HIV prevention costs and their predictors: evidence from the ORPHEA Project in Kenya.
We estimate costs and their predictors for three HIV prevention interventions in Kenya: HIV testing and counselling (HTC), prevention of mother-to-child transmission (PMTCT) and voluntary medical male circumcision (VMMC). As part of the 'Optimizing the Response of Prevention: HIV Efficiency in Africa' (ORPHEA) project, we collected retrospective data from government and non-governmental health facilities for 2011-12. We used multi-stage sampling to determine a sample of health facilities by type, ownership, size and interventions offered totalling 144 sites in 78 health facilities in 33 districts across Kenya. Data sources included key informants, registers and time-motion observation methods. Total costs of production were computed using both quantity and unit price of each input. Average cost was estimated by dividing total cost per intervention by number of clients accessing the intervention. Multivariate regression methods were used to analyse predictors of log-transformed average costs. Average costs were $7 and $79 per HTC and PMTCT client tested, respectively; and $66 per VMMC procedure. Results show evidence of economies of scale for PMTCT and VMMC: increasing the number of clients per year by 100% was associated with cost reductions of 50% for PMTCT, and 45% for VMMC. Task shifting was associated with reduced costs for both PMTCT (59%) and VMMC (54%). Costs in hospitals were higher for PMTCT (56%) in comparison to non-hospitals. Facilities that performed testing based on risk factors as opposed to universal screening had higher HTC average costs (79%). Lower VMMC costs were associated with availability of male reproductive health services (59%) and presence of community advisory board (52%). Aside from increasing production scale, HIV prevention costs may be contained by using task shifting, non-hospital sites, service integration and community supervision.


Role of contact inhibition of locomotion and junctional mechanics in epithelial collective responses to injury.
Epithelial tissues form physically integrated barriers against the external environment protecting organs from infection and invasion. Within each tissue, epithelial cells respond to different challenges that can potentially compromise tissue integrity. In particular, cells collectively respond to injuries by reorganizing their cell-cell junctions and migrating directionally towards the sites of damage. Notwithstanding, the mechanisms that drive collective responses in epithelial aggregates remain poorly understood. In this work, we develop a minimal mechanistic model that is able to capture the essential features of epithelial collective responses to injuries. We show that a model that integrates the mechanics of cells at the cell-cell and cell-substrate interfaces as well as contact inhibition of locomotion (CIL) correctly predicts two key properties of epithelial response to injury as: (1) local relaxation of the tissue and (2) collective reorganization involving the extension of cryptic lamellipodia that extend, on average, up to 3 cell diameters from the site of injury and morphometric changes in the basal regions. Our model also suggests that active responses (like the actomyosin purse string and softening of cell-cell junctions) are needed to drive morphometric changes in the apical region. Therefore, our results highlight the importance of the crosstalk between junctional biomechanics, cell substrate adhesion, and CIL, as well as active responses, in guiding the collective rearrangements that are required to preserve the epithelial barrier in response to injury.


Evaluating current automatic de-identification methods with Veteran's health administration clinical documents.
The increased use and adoption of Electronic Health Records (EHR) causes a tremendous growth in digital information useful for clinicians, researchers and many other operational purposes. However, this information is rich in Protected Health Information (PHI), which severely restricts its access and possible uses. A number of investigators have developed methods for automatically de-identifying EHR documents by removing PHI, as specified in the Health Insurance Portability and Accountability Act "Safe Harbor" method.This study focuses on the evaluation of existing automated text de-identification methods and tools, as applied to Veterans Health Administration (VHA) clinical documents, to assess which methods perform better with each category of PHI found in our clinical notes; and when new methods are needed to improve performance. We installed and evaluated five text de-identification systems "out-of-the-box" using a corpus of VHA clinical documents. The systems based on machine learning methods were trained with the 2006 i2b2 de-identification corpora and evaluated with our VHA corpus, and also evaluated with a ten-fold cross-validation experiment using our VHA corpus. We counted exact, partial, and fully contained matches with reference annotations, considering each PHI type separately, or only one unique 'PHI' category. Performance of the systems was assessed using recall (equivalent to sensitivity) and precision (equivalent to positive predictive value) metrics, as well as the F(2)-measure. Overall, systems based on rules and pattern matching achieved better recall, and precision was always better with systems based on machine learning approaches. The highest "out-of-the-box" F(2)-measure was 67% for partial matches; the best precision and recall were 95% and 78%, respectively. Finally, the ten-fold cross validation experiment allowed for an increase of the F(2)-measure to 79% with partial matches. The "out-of-the-box" evaluation of text de-identification systems provided us with compelling insight about the best methods for de-identification of VHA clinical documents. The errors analysis demonstrated an important need for customization to PHI formats specific to VHA documents. This study informed the planning and development of a "best-of-breed" automatic de-identification application for VHA clinical text.


Natural protein engineering in the Ω-loop: the role of Y221 in ceftazidime and ceftolozane resistance in Pseudomonas-derived cephalosporinase.
A wide variety of clinically observed single amino acid substitutions in the Ω-loop region have been associated with increased minimum inhibitory concentrations and resistance to ceftazidime (CAZ) and ceftolozane (TOL) in Pseudomonas-derived cephalosporinase and other class C β-lactamases. Herein, we demonstrate the naturally occurring tyrosine to histidine substitution of amino acid 221 (Y221H) in Pseudomonas-derived cephalosporinase (PDC) enables CAZ and TOL hydrolysis, leading to similar kinetic profiles (k cat = 2.3 ± 0.2 µM and 2.6 ± 0.1 µM, respectively). Mass spectrometry of PDC-3 establishes the formation of stable adducts consistent with the formation of an acyl enzyme complex, while spectra of E219K (a well-characterized, CAZ- and TOL-resistant comparator) and Y221H are consistent with more rapid turnover. Thermal denaturation experiments reveal decreased stability of the variants. Importantly, PDC-3, E219K, and Y221H are all inhibited by avibactam and the boronic acid transition state inhibitors (BATSIs) LP06 and S02030 with nanomolar IC50 values and the BATSIs stabilize all three enzymes. Crystal structures of PDC-3 and Y221H as apo enzymes and complexed with LP06 and S02030 (1.35-2.10 Å resolution) demonstrate ligand-induced conformational changes, including a significant shift in the position of the sidechain of residue 221 in Y221H (as predicted by enhanced sampling well-tempered metadynamics simulations) and extensive hydrogen bonding between the enzymes and BATSIs. The shift of residue 221 leads to the expansion of the active site pocket, and molecular docking suggests substrates orientate differently and make different intermolecular interactions in the enlarged active site compared to the wild-type enzyme.


[Epithelio-myoepithelial carcinoma of the salivary glands].
Epithelio-myoepithelial carcinoma was singled out as a separate nosological unit in the second revision of the International Histological Classification of Tumors of the Salivary glands (WHO, 1991). For the first time in domestic literature the article describes morphological evidence obtained at investigation of epithelial-myoepithelial carcinoma of the parotid gland using modern technologies.


Exposure of Taiwan residents to polychlorinated biphenyl congeners from farmed, ocean-caught, and imported fish.
This study is to assess PCB levels in five frequently consumed fish species in Taiwan, tilapia, milkfish, white pomfret, hairtail, and cod. Seventeen congeners were measured in fillet samples purchased from major markets in northern, central, and southern Taiwan. All 136 samples had traces of PCBs. The median concentrations were 0.18, 0.46, 0.62, 0.69, and 7.34 ng/g wet wt and 1.01, 0.28, 1.14, 5.06, and 19.3 pg-WHO-TEQ/g lipid in tilapia, milkfish, white pomfret, hairtail, and cod samples, respectively. Cod (the imported fish) had the highest wet weight PCB concentrations. The fish caught off-shore (white pomfret and hairtail) had higher levels than the farmed fish (tilapia and milkfish). The congener profiles varied among species. PCB 105/153 and 126 accounted for more than 28% and 53% of the 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents (WHO-TEQs) in hairtail and cod, respectively; while PCB 156 was the major TEQ contributor in the other species. The estimated median PCB intake of the general public from consumption of the five species ranged from 0.000023 to 0.048 pg-WHO-TEQ/kg/day. It was also found that samples farmed or caught along the southern coast had higher PCB levels than those from other parts of Taiwan, indicating possible elevated PCB contamination around that area.


Model for the Functional Active State of the TS Ribozyme from Molecular Simulation.
Recently, a crystal structure has been reported of a new catalytic RNA, the TS ribozyme, that has been identified through comparative genomics and is believed to be a metalloribozyme having novel mechanistic features. Although this data provides invaluable structural information, analysis suggests a conformational change is required to arrive at a catalytically relevant state. We report results of molecular simulations that predict a spontaneous local rearrangement of the active site, leading to solution structures consistent with available functional data and providing competing mechanistic hypotheses that can be experimentally tested. The two competing hypotheses differ in the proposed identity of the catalytic general acid: either a water molecule coordinating a Mg2+ ion bound at the Watson-Crick edge of residue C7, or the N3 position of residue C7 itself.


Decision making following a prenatal diagnosis of Down syndrome: an integrative review.
Prenatal screening for Down syndrome (DS) is a routine part of prenatal care in many countries, and there is growing interest in the choices women make following a prenatal diagnosis of DS. This review describes what is known about actual and hypothetical decision making following a prenatal diagnosis of DS and adds understanding about the factors that influence women's decision making. A search of empirical studies was conducted through electronic databases, major journals, and reference lists that were published in English between January 1999 and September 2010. Inclusion criteria were that the research explored attitudes toward continuation of pregnancy or induced abortion for DS and included at least 1 variable that explored factors influencing women's decision making following a prenatal diagnosis of DS. Studies that did not specify DS, unpublished manuscripts, review articles, and book chapters were excluded. A total of 11 studies were identified that met the inclusion criteria. The decision to undergo an induced abortion varied depending on whether participants were prospective parents recruited from the general population (23%-33% would terminate), pregnant women at increased risk for having a child with DS (46%-86% would terminate), or women who received a positive diagnosis of DS during the prenatal period (89%-97% terminated). Multiple factors influence women's decision making following a diagnosis of DS, including demographic factors such as religion, maternal age, gestational age, number of existing children, and history of induced abortion. Psychosocial factors including perceived parenting burden/reward, quality of life for a child with DS, attitudes toward and comfort with individuals with disabilities, and support from others also are important influences. Multiple factors influence the decisions pregnant women make following the diagnosis of fetal DS. Therefore, it is critical that health care providers who work with pregnant women are aware of these factors.


Enzymatic arginylation of beta-melanocyte-stimulating hormone and of angiotensin II.
Porcine beta-melanocyte-stimulating hormone and angiotensin II were examined as acceptors in the reaction catalyzed by arginyl-tRNA-protein transferase. Both inhibited enzymatic transfer of [14C]arginine from tRNA to bovine albumin. Inhibition was competitive with albumin and the K-i values were, respectively, 15 and 0.8 muM. The expected arginylated compounds were isolated and characterized. Beta-melanocyte-stimulating hormone and its arginylated product had identical activities in the frog epithelium bioassay. In contrast, the biological activity of angiotensin II was diminished by enzymatic arginylation. The pressor effect of the arginylated derivative on anesthetized rats and its activity on the isolated rat uterus were, respectively, approximately 60% and 20% of those found for the unmodified peptide.


Odontoma-producing intraosseous calcifying odontogenic cyst: case report.
The present report describes a case of odontoma-producing intraosseous calcifying odontogenic cyst in a 36-year-old Black male in the right mandibular bicuspid region. The lesion involved an unerupted permanent canine, which was displaced to the mandible base and a calcified mass that was later recognized as an odontoma. The lesion was surgically removed.


Criminal justice measures for economic data harmonization in substance use disorder research.
The consequences of substance use disorders (SUDs) are varied and broad, affecting many sectors of society and the economy. Economic evaluation translates these consequences into dollars to examine the net economic impact of interventions for SUD, and associated conditions such as HCV and HIV. The nexus between substance use and crime makes criminal justice outcomes particularly significant for estimating the economic impact of SUD interventions, and important for data harmonization. We compared baseline data collected in six NIDA-funded Seek, Test, Treat and Retain (STTR) intervention studies that enrolled HIV-infected/at-risk individuals with SUDs (total n = 3415). Criminal justice measures included contacts with the criminal justice system (e.g., arrests) and criminal offenses. The objective was to develop a list of recommended measures and methods supporting economic data harmonization opportunities in HIV and SUD research, with an initial focus on crime-related outcomes. Criminal justice contacts and criminal offenses were highly variable across studies. When measures grouped by offense classifications were compared, consistencies across studies emerged. Most individuals report being arrested for property or public order crimes (> 50%); the most commonly reported offenses were prostitution/pimping, larceny/shoplifting, robbery, and household burglary. We identified four measures that are feasible and appropriate for estimating the economic consequences of SUDs/HIV/HCV: number of arrests, number of convictions, days of incarceration, and times committing criminal offenses, by type of offense. To account for extreme variation, grouping crimes by offense classification or calculating monthly averages per event allows for more meaningful comparisons across studies.


[Change of the endocrine function of the pancreas in patients with chronic pancreatitis].
There was a study of 19 chronic pancreatitis patients (10 male and 9 female), 11 chronic pancreatitis and pancreatogenic diabetes mellitus patients (8 male and 3 female) and 12 type 2 diabetes mellitus patients (4 male and 8 female) at the age of 30-60 as well as 15 control group subjects at the same age range. The content of the C-peptide and such peptides as INCINE, PAMG-cine and PAMG-tin in the blood serum was subjected to the immunoradiometric assay. It was discovered that there is a trend to the increased C-peptide level in CP patients while the C-peptide level in CP patients with diabetes mellitus was smaller than that in the control group; the C-peptide level in CP patients with type 2 diabetes mellitus was higher as compared to that in the control group. It was shown that erythrocytes of CP patients are less sensitive to insulin action and do not respond to the presence of insulinomimetic peptides under examination during the glucose uptake test. CP patients with diabetes mellitus and type 2 diabetes mellitus patients are more sensitive to the action of insulin and peptides applied. Synthetic insulinomimetic peptides can serve as a means for discovering the functional cell deficiency under the glucose uptake test.


Next-generation sequencing revealed divergence in deletions of the preS region in the HBV genome between different HBV-related liver diseases.
In order to investigate if deletion patterns of the preS region can predict liver disease advancement, the preS region of the hepatitis B virus (HBV) genome in 45 chronic hepatitis B (CHB) and 94 HBV-related hepatocellular carcinoma (HCC) patients was sequenced by next-generation sequencing (NGS) and the percentages of nucleotide deletion in the preS region were analysed. Hierarchical clustering and heatmaps based on deletion percentages of preS revealed different deletion patterns between CHB and HCC patients. Intergenotype comparison also indicated divergence in preS deletions between HBV genotype B and C. No significant difference was found in preS deletion patterns between sera and matched adjacent non-tumour tissues. Based on hierarchical clustering, HCC patients were classed into two groups with different preS deletion patterns and different clinical features. Finally, the support vector machine (SVM) model was trained on preS nucleotide deletion percentages and used to predict HCC versus CHB patients. The prediction performance was assessed with fivefold cross-validation and independent cohort validation. The median area under the curve (AUC) was 0.729 after repeating SVM 500 times with fivefold cross-validations. After parameter optimization, the SVM model was used to predict an independent cohort with 51 CHB patients and 72 HCC patients and the AUC was 0.727. In conclusion, the use of the NGS method revealed a prominent divergence in preS deletion patterns between disease groups and virus genotypes, but not between different tissue types. Quantitative NGS data combined with a machine learning method could be a powerful approach for prediction of the status of different diseases.


Scale-up of extremely low temperature fermentations of grape must by wheat supported yeast cells.
A new biocatalyst was prepared by immobilization of Saccharomyces cerevisiae AXAZ-1 yeast cells on whole wheat grains. This biocatalyst was used for 30 repeated batch fermentations of glucose and grape must at various temperatures. The biocatalyst retained its operational stability for a long period and it was proved capable to produce dry wines of fine clarity even at extremely low temperatures (5 degrees C). After the completion of these fermentations the new biocatalyst was used in a scale-up system of 80 L for wine making at ambient (20 degrees C) and extremely low temperatures (2 degrees C). The scale-up process did not affect the fermentative ability of biocatalyst, even at low temperatures, while the produced wines had almost the same improved aromatic profile compare to free cells as revealed by GC and GC-MS analyses. More specifically the results showed that both systems with immobilized cells (laboratory scale and 80 L bioreactor) increased the formation of esters and produced wines with improved aromatic profile compared to those with free cells. Finally an increase in the percentages of total esters and a decrease in those of higher alcohols was observed in lower fermentation temperatures.


Morbidity and Mortality in Critically Ill Children. II. A Qualitative Patient-Level Analysis of Pathophysiologies and Potential Therapeutic Solutions.
To describe at the individual patient level the pathophysiologic processes contributing to morbidity and mortality in PICUs and therapeutic additions and advances that could potentially prevent or reduce morbidity and mortality. Qualitative content analysis of intensivists' conclusions on pathophysiologic processes and needed therapeutic advances formulated by structured medical record review. Eight children's hospitals affiliated with the Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. A randomly selected cohort of critically ill children with a new functional morbidity or mortality at hospital discharge. New morbidity was assessed using the Functional Status Scale and defined as worsening by two or more points in a single domain from preillness baseline. None. Of 292 children, 175 (59.9%) had a new morbidity and 117 (40.1%) died. The most common pathophysiology was impaired substrate delivery (n = 158, 54.1%) manifesting as global or regional hypoxia or ischemia due to low cardiac output or cardiac arrest. Other frequent pathophysiologies were inflammation (n = 104, 35.6%) related to sepsis, respiratory failure, acute respiratory distress syndrome, or multiple organ dysfunction; and direct tissue injury (n = 64, 21.9%) including brain and spinal cord trauma. Chronic conditions were often noted (n = 156, 53.4%) as contributing to adverse outcomes. Drug therapies (n = 149, 51.0%) including chemotherapy, inotropes, vasoactive agents, and sedatives were the most frequently proposed needed therapeutic advances. Other frequently proposed therapies included cell regeneration (n = 115, 39.4%) mainly for treatment of neuronal injury, and improved immune and inflammatory modulation (n = 79, 27.1%). Low cardiac output and cardiac arrest, inflammation-related organ failures, and CNS trauma were the most common pathophysiologies leading to morbidity and mortality in PICUs. A research agenda focused on better understanding and treatment of these conditions may have high potential to directly impact patient outcomes.


Radical surgery consisting of en bloc corpectomy in recurrence after palliative surgery for spinal metastasis.
We often experience recurrence of spinal metastases after palliative surgery, even with radiotherapy. We examined the clinical outcome of radical surgery containing en bloc corpectomy for patients with recurrent spinal metastasis. Seven patients underwent en bloc corpectomy for recurrent spinal metastases. We assessed the prognosis scores (Tomita, Tokuhashi), pre- and postoperative Frankel scale scores, operation time, intraoperative blood loss, and perioperative complications. The preoperative estimated prognosis was less than six months (two patients), six months to one year (two patients), and over one year (three patients), according to Tokuhashi score. Major perioperative complications were dura mater injury and pleural injury. Neurological improvement was seen in four patients. All patients were ambulatory at discharge and lived longer than the preoperatively estimated life expectancy (range: seven months to four years). Radical surgery consisting of en bloc corpectomy may be a therapeutic choice for patients with recurrent spinal metastases.


Two-part models with stochastic processes for modelling longitudinal semicontinuous data: Computationally efficient inference and modelling the overall marginal mean.
Several researchers have described two-part models with patient-specific stochastic processes for analysing longitudinal semicontinuous data. In theory, such models can offer greater flexibility than the standard two-part model with patient-specific random effects. However, in practice, the high dimensional integrations involved in the marginal likelihood (i.e. integrated over the stochastic processes) significantly complicates model fitting. Thus, non-standard computationally intensive procedures based on simulating the marginal likelihood have so far only been proposed. In this paper, we describe an efficient method of implementation by demonstrating how the high dimensional integrations involved in the marginal likelihood can be computed efficiently. Specifically, by using a property of the multivariate normal distribution and the standard marginal cumulative distribution function identity, we transform the marginal likelihood so that the high dimensional integrations are contained in the cumulative distribution function of a multivariate normal distribution, which can then be efficiently evaluated. Hence, maximum likelihood estimation can be used to obtain parameter estimates and asymptotic standard errors (from the observed information matrix) of model parameters. We describe our proposed efficient implementation procedure for the standard two-part model parameterisation and when it is of interest to directly model the overall marginal mean. The methodology is applied on a psoriatic arthritis data set concerning functional disability.


[Cross allergy between penicillins and other beta lactam antibiotics--the risk is much less than previously thought].
Severe IgE-mediated allergic reactions to penicillins are rare but might be fatal. Because some studies demonstrated a high risk of cross-sensitivity to cephalosporins and carbapenems it has been recommended to avoid these antibiotics in patients with suspected hypersensitivity to penicillins. However, recent studies and analyses conclude that the risk of cross-reactivity was overestimated in the earlier studies and that it is in fact very low for parenteral cephalosporins and perhaps even negligible for carbapenems. The new knowledge has implications for the choice of therapy for bacterial infections in patients with a history of penicillin hypersensitivity, because alternative antibiotic regimens are often inferior to beta-lactam antibiotics. The aim of the present review is to present existing knowledge on cross-sensitivity between beta-lactams, as well as to discuss the management of patients with suspected allergic reactions to these antibiotics.


Molecular characterization and genotyping of human rotavirus strains in Abidjan, Cote d'Ivoire.
In this study, we characterized human rotavirus strains recovered from infants and young children with acute diarrhea in Abidjan, Cote d'Ivoire, during 2000-2004. In total, 719 fecal specimens were collected from children aged 1-60 months with acute infantile gastroenteritis. Examination with a commercial enzyme-linked immunosorbent assay showed the presence of group A rotavirus antigen in 208 diarrheal specimens (28.9%). Polyacrylamide gel electrophoresis of the RNA extracted from rotavirus-positive stools yielded a variety of "long" and "short" RNA electropherotypes, which were used to help select strains for VP4 and VP7 genotyping. VP7 genotype G1 strains were circulating most commonly during the study period (53%), followed by G2 (22%) and G3 (5%) strains. Strains with multiple VP7 genotype reactivity were observed in 7.6% of specimens, and a similar number (8%) could not be typed at all. VP4 P[6] and P[8] strains circulated at similar levels (33%). Strains demonstrating multiple VP4 types were quite common (9%); however, 20% of the strains were untypeable by the methods used. Rotavirus strain diversity in Cote d'Ivoire was similar to that observed in other West African countries.


Cyclic AMP-dependent regulation of fibroblast growth factor-2 messenger RNA levels in rat cortical astrocytes: comparison with fibroblast growth factor-1 and ciliary neurotrophic factor.
The present study was undertaken to investigate the regulatory mechanisms of fibroblast growth factor-1 and -2 (FGF-1 and FGF-2) gene expression compared with ciliary neurotropic factor (CNTF) in rat cortical astrocytes. Glial cells represent a source of different trophic factors and cytokines that can influence the survival of multiple cell populations within the central nervous system. We found that the beta-adrenergic receptor agonist (betaAR) isoproterenol produced a significant induction of FGF-2 gene expression and protein in type I astrocytes. On the contrary, the gene expression for FGF-1 and CNTF is markedly reduced after exposure to isoproterenol. The changes produced by the beta AR agonist is mimicked by cyclic AMP analogues (8-bromo-cAMP) or 3-isobutyl-1-methyl-xanthine, a cAMP phosphodiesterase inhibitor, which indicates that intracellular elevation of this second messenger is responsible for these effects. The regulation of neurotrophic factors by isoproterenol is not restricted to cortical astrocytes and may take place through different mechanisms. Inhibition of protein synthesis prevents the decrease in CNTF without affecting the changes in FGF-1 and FGF-2 gene expression. Coincubation of isoproterenol with actinomycin D, an inhibitor of gene transcription, prevents the modification of neurotrophic factor biosynthesis, indicating that transcriptional mechanisms are indeed involved in these regulatory pathways. However, the determination of FGF-2 mRNA half-life suggests that the effect of the betaAR agonist can be in part the result of mRNA stabilization. The mechanisms that we describe can be important in the maintenance of neuronal homeostasis and may be relevant in the development of alternative strategies for the treatment of acute and chronic neurodegenerative disorders


Intraocular pressure reduction in the untreated fellow eye after selective laser trabeculoplasty.
To investigate the effect of selective laser trabeculoplasty (SLT) on the intraocular pressure (IOP) of untreated fellow eyes in patients with open-angle glaucoma. Retrospective chart review. Charts of all patients who underwent SLT at the University of Texas Southwestern Medical Center at Dallas between September 2003 and May 2006 were reviewed. Each patient had IOP measurements by Goldmann applanation tonometry in both eyes preoperatively, and at 1 hour, 2 weeks, 3 months, and 6 months postoperatively. Patient age, gender, diagnosis, central corneal thickness (CCT), previous intraocular surgeries, and degrees of laser treatment were tabulated for each patient. Patients with a history of previous glaucoma surgery in either eye were excluded as were those who underwent any change in glaucoma medications or further laser or surgical intervention in either eye within 6 months of SLT. Data were analyzed using a paired two-tailed t-test, an unpaired two-tailed t-test, ANOVA, and linear regression. A total of 43 patients were included through 6 months of follow-up. Mean reduction in IOP in the treated eye was 3.9 +/- 0.6 mmHg or 18.8% (p < 0.001) at final exam. Mean IOP reduction in the fellow untreated eye was 2.1 +/- 0.5 mmHg or 11.2% (p < 0.01). Patients with higher preoperative IOPs had a greater reduction in IOP in both eyes (p < 0.001 for treated eyes, and p = 0.02 for untreated eyes). Patients who were on a larger number of glaucoma medications preoperatively had a greater response in both eyes (treated eye p = 0.002, untreated eye p = 0.008). There was no significant difference in IOP response in either eye based on age, gender, CCT, degrees of treatment, or phakic status. SLT produces a sustained and statistically significant IOP reduction in the fellow untreated eyes of patients with open-angle glaucoma. The results of our study support a biological mechanism of action for SLT. Limitations of this study include its retrospective design, relatively small sample size, a possible effect of increased compliance with medical therapy following SLT, and an inherent bias of excluding patients who underwent a change in medications or further laser or surgical therapy during the period under review.


Accelerated parallel algorithm for gene network reverse engineering.
The Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNE) represents one of the most effective tools to reconstruct gene regulatory networks from large-scale molecular profile datasets. However, previous implementations require intensive computing resources and, in some cases, restrict the number of samples that can be used. These issues can be addressed elegantly in a GPU computing framework, where repeated mathematical computation can be done efficiently, but requires extensive redesign to apply parallel computing techniques to the original serial algorithm, involving detailed optimization efforts based on a deep understanding of both hardware and software architecture. Here, we present an accelerated parallel implementation of ARACNE (GPU-ARACNE). By taking advantage of multi-level parallelism and the Compute Unified Device Architecture (CUDA) parallel kernel-call library, GPU-ARACNE successfully parallelizes a serial algorithm and simplifies the user experience from multi-step operations to one step. Using public datasets on comparable hardware configurations, we showed that GPU-ARACNE is faster than previous implementations and is able to reconstruct equally valid gene regulatory networks. Given that previous versions of ARACNE are extremely resource demanding, either in computational time or in hardware investment, GPU-ARACNE is remarkably valuable for researchers who need to build complex regulatory networks from large expression datasets, but with limited budget on computational resources. In addition, our GPU-centered optimization of adaptive partitioning for Mutual Information (MI) estimation provides lessons that are applicable to other domains.


Failure of sequential biliary stenting for unsuccessful common bile duct stone removal.
To determine the factors associated with the failure of stone removal by a biliary stenting strategy. We retrospectively reviewed 645 patients with common bile duct (CBD) stones who underwent endoscopic retrograde cholangiography for stone removal in Siriraj GI Endoscopy center, Siriraj Hospital from June 2009 to June 2012. A total of 42 patients with unsuccessful initial removal of large CBD stones that underwent sequential biliary stenting were enrolled in the present study. The demographic data, laboratory results, stone characteristics, procedure details, and clinical outcomes were recorded and analyzed. In addition, the patients were classified into two groups based on outcome, successful or failed sequential biliary stenting, and the above factors were compared. Among the initial 42 patients with unsuccessful initial removal of large CBD stones, there were 37 successful biliary stenting cases and five failed cases. Complete CBD clearance was achieved in 88.0% of cases. The average number of sessions needed before complete stone removal was achieved was 2.43 at an average of 25 wk after the first procedure. Complications during the follow-up period occurred in 19.1% of cases, comprising ascending cholangitis (14.3%) and pancreatitis (4.8%). The factors associated with failure of complete CBD stone clearance in the biliary stenting group were unchanged CBD stone size after the first biliary stenting attempt (10.2 wk) and a greater number of endoscopic retrograde cholangio-pancreatography sessions performed (4.2 sessions). The sequential biliary stenting is an effective management strategy for the failure of initial large CBD stone removal.


Epigenetic Effects Mediated by Antiepileptic Drugs and their Potential Application.
An epigenetic effect mainly refers to a heritable modulation in gene expression in the short term but does not involve alterations in the DNA itself. Epigenetic molecular mechanisms include DNA methylation, histone modification, and untranslated RNA regulation. Antiepileptic drugs have drawn attention to biological and translational medicine because their impact on epigenetic mechanisms will lead to the identification of novel biomarkers and possible therapeutic strategies for the prevention and treatment of various diseases ranging from neuropsychological disorders to cancers and other chronic conditions. However, these transcriptional and posttranscriptional alterations can also result in adverse reactions and toxicity in vitro and in vivo. Hence, in this review, we focus on recent findings showing epigenetic processes mediated by antiepileptic drugs to elucidate their application in medical experiments and shed light on epigenetic research for medicinal purposes.


Integrated Genomics of Crohn's Disease Risk Variant Identifies a Role for CLEC12A in Antibacterial Autophagy.
The polymorphism ATG16L1 T300A, associated with increased risk of Crohn's disease, impairs pathogen defense mechanisms including selective autophagy, but specific pathway interactions altered by the risk allele remain unknown. Here, we use perturbational profiling of human peripheral blood cells to reveal that CLEC12A is regulated in an ATG16L1-T300A-dependent manner. Antibacterial autophagy is impaired in CLEC12A-deficient cells, and this effect is exacerbated in the presence of the ATG16L1(∗)300A risk allele. Clec12a(-/-) mice are more susceptible to Salmonella infection, supporting a role for CLEC12A in antibacterial defense pathways in vivo. CLEC12A is recruited to sites of bacterial entry, bacteria-autophagosome complexes, and sites of sterile membrane damage. Integrated genomics identified a functional interaction between CLEC12A and an E3-ubiquitin ligase complex that functions in antibacterial autophagy. These data identify CLEC12A as early adaptor molecule for antibacterial autophagy and highlight perturbational profiling as a method to elucidate defense pathways in complex genetic disease.


Saline culture of crops: a genetic approach.
Increasing salinity of soil and water threatens agriculture in arid and semiarid regions. By itself, the traditional engineering approach to the problem is no longer adequate. Genetic science offers the possibility of developing salt-tolerant crops, which, in conjunction with environmental manipulation, could improve agricultural production in saline regions and extend agriculture to previously unsuited regions.


[Chronic septic granulomatosis in a young girl manifesting as invasive pulmonary aspergillosis and flaccid paraplegia].
The invasive Pulmonary Aspergillosis (IPA) is the principal cause of death in patients with chronic granulomatosis disease (CGD). It can happen before age of one and can reveal the (CGD). Usually, the transmission of GSD is linked to x in 65% of cases. We report, the case of a girl aged 3 years issued from consanguine marriage referred to hospital for hemoptysia. We note that at 40 days she presents an suppurate adenitis. She is hypotrophic at--3DS without respiratory problem, she have a splenomegaly. The radiography chest note an alveolar and interstitial opacity bilateral, apical right and basal left. There is a biological inflammatory syndrome. During the evolution, the child presents a paraplegia secondary to compression myelitis. A D5 laminectomy in urgency was done. The vertebral Biopsia, the serology and the culture isolate fumigatus aspergillus the GCD is evoqued confirmed by the NBT test who was negative. --We have to look for GCD in front of pulmonary aspergillus.--The vertebra lesion is secondary to pulmonary lesion.--Our observation is noticeable by the recessive autosomal transmission who was seen in 35% of cases, and by the neurologic complication rarely reported.


Role of antifeeding prophage (Afp) protein Afp16 in terminating the length of the Afp tailocin and stabilizing its sheath.
The Serratia entomophila antifeeding prophage Afp, forms a phage-tail-like particle that acts on the New Zealand grass grub, Costelytra zealandica with a 3-day LD50 of approximately 500 Afp particles per larva. Genes (afp1-18) encoding components of Afp were expressed and their products purified allowing morphological assessment of the products by transmission electron microscopy (TEM). Expression of afp1-15 resulted in the formation of a non-sheathed structure termed the tube-baseplate complex or TBC, composed of an irregular-length tube attached to a baseplate with associated tail fibres. Expression of afp1-16 produced mature, normal-length Afp particles, whereas coexpression of afp16 with afp1-15 in trans resulted in the formation of aberrant Afp particles of variable lengths. A C-terminally truncated Afp16 mutant resulted in a phenotype intermediate between mature Afp and TBC. The addition of purified Afp16 to Afp unravelled by acidic treatment resulted in the formation of shorter tubes when specimen pH was adjusted to 7 than those formed in the absence of Afp16. Analysis of TEM images of purified Afp16 revealed a hexameric ring-like structure similar to that formed by gp3 of phage T4 and gpU of phage λ. Our results suggest that Afp16 terminates tube elongation and is involved in sheath formation.


Prognostic difference between soft tissue abscess and osteomyelitis of the foot in patients with diabetes: data from a consecutive series of 452 hospitalized patients.
From January 2008 to December 2010, 452 patients with diabetes were admitted to our diabetic foot unit because of deep soft tissue abscess (group A: n = 210) or chronic osteomyelitis (group B: n = 242). Patients from group A underwent emergency debridement in the operating room. Patients from group B underwent elective surgery. Twenty-six (5.8%) major amputations were performed: of these, 18 (8.57%) were performed in patients from group A and 8 (3.31%) were performed in patients from group B (p = .024). Multivariate analysis showed the independent role on amputation outcome of the abscess (odds ratio, 2.64; p = .029; confidence interval [CI] 1.11 to 6.28), dialysis treatment (odds ratio, 3.17; p = .039, CI 1.06-9.51), and C-reactive protein > 0.5 mg/dL (odds ratio, 3.75; p = .022, CI 1.21-11.64). In group A, 43 (22.6%) patients healed only with drainage, and 147 (70.0%) minor amputations were performed: 53 (36.1%) at the level of the forefoot and 94 (63.9%) at the level of the midfoot. In group B, 234 (96.7%) minor amputations were performed, 208 (88.9%) at the forefoot and 26 (11.1%) at the midfoot level (p < .001). Fourteen postoperative complications occurred in patients from group A and 2 in patients from group B (p < .001). In group A, 3 patients died during hospitalization, 1 from septic shock and 2 from sudden death. None of the group B patients died. This study demonstrates that the severity of a foot soft tissue abscess is not comparable with that of a chronic osteomyelitis not only because of a higher rate of major amputation, but also because of a much more proximal level of minor amputation.


Segmentation and tracing of single neurons from 3D confocal microscope images.
In order to understand the brain, we need to first understand the morphology of neurons. In the neurobiology community, there have been recent pushes to analyze both neuron connectivity and the influence of structure on function. Currently, a technical road block that stands in the way of these studies is the inability to automatically trace neuronal structure from microscopy. On the image processing side, proposed tracing algorithms face difficulties in low contrast, indistinct boundaries, clutter, and complex branching structure. To tackle these difficulties, we develop Tree2Tree, a robust automatic neuron segmentation and morphology generation algorithm. Tree2Tree uses a local medial tree generation strategy in combination with a global tree linking to build a maximum likelihood global tree. Recasting the neuron tracing problem in a graph-theoretic context enables Tree2Tree to estimate bifurcations naturally, which is currently a challenge for current neuron tracing algorithms. Tests on cluttered confocal microscopy images of Drosophila neurons give results that correspond to ground truth within a margin of ±2.75% normalized mean absolute error.


[An outbreak of Yersinia enterocolitica O:9-infection].
Yersiniosis is a zoonosis that is transmitted from pigs to humans. In January 2006 more cases of Yersinia enterocolitica enterocolitis than expected were reported in Norway. The fact that the isolates belonged to the O:9 serogroup, which is rare in Norway, and the geographical and temporal clustering of the cases, pointed to an outbreak. We have conducted a retrospective study of 11 patients who were diagnosed during this outbreak. The material is based upon applicants' information, patient journals and a questionnaire. In order to disclose the source of infection, a case-control survey was performed. Nine of the 11 patients had enterocolitis and two had septicaemia, both of whom died following a few days of treatment. One patient presented with pseudo- appendicitis while another developed monoarthritis, which persisted for more than three months after the debut of symptoms Treatment with antibiotics was offered in six cases. The case-control analysis indicated that brawn was the probable source of infection. This is the first reported Norwegian outbreak of Y. enterocolitica O:9 disease. The incubation time, disease duration and frequency of intestinal and immunological complications corresponds with previously published data. The frequency of septicaemia exceeds several previously reported outbreaks and retrospective studies of sporadic cases.


Reactive oxygen species regulate activity-dependent neuronal plasticity in Drosophila.
Reactive oxygen species (ROS) have been extensively studied as damaging agents associated with ageing and neurodegenerative conditions. Their role in the nervous system under non-pathological conditions has remained poorly understood. Working with the Drosophila larval locomotor network, we show that in neurons ROS act as obligate signals required for neuronal activity-dependent structural plasticity, of both pre- and postsynaptic terminals. ROS signaling is also necessary for maintaining evoked synaptic transmission at the neuromuscular junction, and for activity-regulated homeostatic adjustment of motor network output, as measured by larval crawling behavior. We identified the highly conserved Parkinson's disease-linked protein DJ-1β as a redox sensor in neurons where it regulates structural plasticity, in part via modulation of the PTEN-PI3Kinase pathway. This study provides a new conceptual framework of neuronal ROS as second messengers required for neuronal plasticity and for network tuning, whose dysregulation in the ageing brain and under neurodegenerative conditions may contribute to synaptic dysfunction.


CD4+ T cells that enter the draining lymph nodes after antigen injection participate in the primary response and become central-memory cells.
We explored the relationship between the time of naive CD4+ T cell exposure to antigen in the primary immune response and the quality of the memory cells produced. Naive CD4+ T cells that migrated into the skin-draining lymph nodes after subcutaneous antigen injection accounted for about half of the antigen-specific population present at the peak of clonal expansion. These late-arriving T cells divided less and more retained the central-memory marker CD62L than the T cells that resided in the draining lymph nodes at the time of antigen injection. The fewer cell divisions were related to competition with resident T cells that expanded earlier in the response and a reduction in the number of dendritic cells displaying peptide-major histocompatibility complex (MHC) II complexes at later times after antigen injection. The progeny of late-arriving T cells possessed the phenotype of central-memory cells, and proliferated more extensively during the secondary response than the progeny of the resident T cells. The results suggest that late arrival into lymph nodes and exposure to antigen-presenting cells displaying lower numbers of peptide-MHC II complexes in the presence of competing T cells ensures that some antigen-specific CD4+ T cells divide less in the primary response and become central-memory cells.


US residency training before and after the 1997 Balanced Budget Act.
Graduate medical education (GME) determines the size and characteristics of the future workforce. The 1997 Balanced Budget Act (BBA) limited Medicare funding for additional trainees in GME. There has been concern that because Medicare is the primary source of GME funding, the BBA would discourage growth in GME. To examine the number of residents in training before and after the BBA, as well as more recent changes in GME by specialty, sex, and type and location of education. Descriptive study using the American Medical Association/Association of American Medical Colleges National GME Census on physicians in Accreditation Council for Graduate Medical Education (ACGME)-accredited programs to examine changes in the number and characteristics of residents before and after the BBA. Differences in the number of physicians in ACGME-accredited training programs overall, by specialty, and by location and type of education. The number of residents and fellows changed little between academic year (AY) 1997 (n = 98,143) and AY 2002 (n = 98,258) but increased to 106,012 in AY 2007, a net increase of 7869 (8.0%) over the decade. The annual number of new entrants into GME increased by 7.6%, primarily because of increasing international medical graduates (IMGs). United States medical school graduates (MDs) comprised 44.0% of the overall growth from 2002 to 2007, followed by IMGs (39.2%) and osteopathic school graduates (18.8%). United States MD growth largely resulted from selection of specialties with longer training periods. From 2002 to 2007, US MDs training in primary care specialties decreased by 2641, while IMGs increased by 3286. However, increasing subspecialization rates led to fewer physicians entering generalist careers. After the 1997 BBA, there appears to have been a temporary halt in the growth of physicians training in ACGME programs; however, the number increased from 2002 to 2007.


Stereotactic Radiotherapy for Ultra-Central Lung Oligometastases in Non-Small-Cell Lung Cancer.
Stereotactic body radiotherapy (SBRT) in ultra-central (UC) lung tumors, defined in the presence of planning target volume (PTV) overlap or direct tumor abutment to the central bronchial tree or esophagus, may be correlated to a higher incidence of severe adverse events. Outcome and toxicity in oligometastatic (≤3 metastases) non-small-cell lung cancer (NSCLC) patients receiving SBRT for UC tumors were evaluated. Oligometastatic NSCLC patients treated with SBRT for UC were retrospectively reviewed. Local control (LC), distant metastasis-free survival (DMFS), progression-free survival (PFS) and overall survival (OS) were calculated. Incidence and grade of toxicity were evaluated. Statistical analysis was performed to assess the impact of clinical and treatment-related variables on outcome and toxicity occurrence. Seventy-two patients were treated to a median biologically effective dose (BED) of 105 (75-132) Gy10. Two-year LC, DMFS, PFS, and OS were 83%, 46%, 43%, and 49%. BED>75 Gy10 was correlated to superior LC (p = 0.02), PFS (p = 0.036), and OS (p < 0.001). Grade ≥3 toxicity rate was 7%, including one fatal esophagitis. No variables were correlated to DMFS or to occurrence of overall and grade ≥3 toxicity. SBRT using dose-intensive schedules improves outcome in NSCLC patients. Overall toxicity is acceptable, although rare but potentially fatal toxicities may occur.


Use of a personal microcomputer for orthoptic therapy.
Personal microcomputers have become almost commonplace in the last few years. Their great flexibility and ability to present graphic images on demand would seem to make them ideal tools for use in a visual training program. We have written such a program for doing fusional vergence therapy that interacts with the patient and stores the results of the training sessions. The features of the program are described and the results from two patients are summarized.


Half-filled energy bands induced negative differential resistance in nitrogen-doped graphene.
Nitrogen-doping brings novel properties and promising applications into graphene, but the underlying mechanism is still in debate. To determine the key factor in motivating the negative differential resistance (NDR) behaviour of nitrogen-doped graphene, the electronic structure and transport properties of an 11-dimer wide nitrogen-doped armchair graphene nanoribbon (N-AGNR) were systematically studied by first principles calculations. Both the effect of interaction between N-dopants and the effect of doping-sublattice on the NDR were examined for the first time. Taking into account the two effects, N-AGNR becomes metallic or semiconducting depending on the doping configuration, and its Fermi level varies in a large range. NDR was firmly verified not to be intrinsic for N-AGNRs. However, it is totally determined by whether nitrogen-doping induces half-filled energy bands (HFEBs) because it is HFEBs that cross the Fermi level and determine the transport properties of N-AGNR under low biases. With the bias increasing, the transmission spectrum near the Fermi level showed a flag shape, and therefore, the corresponding transport channel is totally suppressed at a certain bias, resulting in the NDR behaviour with a configuration-dependent peak-to-valley current ratio (PVCR) up to 10(4). Our findings give new insights into the microscopic mechanism of chemical doping induced NDR behaviour and will be useful in building NDR-based nanodevices in the future.


Ultra-High Signal Detection of Human Embryonic Stem Cells Driven by Two-Dimensional Materials.
We observed a unique bioelectric signal of human embryonic stem cells using direct current-voltage measurements facilitated by few-layered 2D-MoS2 sheets. A 1.828 mA cell signal was achieved (2 orders of magnitude higher than previous electrical-based detection methods) as well as multiple cell reading cycles demonstrating I ∼ 1.9 mA. Native stem cell proliferation, viability, and pluripotency were preserved. Molecular dynamics simulations elucidated the origin of the 2D-MoS2 sheet-assisted increase in current flow. This paves the way for the development of a broadly applicable, fast, and damage-free stem cell detection method capable of identifying pluripotency with virtually any complementary-metal-oxide-semiconductor circuits.


Al2C Monolayer Sheet and Nanoribbons with Unique Direction-Dependent Acoustic-Phonon-Limited Carrier Mobility and Carrier Polarity.
The intrinsic acoustic-phonon-limited carrier mobility (μ) of Al2C monolayer sheet and nanoribbons are investigated using ab initio computation and deformation potential theory. It is found that the polarity of the room-temperature carrier mobility of the Al2C monolayer is direction-dependent, with μ of electron (e) and hole (h) being 2348 and 40.77 cm(2)/V/s, respectively, in the armchair direction and 59.95 (e) and 705.8 (h) in the zigzag direction. More interestingly, one-dimensional Al2C nanoribbons not only can retain the direction-dependent polarity but also may entail even higher mobility, in contrast to either the graphene nanoribbons which tend to exhibit lower μ compared to the two-dimensional graphene or the MoS2 nanoribbons which have reversed polarity compared to the MoS2 sheet. As an example, the Al-terminated zigzag nanoribbon with a width of 4.1 nm exhibits μ of 212.6 (e) and 2087 (h) cm(2)/V/s, while the C-terminated armchair nanoribbon with a width 2.6 nm exhibits μ of 1090 (e) and 673.9 (h) cm(2)/V/s; the C-terminated zigzag nanoribbon with a width 3.7 nm exhibits μ of 177.6 (e) and 1889 (h) cm(2)/V/s, and the Al-terminated armchair nanoribbon with a width 2.4 nm exhibits μ of 6695 (e) and 518.4 (h) cm(2)/V/s. The high carrier mobility, μ, coupled with polarity and direction dependence endows the Al2C sheet and nanoribbons with unique transport properties that can be exploited for special applications in nanoelectronics.


Characteristics of Takayasu Arteritis Patients with Severe Ischemic Events.
Takayasu arteritis (TA) is a rare large-vessel vasculitis that puts patients at high risk of developing severe ischemic events (SIE). Outcomes for TA patients with SIE are poorly understood. We aim to describe the characteristics of TA patients experiencing SIE. All TA patients with at least 1 followup visit seen between 1988 and 2015 were included from 3 academic centers in Ontario, Canada. Diagnosis was based on American College of Rheumatology criteria, physician opinion, and vascular imaging. SIE were defined as cerebrovascular accident (CVA), acute coronary syndrome (ACS), ischemic cardiomyopathy, ischemic blindness, and/or ischemic bowel or limb requiring surgery. Of the 52 patients with TA included in the study, 51 (98%) were female and 22 (42%) were of European descent. The mean age was 31 (SD 12) at the time of diagnosis and the followup time was 6 years (SD 5). Fifteen (29%) experienced an SIE: 5 CVA, 5 ACS, 1 ischemic cardiomyopathy, and 4 limb ischemia. Thirteen out of 15 SIE (87%) occurred at or before diagnosis. Patients with SIE were more likely than those without SIE to be started on corticosteroids combined with immunosuppressants (p = 0.04) and antiplatelet agents (p = 0.004). Outcomes including disease activity and damage scores were similar between patients with and without SIE. SIE are common in patients with TA and occur early in the disease. With aggressive treatment, patients with SIE had a favorable prognosis.


Transient sensorineural hearing loss after overuse of portable headphone cassette radios.
Noise-induced sensorineural hearing loss has been associated with industry for many years. One conservative estimate suggests that 10 million Americans may have industry-related, noise-induced hearing loss. Acoustic trauma from any source, whether associated with work or recreations, is detrimental to hearing. The Occupational Safety and Health Administration has set industrial standards for noise levels, with current standards limiting noise exposure to 95 dBA for 2 hours daily. To date, however, there are no recreational standards. Many portable headphone cassette radios produce peak outputs of more than 100 dBA. Temporary threshold shifts could result from listening levels near the maximum output. Permanent sensorineural loss may result with repeated exposure. A pilot study was conducted in which 16 volunteers listened to headphone sets for 3 hours at their usual maximum level. Six volunteers showed transient shifts of 10 dB, and one volunteer showed a transient shift of approximately 30 dB. These shifts returned to normal within 24 hours. As expected, transient shifts frequently occur with recreational use. Therefore, recreational warnings and standards should be established.


Linearity of network proximity measures: implications for set-based queries and significance testing.
In recent years, various network proximity measures have been proposed to facilitate the use of biomolecular interaction data in a broad range of applications. These applications include functional annotation, disease gene prioritization, comparative analysis of biological systems and prediction of new interactions. In such applications, a major task is the scoring or ranking of the nodes in the network in terms of their proximity to a given set of 'seed' nodes (e.g. a group of proteins that are identified to be associated with a disease, or are deferentially expressed in a certain condition). Many different network proximity measures are utilized for this purpose, and these measures are quite diverse in terms of the benefits they offer. We propose a unifying framework for characterizing network proximity measures for set-based queries. We observe that many existing measures are linear, in that the proximity of a node to a set of nodes can be represented as an aggregation of its proximity to the individual nodes in the set. Based on this observation, we propose methods for processing of set-based proximity queries that take advantage of sparse local proximity information. In addition, we provide an analytical framework for characterizing the distribution of proximity scores based on reference models that accurately capture the characteristics of the seed set (e.g. degree distribution and biological function). The resulting framework facilitates computation of exact figures for the statistical significance of network proximity scores, enabling assessment of the accuracy of Monte Carlo simulation based estimation methods. Implementations of the methods in this paper are available at https://bioengine.case.edu/crosstalker which includes a robust visualization for results viewing. firstname.lastname@example.com or email@example.com. Supplementary data are available at Bioinformatics online.


Total versus subtotal gastrectomy: surgical morbidity and mortality rates in a multicenter Italian randomized trial. The Italian Gastrointestinal Tumor Study Group.
The purpose of this study was to analyze postoperative morbidity and mortality of patients included in a randomized trial comparing total versus subtotal gastrectomy for gastric cancer. There is controversy as to whether the optimal surgery for gastric cancer in the distal half of the stomach is subtotal or total gastrectomy. Although only a randomized trial can resolve this oncologic dilemma, the first step is to demonstrate whether the two procedures are penalized by different postoperative morbidity and mortality rates. A total of 624 patients with cancer in the distal half of the stomach were randomized to subtotal gastrectomy (320) or total gastrectomy (304), both associated with a second-level lymphadenectomy, in a multicenter trial aimed at assessing the oncologic outcome after the two procedures. The end points considered were the occurrence of a postoperative event, complication, or death and length of postoperative stay. Nonfatal complications and death occurred in 9% and 1% of subtotal gastrectomy patients and in 13% and 2% of total gastrectomy patients, respectively. Multivariate analysis of postoperative events showed that splenectomy or resection of adjacent organs was associated with a twofold risk of postoperative complications. Random surgery and extension of surgery influenced the length of stay. The mean length of stay, adjusted for extension of surgery, was 13.8 days for subtotal gastrectomy and 15.4 days for total gastrectomy. Our data show that subtotal and total gastrectomies, with second-level lymphadenectomy, performed as an elective procedure have a similar postoperative complication rate and surgical outcome. A conclusive long-term evaluation of the two operations and an accurate estimate of the oncologic impact of surgery on long-term survival, not penalized by excess surgical risk of one of the two operations, are consequently feasible.


Caveolin-1 single nucleotide polymorphism in antineutrophil cytoplasmic antibody associated vasculitis.
Immunosuppression is cornerstone treatment of antineutrophil cytoplasmic antibody associated vasculitis (AAV) but is later complicated by infection, cancer, cardiovascular and chronic kidney disease. Caveolin-1 is an essential structural protein for small cell membrane invaginations known as caveolae. Its functional role has been associated with these complications. For the first time, caveolin-1 (CAV1) gene variation is studied in AAV. CAV1 single nucleotide polymorphism rs4730751 was analysed in genomic DNA from 187 white patients with AAV from Birmingham, United Kingdom. The primary outcome measure was the composite endpoint of time to all-cause mortality or renal replacement therapy. Secondary endpoints included time to all-cause mortality, death from sepsis or vascular disease, cancer and renal replacement therapy. Validation of results was sought from 589 white AAV patients, from two European cohorts. The primary outcome occurred in 41.7% of Birmingham patients. In a multivariate model, non-CC genotype variation at the studied single nucleotide polymorphism was associated with increased risk from: the primary outcome measure [HR 1.86; 95% CI: 1.14-3.04; p=0.013], all-cause mortality [HR:1.83; 95% CI: 1.02-3.27; p=0.042], death from infection [HR:3.71; 95% CI: 1.28-10.77; p=0.016], death from vascular disease [HR:3.13; 95% CI: 1.07-9.10; p=0.037], and cancer [HR:5.55; 95% CI: 1.59-19.31; p=0.007]. In the validation cohort, the primary outcome rate was far lower (10.4%); no association between genotype and the studied endpoints was evident. The presence of a CC genotype in Birmingham is associated with protection from adverse outcomes of immunosuppression treated AAV. Lack of replication in the European cohort may have resulted from low clinical event rates. These findings are worthy of further study in larger cohorts.


[Tuberculosis infection among teenagers].
Infection with tuberculosis was studied in 3509 adolescents aged 15 years from various social groups via twice BCG revaccination by analyzing the responses to Mantoux tests with 2 TU of tuberculin purified protein derivative and by following them up for 3 years with an annual examination of the same group. The rates of infection among the teenagers was found to be 32.1% and higher (58.5%) in persons without vaccination signs, but with the latter they depend upon the time after BCG vaccination: 0.7% 3 years after the second revaccination, 30.2% after the first revaccination, and 66.8% 15 years following the first vaccination. The timely and qualitative antituberculosis immunization during twice revaccination contributes to reduced infection rates among teenagers.


Sequence, biophysical, and structural analyses of the PstS lipoprotein (BB0215) from Borrelia burgdorferi reveal a likely binding component of an ABC-type phosphate transporter.
The Lyme disease agent Borrelia burgdorferi, which is transmitted via a tick vector, is dependent on its tick and mammalian hosts for a number of essential nutrients. Like other bacterial diderms, it must transport these biochemicals from the extracellular milieu across two membranes, ultimately to the B. burgdorferi cytoplasm. In the current study, we established that a gene cluster comprising genes bb0215 through bb0218 is cotranscribed and is therefore an operon. Sequence analysis of these proteins suggested that they are the components of an ABC-type transporter responsible for translocating phosphate anions from the B. burgdorferi periplasm to the cytoplasm. Biophysical experiments established that the putative ligand-binding protein of this system, BbPstS (BB0215), binds to phosphate in solution. We determined the high-resolution (1.3 Å) crystal structure of the protein in the absence of phosphate, revealing that the protein's fold is similar to other phosphate-binding proteins, and residues that are implicated in phosphate binding in other such proteins are conserved in BbPstS. Taken together, the gene products of bb0215-0218 function as a phosphate transporter for B. burgdorferi.


Semiautomatic carotid lumen segmentation for quantification of lumen geometry in multispectral MRI.
Quantitative information about the geometry of the carotid artery bifurcation is relevant for investigating the onset and progression of atherosclerotic disease. This paper proposes an automatic approach for quantifying the carotid bifurcation angle, carotid area ratio, carotid bulb size and the vessel tortuosity from multispectral MRI. First, the internal and external carotid centerlines are determined by finding a minimum cost path between user-defined seed points where the local costs are based on medialness and intensity. The minimum cost path algorithm is iteratively applied after curved multi-planar reformatting to refine the centerline. Second, the carotid lumen is segmented using a topology preserving geodesic active contour which is initialized by the extracted centerlines and steered by the MR intensities. Third, the bifurcation angle and vessel tortuosity are automatically extracted from the segmented lumen. The methods for centerline tracking and lumen segmentation are evaluated by comparing their accuracy to the inter- and intra-observer variability on 48 datasets (96 carotid arteries) acquired as part of a longitudinal population study. The evaluation reveals that 94 of 96 carotid arteries are segmented successfully. The distance between the tracked centerlines and the reference standard (0.33 mm) is similar to the inter-observer variation (0.32 mm). The lumen segmentation accuracy (average DSC=0.89, average mean absolute surface distance=0.31 mm) is close to the inter-observer variation (average dice=0.92, average mean surface distance=0.23 mm). The correlation coefficient of manually and automaticly derived bifurcation angle, carotid proximal area ratio, carotid proximal bulb size and vessel totuosity quantifications are close to the correlation of these measures between observers. This demonstrates that the automated method can be used for replacing manual centerline annotation and manual contour drawing for lumen segmentation in MRIs data prior to quantifying the carotid bifurcation geometry.


Coronary allograft vasculopathy managed by Flash ostial balloon in a pediatric patient.
Coronary allograft vasculopathy (CAV) is the most significant cause of morbidity and mortality in heart transplant recipients. Inflammation and endothelial dysfunction caused by graft rejection and viral infections leads to a combination of circumferential intimal fibromuscular hyperplasia, atherosclerosis, and inflammation affecting all layers of the vessel wall. Though obstructive CAV is often asymptomatic, posing a diagnostic challenge in post-transplant patients, early diagnosis and treatment aid faster recovery and improved outcomes. The role of percutaneous coronary intervention in the treatment of CAV is unknown and not well studied in the pediatric population. We present a first-in-human case of ostial left main coronary artery disease managed with flaring of the ostial coronary stent using a Flash ostial balloon in a pediatric patient with history of an orthotopic heart transplant.


Assessment and management of patients with venous, arterial, and diabetic/neuropathic lower extremity wounds.
Most healthcare providers recognize that management of lower extremity wounds presents a difficult challenge. These chronic wounds significantly impact the quality of life for individuals and have implications for costs and utilization of healthcare resources. Lower extremity wounds can be due to a myriad of different diseases, but the primary causes are chronic venous insufficiency, lower extremity arterial disease, and diabetes/neuropathy. Differential assessment is necessary prior to implementation of management strategies in order to address the etiology and pathogenesis factors that are related to each type of leg wound. This article presents an overview of the risk and predisposing factors for venous, arterial, and diabetic/neuropathic wounds. Additionally, it addresses issues of differential assessment including typical locations, common clinical characteristics, typical wound appearance, key management issues, considerations for alternative treatments, collaborative care, and patient/family education.


Topoisomerase 1 Promoter Variants and Benefit from Irinotecan in Metastatic Colorectal Cancer Patients.
Topoisomerase 1 (topo-1) is an important target for the treatment of metastatic colorectal cancer (CRC). The aim of the present study was to evaluate the correlation between topo-1 single-nucleotide polymorphisms (SNPs) and clinical outcome in metastatic CRC (mCRC) patients. With the use of specific software (PROMO 3.0), we performed an in silico analysis of topo-1 promoter SNPs; the rs6072249 and rs34282819 SNPs were included in the study. DNA was extracted from 105 mCRC patients treated with FOLFIRI ± bevacizumab in the first line. SNP genotyping was performed by real-time PCR. Genotypes were correlated with clinical parameters (objective response rate, progression-free survival, and overall survival). No single genotype was significantly associated with clinical variables. The G allelic variant of rs6072249 topo-1 SNP is responsible for GC factor and X-box-binding protein transcription factor binding. The same allelic variant showed a nonsignificant trend toward a shorter progression-free survival (GG, 7.5 months; other genotypes, 9.3 months; HR 1.823, 95% CI 0.8904-3.734; p = 0.1). Further analyses are needed to confirm that the topo-1 SNP rs6072249 and transcription factor interaction could be a part of tools to predict clinical outcome in mCRC patients treated with irinotecan-based regimens.


Redox sensing properties of the ryanodine receptor complex.
The release mechanism regulating SR Ca2+ homeostasis is significantly more sensitive than the uptake mechanisms. The exquisite sensitivity exhibited by ryanodine-sensitive Ca2+ channel complexes (i.e., ryanodine receptors, RyRs) to functional perturbation by chemically diverse sulfhydryl-modifying compounds can include phases of activation and inhibition that are dependent on the concentration of the reagent used, the length of exposure, and the nature of the chemical reaction the reagent undertakes with sulfhydryl groups. However the exquisite sensitivity of RyR function to sulfhydryl modification has been generally viewed as significant only in pathophysiological processes. The present paper addresses possible physiological importance of the redox sensing properties of the ryanodine receptor complexes (RyRs) and proposes an underlying mechanism. New data is presented that directly measure the pKa of hyperreactive thiols that occur when the closed conformation of the RyR channel complex is assumed, and that appear to be an integral component of the redox sensor.


[Inhibition of Proteus sp. by Nalidixic acid].
The investigation comprised 192-positive and Gram-negative strains of bacteria, including 111 Proteus sp. The degree of resistance of these strains to nalidixic-acid was investigated on blood agar with 25 mug, 40 mug, and 50 mug nalidixin-acid per ml medium. None of the Proteus strains were able to grow on medium with 50 mug nalidixic-acid per ml, whereas Streptococcus sp., Corynebacterium pyogenes, Peptococcus indolicus, Pseudomonas aeruginosa, and beta-toxic staphylococci all were found resistant to this concentration (Tables I and II), and could be reisolated in pure culture after having grown together with a Proteus strain on such medium (Table III). Blood agar with 50 mug nalidixic-acid per ml is therefore suitable for isolation of the above mentioned Gram-positive bacteria and Pseudomonas aeruginosa from Proteus contaminated material.


The threshold pattern of calcineurin-dependent gene expression is altered by loss of the endogenous inhibitor calcipressin.
Calcineurin links calcium signaling to transcriptional responses in the immune, nervous and cardiovascular systems. To determine the function of the calcipressins, a family of putative calcineurin inhibitors, we assessed the calcineurin-dependent process of T cell activation in mice engineered to lack the gene encoding calcipressin 1 (Csp1). Csp1 regulated calcineurin in vivo, and genes triggered in an immune response had unique transactivation thresholds for T cell receptor stimulation. In the absence of Csp1, the apparent transactivation thresholds for all these genes were shifted because of enhanced calcineurin activity. This unbridled calcineurin activity drove Fas ligand expression, which normally requires high T cell receptor stimulation and results in the premature death of T helper type 1 cells. Thus, calcipressins modulate the pattern of calcineurin-dependent transcription, and may influence calcineurin activity beyond calcium to integrate a broad array of signals into the cellular response.


Temporal analysis of lipopolysaccharide-induced sickness behavior in virgin and lactating female rats.
Lipopolysaccharide (LPS), an endotoxin that originates from the cell wall of Gram-negative bacteria, activates the immune system to release proinflammatory cytokines and to induce sickness behavior. The present study sought to characterize the time-dependent effects of LPS on fever, body weight, and food and water consumption in female virgin and lactating rats exposed to an LPS dose previously reported to induce sickness behavior in pregnant female rats. Virgin female Wistar rats in the estrous phase and lactating female Wistar rats on the third day of lactation received 100 µg/kg LPS or saline solution. Tympanic temperature, body weight, and food and water consumption were assessed 0, 2, 24, 48, 72, 96, and 120 h after treatment. In lactating female rats, tympanic temperature was attenuated compared with virgin females. Food consumption and body weight gain in both groups decreased, but lactating rats consumed more food than virgin rats. Water consumption increased at different time points. LPS exposure induced several signs of sickness behavior, including decreases in food consumption and body weight gain, and induced adipsia in both virgin and lactating female rats. Because the time course and profile of fever varied between lactating and nonlactating animals, these responses appeared to depend on the physiological state of female animals.


Magnetically recoverable core-shell nanocomposites with enhanced photocatalytic activity.
Core-shell structured Fe(3)O(4)/SiO(2)/TiO(2) nanocomposites with enhanced photocatalytic activity that are capable of fast magnetic separation have been successfully synthesized by combining two steps of a sol-gel process with calcination. The as-obtained core-shell structure is composed of a central magnetite core with a strong response to external fields, an interlayer of SiO(2), and an outer layer of TiO(2) nanocrystals with a tunable average size. The convenient control over the size and crystallinity of the TiO(2) nanocatalysts makes it possible to achieve higher photocatalytic efficiency than that of commercial photocatalyst Degussa P25. The photocatalytic activity increases as the thickness of the TiO(2) nanocrystal shell decreases. The presence of SiO(2) interlayer helps to enhance the photocatalytic efficiency of the TiO(2) nanocrystal shell as well as the chemical and thermal stability of Fe(3)O(4) core. In addition, the TiO(2) nanocrystals strongly adhere to the magnetic supports through covalent bonds. We demonstrate that this photocatalyst can be easily recycled by applying an external magnetic field while maintaining their photocatalytic activity during at least eighteen cycles of use.


Recent experience with heart transplantation.
The major factors contributing to the recommencement of clinical heart transplantation in the United Kingdom last year were the steadily improving results from Stanford University, the clarification of the diagnosis of brain death, and advances in preserving donor hearts. Twelve men aged 16 to 52 years received heart transplants at Papworth Hospital from January 1979 to July 1980. Six had cardiomyopathies and six ischaemic heart disease. The donors were aged 16 to 35 (mean 21) years. A combination of road and air transport was used to transport the heart to Papworth in seven cases. The total donor heart ischaemic time ranged from 108 to 171 minutes (mean 151), and early graft function was satisfactory in all cases. Postoperative management was directed towards preventing rejection and infection. Equine antihuman thymocyte globulin, prednisolone, and azathioprine were used for immunosuppression. Endomyocardial biopsy was performed every 10 to 14 days during the early postoperative period. There were three deaths: one at 17 days from brain damage and two at 59 and 76 days from rejection. Of the remaining nine patients six left hospital and three returned to work. The number of patients who might benefit from heart transplantation is large, but the cost is high. The cost would fall if an effective non-toxic immunosuppressive agent were developed. Meanwhile, a careful evaluation of the benefits of heart transplantation should continue.


Defining digital coaching: a qualitative inductive approach.
The term 'digital coaching' is widely used but ill-defined. The present study therefore investigates how digital coaching is defined and how it differentiates from face-to-face coaching and other digital-technology-enabled (DT-enabled) formats, such as digital training, digital mentoring, or digital consulting. A qualitative inductive approach was chosen for more in-depth and open-minded content. Based on previous studies on the importance of asking coaches working in the field, 260 coaches working in the field of digital coaching were surveyed. The given answers depict the importance of differing between forms of DT-enabled coaching. Thus, digital coaching is a DT-enabled, synchronous conversation between a human coach and a human coachee, which is different to artificial intelligence (AI) coaching and coaching that is supported by asynchronous digital and learning communication technologies. Due to this definition and differentiation, future studies can explore the digital coaching process and its effectiveness - particularly in comparison to other formats. Furthermore, this clear definition enables practitioners to maintain professional standards and manage client's expectations of digital coaching while helping clients understand what to expect from digital coaching.


Cross talk between O-GlcNAcylation and phosphorylation: roles in signaling, transcription, and chronic disease.
O-GlcNAcylation is the addition of β-D-N-acetylglucosamine to serine or threonine residues of nuclear and cytoplasmic proteins. O-linked N-acetylglucosamine (O-GlcNAc) was not discovered until the early 1980s and still remains difficult to detect and quantify. Nonetheless, O-GlcNAc is highly abundant and cycles on proteins with a timescale similar to protein phosphorylation. O-GlcNAc occurs in organisms ranging from some bacteria to protozoans and metazoans, including plants and nematodes up the evolutionary tree to man. O-GlcNAcylation is mostly on nuclear proteins, but it occurs in all intracellular compartments, including mitochondria. Recent glycomic analyses have shown that O-GlcNAcylation has surprisingly extensive cross talk with phosphorylation, where it serves as a nutrient/stress sensor to modulate signaling, transcription, and cytoskeletal functions. Abnormal amounts of O-GlcNAcylation underlie the etiology of insulin resistance and glucose toxicity in diabetes, and this type of modification plays a direct role in neurodegenerative disease. Many oncogenic proteins and tumor suppressor proteins are also regulated by O-GlcNAcylation. Current data justify extensive efforts toward a better understanding of this invisible, yet abundant, modification. As tools for the study of O-GlcNAc become more facile and available, exponential growth in this area of research will eventually take place.


Identification of chromosomal translocations in leukemias by hybridization with oligonucleotide microarrays.
Identification of chromosomal rearrangements is important for a precise risk-stratified diagnosis of hematologic malignancies. As the number of known translocations, specific for different types of leukemia increases, it takes ever more time and increasing amounts of patient's material to screen a single patient with individual polymerase chain reactions (PCR). The aim of this study was to develop a new approach combining specificity with high-throughput sufficient for rapid screening of clinical samples for the presence of numerous translocations. We designed an oligonucleotide microarray and used hybridization with microarrays in combination with multiplex reverse transcription-polymerase chain reaction (RT-PCR) assay for accurate and rapid identification of some major leukemias. The following translocations were used as prototypic: t(9;22) p210 and p190, t(4;11), t(12;21), and t(15;17). This approach was tested on five different cell cultures carrying translocations and on 22 clinical samples from leukemic patients. Distinctive hybridization signals were obtained for all types of chimeric transcripts from cell lines with translocations. Both the type of translocation and the splice variant were determined. The data demonstrated high specificity and reproducibility of the method. Analysis of the 22 clinical samples using the microarray-based approach showed complete agreement with standard PCR analysis. Our data suggest that oligonucleotide microarrays can be used as an efficient, alternative approach to the traditional post-PCR Southern blot analysis. The oligonucleotide microarray approach appears suitable for clinical screening of major risk-stratifying translocations in patients with leukemia.


Proxy reports in Parkinson's disease: caregiver and patient self-reports of quality of life and physical activity.
We evaluated patient-proxy agreement in a population of veterans with Parkinson's disease and compared levels of agreement by patient subgroups. Patient and caregiver pairs completed questionnaires composed of standard measures and additional demographic and activity questions. Participants completed the Center for Epidemiologic Studies Depression Scale (CES-D), the PD Questionnaire 39 (PDQ-39), and three questions regarding physical activity. Caregivers completed proxy forms of the PDQ-39 and the physical activity questionnaire. The proxy forms asked caregivers to choose the answers that best described their "friend's/patient's situation." The results of our comparison of patient and proxy reports of quality of life were consistent with findings in other diseases. On average, proxies rated patient disability higher and quality of life lower than did patients. However, our comparison of patient and proxy reports of frequency of exercise diverged from previously published work. Less agreement was observed between patient and proxy reports of physical activity, even though this is a more objective variable than are the domains measured by the PDQ-39. Proxy reports may diverge appreciably from patient self-reports. These differences should be considered in research design and clinical decision making. Alternative approaches to the measurement of patient relevant outcomes could supplement traditional, retrospective self-reports.


Density of somatic innervation on mammalian autonomic ganglion cells is inversely related to dendritic complexity and preganglionic convergence.
I have studied superior cervical ganglion cells in mouse, hamster, rat, guinea pig, and rabbit by electron microscopy to determine how the distribution of synapses on these neurons is affected by the systematic differences in dendritic morphology and preganglionic convergence that are evident in the superior cervical ganglia of these species (Purves, D., and J. W. Lichtman (1985) Science 228: 298-302). The density of dendritic innervation is approximately the same in these animals regardless of target cell geometry (and always greater than the density of synapses on the cell soma); however, more complex ganglion cells, which are innervated by commensurately more axons, receive progressively fewer cell body synapses than geometrically simpler ganglion cells. Evidently the somatic membrane becomes a less favorable site for synapse formation as dendritic complexity and the number of inputs increase. This paradoxical decrease in the density of somatic innervation as preganglionic convergence increases may reflect competitive interactions between the axons innervating individual ganglion cells.


Outpatient-based bone marrow transplantation for hematologic malignancies: cost saving or cost shifting?
To determine whether a shift in care from an inpatient-based to an outpatient-based bone marrow transplantation (BMT) program decreased charges to payers without increasing clinical complications or out-of-pocket costs to patients. This nonrandomized prospective cohort study compared clinical and economic outcomes for 132 consecutive BMT patients with hematologic malignancies who received either inpatient- or outpatient-based BMT care. Seventeen of 132 BMT patients underwent outpatient-based BMT. Compared with the inpatient-based group, the outpatient-based group had a markedly lower mean number of inpatient hospital days (22 v 47; P <.001) and decreased mean inpatient facility charges ($61,059 less per patient; P <.0001) but had higher mean outpatient facility charges ($49,732 higher; P <. 0001). Total professional fees were similar for the groups. The mean total charge to payers was only 7% less ($12,652; P =.21) for outpatient-based BMT than for inpatient-based BMT, but total charge was 34% less for outpatient compared with inpatient BMT ($54,240; P = 0.056) in a subset of patients who had a standard rather than high risk of treatment failure. There was no significant difference between groups in out-of-pocket costs for transportation, lodging, meals, home nursing, household assistance, child care, medication expenses, or unreimbursed medical bills. There also was no significant difference between groups in reported income lost, involuntary unemployment, or months of disability. The two groups had similar rates of major complications, including death, significant acute graft-versus-host disease, and veno-occlusive disease of the liver. Increased use of outpatient-based BMT should produce substantial cost savings for payers without adverse effects on patients for those patients who do not have a high risk of treatment failure.


TEDE per cumulated activity for family members exposed to adult patients treated with 131I.
In 1997, the United States Nuclear Regulatory Commission amended its criteria under which patients administered radioactive materials could be released from the hospital. The revised criteria ensures that the total effective dose equivalent (TEDE) to any individual exposed to the released patient will not likely exceed 5 mSv. Licensees are recommended to use one of the three options to release the patient in accordance with these regulatory requirements: administered activity, measured dose rate, or patient-specific dose calculation. The NRC's suggested calculation method is based on the assumption that the patient (source) and a family member (target) are each considered to be points in space. This point source/target assumption has been shown to be conservative in comparison to more realistic guidelines. In this present study, the effective doses to family members were calculated using a series of revised Oak Ridge National Laboratory stylised phantoms coupled with a Monte Carlo radiation transport code. A set of TEDE per cumulated activity values were calculated for three different distributions of (131)I (thyroid, abdomen and whole body), various separation distances and two exposure scenarios (face-to-face standing and side-by-side lying). The results indicate that an overestimation of TEDE per cumulated activity based on the point source/target method was >2-fold. The values for paediatric phantoms showed a strong age-dependency, which showed that dosimetry for children should be separately considered instead of using adult phantoms as a substitute. On the basis of the results of this study, a licensee may use less conservative patient-specific release criteria and provide the patient and the family members with more practical dose avoidance guidelines.


Long-term safety and efficacy of tafamidis for the treatment of hereditary transthyretin amyloid polyneuropathy: results up to 6 years.
The objective of the present study was to evaluate the long-term safety and efficacy of tafamidis in treating hereditary transthyretin amyloid polyneuropathy. A prospectively planned interim analysis was conducted on an on-going, phase III, open-label extension study following an 18-month, randomized, controlled study and 12-month, open-label extension study in ATTRV30M patients and a single-arm, open-label study in non-ATTRV30M patients. Thirty-seven ATTRV30M patients received placebo for 18 months, then switched to tafamidis and 38 ATTRV30M patients and 18 non-ATTRV30M patients continuously received tafamidis from day 1, up to 6 years. Long-term tafamidis was associated with a favourable safety/tolerability profile, without any unexpected adverse events. Patients initiating tafamidis at the start of the randomized study had less polyneuropathy progression versus those switching to tafamidis following 18 months of placebo and were less likely to progress to the next ambulatory stage after up to 6 years follow-up. In the patients who switched from placebo to tafamidis, polyneuropathy progression and deterioration in quality of life slowed significantly during long-term tafamidis treatment as compared with the previous placebo treatment. In non-ATTRV30M patients, some polyneuropathy progression was observed across all efficacy measures. These data provide evidence for the long-term (up to 6 years) safety and efficacy of tafamidis.ClinicalTrials.gov: NCT00925002.


Maternal High Fat Diet in Lactation Impacts Hypothalamic Neurogenesis and Neurotrophic Development, Leading to Later Life Susceptibility to Obesity in Male but Not Female Mice.
Early life nutrition can reprogram development and exert long-term consequences on body weight regulation. In mice, maternal high-fat diet (HFD) during lactation predisposed male but not female offspring to diet-induced obesity when adult. Molecular and cellular changes in the hypothalamus at important time points are examined in the early postnatal life in relation to maternal diet and demonstrated sex-differential hypothalamic reprogramming. Maternal HFD in lactation decreased the neurotropic development of neurons formed at the embryo stage (e12.5) and impaired early postnatal neurogenesis in the hypothalamic regions of both males and females. Males show a larger increased ratio of Neuropeptide Y (NPY) to Pro-opiomelanocortin (POMC) neurons in early postnatal neurogenesis, in response to maternal HFD, setting an obese tone for male offspring. These data provide insights into the mechanisms by which hypothalamic reprograming by early life overnutrition contributes to the sex-dependent susceptibility to obesity in adult life in mice.


Antitumor effects of histone deacetylase inhibitor on Ewing's family tumors.
A chimeric protein, EWS-Fli1, identified in most Ewing's family tumors (EFTs) has been shown to be associated with the tumorigenicity of EFTs. We have previously reported that p21(Waf1/Cip1) expression was inhibited by EWS-Fli1 in EFTs. Histone deacetylase inhibitors (HDACIs) are known to up-regulate p21(Waf1/Cip1) expression in various cells and show promise as a cancer therapy. Here, we demonstrate the possible involvement of EWS-Fli1 in the activities of both histone acetylation and deacetylation, as well as the potential use of HDACIs as an antitumor agent for EFTs. A novel HDACI, FK228, strongly induced p21(Waf1/Cip1) expression, leading to the hypophosphorylation of retinoblastoma protein (Rb) in EFT cells. Results indicated that EWS-Fli1 deregulated histone acetylation through both the repression of histone acetyltransferase (HAT) and the enhancement of histone deacetylase (HDAC) activities in EFT cells. FK228 treatment blocked both of the abnormal functions of EWS-Fli1. Expressions of EWS-Fli1 protein and mRNA were also inhibited by HDACIs. We suggest that HDACIs might inhibit the expression of EWS-Fli1 via the suppression of the EWS promoter activity. FK228 demonstrated potent growth inhibitory effects on EFT cells at nanomolar concentrations, as well as an apparent distinction in the apoptotic effects between EFT and normal cells. Moreover, intraperitoneal administration of FK228 significantly inhibited tumor growth and induced apoptosis in EFTs in vivo. These results suggest that HDACI might be a promising reagent for use in molecular-based chemotherapy against EFTs.


Classification Model for Differentiating Post-ACLR Individuals Using Loading Rate Variation.
In post-ACLR individuals, gait variability often represents the presence of altered motor control. Quantifying variable limb loading is challenging, yet nonlinear analyses have been successful in detecting changes in gait variability due to altered motor control. Here, nonlinear metrics were derived and used to train multiple machine learning models to classify between healthy controls and post-ACLR individuals. The metrics were extracted from individuals' vertical ground reaction force data during a fast-walking trial as variable limb loading is exacerbated when the system is stressed and being challenged. It was hypothesized that effective differentiation between healthy control and post-ACLR individuals would be achieved using machine learning models derived from limb loading rate variability measures. Seventeen healthy control and fourteen post-ACLR participants with measured between-limb loading rate asymmetries completed the walking protocol. Ground reaction force data was collected on an instrumented treadmill where they performed walking trials at 1.5 m/s. Nonlinear limb loading rate measures extracted from the healthy controls and post-ACLR participants' data served as inputs to the models in order to train them to distinguish between the two states. A Decision Tree Classifier that utilized a bagging strategy was the best model for distinguishing between healthy control and post-ACLR participants. The model was successful in classifying participants, reporting an accuracy score of 73%, precision score of 100%, and an AUC score of 0.77, despite the smaller dataset. The ability to detect and classify post-ACLR loading rate variation has significant clinical implications, as these methods could be implemented in clinical settings to diagnose pathological limb loading dynamics and/or altered motor control.Clinical Relevance- This classification model can be easily integrated into the clinic to help diagnose pathological limb loading based solely on vertical ground reaction forces and can aid clinicians in providing data-driven metrics to help inform rehabilitation decisions.