clinically significant side effects being seen. In conclusion, analysis of the results of this study suggests that low-dose amiodarone is well tolerated in the management of chronic AF in a selected patient population. The more aggressive interventional radiofrequency ablation technique is significantly more effective and more reliable in the long-term clinical treatment of drug-resistant AF.


Systematic quality improvement in medicine: everyone can do it.
In this brief review, written from the perspective of a physician-leader who has fostered the development of comprehensive quality improvement efforts at two academic medical centers, I review the need for improvement, some conceptual barriers that must be overcome, the goals of a comprehensive quality improvement (QI) effort, some of the results we have obtained, and some observations on how to develop a culture of continuous improvement in an academic medical center. The mandate for quality improvement is clear; current healthcare is wasteful and error-prone, leading to excessive morbidity and mortality and unsustainably high costs. Successful quality improvement requires the abandonment of two paradigms: the craft model of medical practice and the notion that many forms of harm to patients are not preventable. I will describe how dramatic improvement has been achieved in reducing, by up to 10-fold, rates of central line infections, ventilator-associated pneumonias, peritonitis in peritoneal dialysis patients, and mortality due to cardiac arrest in hospital. I will describe as well how these methods can improve access to out-patient clinics dramatically and enhance the reliability and safety of hand-offs between covering physicians. To develop and maintain systematic quality improvement in all phases of medical care we must articulate a culture in which: everyone working at the medical center makes improvements every day; front-line staff, who know best how the work is done, are empowered to improve the processes of care; and multidisciplinary teams create the protocols that reduce variation that is due to physician preference, leaving only the variation required by the individual needs of patients. I will review as well the crucial elements of education of trainees and faculty members needed to guide and sustain a culture of quality. Finally, I will add some observations on how oversight boards and medical center leaders can help create systematic quality improvement in their medical centers.


The effect of camicinal (GSK962040), a motilin agonist, on gastric emptying and glucose absorption in feed-intolerant critically ill patients: a randomized, blinded, placebo-controlled, clinical trial.
The promotility agents currently available to treat gastroparesis and feed intolerance in the critically ill are limited by adverse effects. The aim of this study was to assess the pharmacodynamic effects and pharmacokinetics of single doses of the novel gastric promotility agent motilin agonist camicinal (GSK962040) in critically ill feed-intolerant patients. A prospective, randomized, double-blind, parallel-group, placebo-controlled, study was performed in mechanically ventilated feed-intolerant patients [median age 55 (19-84), 73 % male, APACHE II score 18 (5-37) with a gastric residual volume ≥200 mL]. Gastric emptying and glucose absorption were measured both pre- and post-treatment after intragastric administration of 50 mg (n = 15) camicinal and placebo (n = 8) using the (13)C-octanoic acid breath test (BTt1/2), acetaminophen concentrations, and 3-O-methyl glucose concentrations respectively. Following 50 mg enteral camicinal, there was a trend to accelerated gastric emptying [adjusted geometric means: pre-treatment BTt1/2 117 minutes vs. post- treatment 76 minutes; 95 % confidence intervals (CI; 0.39, 1.08) and increased glucose absorption (AUC240min pre-treatment: 28.63 mmol.min/L vs. post-treatment: 71.63 mmol.min/L; 95 % CI (1.68, 3.72)]. When two patients who did not have detectable plasma concentrations of camicinal were excluded from analysis, camicinal accelerated gastric emptying (adjusted geometric means: pre-treatment BTt1/2 121 minutes vs. post-treatment 65 minutes 95 % CI (0.32, 0.91) and increased glucose absorption (AUC240min pre-treatment: 33.04 mmol.min/L vs. post-treatment: 74.59 mmol.min/L; 95 % CI (1.478, 3.449). In those patients receiving placebo gastric emptying was similar pre- and post-treatment. When absorbed, a single enteral dose of camicinal (50 mg) accelerates gastric emptying and increases glucose absorption in feed-intolerant critically ill patients. The study protocol was registered with the US NIH clinicaltrials.gov on 23 December 2009 (Identifier NCT01039805 ).


Nutrition as an important mediator of the impact of background variables on outcome in middle childhood.
Adequate nutrition is fundamental to the development of a child's full potential. However, the extent to which malnutrition affects developmental and cognitive outcomes in the midst of co-occurring risk factors remains largely understudied. We sought to establish if the effects of nutritional status varied according to diverse background characteristics as well as to compare the relative strength of the effects of poor nutritional status on language skills, motor abilities, and cognitive functioning at school age. This cross-sectional study was conducted among school-age boys and girls resident in Kilifi District in Kenya. We hypothesized that the effects of area of residence, school attendance, household wealth, age and gender on child outcomes are experienced directly and indirectly through child nutritional status. The use of structural equation modeling (SEM) allowed the disaggregation of the total effect of the explanatory variables into direct effects (effects that go directly from one variable to another) and indirect effects. Each of the models tested for the four child outcomes had a good fit. However, the effects on verbal memory apart from being weaker than for the other outcomes, were not mediated through nutritional status. School attendance was the most influential predictor of nutritional status and child outcomes. The estimated models demonstrated the continued importance of child nutritional status at school-age.


Neuroprotective effects of daidzein on focal cerebral ischemia injury in rats.
Daidzein, a plant extract, has antioxidant activity. It is hypothesized, in this study, that daidzein exhibits neuroprotective effects on cerebral ischemia. Rat models of middle cerebral artery occlusion were intraperitoneally administered daidzein. Biochemical and immunohistochemical tests showed that superoxide dismutase and nuclear respiratory factor 1 expression levels in the brain tissue decreased after ischemia and they increased obviously after daidzein administration; malondialdehyde level and apoptosis-related cysteine peptidase caspase-3 and caspase-9 immunoreactivity in the brain tissue increased after ischemia and they decreased obviously after daidzein administration. Hematoxylin-eosin staining and luxol fast blue staining results showed that intraperitoneal administration of daidzein markedly alleviated neuronal damage in the ischemic brain tissue. These findings suggest that daidzein exhibits neuroprotective effects on ischemic brain tissue by decreasing oxygen free radical production, which validates the aforementioned hypothesis.


Predicting success: patterns of cortical activation and deactivation prior to response inhibition.
The present study investigated the relationships between attention and other preparatory processes prior to a response inhibition task and the processes involved in the inhibition itself. To achieve this, a mixed fMRI design was employed to identify the functional areas activated during both inhibition decision events and the block of trials following a visual cue introduced 2 to 7 sec prior (cue period). Preparing for successful performance produced increases in activation for both the cue period and the inhibition itself in the frontoparietal cortical network. Furthermore, preparation produced activation decreases in midline areas (insula and medial prefrontal) argued to be responsible for monitoring internal emotional states, and these cue period deactivations alone predicted subsequent success or failure. The results suggest that when cues are provided to signify the imminent requirement for behavioral control, successful performance results from a coordinated pattern of preparatory activation in task-relevant areas and deactivation of task-irrelevant ones.


Decreased cortical response to verbal working memory following sleep deprivation.
To investigate the cerebral hemodynamic response to verbal working memory following sleep deprivation. Subjects were scheduled for 3 functional magnetic resonance imaging scanning visits: an initial screening day (screening state), after a normal night of sleep (rested state), and after 30 hours of sleep deprivation (sleep-deprivation state). Subjects performed the Sternberg working memory task alternated with a control task during an approximate 13-minute functional magnetic resonance imaging scan. Inpatient General Clinical Research Center and outpatient functional magnetic resonance imaging center. Results from 33 men (mean age, 28.6 +/- 6.6 years) were included in the final analyses. None. Subjects performed the same Sternberg working memory task at the 3 states within the magnetic resonance imaging scanner. Neuroimaging data revealed that, in the screening and rested states, the brain regions activated by the Sternberg working memory task were found in the left dorsolateral prefrontal cortex, Broca's area, supplementary motor area, right ventrolateral prefrontal cortex, and the bilateral posterior parietal cortexes. After 30 hours of sleep deprivation, the activations in these brain regions significantly decreased, especially in the bilateral posterior parietal cortices. Task performance also decreased. A repeated-measures analysis of variance revealed that subjects at the screening and rested states had similar activation patterns, with each having significantly more activation than during the sleep-deprivation state. These results suggest that human sleep-deprivation deficits are not caused solely or even predominantly by prefrontal cortex dysfunction and that the paretal cortex, in particular, and other brain regions involved in verbal working memory exhibit significant sleep-deprivation vulnerability.


Totally Robotic Versus Totally Laparoscopic Surgery for Rectal Cancer.
In this study, perioperative and short-term postoperative results of totally robotic versus totally laparoscopic rectal resections for cancer were investigated in a comparative manner by considering risk factors including obesity, male sex, and neoadjuvant treatment. In addition to overall comparison, the impact of sex, obesity (body mass index ≥30 kg/m), and neoadjuvant treatment was assessed in patients who had a total mesorectal excision (TME). Operative time was longer in the robotic group (P<0.001). In obese patients who underwent TME, the mean length of hospital stay was shorter (7±2 vs. 9±4 d, P=0.01), and the mean number of retrieved lymph nodes was higher (30±19 vs. 23±10, P=0.02) in the robotic group. Totally robotic and totally laparoscopic surgery appears to be providing similar outcomes in patients undergoing rectal resections for cancer. Selective use of a robot may have a role for improving postoperative outcomes in some challenging cases including obese patients undergoing TME.


Application of density functional theory and vibrational spectroscopy toward the rational design of ionic liquids.
Density functional theory methods in combination with vibrational spectroscopy are used to investigate possible variants of molecular structure of the ion pairs of several imidazolium-based ionic liquids (ILs). Multiple stable structures are determined with the anion positioned (a) near to the C2 atom of the imidazolium ring, (b) between N1 and C5, (c) between N3 and C4, and (d) between C4 and C5. Chloride and bromide anions in vacuum also occupy positions above or below the imidazolium ring, but in the condensed state these positions are destabilized. In comparison with the halides that almost equally occupy the positions (a-d), tetrafluoroborate and hexafluorophosphate anions strongly prefer position (a). The position and the type of the anion influence the conformation of the side chains bound to the imidazolium N1 atom, which are able to adopt in vacuum all usual staggered or eclipsed conformations, although in the liquid state some of the conformations are present only as minor forms if at all. Vibrations of the cations depend both on the conformational changes and on the association with the anion. The formation of the ion pairs influences mainly stretching and out-of-plane vibrations of the imidazolium C-H groups and stretching vibrations of the perfluoroanions. Other modes of the ions retain their individuality and practically do not mix. This allows "interionic" vibrations to be separated and to regard the couple of the ions as an anharmonic oscillator. Such a model correlates the molecular structure of various ILs and their melting points without involving the energy of the interaction between the cations and anions but explains structure-melting point correlations on the grounds of quasy-elastic properties.


Best (but oft-forgotten) practices: propensity score methods in clinical nutrition research.
In observational studies, treatment assignment is a nonrandom process and treatment groups may not be comparable in their baseline characteristics, a phenomenon known as confounding. Propensity score (PS) methods can be used to achieve comparability of treated and nontreated groups in terms of their observed covariates and, as such, control for confounding in estimating treatment effects. In this article, we provide a step-by-step guidance on how to use PS methods. For illustrative purposes, we used simulated data based on an observational study of the relation between oral nutritional supplementation and hospital length of stay. We focused on the key aspects of PS analysis, including covariate selection, PS estimation, covariate balance assessment, treatment effect estimation, and reporting. PS matching, stratification, covariate adjustment, and weighting are discussed. R codes and example data are provided to show the different steps in a PS analysis.


An RNAi-based system for loss-of-function analysis identifies Raf1 as a crucial mediator of BCR-ABL-driven leukemogenesis.
Genetic loss-of-function studies in murine tumor models have been essential in the analysis of downstream mediators of oncogenic transformation. Unfortunately, these studies are frequently limited by the availability of genetically modified mouse strains. Here we describe a versatile method allowing the efficient expression of an oncogene and simultaneous knockdown of targets of interest (TOI) from a single retroviral vector. Both oncogene and TOI-specific miR30-based shRNA are under the control of the strong viral long terminal repeat promoter, resulting in a single shared RNA transcript. Using this vector in a murine syngeneic BM transplantation model for BCR-ABL-induced chronic myeloid leukemia, we find that oncogene expression and target knockdown in primary hematopoietic cells with this vector is efficient both in vitro and in vivo, and demonstrate that Raf1, but not BRAF, modulates BCR-ABL-dependent ERK activation and transformation of hematopoietic cells. This expression system could facilitate genetic loss-of-function studies and allow the rapid validation of potential drug targets in a broad range of oncogene-driven murine tumor models.


Nearly finished genomes produced using gel microdroplet culturing reveal substantial intraspecies genomic diversity within the human microbiome.
The majority of microbial genomic diversity remains unexplored. This is largely due to our inability to culture most microorganisms in isolation, which is a prerequisite for traditional genome sequencing. Single-cell sequencing has allowed researchers to circumvent this limitation. DNA is amplified directly from a single cell using the whole-genome amplification technique of multiple displacement amplification (MDA). However, MDA from a single chromosome copy suffers from amplification bias and a large loss of specificity from even very small amounts of DNA contamination, which makes assembling a genome difficult and completely finishing a genome impossible except in extraordinary circumstances. Gel microdrop cultivation allows culturing of a diverse microbial community and provides hundreds to thousands of genetically identical cells as input for an MDA reaction. We demonstrate the utility of this approach by comparing sequencing results of gel microdroplets and single cells following MDA. Bias is reduced in the MDA reaction and genome sequencing, and assembly is greatly improved when using gel microdroplets. We acquired multiple near-complete genomes for two bacterial species from human oral and stool microbiome samples. A significant amount of genome diversity, including single nucleotide polymorphisms and genome recombination, is discovered. Gel microdroplets offer a powerful and high-throughput technology for assembling whole genomes from complex samples and for probing the pan-genome of naturally occurring populations.


Snail plays a key role in E-cadherin-preserved esophageal squamous cell carcinoma.
Snail is a zinc-finger transcription factor that triggers the epithelial-mesenchymal transition (EMT) by directly repressing E-cadherin expression. However, the relationship between E-cadherin and Snail expression remains unclear in esophageal squamous cell carcinoma (ESCC). The purpose of the present study was to evaluate the clinical significance of E-cadherin and Snail expression in ESCC. Immunohistochemistry was used to investigate the expression of E-cadherin and Snail proteins in 194 patients with ESCC. The relationship between expression of these proteins and clinicopathological factors was analyzed, and the usefulness of Snail in disease prognosis was evaluated in relation to E-cadherin expression. E-cadherin expression was preserved in 41.2% of tumors, and Snail expression was confirmed in 61.7%. Tumors with reduced E-cadherin expression invaded deeper (P<0.0001), had more lymph node metastasis (P<0.0001) and had more lymphatic invasion (P=0.0011) than tumors with preserved expression. Tumors that were positive for Snail expression invaded deeper (P=0.0385), had more distant lymph node metastasis (pM) (P=0.0051) and had a more advanced stage (P=0.0044) than those that were negative for Snail expression. Snail expression was not significantly correlated with reduced E-cadherin expression. Patients with reduced E-cadherin expression or positive Snail expression had poor clinical outcomes. In the preserved E-cadherin group, overall survival rate was better in patients with negative Snail expression than in those with positive Snail expression (P=0.035). Snail appears to play a key role in preserved E-cadherin expression. Further studies on other molecules in the pathways related to reduced E-cadherin expression in ESCC from the view-point of EMT are necessary.


Dental care utilization and retirement.
The authors examine the relationship of dental care coverage, retirement, and utilization in an aging population using data from the Health and Retirement Study (HRS). The authors estimate dental care use as a function of dental care coverage status, retirement, and individual and household characteristics. They also estimate a multivariate model controlling for potentially confounding variables. The authors show that that the loss of income and dental coverage associated with retirement may lead to lower use rates but this effect may be offset by other unobserved aspects of retirement including more available free time leading to an overall higher use rate. The authors conclude from this study that full retirement accompanied by reduced income and dental insurance coverage produces lower utilization of dental services. However, they also show that retirement acts as an independent variable, whereas income, coverage, and free time (unobserved) act as intervening variables.


Features of Human CD3+CD20+ T Cells.
Monoclonal Abs against CD20 reduce the number of relapses in multiple sclerosis (MS); commonly this effect is solely attributed to depletion of B cells. Recently, however, a subset of CD3(+)CD20(+) T cells has been described that is also targeted by the anti-CD20 mAb rituximab. Because the existence of cells coexpressing CD3 and CD20 is controversial and features of this subpopulation are poorly understood, we studied this issue in detail. In this study, we confirm that 3-5% of circulating human T cells display CD20 on their surface and transcribe both CD3 and CD20. We report that these CD3(+)CD20(+) T cells pervade thymus, bone marrow, and secondary lymphatic organs. They are found in the cerebrospinal fluid even in the absence of inflammation; in the cerebrospinal fluid of MS patients they occur at a frequency similar to B cells. Phenotypically, these T cells are enriched in CD8(+) and CD45RO(+) memory cells and in CCR7(-) cells. Functionally, they show a higher frequency of IL-4-, IL-17-, IFN-γ-, and TNF-α-producing cells compared with T cells lacking CD20. CD20-expressing T cells respond variably to immunomodulatory treatments given to MS patients: they are reduced by fingolimod, alemtuzumab, and dimethyl fumarate, whereas natalizumab disproportionally increases them in the blood. After depletion by rituximab, they show earlier and higher repopulation than CD20(+) B cells. Taken together, human CD3(+)CD20(+) T cells pervade lymphatic organs and the cerebrospinal fluid, have a strong ability to produce different cytokines, and respond to MS disease modifying drugs.


Simulation of radiation damage to lung cells after exposure to radon decay products.
Exposure to radon and radon decay products represents one of the greatest risks of ionizing radiation from natural sources in some residential and working areas. Recently increasing attention has been paid to accurate estimations of this health risk by using various models. In the presented study, a bystander model was used to predict biological effects of radon products on lung tissue target cells. The model considers radiation response as a superposition of the direct alpha particles hit effect and the bystander (cells communication) effect. Energy deposition in the lung tissue and in the air gap was calculated using the Bethe-Bloch equation. The exponential distribution of radon progenies in the mucous layer of smokers and non-smokers was evaluated. The excess relative risk value of lung cancer occurrence per unit exposure obtained in our study was ERR/WLM=0.0047 for smokers and ERR/WLM=0.0171 (taking into account the environment in radioactive ore mines) for non-smokers. Other published results give the average excess relative risk values per unit exposure in the dwellings for smokers ERR=0.050 per 100 Bq.m(-3) and for non-smokers ERR=0.198 per 100 B.qm(-3). Results presented in this study are in good agreement with the published epidemiological data on lung cancer incidence for mines and residential areas. The bystander model is suitable for radon risk prediction in dwellings and at workplaces (residential and working areas).


Incremental value of cardiac imaging in patients presenting to the emergency department with chest pain and without ST-segment elevation: a multicenter study.
We hypothesized that imaging of regional myocardial function (RF) and perfusion (PER) will add incremental value for both diagnosis and short-term prognosis to routine demographic, clinical, and electrocardiographic findings in patients presenting to the emergency department (ED) with chest pain and without ST-segment elevation on the electrocardiogram. We compared contrast echocardiography (CE) with gated single-photon emission computed tomography (SPECT) for this purpose. Both CE and SPECT readings included separate and composite assessments of both RF and PER. Adverse events in the first 48 hours after ED presentation included acute myocardial infarction, emergent revascularization, and cardiac-related death. Concordance between CE and SPECT was 77% (73% to 82%) for all territories, with a higher concordance for the anterior wall of 84% (78% to 89%). Of the 203 patients recruited for the study, 38 (19%) had a cardiac event within 48 hours of ED presentation: 21 had acute myocardial infarction, 16 underwent an urgent revascularization procedure, and 1 died. In multivariate logistic regression models, the number of abnormal segments on CE and SPECT were significant predictors (P <.05) of cardiac events. The composite scores on CE provided 17% incremental information (P =.009, n = 203) and gated SPECT provided 23.5% additional information (P =.020, n = 163) for predicting cardiac events compared with routine demographic, clinical, and electrocardiographic variables. RF and composite evaluation was superior on SPECT compared with CE, whereas PER alone was not. Cardiac imaging of RF and PER at the time of ED presentation offers substantially greater diagnostic and prognostic information for early cardiac events in patients presenting to the ED with chest pain and no ST elevation than does the routine demographic, clinical, and electrocardiographic assessment.


Pubovaginal slings for stress urinary incontinence following radical cystectomy and orthotopic neobladder reconstruction in women.
We evaluated the clinical efficacy of pubovaginal slings for new onset stress urinary incontinence following radical cystectomy and orthotopic lower urinary tract reconstruction in women. Between June 1990 and July 2002, 101 female patients with primary transitional cell carcinoma of the bladder were treated with radical cystectomy and orthotopic ileal neobladder reconstruction. Four patients 61 to 73 years old underwent pubovaginal slings (autologous rectus fascia in 2 and dermal graft in 2) for stress urinary incontinence persisting 9 to 20 months following reconstruction with a Studer (2) or T pouch (2) ileal neobladder. Pre-cystectomy continence was excellent in 3 patients, while 1 had mild stress incontinence. All patients had high grade, muscle invasive transitional cell carcinoma and/or carcinoma in situ with negative urethral margins and 3 of the 4 had lymph node negative disease on pathological examination. Two patients were treated with transurethral bulking material 4 to 5 months prior to the sling procedure without noticeable improvement. Two patients who underwent autologous pubovaginal slings had significant complications arising from dissection in the retropubic space, including 1 entero-pouch fistula and 1 enterotomy resulting in an enterocutaneous fistula, sepsis and subsequent death. These 2 patients had persistent stress incontinence despite the sling procedures and they ultimately underwent conversion to continent cutaneous urinary diversions. Two patients were treated with a dermal graft sling using infrapubic bone anchors through a transvaginal approach, obviating the need to enter the pelvis. These patients had uneventful postoperative courses and they are currently hypercontinent, performing intermittent catheterization with complete daytime continence and only occasional nighttime leakage 3 and 9 months following sling surgery. Pubovaginal sling procedures for incontinence following orthotopic neobladder reconstruction in women may be complicated due to extensive pelvic surgery. Dissection in the retropubic space should be avoided because potentially fatal complications may occur. Slings using infrapubic bone anchors may provide the best option in such patients in whom conservative management has failed because the pelvis need not be violated.


Spot urine albumin to creatinine ratio and serum cystatin C are effective for detection of diabetic nephropathy in childhood diabetic patients.
Spot urinary albumin to creatinine ratio (ACR) measurement has been suggested as a surrogate to 24-hr urine collection for the assessment of microalbuminuria, and cystatin C (cysC) is known as an advantageous marker for renal function. The aim of this study was to evaluate the clinical values of spot urinary ACR and serum cysC for the assessment of diabetic nephropathy instead of 24-hr urine microalbumin in children and adolescents with diabetes. A total of 113 children and adolescents (age 12-19 yr, M:F = 47:66) with type 1 or 2 diabetes were enrolled. We evaluated the validity of spot urine ACR and serum cysC, and then compared them to 24-hr urine microalbumin and creatinine clearance. Spot urine ACR was correlated with 24-hr urine albumin excretion (R(2) = 0.828, P = 0.001) and creatinine clearance (R(2) = 0.249, P = 0.017). The ROC curve analysis of serum cysC demonstrated higher diagnostic accuracy than that of serum creatinine (AUC 0.732 vs 0.615). Both the measurements of spot urine ACR and serum cysC might better predict the presence of diabetic nephropathy than 24-hr urine microalbumin in childhood diabetic patients.


An Evolutionary Approach for Identifying Driver Mutations in Colorectal Cancer.
The traditional view of cancer as a genetic disease that can successfully be treated with drugs targeting mutant onco-proteins has motivated whole-genome sequencing efforts in many human cancer types. However, only a subset of mutations found within the genomic landscape of cancer is likely to provide a fitness advantage to the cell. Distinguishing such "driver" mutations from innocuous "passenger" events is critical for prioritizing the validation of candidate mutations in disease-relevant models. We design a novel statistical index, called the Hitchhiking Index, which reflects the probability that any observed candidate gene is a passenger alteration, given the frequency of alterations in a cross-sectional cancer sample set, and apply it to a mutational data set in colorectal cancer. Our methodology is based upon a population dynamics model of mutation accumulation and selection in colorectal tissue prior to cancer initiation as well as during tumorigenesis. This methodology can be used to aid in the prioritization of candidate mutations for functional validation and contributes to the process of drug discovery.


Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon.
Gram-negative septicemia elicits multiple abnormalities of the coagulation system. Although products of coagulation can lead to clot formation, thereby potentiating organ damage, recent work has shown that low concentrations of thrombin can protect animals from the shock state. Because these amounts of thrombin also lead to formation in vivo of the anticoagulant enzyme, activated protein C, we examined the role of protein C in modulation of Escherichia coli shock in baboons. First, we infused activated protein C and lethal concentrations of E. coli organisms, which prevented the coagulopathic, hepatotoxic, and lethal effects of E. coli. Second, using an antibody to protein C we blocked protein C activation in vivo to determine if this influenced the response to lethal and sublethal concentrations of E. coli organisms. Under these conditions the response to lethal concentrations of E. coli organisms was made more severe and the response to sublethal concentrations of E. coli was made lethal. The coagulopathic, hepatotoxic, and lethal responses in this latter case were prevented by infusion of exogenous protein C.


Myeloid-Specific Gene Deletion of Protein Phosphatase 2A Magnifies MyD88- and TRIF-Dependent Inflammation following Endotoxin Challenge.
Protein phosphatase 2A (PP2A) is a member of the intracellular serine/threonine phosphatases. Innate immune cell activation triggered by pathogen-associated molecular patterns is mediated by various protein kinases, and PP2A plays a counter-regulatory role by deactivating these kinases. In this study, we generated a conditional knockout of the α isoform of the catalytic subunit of PP2A (PP2ACα). After crossing with myeloid-specific cre-expressing mice, effective gene knockout was achieved in various myeloid cells. The myeloid-specific knockout mice (lyM-PP2Afl/fl) showed higher mortality in response to endotoxin challenge and bacterial infection. Upon LPS challenge, serum levels of TNF-α, KC, IL-6, and IL-10 were significantly increased in lyM-PP2Afl/fl mice, and increased phosphorylation was observed in MAPK pathways (p38, ERK, JNK) and the NF-κB pathway (IKKα/β, NF-κB p65) in bone marrow-derived macrophages (BMDMs) from knockout mice. Heightened NF-κB activation was not associated with degradation of IκBα; instead, enhanced phosphorylation of the NF-κB p65 subunit and p38 phosphorylation-mediated TNF-α mRNA stabilization appear to contribute to the increased TNF-α expression. In addition, increased IL-10 expression appears to be due to PP2ACα-knockout-induced IKKα/β hyperactivation. Microarray experiments indicated that the Toll/IL-1R domain-containing adaptor inducing IFN-β/ TNFR-associated factor 3 pathway was highly upregulated in LPS-treated PP2ACα-knockout BMDMs, and knockout BMDMs had elevated IFN-α/β production compared with control BMDMs. Serum IFN-β levels from PP2ACα-knockout mice treated with LPS were also greater than those in controls. Thus, we demonstrate that PP2A plays an important role in regulating inflammation and survival in the setting of septic insult by targeting MyD88- and Toll/IL-1R domain-containing adaptor inducing IFN-β-dependent pathways.


Autism Spectrum Disorder and Fetal Alcohol Spectrum Disorder: A Literature Review.
Fetal alcohol spectrum disorders (FASD) are a group of conditions associated with the effects of prenatal alcohol exposure and characterized by somatic and neuropsychological alterations. On the other hand, autism spectrum disorder (ASD) is characterized by a multifaceted neurobehavioral syndrome. Since alcohol can affect every stage of brain development, some authors hypothesized that in utero alcohol exposure might be linked to an increased risk of ASD in subjects with genetic vulnerability. The present review aimed to summarize the available literature on the possible association between FASD and ASD, also focusing on the reported clinical overlaps and on the possible shared pathogenic mechanisms. Studies in this field have stressed similarities and differences between the two conditions, leading to controversial results. The available literature also highlighted that both the disorders are often misdiagnosed or underdiagnosed, stressing the need to broaden the perspective, paying specific attention to milder presentations and sub-syndromic traits.


Paradoxical diuresis after vasopressin administration to patients with neurohypophyseal diabetes insipidus treated with chlorpropamide, carbamazepine or clofibrate.
1. Chlorpropamide, carbamazepine and clofibrate have an antidiuretic action in patients with neurohypophyseal diabetes insipidus which is qualitatively similar to that of antidiuretic hormone (ADH). 2. An additive antidiuretic effect is produced by combination of chlorpropamide and carbamazepine with small dosages of ADH. 3. After an immediate and transient antidiuresis, a single intravenous bolus injection of lysine vasopressin given during treatment with chlorpropamide, chlorpropamide with a continuous intravenous infusion of lysine vasopressin, carbamazepine or clofibrate, resulted in increased water diuresis for 12-24 h or longer. 4. This paradoxical diuresis was not observed during treatment with chlorothiazide. 5. It is suggested that the antidiuretic action of chlorpropamide, carbamazepine and clofibrate is localized at the receptor site for ADH in the distal renal tubular cell.


Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT): A Bayesian Adaptive Platform Trial to Develop Precision Medicines for Patients With Glioblastoma.
Adequately prioritizing the numerous therapies and biomarkers available in late-stage testing for patients with glioblastoma (GBM) requires an efficient clinical testing platform. We developed and implemented INSIGhT (Individualized Screening Trial of Innovative Glioblastoma Therapy) as a novel adaptive platform trial (APT) to develop precision medicine approaches in GBM. INSIGhT compares experimental arms with a common control of standard concurrent temozolomide and radiation therapy followed by adjuvant temozolomide. The primary end point is overall survival. Patients with newly diagnosed unmethylated GBM who are IDH R132H mutation negative and with genomic data available for biomarker grouping are eligible. At the initiation of INSIGhT, three experimental arms (neratinib, abemaciclib, and CC-115), each with a proposed genomic biomarker, are tested simultaneously. Initial randomization is equal across arms. As the trial progresses, randomization probabilities adapt on the basis of accumulating results using Bayesian estimation of the biomarker-specific probability of treatment impact on progression-free survival. Treatment arms may drop because of low probability of treatment impact on overall survival, and new arms may be added. Detailed information on the statistical model and randomization algorithm is provided to stimulate discussion on trial design choices more generally and provide an example for other investigators developing APTs. INSIGhT (NCT02977780) is an ongoing novel biomarker-based, Bayesian APT for patients with newly diagnosed unmethylated GBM. Our goal is to dramatically shorten trial execution timelines while increasing scientific power of results and biomarker discovery using adaptive randomization. We anticipate that trial execution efficiency will also be improved by using the APT format, which allows for the collaborative addition of new experimental arms while retaining the overall trial structure.


Ongoing Efforts to Improve Antimicrobial Utilization in Hospitals among African Countries and Implications for the Future.
There are serious concerns with rising antimicrobial resistance (AMR) across countries increasing morbidity, mortality and costs. These concerns have resulted in a plethora of initiatives globally and nationally including national action plans (NAPs) to reduce AMR. Africa is no exception, especially with the highest rates of AMR globally. Key activities in NAPs include gaining a greater understanding of current antimicrobial utilization patterns through point prevalence surveys (PPS) and subsequently instigating antimicrobial stewardship programs (ASPs). Consequently, there is a need to comprehensively document current utilization patterns among hospitals across Africa coupled with ASP studies. In total, 33 PPS studies ranging from single up to 18 hospitals were documented from a narrative review with typically over 50% of in-patients prescribed antimicrobials, up to 97.6% in Nigeria. The penicillins, ceftriaxone and metronidazole, were the most prescribed antibiotics. Appreciable extended prescribing of antibiotics up to 6 days or more post-operatively was seen across Africa to prevent surgical site infections. At least 19 ASPs have been instigated across Africa in recent years to improve future prescribing utilizing a range of prescribing indicators. The various findings resulted in a range of suggested activities that key stakeholders, including governments and healthcare professionals, should undertake in the short, medium and long term to improve future antimicrobial prescribing and reduce AMR across Africa.


The North-Western Italian experience with anti IL-5 therapy amd comparison with regulatory trials.
The severe forms of asthma represent a major burden, because of severity of symptoms, costs and impact on everyday life. Recently, Mepolizumab (MEP) was approved and marketed for the treatment of hypereosinophilic severe asthma. This anti-IL-5 monoclonal antibody reduced exacerbation rates and oral corticosteroid (OCS) use in well selected patients. The aim of this study was to evaluate the characteristics of patients receiving MEP in a real-life setting. Thus, we describe a retrospective analysis of patients treated with MEP in six centres in North Western Italy, including those who participated in the main regulatory trials. The baseline data, before prescription, from six North Western Italy severe asthma clinics, between June 1st 2017 and December 31st 2017, were evaluated. The collected real-life data were then compared with those of SIRUS, MENSA, DREAM and MUSCA trials. Sixty-five patients were included (45% female; mean age 56 years; age range 19-84). Main observed differences with regulatory trials could be observed in eosinophils blood count at baseline, where the mean of our real-life patients (653 cells/μL) was overall higher than the one of all trials (240 cells/μL, 296 cells/μL, 253 cells/μL; p < 0.0001). The incidence of polyposis was also significantly higher in our sample (72% vs. 24%, 49%, 10%, 19%; p < 0.0001). The daily average dose of OCS was lower in our real-life patients (9 mg), if compared with SIRIUS (13.7 mg), MENSA (13.2) and MUSCA (13), and similar to the data published in DREAM (10.8). The comparison of real-life patients' characteristics with regulatory trials, displayed several apparent discrepancies. The demographic and clinical aspects were similar in all groups, whereas other features (eosinophil count, pulmonary function FEV1%) differed. These data, for the first time, could represent a basis for a more accurate prescription of the drug.


Pregnancy cohorts and biobanking in sub-Saharan Africa: a systematic review.
Technological advances and high throughput biological assays can facilitate discovery science in biobanks from population cohorts, including pregnant women. Biological pathways associated with health outcomes differ depending on geography, and high-income country data may not generalise to low-resource settings. We conducted a systematic review to identify prospective pregnancy cohorts in sub-Saharan Africa (SSA) that include biobanked samples with potential to enhance discovery science opportunity. Inclusion criteria were prospective data collection during pregnancy, with associated biobanking in SSA. Data sources included: scientific databases (with comprehensive search terms), grey literature, hand searching applicable reference lists and expert input. Results were screened in a three-stage process based on title, abstract and full text by two independent reviewers. The review is registered on PROSPERO (CRD42019147483). Fourteen SSA studies met the inclusion criteria from database searches (n=8), reference list searches (n=2) and expert input (n=4). Three studies have ongoing data collection. The most represented countries were South Africa and Mozambique (Southern Africa) (n=3), Benin (Western Africa) (n=4) and Tanzania (Eastern Africa) (n=4); including an estimated 31 763 women. Samples commonly collected were blood, cord blood and placenta. Seven studies collected neonatal samples. Common clinical outcomes included maternal and perinatal mortality, malaria and preterm birth. Increasingly numerous pregnancy cohorts in SSA that include biobanking are generating a uniquely valuable resource for collaborative discovery science, and improved understanding of the high regional risks of maternal, fetal and neonatal morbidity and mortality. Future studies should align protocols and consider their added value and distinct contributions.


Improved Diagnostics Help to Identify Clinical Features and Biomarkers That Predict Mycoplasma pneumoniae Community-acquired Pneumonia in Children.
There are no reliable signs or symptoms that differentiate Mycoplasma pneumoniae (Mp) infection in community-acquired pneumonia (CAP) from other etiologies. Additionally, current diagnostic tests do not reliably distinguish between Mp infection and carriage. We previously determined that the measurement of Mp-specific immunoglobulin M antibody-secreting cells (ASCs) by enzyme-linked immunospot assay allowed for differentiation between infection and carriage. Using this new diagnostic test, we aimed to identify clinical and laboratory features associated with Mp infection. This is a prospective cohort study of children, 3-18 years of age, with CAP from 2016 to 2017. Clinical features and biomarkers were compared between Mp-positive and -negative groups by Mann-Whitney U test or Fisher exact test, as appropriate. Area under the receiver operating characteristic curve (AUC) differences and optimal thresholds were determined by using the DeLong test and Youden J statistic, respectively. Of 63 CAP patients, 29 were Mp-positive (46%). Mp positivity was statistically associated with older age (median, 8.6 vs 4.7 years), no underlying disease, family with respiratory symptoms, prior antibiotic treatment, prolonged prodromal respiratory symptoms and fever, and extrapulmonary (skin) manifestations. Lower levels of C-reactive protein, white blood cell count, absolute neutrophil count, and procalcitonin (PCT), specifically PCT <0.25 μg/L, were statistically associated with Mp infection. A combination of age >5 years (AUC = 0.77), prodromal fever and respiratory symptoms >6 days (AUC = 0.79), and PCT <0.25 μg/L (AUC = 0.81) improved diagnostic performance (AUC = 0.90) (P = .05). A combination of clinical features and biomarkers may aid physicians in identifying patients at high risk for Mp CAP.


Ouabain and insulin induce sodium pump endocytosis in renal epithelium.
Cardiotonic steroids signaling through the basolateral sodium pump (Na/K-ATPase) have been shown to alter renal salt handling in intact animals. Because the relationship between renal salt handling and blood pressure is a key determinant of hypertension, and patients with insulin resistance are frequently hypertensive, we chose to examine whether there might be competition for resources necessary for receptor-mediated endocytosis. In LLC-PK1 cells, the Na/K-ATPase-α1 and carcinoembryonic antigen cell adhesion molecule 1, a plasma membrane protein that promotes receptor-mediated endocytosis, colocalized in the plasma membranes and translocated to the intracellular region in response to ouabain. Either ouabain or insulin alone caused accumulation of and carcinoembryonic antigen cell adhesion molecule, as well as insulin receptor-β, and epidermal growth factor receptor in early endosomes, but no synergy was demonstrable. Like ouabain, insulin also caused c-Src activation. When caveolin or Na/K-ATPase-α1 expression was knocked down with small interfering RNA, insulin but not ouabain induced carcinoembryonic antigen cell adhesion molecule 1, insulin receptor-β, and epidermal growth factor receptor endocytosis. To determine whether this might be relevant to salt handling in vivo, we examined salt loading in mice with null renal carcinoembryonic antigen cell adhesion molecule 2 expression. The null renal carcinoembryonic antigen cell adhesion molecule 2 animals demonstrated greater increases in blood pressure with increases in dietary salt than control animals. These data demonstrate that cardiotonic steroids and insulin compete for cellular endocytosis resources and suggest that, under conditions where circulating insulin concentrations are high, cardiotonic steroid-mediated natriuresis could be impaired.


Muscle-damaging exercise 48 h prior to a maximal incremental exercise treadmill test reduces time to exhaustion: is it time to reconsider our pretest procedures?
Pretest guidelines typically stipulate that no exercise should be performed 48 h prior to a maximal incremental exercise [Formula: see text] test. However, no study has specifically investigated if this timescale alters key outcome variables associated with [Formula: see text]. Twenty apparently healthy males split into two equal groups performed [Formula: see text] during three visits (visits 1 - [Formula: see text]EXP1, 2 - [Formula: see text]EXP2 and 4 - [Formula: see text]EXP3). The experimental group only, performed muscle-damaging exercise during visit 3. From [Formula: see text]EXP2 to [Formula: see text]EXP3 average time to exhaustion (TTE) decreased by 45 s (9%) (p < 0.01), maximum blood lactate decreased by 1.2 mmol/L (11%) (p = 0.03), and perceived readiness decreased by 8 mm (18%) (p = 0.01). There were no changes in any [Formula: see text] variables in the control group (p ≥ 0.37). Performing [Formula: see text] 48 h following muscle-damaging exercise impairs specific, but not all, physiological outcome variables.


Alginate/Poly(γ-glutamic Acid) Base Biocompatible Gel for Bone Tissue Engineering.
A technique for synthesizing biocompatible hydrogels by cross-linking calcium-form poly(γ-glutamic acid), alginate sodium, and Pluronic F-127 was created, in which alginate can be cross-linked by Ca(2+) from Ca-γ-PGA directly and γ-PGA molecules introduced into the alginate matrix to provide pH sensitivity and hemostasis. Mechanical properties, swelling behavior, and blood compatibility were investigated for each hydrogel compared with alginate and for γ-PGA hydrogel with the sodium form only. Adding F-127 improves mechanical properties efficiently and influences the temperature-sensitive swelling of the hydrogels but also has a minor effect on pH-sensitive swelling and promotes anticoagulation. MG-63 cells were used to test biocompatibility. Gelation occurred gradually through change in the elastic modulus as the release of calcium ions increased over time and caused ionic cross-linking, which promotes the elasticity of gel. In addition, the growth of MG-63 cells in the gel reflected nontoxicity. These results showed that this biocompatible scaffold has potential for application in bone materials.


Occupational therapy in pediatric lead exposure prevention.
Environmental lead is a toxic substance that is affecting the growth and development of 3 to 4 million U.S. preschool children today, with effects ranging from learning disabilities to death. This review of environmental lead sources and effects on children provides a background for comprehensive prevention of childhood lead exposure. Prevention strategies at the child, family, and community levels allow for widespread protection of child health and development. Prevention begins with an understanding of the person-environment-occupation framework for the factors that contribute to children at risk for lead exposure. An open system model is presented with specific interventions at the child, family, and community levels, providing innovative, integrated contributions by occupational therapy practitioners for lead exposure prevention and health promotion of children who have been exposed to environmental lead.


Cleavage of lamin A by Mch2 alpha but not CPP32: multiple interleukin 1 beta-converting enzyme-related proteases with distinct substrate recognition properties are active in apoptosis.
Although proteases related to the interleukin 1 beta-converting enzyme (ICE) are known to be essential for apoptotic execution, the number of enzymes involved, their substrate specificities, and their specific roles in the characteristic biochemical and morphological changes of apoptosis are currently unknown. These questions were addressed using cloned recombinant ICE-related proteases (IRPs) and a cell-free model system for apoptosis (S/M extracts). First, we compared the substrate specificities of two recombinant human IRPs, CPP32 and Mch2 alpha. Both enzymes cleaved poly-(ADP-ribose) polymerase, albeit with different efficiencies. Mch2 alpha also cleaved recombinant and nuclear lamin A at a conserved VEID decreases NG sequence located in the middle of the coiled-coil rod domain, producing a fragment that was indistinguishable from the lamin A fragment observed in S/M extracts and in apoptotic cells. In contrast, CPP32 did not cleave lamin A. The cleavage of lamin A by Mch2 alpha and by S/M extracts was inhibited by millimolar concentrations of Zn2+, which had a minimal effect on cleavage of poly (ADP-ribose) polymerase by CPP32 and by S/M extracts. We also found that N-(acetyltyrosinylvalinyl-N epsilon-biotinyllysyl)aspartic acid [(2,6-dimethylbenzoyl)oxy]methyl ketone, which derivatizes the larger subunit of active ICE, can affinity label up to five active IRPs in S/M extracts. Together, these observations indicate that the processing of nuclear proteins in apoptosis involves multiple IRPs having distinct preferences for their apoptosis-associated substrates.


Sleep and the epidemic of obesity in children and adults.
Sleep is an important modulator of neuroendocrine function and glucose metabolism in children as well as in adults. In recent years, sleep curtailment has become a hallmark of modern society with both children and adults having shorter bedtimes than a few decades ago. This trend for shorter sleep duration has developed over the same time period as the dramatic increase in the prevalence of obesity. There is rapidly accumulating evidence from both laboratory and epidemiological studies to indicate that chronic partial sleep loss may increase the risk of obesity and weight gain. The present article reviews laboratory evidence indicating that sleep curtailment in young adults results in a constellation of metabolic and endocrine alterations, including decreased glucose tolerance, decreased insulin sensitivity, elevated sympathovagal balance, increased evening concentrations of cortisol, increased levels of ghrelin, decreased levels of leptin, and increased hunger and appetite. We also review cross-sectional epidemiological studies associating short sleep with increased body mass index and prospective epidemiological studies that have shown an increased risk of weight gain and obesity in children and young adults who are short sleepers. Altogether, the evidence points to a possible role of decreased sleep duration in the current epidemic of obesity.


The distributed genome hypothesis as a rubric for understanding evolution in situ during chronic bacterial biofilm infectious processes.
Most chronic infectious disease processes associated with bacteria are characterized by the formation of a biofilm that provides for bacterial attachment to the host tissue or the implanted medical device. The biofilm protects the bacteria from the host's adaptive immune response as well as predation by phagocytic cells. However, the most insidious aspect of biofilm biology from the host's point of view is that the biofilm provides an ideal setting for bacterial horizontal gene transfer (HGT). HGT provides for large-scale genome content changes in situ during the chronic infectious process. Obviously, for HGT processes to result in the reassortment of alleles and genes among bacterial strains, the infection must be polyclonal (polymicrobial) in nature. In this review, we marshal the evidence that all of the factors are present in biofilm infections to support HGT that results in the ongoing production of novel strains with unique combinations of genic characteristics and that the continual production of large numbers of novel, but related bacterial strains leads to persistence. This concept of an infecting population of bacteria undergoing mutagenesis to produce a 'cloud' of similar strains to confuse and overwhelm the host's immune system parallels genetic diversity strategies used by viral and parasitic pathogens.


Are there adverse consequences of quizzing during informed consent for HIV research?
While quizzing during informed consent for research to ensure understanding has become commonplace, it is unclear whether the quizzing itself is problematic for potential participants. In this study, we address this issue in a multinational HIV prevention research trial enrolling injection drug users in China and Thailand. Enrolment procedures included an informed consent comprehension quiz. An informed consent survey followed. 525 participants completed the informed consent survey (Heng County, China¼255, Xinjiang, China¼229, Chiang Mai, Thailand¼41). Mean age was 33 and mean educational level was 8 yrs. While quizzing was felt to be a good way to determine if a person understands the nature of clinical trial participation (97%) and participants did not generally find the quiz to be problematic, minorities of respondents felt pressured (6%); anxious (5%); bored (5%); minded (5%); and did not find the questions easy (13%). In multivariate analysis, lower educational level was associated with not minding the quizzing (6e10 yrs vs 0e5 yrs: OR¼0.27, p¼0.03; more than 11 yrs vs 0e5 yrs: OR¼0.18, p¼0.03). There were also site differences (Heng County vs Xinjiang) in feeling anxious (OR¼0.07; p¼<0.01), not minding (OR¼0.26; p¼0.03), being bored (OR¼0.25; p¼0.01) and not finding the questions easy (OR¼0.10; p¼<0.01). Quizzing during the informed consent process can be problematic for a minority of participants. These problems may be associated with the setting in which research takes place and educational level. Further research is needed to develop, test and implement alternative methods of ensuring comprehension of informed consent. clinicaltrials.gov number NCT00270257.


A Plasmodium falciparum copper-binding membrane protein with copper transport motifs.
Copper is an essential catalytic co-factor for metabolically important cellular enzymes, such as cytochrome-c oxidase. Eukaryotic cells acquire copper through a copper transport protein and distribute intracellular copper using molecular chaperones. The copper chelator, neocuproine, inhibits Plasmodium falciparum ring-to-trophozoite transition in vitro, indicating a copper requirement for malaria parasite development. How the malaria parasite acquires or secretes copper still remains to be fully elucidated. PlasmoDB was searched for sequences corresponding to candidate P. falciparum copper-requiring proteins. The amino terminal domain of a putative P. falciparum copper transport protein was cloned and expressed as a maltose binding fusion protein. The copper binding ability of this protein was examined. Copper transport protein-specific anti-peptide antibodies were generated in chickens and used to establish native protein localization in P. falciparum parasites by immunofluorescence microscopy. Six P. falciparum copper-requiring protein orthologs and a candidate P. falciparum copper transport protein (PF14_0369), containing characteristic copper transport protein features, were identified in PlasmoDB. The recombinant amino terminal domain of the transport protein bound reduced copper in vitro and within Escherichia coli cells during recombinant expression. Immunolocalization studies tracked the copper binding protein translocating from the erythrocyte plasma membrane in early ring stage to a parasite membrane as the parasites developed to schizonts. The protein appears to be a PEXEL-negative membrane protein. Plasmodium falciparum parasites express a native protein with copper transporter characteristics that binds copper in vitro. Localization of the protein to the erythrocyte and parasite plasma membranes could provide a mechanism for the delivery of novel anti-malarial compounds.


Toyota drivers' experiences with Dynamic Radar Cruise Control, Pre-Collision System, and Lane-Keeping Assist.
Advanced crash avoidance and driver assistance technologies potentially can prevent or mitigate many crashes. Previous surveys with drivers have found favorable opinions for many advanced technologies; however, these surveys are not necessarily representative of all drivers or all systems. As the technologies spread throughout the vehicle fleet, it is important to continue studying driver acceptance and use of them. This study focused on 2010-2013 Toyota Sienna and Prius models that were equipped with adaptive cruise control, forward collision avoidance, and lane departure warning and prevention (Prius models only). Telephone interviews were conducted in summer 2013 with 183 owners of vehicles with these technologies. About 9 in 10 respondents wanted adaptive cruise control and forward collision avoidance on their next vehicle, and 71% wanted lane departure warning/prevention again. Males and females reported some differences in their experiences with the systems; for example, males were more likely to have turned on lane departure warning/prevention than females, and when using this system, males reported more frequent warnings than did females. Relative to older drivers, drivers age 40 and younger were more likely to have seen or heard a forward collision warning. Consistent with the results in previous surveys of owners of luxury vehicles, the present survey found that driver acceptance of the technologies was high, although less so for lane departure warning/prevention. Experiences with the Toyota systems differed by driver age and gender to a greater degree than in previous surveys, suggesting that the responses of drivers may begin to differ as crash avoidance technology becomes available on a wider variety of vehicles. Crash avoidance technologies potentially can prevent or mitigate many crashes, but their success depends in part on driver acceptance. These systems will be effective only to the extent that drivers use them.


Effect of pre-performance lower-limb massage on thirty-meter sprint running.
Massage is a commonly utilized therapy within sports, frequently intended as an ergogenic aid prior to performance. However, evidence as to the efficacy of massage in this respect is lacking, and massage may in some instances reduce force production. The aim of this study was to investigate the effect of massage on subsequent 30-m sprint running performance. Male university level repeat sprint sports players volunteered for the study (n = 37). After each of 3 treatment conditions, subjects completed a standardized warm-up followed by three 30-m sprint trials in a counterbalanced crossover design. Treatment conditions were 15 minutes of lower-limb massage (M), 15 minutes of placebo ultrasound (PU), and rest (R). Thirty-meter sprint times were recorded (including 10-m split times) for the 3 trials under each condition. Best times at 10 m (M: 1.85 +/- 0.09 seconds, PU: 1.84 +/- 0.11 seconds, R: 1.83 +/- 0.10 seconds) and 30 m (M: 4.41 +/- 0.27 seconds, PU: 4.39 +/- 0.28 seconds, R: 4.39 +/- 0.28 seconds) were not significantly different (p > 0.05). There was no significant treatment, trial, or interaction effect for 10- or 30-m sprint times (p > 0.05). No difference was seen in the location of subjects' best times across the 3 trials (p > 0.05). Relative to placebo or control, the results of this study showed that a controlled 15-minute lower-limb massage administered prior to warm-up had no significant effect on subsequent 30-m sprint performance. Massage remains indicated prior to performance where other benefits, such as reduced muscle spasm and psychological stress, might be served to the athlete.


Activating the motor system through action observation: is this an efficient approach in adults and children?
Observing an action performed by another person to learn a new movement is a frequent experience in adult daily life, such as in sports. However, it is an especially common circumstance during the development of motor skills in childhood. Studies on healthy humans indicate that action observation induces a facilitation in the observer's motor system. This effect is supported by an action-perception matching mechanism available both in adults and in children. Because of the simplicity of action observation, it has been proposed to apply this method in clinical contexts. After a brief, non-exhaustive introduction of the essential features underlying action observation in healthy people, we review recent studies reporting beneficial effects of rehabilitative training based on a combination of action perception and execution. We focus on therapeutic interventions for patients with upper-limb motor disabilities such as adults after stroke or children with hemiplegia due to cerebral palsy. Further, we consider data from basic science demonstrating that the facilitation induced by visual perception of the action can be modulated by the combination of multimodal stimuli related to the movement (e.g. visual and acoustic action-related inputs). In line with this, we discuss possible new directions to improve basic knowledge and therapeutic applications of action observation.


Civilian stressors associated with alcohol use disorders in the National Guard.
Alcohol use disorders are a serious public health concern among soldiers. Although deployment-related exposures have been linked with alcohol use disorders in soldiers, less is understood about the link between modifiable, civilian stressors and post-deployment alcohol use disorders. To (1) compare the influence of civilian stressors and deployment-related traumatic events and stressors on post-deployment alcohol use disorders among Army National Guardsmen primarily deployed to Afghanistan and Iraq; and (2) evaluate whether civilian stressors influence a different set of alcohol use disorder phenotypes than deployment-related traumatic events and stressors. A cohort of Ohio National Guard soldiers was recruited in 2008-2009 and interviewed three times over 3 years. The analytic sample included Ohio National Guard soldiers who had been deployed by 2008-2009, had participated in at least one follow-up wave, had reported consuming at least one alcoholic drink in their lifetime, and had non-missing data on alcohol use disorders (n=1,095). Analyses were conducted in 2013. In a model including measures of civilian stressors and deployment-related traumatic events, only civilian stressors (OR=2.07, 95% CI=1.46, 2.94) were associated with subsequent alcohol use disorder. The effects of civilian stressors were only present among people with no history of alcohol use disorder. Independent of deployment-related exposures, post-deployment civilian stressors are associated with the onset of alcohol use disorder among reserve-component soldiers. Concerted investment to address daily civilian difficulties associated with reintegration into civilian life may be needed to prevent new cases of alcohol use disorders among returning military personnel.


Diet and healthy ageing 2100: will we globalise local knowledge systems?
Diet and health clearly are linked intrinsically. Today, more than ever food is functionalized and tailor made for specific groups (e.g. athletes, the elderly, and people with specific conditions). Increased life expectancy has resulted in an increase in the quest for diets which allow for a healthy ageing. In looking back 100 years, we try to assess how of our diets will evolve in the next 100 years and how this may be linked to a 'healthier ageing'. Our argument centres around a series of dichotomies which we used to explain the main changes in dietary habits and how this impacts on health--the continuous move from dietary traditions which are local, low in technological input and based on empiricism, to diets which are global, require high technological input and are science-based. The innovations our societies have achieved over the last century have allowed us to improve our diet based on a better scientific understanding of the health benefits of such diets, but this is often not achieved due to commercial considerations. This will require that all sectors of the food industry work towards healthy and economically affordable diets. In addition, there will be a continuous demand by the consumers to ascertain that 'our' foods are not only healthy but also convenient and easy to prepare. Healthy ageing will require us to look at a multitude of aspects of foods, to integrate this knowledge and to apply it in all sectors of food production.


Clarifying the impact of polycomb complex component disruption in human cancers.
The dysregulation of proper transcriptional control is a major cause of developmental diseases and cancers. Polycomb proteins form chromatin-modifying complexes that transcriptionally silence genome regions in higher eukaryotes. The BCL6 corepressor (BCOR) complex comprises ring finger protein 1B (RNF2/RING1B), polycomb group ring finger 1 (PCGF1), and lysine-specific demethylase 2B (KDM2B) and is uniquely recruited to nonmethylated CpG islands, where it removes histone H3K36me2 and induces repressive histone H2A monoubiquitylation. Germline BCOR mutations have been detected in patients with oculofaciocardiodental and Lenz microphthalmia syndromes, which are inherited conditions. Recently, several variants of BCOR and BCOR-like 1 (BCORL1) chimeric fusion transcripts were reported in human cancers, including acute promyelocytic leukemia, bone sarcoma, and hepatocellular carcinoma. In addition, massively parallel sequencing has identified inactivating somatic BCOR and BCORL1 mutations in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia, medulloblastoma, and retinoblastoma. More importantly, patients with AML and MDS with BCOR mutations exhibit poor prognosis. This perspective highlights the detection of BCOR mutations and fusion transcripts of BCOR and BCORL1 and discusses their importance for diagnosing cancer subtypes and estimating the treatment responses of patients. Furthermore, this perspective proposes the need for additional functional studies to clarify the oncogenic mechanism by which BCOR and BCORL1 are disrupted in cancers, and how this may lead to the development of novel therapeutics.


Hepatitis B Virus genotypic differences map structurally close to NRTI resistance hot spots.
Despite the availability of a Hepatitis B Virus (HBV) vaccine, there are approximately 350 million people that are chronically infected with this virus that can cause liver cirrhosis and hepatocellular carcinoma. Currently, most approved anti-HBV drugs are nucleoside RT inhibitors (NRTIs) that target the viral enzyme reverse transcriptase (RT or P gene product). They suppress viral replication very efficiently but require long-term therapies, which invariably lead to the development of drug resistant viral strains with drug resistance mutations at the P gene. Because the reading frames of the P and S (surface antigen) genes partially overlap, selection of NRTI-resistance mutations may impart changes on the surface structural landscape of the virus. Conversely, genotypic differences on viral surface residues may also change the amino acid composition of the P gene and in terms affect HBV RT properties such as susceptibility to NRTIs. Interestingly, several studies have shown that patients infected with HBV from various genotypes respond differently to NRTI therapies. Here, we built a three-dimensional homology model of the catalytic core of HBV RT using HIV-1 RT as a template. We then mapped on the molecular model the residues that vary among various HBV genotypes. Surprisingly, the genotypic variability residues are generally in the vicinity of residues that are involved in NRTI resistance. Our results suggest that emergence of NRTI resistance mutations in HBV RT may be constrained by structural interactions with residues that vary among different genotypes.


Biological Role and Therapeutic Targeting of TGF-β3 in Glioblastoma.
Transforming growth factor (TGF)-β contributes to the malignant phenotype of glioblastoma by promoting invasiveness and angiogenesis and creating an immunosuppressive microenvironment. So far, TGF-β1 and TGF-β2 isoforms have been considered to act in a similar fashion without isoform-specific function in glioblastoma. A pathogenic role for TGF-β3 in glioblastoma has not been defined yet. Here, we studied the expression and functional role of endogenous and exogenous TGF-β3 in glioblastoma models. TGF-β3 mRNA is expressed in human and murine long-term glioma cell lines as well as in human glioma-initiating cell cultures with expression levels lower than TGF-β1 or TGF-β2 in most cell lines. Inhibition of TGF-β3 mRNA expression by ISTH2020 or ISTH2023, two different isoform-specific phosphorothioate locked nucleic acid (LNA)-modified antisense oligonucleotide gapmers, blocks downstream SMAD2 and SMAD1/5 phosphorylation in human LN-308 cells, without affecting TGF-β1 or TGF-β2 mRNA expression or protein levels. Moreover, inhibition of TGF-β3 expression reduces invasiveness in vitro Interestingly, depletion of TGF-β3 also attenuates signaling evoked by TGF-β1 or TGF-β2 In orthotopic syngeneic (SMA-560) and xenograft (LN-308) in vivo glioma models, expression of TGF-β3 as well as of the downstream target, plasminogen-activator-inhibitor (PAI)-1, was reduced, while TGF-β1 and TGF-β2 levels were unaffected following systemic treatment with TGF-β3 -specific antisense oligonucleotides. We conclude that TGF-β3 might function as a gatekeeper controlling downstream signaling despite high expression of TGF-β1 and TGF-β2 isoforms. Targeting TGF-β3in vivo may represent a promising strategy interfering with aberrant TGF-β signaling in glioblastoma. Mol Cancer Ther; 16(6); 1177-86. ©2017 AACR.


Period-doubling behavior in frontal polymerization of multifunctional acrylates.
Front dynamics in the frontal polymerization of two multifunctional acrylate monomers, 1,6-hexanediol diacrylate (HDDA) and trimethylolpropane ethoxylate triacrylate (TMPTA), with Lupersol 231 [1,1-di(t-butylperoxy)-3,3,5-trimethylcyclohexane] as the initiator, are studied. In most frontal polymerization systems, the dynamics are associated with a planar front propagating through the sample. However, in some cases, front behavior can be altered: the front becomes nonplanar characterized by complex patterns like spin modes and pulsations. To determine how these periodic and aperiodic modes arise, reactant solutions consisting of HDDA diluted with diethyl phthalate (DEP) and TMPTA diluted with dimethyl sulfoxide (DMSO) were used in the study. In the study we reveal frontal behavior characteristic of period-doubling behavior, a doubling of spin heads that degenerate into an apparently chaotic mode. Also, a pulsating symmetric mode has been observed. These observations have a striking similarity to observations made in studies of self-propagating high-temperature synthesis (SHS) in which the addition of an inert diluent afforded a rich variety of dynamical behavior. The degree of cross-linking has also been found to be a bifurcation parameter. The energy of activation of multifunctional acrylate polymerization is a strong function of the degree of polymerization. By adding a monoacrylate (benzyl acrylate: BzAc), such that the front temperature was invariant, we observed a period-doubling bifurcation sequence through changes in the energy of activation, which has not been previously reported. (c) 1999 American Institute of Physics.


The histone gene cell cycle regulator HiNF-P is a unique zinc finger transcription factor with a novel conserved auxiliary DNA-binding motif.
Accumulation of histone proteins is necessary for packaging of replicated DNA during the S phase of the cell cycle. Different mechanisms operate to regulate histone protein levels, and induction of human histone gene expression at the G1-S phase transition plays a critical role. The zinc finger HiNF-P and coactivator p220 (NPAT) proteins are key regulators of histone gene expression. Here, we describe a novel HiNF-P-specific conserved region (PSCR) located within the C-terminus that is present in HiNF-P homologues of all metazoan species that have been examined. The PSCR motif is required for activation of histone H4 gene transcription and contributes to DNA binding of HiNF-P. Thus, the PSCR module represents an auxiliary DNA-binding determinant that plays a critical role in mediating histone gene expression during the cell cycle and defines HiNF-P as a unique cell cycle regulatory member of the zinc finger transcription factor family.


Nucleus accumbens muscarinic receptors in the control of behavioral depression: antidepressant-like effects of local M1 antagonist in the Porsolt swim test.
Systemically administered cholinomimetics or cholinesterase inhibitors can depress behavior in humans and animals, whereas antimuscarinic agents reverse this effect or even produce euphoria. Although these effects have been well documented, the specific brain regions that mediate them remain largely unknown. In the present experiments, muscarinic agonists and antagonists were locally injected into the nucleus accumbens of female Sprague-Dawley rats to test for their effects on behavioral depression in the Porsolt swim test and locomotor activity. Local, microinjections of the drugs in the accumbens elicited behaviors that were similar to the systemic effects reported in other studies. Injection of the non-specific agonist arecoline (40 and 80 microg) dose-dependently inhibited swimming and escape behavior. This may be mediated in part by accumbens M1 receptors because blocking these receptors with the specific antagonist pirenzepine (17.5 and 35.0 microg) did the opposite by increasing swimming. Gallamine (0.13, 0.44, and 0.88 microg), an antagonist at M2 receptors, dose-dependently decreased swimming. Two-way microdialysis suggested that this was in part due to the release of ACh by blocking M2 autoreceptors. Scopolamine, a mixed M1/M2 receptor antagonist, also released ACh but did not decrease swimming, probably because the M1 receptors were blocked; the drug (1.0 microg) increased swimming time, much like pirenzepine. With the exception of arecoline, none of the drugs significantly affected locomotor activity in a photocell cage. Arecoline (40 microg), which had decreased swimming, reduced activity. The present study suggests that muscarinic receptors in the nucleus accumbens can control immobility in the Porsolt swim test. The onset of immobility may depend on the activation of post-synaptic M1 receptors.


Interaction of Au(iii) and Pt(ii) complexes with Na/K-ATPase: experimental and theoretical study of reaction stoichiometry and binding sites.
The present paper deals with investigation of the interaction between selected simple structure Au(iii) ([AuCl4]-, [AuCl2(dmso)2]+, [AuCl2(bipy)]+) and Pt(ii) ([PtCl2(dmso)2]) complexes with Na/K-ATPase as the target enzyme, using an experimental and theoretical approach. Reaction stoichiometries and binding constants for these enzyme/complex systems were determined, while kinetic measurements were used in order to reveal the type of inhibition. Based on the results obtained by quantum mechanical calculations (electrostatic surface potential (ESP), volume and surface of the complexes) the nature of the investigated complexes was characterized. By using the solvent accessible surface area (SASA) applied on specific inhibitory sites (ion channel and intracellular domains) the nature of these sites was described. Docking studies were used to determine the theoretical probability of the non-covalent metal binding site positions. Inhibition studies implied that all the investigated complexes decreased the activity of the enzyme while the kinetic analysis indicated an uncompetitive mode of inhibition for the selected complexes. Docking results suggested that the main inhibitory site of all these complexes is located in the ion translocation pathway on the extracellular side in the E2P enzyme conformation, similar to the case of cardiac glycosides, specific Na/K-ATPase inhibitors. Also, based on our knowledge, the hydrolyzed forms of [AuCl4]- and [PtCl2(dmso)2] complexes were investigated for the first time by theoretical calculations in this paper. Thereby, a new inhibitory site situated between the M2 and M4 helices was revealed. Binding in this site induces conformational changes in the enzyme domains and perturbs the E1-E2P conformational equilibrium, causing enzyme inhibition.


Genetic control of F cells in human adults.
Hb F levels were determined on samples from 750 normal blood donors. Six individuals (0.8%) had Hb F levels in excess of 1.1%, the upper end of the continuous distribution. Eight individuals at the upper end and 7 individuals at the lower end of the range were selected for family studies. These studies revealed that the control of Hb F levels in adults, as judged by the more sensitive F-cell technique, has a major genetic component. Structural analysis of the Hb F in several cases demonstrated that both G gamma and A gamma chains were present, but in variable proportions. These results are discussed in light of current concepts of adult F-cell production.


Distribution of developmental myosin heavy chains in adult rabbit extraocular muscle: identification of a novel embryonic isoform absent in fetal limb.
To identify embryonic and neonatal/fetal myosin heavy chains (MyHCs) in rabbit extraocular muscle (EOM) by electrophoretic and immunochemical analyses and to describe the distribution of these two MyHC isoforms in the endplate zone (EPZ) and the distal and proximal segments of EOM fibers. SDS-PAGE and Western blot analysis using monoclonal antibodies (mAbs) against embryonic and neonatal/fetal MyHCs were performed on MyHC isoforms from rabbit adult and neonatal EOM and fetal limb muscles. Immunohistochemical analysis was performed along the entire length of the rabbit superior rectus muscles, using these and other mAbs. Western blot analysis showed that adult rabbit EOM had two embryonic MyHC bands: a weakly stained band that comigrated with the embryonic MyHC from fetal limb muscles, and a strongly stained band of lower electrophoretic mobility for which there was no limb counterpart. Three anti-embryonic MyHC mAbs stained muscle fibers, predominantly in the orbital layer, and staining was localized distal and proximal to the EPZ but not in the EPZ itself. There, most fibers expressed the EOM-specific fast MyHC, although some fibers expressed alpha-cardiac MyHC. Anti-neonatal/fetal MyHC mAb failed to stain in Western blot analysis but stained scattered fibers predominantly in the global layer, and there was no specific absence of staining at the EPZ. There are two electrophoretically distinct isoforms of embryonic MyHCs in adult rabbit EOM. These isoforms are expressed in orbital fibers but are excluded from the EPZ, where EOM-specific fast MyHC is strongly expressed. Neonatal and fetal MyHC is weakly expressed in the EOM, but is not excluded from the EPZ.


Dynamic regulation of circulating microRNA during acute exhaustive exercise and sustained aerobic exercise training.
MicroRNAs (miRNAs) are intracellular mediators of essential biological functions. Recently, plasma-based 'circulating' miRNAs (c-miRNAs) have been shown to control cellular processes, but the c-miRNA response to human exercise remains unknown. We sought to determine whether c-miRNAs are dynamically regulated in response to acute exhaustive cycling exercise and sustained rowing exercise training using a longitudinal, repeated measures study design. Specifically, c-miRNAs involved in angiogenesis (miR-20a, miR-210, miR-221, miR-222, miR-328), inflammation (miR-21, miR-146a), skeletal and cardiac muscle contractility (miR-21, miR-133a), and hypoxia/ischaemia adaptation (miR-21, miR-146a, and miR-210) were measured at rest and immediately following acute exhaustive cycling exercise in competitive male rowers (n = 10, age = 19.1 ± 0.6 years) before and after a 90 day period of rowing training. Distinct patterns of c-miRNA response to exercise were observed and adhered to four major profiles: (1) c-miRNA up-regulated by acute exercise before and after sustained training (miR-146a and miR-222), (2) c-miRNA responsive to acute exercise before but not after sustained training (miR-21 and miR-221), (3) c-miRNA responsive only to sustained training (miR-20a), and (4) non-responsive c-miRNA (miR-133a, miR-210, miR-328). Linear correlations were observed between peak exercise levels of miR-146a and VO2max (r = 0.63, P = 0.003) and between changes in resting miR-20a and changes in VO2max (pre-training vs. post-training, r = 0.73; P = 0.02). Although future work is required, these results suggest the potential value of c-miRNAs as exercise biomarkers and their possible roles as physiological mediators of exercise-induced cardiovascular adaptation.


Functional brain networks for sensory maintenance in top-down selective attention to audiovisual inputs.
Sensory maintenance in top-down selective attention to audiovisual inputs involves distributed cortical activations, while the connectivity between the widespread cortical regions has not been well understood. Graph theory has been demonstrated to be a useful tool in the analysis of brain networks. In this study, we used graph theoretical analysis to investigate the functional brain networks for sensory maintenance in top-down selective attention to audiovisual inputs. Electroencephalograms (EEGs) of 30 channels were recorded from 13 young healthy subjects during a passive view task and a top-down intersensory selective attention task. Phase synchronization indices of EEG signals in pair were computed to construct weighted brain networks. We found small-world properties of the brain networks during both passive view state and top-down selective attentional state in α, β, and γ bands. In addition, the significantly increased clustering coefficient and decreased characteristic path length were observed for brain networks during attentional state compared with passive view state in both β band and γ band. Our results suggest that functional brain networks in higher frequency bands, i.e., β band and γ band, are integrated in different ways during attentional state compared with passive view state.


Decoding Digits and Dice with Magnetoencephalography: Evidence for a Shared Representation of Magnitude.
Numerical format describes the way magnitude is conveyed, for example, as a digit ("3") or Roman numeral ("III"). In the field of numerical cognition, there is an ongoing debate of whether magnitude representation is independent of numerical format. Here, we examine the time course of magnitude processing when using different symbolic formats. We presented participants with a series of digits and dice patterns corresponding to the magnitudes of 1 to 6 while performing a 1-back task on magnitude. Magnetoencephalography offers an opportunity to record brain activity with high temporal resolution. Multivariate pattern analysis applied to magnetoencephalographic data allows us to draw conclusions about brain activation patterns underlying information processing over time. The results show that we can cross-decode magnitude when training the classifier on magnitude presented in one symbolic format and testing the classifier on the other symbolic format. This suggests a similar representation of these numerical symbols. In addition, results from a time generalization analysis show that digits were accessed slightly earlier than dice, demonstrating temporal asynchronies in their shared representation of magnitude. Together, our methods allow a distinction between format-specific signals and format-independent representations of magnitude showing evidence that there is a shared representation of magnitude accessed via different symbols.


Successful resection of localized intestinal lymphangiectasia post-Fontan: role of (99m)technetium-dextran scintigraphy.
Intestinal lymphangiectasia is a well-recognized complication of the Fontan procedure, occurring in up to 24% of patients. Because of the loss of chylous fluid into the gut lumen, protein-losing enteropathy results as well as lymphopenia and hypogammaglobulinaemia. In some cases, dilated lymphatics in the intestinal serosa or mesentery also rupture, causing chylous ascites. Standard medical and cardiac surgical interventions are generally ineffective and the condition is frequently lethal. We report a case of intractable and life-threatening chylous ascites and chylothorax in a 14-year-old girl, associated with intestinal lymphangiectasia and protein-losing enteropathy after a Fontan procedure for tricuspid atresia. The condition was refractory to all standard medical therapies, including dietary modifications, diuretics, corticosteroid therapy, albumin infusions, octreotide, heparin, bowel rest, and parenteral nutrition. Cardiac surgery to optimize her hemodynamic status was also ineffective and large volume pleural and ascitic fluid losses continued. Having exhausted all other therapeutic modalities, (99m)technetium-dextran scintigraphy was performed to assess the extent of intestinal protein loss and the potential for surgical intervention. Scintigraphy suggested localized protein loss from the proximal jejunum and subsequent segmental resection was effective. Postoperatively, ascites and pleural effusions resolved, and there was no evidence of short bowel syndrome. Growth has accelerated and the patient has entered puberty. There is mild persistent intestinal protein loss requiring diuretic therapy. Ascites or pleural effusions are absent, and the patient remains well >2 years after surgery. Intestinal lymphangiectasia post-Fontan procedures has traditionally been ascribed to hemodynamic factors such as raised systemic venous pressure, which would predispose to a generalized intestinal lesion. However, in this case, scintigraphy demonstrated a localized, surgically correctible lesion. To our knowledge, this is the first reported case of the use of (99m)technetium-dextran scintigraphy for this indication and of successful partial small bowel resection in such a case.


Diagnosis and management of temperature abnormality in ICUs: a EUROBACT investigators' survey.
Although fever and hypothermia are common abnormal physical signs observed in patients admitted to intensive care units (ICU), little data exist on their optimal management. The objective of this study was to describe contemporary practices and determinants of management of temperature abnormalities among patients admitted to ICUs. Site leaders of the multi-national EUROBACT study were surveyed regarding diagnosis and management of temperature abnormalities among patients admitted to their ICUs. Of the 162 ICUs originally included in EUROBACT, responses were received from 139 (86%) centers in 23 countries in Europe (117), South America (8), Asia (5), North America (4), Australia (3) and Africa (2). A total of 117 (84%) respondents reported use of a specific temperature threshold in their ICU to define fever. A total of 14 different discrete levels were reported with a median of 38.2°C (inter-quartile range, IQR, 38.0°C to 38.5°C). The use of thermometers was protocolized in 91 (65%) ICUs and a wide range of methods were reportedly used, with axillary, tympanic and urinary bladder sites as the most common as primary modalities. Only 31 (22%) of respondents indicated that there was a formal written protocol for temperature control among febrile patients in their ICUs. In most or all cases practice was to control temperature, to use acetaminophen, and to perform a full septic workup in febrile patients and that this was usually directed by physician order. While reported practice was to treat nearly all patients with neurological impairment and most patients with acute coronary syndromes and infections, severe sepsis and septic shock, this was not the case for most patients with liver failure and fever. A wide range of definitions and management practices were reported regarding temperature abnormalities in the critically ill. Documenting temperature abnormality management practices, including variability in clinical care, is important to inform planning of future studies designed to optimize infection and temperature management strategies in the critically ill.


A new hypervolume approach for assessing environmental risks.
Assessing risks of uncertain but potentially damaging events, such as environmental disturbances, disease outbreaks and pest invasions, is a key analytical step that informs subsequent decisions about how to respond to these events. We present a continuous risk measure that can be used to assess and prioritize environmental risks from uncertain data in a geographical domain. The metric is influenced by both the expected magnitude of risk and its uncertainty. We demonstrate the approach by assessing risks of human-mediated spread of Asian longhorned beetle (ALB, Anoplophora glabripennis) in Greater Toronto (Ontario, Canada). Information about the human-mediated spread of ALB through this urban environment to individual geographical locations is uncertain, so each location was characterized by a set of probabilistic rates of spread, derived in this case using a network model. We represented the sets of spread rates for the locations by their cumulative distribution functions (CDFs) and then, using the first-order stochastic dominance rule, found ordered non-dominant subsets of these CDFs, which we then used to define different classes of risk across the geographical domain, from high to low. Because each non-dominant subset was estimated with respect to all elements of the distribution, the uncertainty in the underlying data was factored into the delineation of the risk classes; essentially, fewer non-dominant subsets can be defined in portions of the full set where information is sparse. We then depicted each non-dominant subset as a point cloud, where points represented the CDF values of each subset element at specific sampling intervals. For each subset, we then defined a hypervolume bounded by the outermost convex frontier of that point cloud. This resulted in a collection of hypervolumes for every non-dominant subset that together serve as a continuous measure of risk, which may be more practically useful than averaging metrics or ordinal rank measures. Overall, the approach offers a rigorous depiction of risk in a geographical domain when the underlying estimates of risk for individual locations are represented by sets or distributions of uncertain estimates. Our hypervolume-based approach can be used to compare assessments made with different datasets and assumptions.


Size and synchronization of auditory cortex promotes musical, literacy, and attentional skills in children.
Playing a musical instrument is associated with numerous neural processes that continuously modify the human brain and may facilitate characteristic auditory skills. In a longitudinal study, we investigated the auditory and neural plasticity of musical learning in 111 young children (aged 7-9 y) as a function of the intensity of instrumental practice and musical aptitude. Because of the frequent co-occurrence of central auditory processing disorders and attentional deficits, we also tested 21 children with attention deficit (hyperactivity) disorder [AD(H)D]. Magnetic resonance imaging and magnetoencephalography revealed enlarged Heschl's gyri and enhanced right-left hemispheric synchronization of the primary evoked response (P1) to harmonic complex sounds in children who spent more time practicing a musical instrument. The anatomical characteristics were positively correlated with frequency discrimination, reading, and spelling skills. Conversely, AD(H)D children showed reduced volumes of Heschl's gyri and enhanced volumes of the plana temporalia that were associated with a distinct bilateral P1 asynchrony. This may indicate a risk for central auditory processing disorders that are often associated with attentional and literacy problems. The longitudinal comparisons revealed a very high stability of auditory cortex morphology and gray matter volumes, suggesting that the combined anatomical and functional parameters are neural markers of musicality and attention deficits. Educational and clinical implications are considered.


The pathogen recognition receptor NOD2 regulates human FOXP3+ T cell survival.
The expression of pathogen recognition receptors in human FOXP3+ T regulatory cells is established, yet the function of these receptors is currently obscure. In the process of studying the function of both peripheral and lamina propria FOXP3+ lymphocytes in patients with the human inflammatory bowel disease Crohn's disease, we observed a clear deficiency in the quantity of FOXP3+ lymphocytes in patients with disease-associated polymorphisms in the pathogen recognition receptor gene NOD2. Subsequently, we determined that the NOD2 ligand, muramyl dipeptide (MDP), activates NF-kappaB in primary human FOXP3+ T cells. This activation is functionally relevant, as MDP-stimulated human FOXP3+ T cells are protected from death receptor Fas-mediated apoptosis. Importantly, apoptosis protection was not evident in MDP-stimulated FOXP3+ T cells isolated from a patient with the disease-associated polymorphism. Thus, we propose that one function of pathogen recognition receptors in human T regulatory cells is the protection against death receptor-mediated apoptosis in a Fas ligand-rich environment, such as that of the inflamed intestinal subepithelial space.