Towards a comprehensive framework for movement and distortion correction of diffusion MR images: Within volume movement.
Most motion correction methods work by aligning a set of volumes together, or to a volume that represents a reference location. These are based on an implicit assumption that the subject remains motionless during the several seconds it takes to acquire all slices in a volume, and that any movement occurs in the brief moment between acquiring the last slice of one volume and the first slice of the next. This is clearly an approximation that can be more or less good depending on how long it takes to acquire one volume and in how rapidly the subject moves. In this paper we present a method that increases the temporal resolution of the motion correction by modelling movement as a piecewise continous function over time. This intra-volume movement correction is implemented within a previously presented framework that simultaneously estimates distortions, movement and movement-induced signal dropout. We validate the method on highly realistic simulated data containing all of these effects. It is demonstrated that we can estimate the true movement with high accuracy, and that scalar parameters derived from the data, such as fractional anisotropy, are estimated with greater fidelity when data has been corrected for intra-volume movement. Importantly, we also show that the difference in fidelity between data affected by different amounts of movement is much reduced when taking intra-volume movement into account. Additional validation was performed on data from a healthy volunteer scanned when lying still and when performing deliberate movements. We show an increased correspondence between the "still" and the "movement" data when the latter is corrected for intra-volume movement. Finally we demonstrate a big reduction in the telltale signs of intra-volume movement in data acquired on elderly subjects.


Magnetic resonance microimaging of intraaxonal water diffusion in live excised lamprey spinal cord.
Anisotropy of water diffusion in axon tracts, as determined by diffusion-weighted MRI, has been assumed to reflect the restriction of water diffusion across axon membranes. Reduction in this anisotropy has been interpreted as degeneration of axons. These interpretations are based primarily on a priori reasoning that has had little empirical validation. We used the experimental advantages of the sea lamprey spinal cord, which contains several very large axons, to determine whether intraaxonal diffusion is isotropic and whether anisotropy is attributable to restriction of water mobility by axon surface membranes. Through the application of magnetic resonance microimaging, we were able to measure the purely intraaxonal diffusion characteristics of the giant reticulospinal axons (20-40 microm in diameter). The intraaxonal apparent diffusion coefficients of water parallel (longitudinal ADC, l-ADC) and perpendicular (transverse ADC, t-ADC) to the long axis were 0.98 +/- 0.06 (10(-3) mm2 sec) and 0.97 +/- 0.11 (10(-3) mm2 sec), respectively. In white matter regions that included multiple axons, l-ADCs were almost identical regardless of axon density in the sampled axon tract. By comparison, t-ADCs were reduced and varied inversely with the number of axons (and thus axolemmas) in a fixed cross-sectional area. Thus, diffusion was found to be isotropic when measured entirely within a single axon and anisotropic when measured in regions that included multiple axons. These findings support the hypothesis that the cell membrane is the primary source of diffusion anisotropy in fiber tracts of the central nervous system.


Evaluating the Initiation of Novel Oral Anticoagulants in Medicare Beneficiaries.
As alternatives to warfarin, 2 novel oral anticoagulants (NOACs), dabigatran and rivaroxaban, were approved in 2010 and 2011 to prevent stroke and other thromboembolic events in patients with atrial fibrillation. It is unclear how patient characteristics are associated with the initiation of anticoagulants. To evaluate how patient demographics, clinical characteristics, types of insurance, and patient out-of-pocket spending affect the initiation of warfarin and 2 NOACs--dabigatran and rivaroxaban. We used pharmacy claims data from a 5% random sample of Medicare beneficiaries to identify patients who were newly diagnosed with atrial fibrillation between October 1, 2010, and October 31, 2012, and who were prescribed an oral anticoagulant within 60 days of diagnosis. We identified key predictors of initiation of NOACs using a multinomial logistic regression model with generalized logit link. Patients who were black and who had a history of acute myocardial infarction, stroke or transient ischemic attack, chronic kidney disease, or congestive heart failure were significantly associated with lower odds of receiving NOACs compared with warfarin. Age greater than 65 years, a history of hypertension, and use of nonsteroidal anti-inflammatory drugs were positively associated with the initiation of NOACs. Rivaroxaban was most likely to be initiated among women, followed by warfarin and dabigatran. Individuals receiving a low-income subsidy were more likely to initiate warfarin than NOACs, even though they paid little copayment. Individuals with supplemental Part D drug coverage, such as national Programs for All-Inclusive Care for the Elderly or employer-sponsored plans, were more likely to initiate NOACs compared with warfarin. We found that race, sex, type of Part D plans, and some clinical conditions were associated with the initiation of NOACs relative to warfarin. But patient demographic and clinical characteristics did not appear to affect which particular NOAC patients initiated.


Global analysis of mRNA stability in the archaeon Sulfolobus.
Transcript half-lives differ between organisms, and between groups of genes within the same organism. The mechanisms underlying these differences are not clear, nor are the biochemical properties that determine the stability of a transcript. To address these issues, genome-wide mRNA decay studies have been conducted in eukaryotes and bacteria. In contrast, relatively little is known about RNA stability in the third domain of life, Archaea. Here, we present a microarray-based analysis of mRNA half-lives in the hyperthermophilic crenarchaea Sulfolobus solfataricus and Sulfolobus acidocaldarius, constituting the first genome-wide study of RNA decay in archaea. The two transcriptomes displayed similar half-life distributions, with medians of about five minutes. Growth-related genes, such as those involved in transcription, translation and energy production, were over-represented among unstable transcripts, whereas uncharacterized genes were over-represented among the most stable. Half-life was negatively correlated with transcript abundance and, unlike the situation in other organisms, also negatively correlated with transcript length. The mRNA half-life distribution of Sulfolobus species is similar to those of much faster growing bacteria, contrasting with the earlier observation that median mRNA half-life is proportional to the minimal length of the cell cycle. Instead, short half-lives may be a general feature of prokaryotic transcriptomes, possibly related to the absence of a nucleus and/or more limited post-transcriptional regulatory mechanisms. The pattern of growth-related transcripts being among the least stable in Sulfolobus may also indicate that the short half-lives reflect a necessity to rapidly reprogram gene expression upon sudden changes in environmental conditions.


The effect of Nigella sativa L. (black cumin seed) on intractable pediatric seizures.
Despite the availability and use of numerous antiepileptic drugs (AEDs), nearly 15% of childhood epilepsy cases are resistant to treatment. However, in traditional medicine, Nigella Sativa L. ("black cumin seed") has been known for its anticonvulsant effects. This plant is naturally distributed in Iran and has been widely used as a natural remedy for a long time. In this study the efficacy of this agent in reducing the frequency of seizures in childhood refractory epilepsy was assessed. In this double-blinded crossover clinical trial conducted on children with refractory epilepsy, the aqueous extract of black seed was administered as an adjunct therapy and the effects were compared with those of a placebo. Twenty-three children were entered in the study and 20 remained in the study (13 months to 13 years old, 10 boys and 10 girls). All patients were receiving constant treatment for at least one month before the study. They received extract (40 mg/kg/8 h) or placebo for a period of four weeks and between these periods for two weeks they received only their pre-existing anti-epileptic drugs (AEDs). The mean frequency of seizures decreased significantly during treatment with extract (p<0.05). It can be concluded that the water extract of Nigella sativa L. has antiepileptic effects in children with refractory seizures.


A genome-wide association study of suicidal behavior.
Genome wide array studies have reported limited success in identifying genetic markers conferring risk for suicidal behavior (SB). This may be attributable to study designs with primary outcome other than SB. We performed a GWAS on suicides and cases with a history of nonfatal suicide attempts compared with psychiatric controls and healthy volunteers. A consortium of USA, Canadian and German teams assembled two groups of cases (suicide attempters and suicides, N = 577) and non-attempter psychiatric and healthy controls (N = 1,233). Logistic regression was used to test genotype-suicidal behavior association. The test was repeated separating suicide attempt and completed suicide as outcomes. No SNP reached genome-wide significance, but several SNPs within STK3, ADAMTS14, PSME2, and TBX20 genes reached P < 1 × 10(-5) . The top SNPs for the suicide attempt analysis included two from DPP10, one from CTNNA3 and one from STK32B. In the suicide analysis we found seven SNPs from the TBX20 gene in the top hits. Pathway analysis identified the following pathways: "Cellular Assembly and Organization," "Nervous System Development and Function," "Cell Death and Survival," "Immunological Disease," "Infectious Disease," and "Inflammatory Response." The top genes in the SB analysis did not overlap with those in the ideation analysis. No genome wide significant results suggest that susceptibility to SB has genetic risk factors with smaller effect sizes. The strongest candidate genes, ADAMTS14, and PSME2 (both linked to inflammatory response), STK3 (neuronal cell death), and TBX20 (brainstem motor neuron development), have not been previously reported in association with suicide and warrant further study.


Identification of differentially expressed proteins in curcumin-treated prostate cancer cell lines.
Due to high prevalence and slow progression of prostate cancer, primary prevention appears to be attractive strategy for its eradication. During the last decade, curcumin (diferuloylmethane), a natural compound from the root of turmeric (Curcuma longa), was described as a potent chemopreventive agent. Curcumin exhibits anti-inflammatory, anticarcinogenic, antiproliferative, antiangiogenic, and antioxidant properties in various cancer cell models. This study was designed to identify proteins involved in the anticancer activity of curcumin in androgen-dependent (22Rv1) and -independent (PC-3) human prostate cancer cell lines using two-dimensional difference in gel electrophoresis (2D-DIGE). Out of 425 differentially expressed spots, we describe here the MALDI-TOF-MS analysis of 192 spots of interest, selected by their expression profile. This approach allowed the identification of 60 differentially expressed proteins (32 in 22Rv1 cells and 47 in PC-3 cells). Nineteen proteins are regulated in both cell lines. Further bioinformatic analysis shows that proteins modulated by curcumin are implicated in protein folding (such as heat-shock protein PPP2R1A; RNA splicing proteins RBM17, DDX39; cell death proteins HMGB1 and NPM1; proteins involved in androgen receptor signaling, NPM1 and FKBP4/FKBP52), and that this compound could have an impact on miR-141, miR-152, and miR-183 expression. Taken together, these data support the hypothesis that curcumin is an interesting chemopreventive agent as it modulates the expression of proteins that potentially contribute to prostate carcinogenesis.


Optically Unraveling the Edge Chirality-Dependent Band Structure and Plasmon Damping in Graphene Edges.
The nontrivial topological origin and pseudospinorial character of electron wavefunctions make edge states possess unusual electronic properties. Twenty years ago, the tight-binding model calculation predicted that zigzag termination of 2D sheets of carbon atoms have peculiar edge states, which show potential application in spintronics and modern information technologies. Although scanning probe microscopy is employed to capture this phenomenon, the experimental demonstration of its optical response remains challenging. Here, the propagating graphene plasmon provides an edge-selective polaritonic probe to directly detect and control the electronic edge state at ambient condition. Compared with armchair, the edge-band structure in the bandgap gives rise to additional optical absorption and strongly absorbed rim at zigzag edge. Furthermore, the optical conductivity is reconstructed and the anisotropic plasmon damping in graphene systems is revealed. The reported approach paves the way for detecting edge-specific phenomena in other van der Waals materials and topological insulators.


The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST): development, reliability and feasibility.
The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) was developed for the World Health Organization (WHO) by an international group of substance abuse researchers to detect psychoactive substance use and related problems in primary care patients. This report describes the new instrument as well as a study of its reliability and feasibility. The study was conducted at participating sites in Australia, Brazil, Ireland, India, Israel, the Palestinian Territories, Puerto Rico, the United Kingdom and Zimbabwe. Sixty per cent of the sample was recruited from alcohol and drug abuse treatment facilities; the remainder was drawn from general medical settings and psychiatric facilities. The study was concerned primarily with test item reliability, using a simple test-retest procedure to determine whether subjects would respond consistently to the same items when presented in an interview format on two different occasions. Qualitative and quantitative data were also collected to evaluate the feasibility of the screening items and rating format. A total of 236 volunteer participants completed test and retest interviews at nine collaborating sites. Slightly over half of the sample (53.6%) was male. The mean age of the sample was 34 years and they had completed, on average, 10 years of education. The average test-retest reliability coefficients (kappas) ranged from a high of 0.90 (consistency of reporting 'ever' use of substance) to a low of 0.58 (regretted what was done under influence of substance). The average kappas for substance classes ranged from 0.61 for sedatives to 0.78 for opioids. In general, the reliabilities were in the range of good to excellent, with the following items demonstrating the highest kappas across all drug classes: use in the last 3 months, preoccupied with drug use, concern expressed by others, troubled by problems related to drug use, intravenous drug use. Qualitative data collected at the end of the retest interview suggested that the questions were not difficult to answer and were consistent with patients' expectations for a health interview. The data were used to guide the selection of a smaller set of items that can serve as the basis for more extensive validation research. The ASSIST items are reliable and feasible to use as part of an international screening test. Further evaluation of the screening test should be conducted.


Studies on the control of visceral leishmaniasis: validation of the Falcon assay screening test--enzyme-linked immunosorbent assay (FAST-ELISA) for field diagnosis of canine visceral leishmaniasis.
The Falcon assay screening test-enzyme-linked immunosorbent assay (FAST-ELISA), the latest version of the enzyme-linked immunosorbent assay, uses antigen-coated beads. A 96-well plate can be run in 20 min without electricity or expensive equipment. We compared the FAST-ELISA, a standard ELISA, and an indirect immunofluorescent assay (IFA) for evaluation of canine leishmaniasis under field conditions using samples from 161 dogs from our longitudinal study in the endemic area of Jacobina, Bahia, Brazil. Organisms were isolated by culture (NN medium) or by inoculation of hamsters with samples from 59 of the dogs. When plasma were tested, we found a sensitivity of 88% and a specificity of 90% using the FAST-ELISA with a spectrophotometer. Using the same plasma samples, the IFA had a sensitivity of 75% and a specificity of 93%. The standard ELISA had a sensitivity of 90% and a specificity of 85%. When whole blood was tested with the FAST-ELISA, we found a sensitivity of 85%. There was no significant difference between visual and spectrophotometric results with plasma or whole blood. The FAST-ELISA system provides a sensitive, specific, and field-adaptable test for canine visceral leishmaniasis, which can be evaluated quickly without the use of a microscope or spectrophotometer.


A systematic review and quantitative analysis of neurocognitive outcomes in children with four chronic illnesses.
Concern has been expressed that infants and children exposed to uneventful surgery and anesthesia may incur neurological injury that becomes manifest in poor scholastic performance or future learning difficulties. A recent meta-analysis of seven clinical studies examined the relationship between learning or behavior difficulties and pediatric exposure to anesthesia/surgery and reported an odds ratio of 1.4; however, the level of association and causal factors remain unclear. The purpose of our study is to provide context to the pediatric anesthesia neurotoxicity question by reviewing the evidence linking four childhood illnesses with neurocognitive development. In the present review, we have sought to quantify the magnitude of the impact of chronic illness on neurocognitive development through a systematic review of publications that report the developmental trajectory of patients with four childhood diseases: cystic fibrosis (CF), hemophilia A, end-stage renal disease (ESRD) and end-stage liver disease (ESLD). Studies were identified by searching the electronic databases OVID MEDLINE and Pubmed and scanning reference lists of articles by two authors. Limits were applied to the English language and to humans. We used the following search terms: CF, hemophilia A, ESRD, ESLD in combination with academic performance, educational status, educational measurement, learning, achievement, developmental delay, learning disabilities, intellectual disabilities, behavioral disorders, intelligence quotient (IQ), cognition, school problems, absenteeism, school attendance, anxiety, learning regression, or developmental regression. The search strategy was reviewed independently by all four authors. Eligibility assessment was performed independently in an unblinded standardized manner by two authors who chose relevant articles from the overall search results by scanning the titles and abstracts of articles and from the references within citations. The full-text publications were reviewed by all four authors. All pertinent data related to the objectives were collected and independently reviewed by two authors. The data were summarized in the form reported in the studies. When possible, reported data were submitted to analysis with the Mantel-Haenszel method using a random effects model. Analyses were performed using the Review Manager computer program. In the studies retrieved, the main outcomes were measures of intellectual or cognitive characteristics, as exemplified by the Wechsler battery of tests. Reporting of measures of achievement (for example, GPA) was rare. Children with CF and hemophilia A did not appear disadvantaged by their disease as general intelligence levels were comparable with the general population norms. In children with ESRD, mean IQ reported during dialysis improved after transplantation. Although they improved relative to their pretransplantation cognitive functioning, children with ESLD who received transplants are approximately eight IQ points below the population norm. Overall, the results suggest that the burden of chronic childhood illness, by itself, does not impair cognitive development in children with hemophilia A and CF. Children with ESRD and ESLD, despite optimal management, show a mild cognitive deficit compared with the population norm. Given the impact of these four specific chronic illnesses on neurocognitive outcome in children and the improvement in IQ post-transplant in both ESRD and ESLD, the results suggest that the effect of an uncontrolled confounding illness on neurocognitive development is small.


Determination of optimum polymeric coagulant in palm oil mill effluent coagulation using multiple-objective optimisation on the basis of ratio analysis (MOORA).
The main limitation of a conventional palm oil mill effluent (POME) ponding system lies in its inability to completely decolourise effluent. Decolourisation of effluent is aesthetically and environmentally crucial. However, determination of the optimum process parameters is becoming more complex with the increase of the number of coagulants and responses. The primary objective of this study is to determine the optimum polymeric coagulant in the coagulation-flocculation process of palm oil mill effluent by considering all output responses, namely lignin-tannin, low molecular mass coloured compounds (LMMCC), chemical oxygen demand (COD), ammonia nitrogen (NH3-N), pH and conductivity. Here, multiple-objective optimisation on the basis of ratio analysis (MOORA) is employed to discretely measure multiple response characteristics of five different types of coagulants as a function of assessment value. The optimum coagulant is determined based on the highest assessment value and was identified as QF25610 (cationic polyacrylamide). On the other hand, the lowest assessment value was represented by AN1800 (anionic polyacrylamide). This study highlights the simplicity of MOORA approach in handling various input and output parameters, and it may be useful in other wastewater treatment processes as well.


The role of essential fatty acids and prostaglandins in the premenstrual syndrome.
Many of the features of the premenstrual syndrome are similar to the effects produced by the injection of prolactin. Some women with the premenstrual syndrome have elevated prolactin levels, but in most the prolactin concentrations are normal. It is possible that women with the syndrome are abnormally sensitive to normal amounts of prolactin. There is evidence that prostaglandin E1, derived from dietary essential fatty acids, is able to attenuate the biologic actions of prolactin and that in the absence of prostaglandin E1 prolactin has exaggerated effects. Attempts were made, therefore, to treat women who had the premenstrual syndrome with gamma-linolenic acid, an essential fatty acid precursor of prostaglandin E1. Gamma-linolenic acid is found in human, but not cows', milk and in evening primrose oil, the preparation used in these studies. Three double-blind, placebo-controlled studies, one large open study on women who had failed other kinds of therapy for the premenstrual syndrome and one large open study on new patients all demonstrated that evening primrose oil is a highly effective treatment for the depression and irritability, the breast pain and tenderness, and the fluid retention associated with the premenstrual syndrome. Nutrients known to increase the conversion of essential fatty acids to prostaglandin E1 include magnesium, pyridoxine, zinc, niacin and ascorbic acid. The clinical success obtained with some of these nutrients may in part relate to their effects on essential fatty acid metabolism.


The epidemiology of adverse drug events and medication errors among psychiatric inpatients in Japan: the JADE study.
Knowledge of the epidemiology of adverse drug events (ADEs) and medication errors in psychiatric inpatients is limited outside Western countries. The nature of ADEs and medication errors are important for improving the quality of care worldwide; therefore, we conducted the Japan Adverse Drug Events Study, a series of cohort studies at several settings in Japan. This report included 448 inpatients with 22,733 patient-days in a psychiatric hospital and psychiatric units at a tertiary care teaching hospital over 1 year. Four psychiatrists and two other physicians reviewed all medical charts and related documents to identify suspected incidents. The physicians later classified those incidents into ADEs, potential ADEs, medication errors, or exclusions and evaluated the severity and preventability if the incidents were events. During the study period, we identified 955 ADEs and 398 medication errors (incidence: 42.0 and 17.5 per 1000 patient-days, respectively). Among ADEs, 1.4 %, 28 %, and 71 % were life-threatening, serious, and significant, respectively. Antipsychotics were associated with half of all ADEs. The incidence of medication errors was higher in medical care units than in acute and nursing care units (40.9, 15.6, and 17.4 per 1000 patient-days, respectively). The monitoring and ordering stages were the most common error stages (39 % and 34 % of all medication errors, respectively), and 76 % of medication errors with ADEs were found at the monitoring stage. Non-psychiatric drugs were three times as likely to cause ADEs with errors compared to psychiatric drugs. Antipsychotic use, inadequate monitoring, and treatment of physical ailments by psychiatrists may contribute to the high incidence of medication errors and ADEs among psychiatric inpatients in Japan. Psychiatrists should be cautious in prescribing antipsychotics or unfamiliar medications for physical problems in their psychiatric patients, and should monitor patients after medication administration.


Effect of armor and carrying load on body balance and leg muscle function.
This study investigated the impact of weight and weight distribution of body armor and load carriage on static body balance and leg muscle function. A series of human performance tests were conducted with seven male, healthy, right-handed military students in seven garment conditions with varying weight and weight distributions. Static body balance was assessed by analyzing the trajectory of center of plantar pressure and symmetry of weight bearing in the feet. Leg muscle functions were assessed by analyzing the peak electromyography amplitude of four selected leg muscles during walking. Results of this study showed that uneven weight distribution of garment and load beyond an additional 9 kg impaired static body balance as evidenced by increased sway of center of plantar pressure and asymmetry of weight bearing in the feet. Added weight on non-dominant side of the body created greater impediment to static balance. Increased garment weight also elevated peak EMG amplitude in the rectus femoris to maintain body balance and in the medial gastrocnemius to increase propulsive force. Negative impacts on balance and leg muscle function with increased carrying loads, particularly with an uneven weight distribution, should be stressed to soldiers, designers, and sports enthusiasts.


Identification of viral antigens recognized by ocular infiltrating T cells from patients with varicella zoster virus-induced uveitis.
Varicella zoster virus (VZV) is a common cause of infectious uveitis associated with an intraocular inflammatory response involving virus-specific T cells. In the current study, the functional characteristics and the antigen specificity of VZV-reactive T cells recovered from intraocular fluid (IOF) samples of five patients with VZV were determined. B-cell lines were infected with a comprehensive panel of recombinant vaccinia viruses expressing 11 individual VZV open reading frames (ORFs), or alternatively pulsed with the corresponding peptides to generate antigen-presenting cells (APCs). T-cell responsiveness of the IOF-derived VZV-specific T cells toward APCs was monitored by interferon (IFN)-gamma enzyme-linked immunosorbent spot-forming assays on bulk T-cell cultures and subsequently T-cell clones (TCCs). The cytokine-secretion profile and cytotoxicity of the VZV-specific TCCs was determined by ELISA and flow cytometry, respectively. T-cell reactivity to VZV proteins encoded by ORF4, -10, -14, -18, -29, -31, -61, -62, -63, -67, and -68 was demonstrated, but specificity varied individually. T-cell epitopes on ORF62 and -68 were delineated. The TCCs secreted IFNgamma, but relatively low levels of interleukin-4 and -5, in response to VZV antigen-expressing APCs. The TCCs induced antigen-specific cytotoxic T-cell activity. The results suggest that the intraocular VZV-specific T-cell response in the patients with VZV analyzed is directed to a broad spectrum of VZV antigens, including the latency-associated VZV proteins from ORFs 4, 29, 63, and particularly ORF62. This local T-cell response was in part mediated by cytotoxic CD4(+) T cells with a Th1/0-like effector memory phenotype.


Malignant mesothelioma following repeated exposures to cosmetic talc: A case series of 75 patients.
Asbestos is the primary known cause of malignant mesothelioma. Some cosmetic talc products have been shown to contain asbestos. Recently, repeated exposures to cosmetic talc have been implicated as a cause of mesothelioma. Seventy-five individuals (64 females; 11 males) with malignant mesothelioma, whose only known exposure to asbestos was repeated exposures to cosmetic talcum powders, were reviewed in medical-legal consultation. Out of the 75 cases, 11 were examined for asbestiform fibers. All subjects had pathologically confirmed malignant mesothelioma. The mean age at diagnosis was 61 ± 17 years. The mean latency from exposure to diagnosis was 50 ± 13 years. The mean exposure duration was 33 ± 16 years. Four mesotheliomas (5%) occurred in individuals working as barbers/cosmetologists, or in a family member who swept the barber shop. Twelve (16%) occurred in individuals less than 45 years old (10 females; 2 males). Forty-eight mesotheliomas were pleural (40 females; 8 males), 23 were peritoneal (21 females; 2 males). Two presented with concomitant pleural and peritoneal disease. There was one pericardial, and one testicular mesothelioma. The majority (51) were of the epithelioid histological subtype, followed by 13 biphasic, 8 sarcomatoid, 2 lymphohistiocytoid, and 1 poorly differentiated. Of the 11 individuals whose nontumorous tissues were analyzed for the presence of asbestiform fibers, all showed the presence of anthophyllite and/or tremolite asbestos. Mesotheliomas can develop following exposures to cosmetic talcum powders. These appear to be attributable to the presence of anthophyllite and tremolite contaminants in cosmetic talcum powder.


Production of autoantibodies by human-human hybridomas.
Peripheral blood lymphocytes and splenocytes of patients with autoimmune disease were used to prepare human-human hybridomas that produce autoantibodies. Because exogenous immunization was not used, the hybridoma antibodies were derived from B cells that spontaneously produced autoantibodies. 108 hybrids grew from 4,254 wells (2.5%). Optimal conditions for obtaining hybridomas with the GM 4672 myeloma line included initial growth in 2-ml wells, the use of 44% polyethylene glycol, a mononuclear cell/GM 4672 cell ratio 5:1, and prior stimulation of the B lymphocytes with pokeweed mitogen. Hybridoma supernatants had activity against ssDNA, platelets, and erythrocytes. The results demonstrate the feasibility of producing human-human hybridomas from lymphocytes of patients with various autoimmune diseases.


Injury Mortality in Vietnam: Patterns and Trends, 2005-2013.
Injury is a growing public health problem worldwide. Deaths due to injuries account for 10% of the world's mortality. More than 90% of the world's injury-related deaths occur in low- and middle-income countries such as Vietnam. The public health burden has been recognized by government; however, there is a need to study and better understand the epidemiology and trends for injuries and injury-related mortality to be able to better address this burden. In this article, we analyze the patterns and trends in injury mortality from 2005 to 2013 in Vietnam. All registered deaths from injuries from January 2005 to December 2013 were extracted from the Ministry of Health death recording system (A6). Mortality rates per 100 000 population per year were calculated. A linear regression model was used to estimate the injury mortality trends. In the 9-year period, 313 101 deaths due to injuries were recorded in the A6 system; this accounts for about 10% of all deaths. The leading causes of injury-related death were road traffic injuries among the entire population, while drowning was the leading cause of death among children. Other unintentional injuries including occupational, fall, poisoning, and exposure to electric current also accounted for a substantial proportion of the burden of injury. There is a significant reduction trend found in drowning among children 0 to 18 years of age and significant increasing trends in intentional injury causes. While injuries have been recognized as a public health problem in Vietnam in the last decade, as seen by our analysis, there is a need for concerted action to reduce their burden. Of particular concern is the increasing prominence of intentional injuries. Improved data systems, increasing the awareness in the community, and making appropriate policies and implementing them, as well as implementing effective, evidence-based interventions are all key to decreasing this burden. This is an important study describing injury mortality in Vietnam for the period 2005-2013. The results of the study show that injury death remains an important public health issue that needs more attention from government and relevant agencies.


Migration of the Fungal Protein Cryptogein within Tobacco Plants.
Cryptogein (CRY), a protein secreted by Phytophthora cryptogea, causes necrosis on tobacco (Nicotiana tabacum) plants at the site of application (the stem or the roots) and also on distant leaves. Autoradiography of plantlets after root absorption of radioiodinated CRY demonstrated a rapid migration of the label to the leaf lamina via the veins. Using an anti-CRY antiserum, a CRY-related antigen was detected in the stem and leaves of CRY-treated plants at a distance from the site of application. This antigen had the same molecular weight as CRY and was detected in the leaves as early as 1 hour after stem treatment, i.e. long before necrosis was detectable. The antigen was also detected in plants inoculated with P. cryptogea. The distant location of the necrosis induced by the fungus or by CRY can be ascribed to the migration of this protein, which is toxic to tobacco cells. It is proposed that CRY, which also elicits defense reactions in tobacco, might contribute to the hypersensitive response of tobacco to P. cryptogea.


Influence of scattered trees in grazing areas on soil properties in the Piedmont region of the Colombian Amazon.
Trees dispersed in grazing areas are contribute to the sustainability of livestock systems. The interactions between trees and soil are ecological processes that allow the modification of the biology, fertility, and physics of the soil. This study was aimed to assess the influence of dispersed trees in pastures on soil properties in grazing areas for dual-purpose cattle systems in the Piedmont region of the Colombian Amazon. The work was done in grazing areas with scattered trees at the Centro de Investigaciones Amazónicas CIMAZ-Macagual in Florencia-Caquetá-Colombia. We evaluated the effect of five tree species, Andira inermis, Bellucia pentámera, Guarea Guidonia, Psidium guajava and Zygia longifolia, on soil properties (up to 30 cm soil depth) under and outside the influence of the crown. Under the tree crown, three points were systematically taken in different cardinal positions. This was done at a distance corresponding to half the radius of the tree crown. The sampling points in the open pasture area (out of crown) were made in the same way, but at 15 m from the crown border. The ANOVA showed significant interaction (P < 0.0001) between tree species and location for macrofauna abundance up to 30 cm soil depth. For this reason, we performed the comparison between locations for each tree species. Chemical soil variables up to 10 cm soil depth only showed interaction of tree species-location for exchangeable potassium (P = 0.0004). Soil physical soil characteristics up to 30 cm soil depth only showed interaction of tree species-location at 20 cm soil depth (P = 0.0003). The principal component analysis for soil properties explained 61.1% of the total variability of the data with the two first axes. Using Monte Carlo test, we found crown effect for all species. Trees help to control exchangeable mineral elements that can affect the soil, potentiate basic cations such as magnesium and potassium, increase the abundance of soil macrofauna; but some trees with high ground level of shade in grazing areas could increase soil compaction due to the greater concentration of cattle in these areas.


[Communication process in consultation of patients with incurable disease: a prospective study].
Patients wish to be fully informed about their health, but some information and its disclosure may pose special challenges depending on the severity of the illness. This prospective observational study investigates the content of information about the disease and treatment, as well as the process by which information is disclosed as part of 51 consultations with people with malignant gliomas. Patients and their relatives were fully informed of the diagnosis and treatments (types, risks, practical details), but disease progression with and without treatment, like the prognosis, was rarely addressed. Relatives were more likely than patients to ask questions related to the severity of the illness and the prognosis, leaving doctors in the difficult position of determining whether and how the information may be disclosed. Ethical issues related to informed consent are discussed in light of an incurable disease with a fast progression.


Causal influence of gamma oscillations on the sensorimotor rhythm.
Gamma oscillations of the electromagnetic field of the brain are known to be involved in a variety of cognitive processes, and are believed to be fundamental for information processing within the brain. While gamma oscillations have been shown to be correlated with brain rhythms at different frequencies, to date no empirical evidence has been presented that supports a causal influence of gamma oscillations on other brain rhythms. In this work, we study the relation of gamma oscillations and the sensorimotor rhythm (SMR) in healthy human subjects using electroencephalography. We first demonstrate that modulation of the SMR, induced by motor imagery of either the left or right hand, is positively correlated with the power of frontal and occipital gamma oscillations, and negatively correlated with the power of centro-parietal gamma oscillations. We then demonstrate that the most simple causal structure, capable of explaining the observed correlation of gamma oscillations and the SMR, entails a causal influence of gamma oscillations on the SMR. This finding supports the fundamental role attributed to gamma oscillations for information processing within the brain, and is of particular importance for brain-computer interfaces (BCIs). As modulation of the SMR is typically used in BCIs to infer a subject's intention, our findings entail that gamma oscillations have a causal influence on a subject's capability to utilize a BCI for means of communication.


Parylene to silicon nitride bonding for post-integration of high pressure microfluidics to CMOS devices.
High pressure-rated channels allow microfluidic assays to be performed on a smaller footprint while keeping the throughput, thanks to the higher enabled flow rates, opening up perspectives for cost-effective integration of CMOS chips to microfluidic circuits. Accordingly, this study introduces an easy, low-cost and efficient method for realizing high pressure microfluidics-to-CMOS integration. First, we report a new low temperature (280 °C) Parylene-C wafer bonding technique, where O(2) plasma-treated Parylene-C bonds directly to Si(3)N(4) with an average bonding strength of 23 MPa. The technique works for silicon wafers with a nitride surface and uses a single layer of Parylene-C deposited only on one wafer, and allows microfluidic structures to be easily formed by directly bonding to the nitride passivation layer of the CMOS devices. Exploiting this technology, we demonstrated a microfluidic chip burst pressure as high as 16 MPa, while metal electrode structures on the silicon wafer remained functional after bonding.


Performance of Class I composite restorations when polished immediately or after one-day water storage.
This study investigated the effects on gap formation in Class I restorations (observed by vertical and horizontal forms of inspection) and on the mechanical properties of nine resin composite filling materials when the restorations were subject to finishing immediately after setting or after one-day water storage. Class I restorations with resin composite fillings were polished either immediately (3 min) after setting or after one-day water storage. Interfacial gap formation (observed by vertical inspection) was assessed using 14 gap measurement points along the interface between the restoration and cavity walls and floor (n = 10 per resin composite; total points measured per time point = 140). For marginal gaps formed at cavosurface margins in Class I cavities and in Teflon molds, marginal gap formation (observed by horizontal inspection) was assessed by measuring the maximum gap-width and opposing width (if any). Effects on mechanical properties were assessed by measuring shear bond strengths to enamel and dentin, flexural strength and modulus. After one-day storage, marginal gap-widths in Class I restorations were significantly decreased for all composites, alongside a significant increase in shear bond strengths to enamel and dentin, flexural strength and modulus. Resin composite-filled Class I restorations which were polished after one-day delay presented lower gap formation compared with finishing immediately after setting.


Cloning and characterization of the gene coding for cytoplasmic seryl-tRNA synthetase from Saccharomyces cerevisiae.
We have screened a Saccharomyces cerevisiae expression library with antibodies against seryl-tRNA synthetase (SerRS) from baker's yeast. In this way we obtained clones which contain serS, the structural gene for seryl-tRNA synthetase. Genomic Southern blots show that the serS gene resides on a 5.0 kb SalI fragment. Nucleotide sequence analysis of the genes revealed a single open reading frame from which we deduced the amino acid sequence of the enzyme consistent with that of two peptides isolated from SerRS. The enzyme is comprised of 462 amino acids consistent with earlier determinations of its molecular weight. The codon usage of serS is typical of abundant yeast proteins. Nuclease S1 analysis of serS mRNA defined the RNA initiation site 20-40 bases downstream from an AT rich sequence containing the TATA box and 21-39 nucleotides upstream of the translation initiation codon. Yeast strains transformed with the cloned gene overproduce seryl-tRNA synthetase in vivo.


Herbivore-induced resistance against microbial pathogens in Arabidopsis.
Caterpillars of the herbivore Pieris rapae stimulate the production of jasmonic acid (JA) and ethylene (ET) in Arabidopsis (Arabidopsis thaliana) and trigger a defense response that affects insect performance on systemic tissues. To investigate the spectrum of effectiveness of P. rapae-induced resistance, we examined the level of resistance against different pathogens. Although the necrotrophic fungus Alternaria brassicicola is sensitive to JA-dependent defenses, herbivore-induced resistance was not effective against this pathogen. By contrast, caterpillar feeding significantly reduced disease caused by the bacterial pathogens Pseudomonas syringae pv tomato and Xanthomonas campestris pv armoraciae. However, this effect was apparent only locally in caterpillar-damaged tissue. Arabidopsis mutants jar1, coi1, ein2, sid2, eds5, and npr1 showed wild-type levels of P. rapae-induced protection against P. syringae pv tomato, suggesting that this local, herbivore-induced defense response does not depend exclusively on either JA, ET, or salicylic acid (SA). Resistance against the biotroph Turnip crinkle virus (TCV) requires SA, but not JA and ET. Nevertheless, herbivore feeding strongly affected TCV multiplication and TCV lesion formation, also in systemic tissues. Wounding alone was not effective, but application of P. rapae regurgitate onto the wounds induced a similar level of protection. Analysis of SA-induced PATHOGENESIS RELATED-1 (PR-1) expression revealed that P. rapae grazing primed Arabidopsis leaves for augmented expression of SA-dependent defenses. Pharmacological experiments showed that ET acts synergistically on SA-induced PR-1, suggesting that the increased production of ET upon herbivore feeding sensitizes the tissue to respond faster to SA, thereby contributing to an enhanced defensive capacity toward pathogens, such as TCV, that trigger SA-dependent defenses upon infection.


Phase I clinical and pharmacokinetic study of protein kinase C-alpha antisense oligonucleotide ISIS 3521 administered in combination with 5-fluorouracil and leucovorin in patients with advanced cancer.
The present study was designed to determine the maximum tolerated dose (MTD), toxicity profile, pharmacokinetics (PKs), and antitumor activity of the protein kinase C-alpha antisense oligonucleotide ISIS 3521 (ISIS Pharmaceuticals, Inc., Carlsbad, CA) when administered in combination with 5-fluorouracil (5-FU) and leucovorin (LV). Patients with refractory solid tumors received ISIS 3521 as a 21-day continuous infusion administered simultaneously with 5-FU and LV given daily for 5 days repeated every 4-5 weeks (one cycle). 5-FU and ISIS 3521 PK analysis were performed on samples taken during the first cycle in all patients. Fifteen patients received ISIS 3521 at one of three dose levels: (a) 1.0 (n = 3 patients); (b) 1.5 (n = 3 patients); and (c) 2.0 (n = 9 patients) mg/kg/day. All patients simultaneously received 5-FU (425 mg/m(2)/day) and LV (20 mg/m(2)/day) for 5 consecutive days. Grade 1-2 toxicities included alopecia, fatigue, mucositis, diarrhea, anorexia, nausea/vomiting, and tumor pain. One patient had grade 3 chest pain considered to be related to 5-FU therapy, another patient had dose-limiting grade 3 mucositis resolving in <7 days, and one patient with a history of gastritis had an acute upper gastrointestinal bleed thought to be 5-FU-induced toxicity. Five patients developed cycle 1 grade 4 neutropenia, which resolved without colony-stimulating factors before the next treatment cycle. There were no effects on prothrombin time and activated partial thromboplastin time. A clinically defined MTD was not reached. The character and severity of these toxicities do not seem to be dose related, and, as such, there was no classical dose-limiting toxicity defining the MTD. ISIS 3521 PKs in the presence of 5-FU was consistent with those reported previously. 5-FU PK parameters were also similar in the presence or absence of ISIS 3521. Six of 14 patients ( approximately 43%) across all dose cohorts had an improvement in measurable tumor response ranging from minor reduction in tumor size (4 patients) to objective partial response (>50% reduction in tumor size, 2 patients). ISIS 3521 is tolerable at its recommended single-agent dose when given with 5-FU and LV. There is no apparent PK interaction between ISIS 3521 and 5-FU and LV. Antitumor activity was observed with the combination; however, it is uncertain whether clinical activity is a result of enhanced drug interaction. Our study warrants further exploration of efficacy in a Phase II and/or Phase III clinical trial setting.


Coordination chemistry of stannylene-based Lewis pairs - insertion into M-Cl and M-C bonds. From base stabilized stannylenes to bidentate ligands.
The coordination chemistry of intramolecular stannylene phosphorus Lewis pairs incorporated into four membered ring systems is presented. Previously reported coordination chemistry of stannylene and phosphorus towards palladium(0) is extended by using Pd(nbe)3 as a precursor, yielding co-ligand free complexes. An equilibrium of one or two stannylene phosphorus ligands coordinated to Pd(0) was observed with tin acting either as a donor or an acceptor towards palladium. Furthermore, the reactions with transition metal(i) chlorides, [(cod)IrCl]2, [(cod)RhCl]2 and Me2SAuCl are reported. They proceed via insertion of stannylene into the M-Cl bonds, yielding metal complexes with chelating stannide phosphorus ligands. For gold, a dinuclear complex with bridging P-Sn ligands was formed. Furthermore, the reaction of a P → Sn Lewis pair in a three membered ring system with (cod)PtMe2 is reported.


Mycobacterium bovis BCG-infected neutrophils and dendritic cells cooperate to induce specific T cell responses in humans and mice.
Neutrophils are increasingly thought to modulate dendritic cell (DC) functions. We investigated the role of the neutrophil-DC partnership in the response to Mycobacterium bovis BCG-the vaccine used against tuberculosis. We compared neutrophil-DC crosstalk in humans and mice, searching for functional differences. In both species, neutrophils captured fluorescent BCG-enhanced green fluorescent protein (EGFP) and were more phagocytic than DC. Non-apoptotic BCG-infected neutrophils clustered with immature DC, establishing intimate contacts with dendrites, at which fluorescent intact bacilli were observed. Physical interactions between neutrophils and DC were required for DC activation. Human BCG-infected DC produced interleukin (IL)-10, an inhibitory cytokine, whereas DC exposed to BCG-infected neutrophils produced low to undetectable amounts of the cytokine. Mouse BCG-infected neutrophils induced sustained IL-2 production by DC. Human DC exposed to BCG-infected neutrophils stimulated recall T cell reactivity from vaccinated donors. Mouse DC infected with recombinant ovalbumin (OVA)-producing BCG (rBCG(ova)) elicited proliferation of TCR-OVA-transgenic CD4 and CD8 T cells. Moreover, exposing DC to rBCG(ova)-infected neutrophils enhanced OVA presentation. Thus, in mice and humans, neutrophils help DC to cross-present BCG antigens to T cells. Our results suggest that this "ménage à trois" involving neutrophils, DC and T cells plays a major role in the immune response to BCG.


Fas transduces activation signals in normal human T lymphocytes.
The Fas gene encodes a cell surface molecule that is a member of the the nerve growth factor/tumor necrosis factor receptor family of proteins and can mediate programmed cell death (apoptosis) in certain transformed cell lines. To characterize further the biological function of Fas, particularly with regard to its function in normal cells, a panel of monoclonal antibodies (mAbs) was generated against the extracellular portion of human Fas. Some of these mAbs induced apoptosis in transformed cell lines expressing Fas, but only when immobilized on the culture vessel. One of the new Fas mAbs (M38) was used for studies on normal lymphoid cells and found to stimulate the proliferation of purified human T cells and thymocytes when immobilized on culture wells along with CD3 antibody. T cell proliferation induced by Fas mAb was largely interleukin 2 independent and was demonstrated to be due to a direct effect on the precursor T cell. Thus, the data demonstrate that in addition to a role in the induction of apoptosis in certain transformed cell lines, the Fas protein may also play an important role in the activation and proliferation of normal T cells.


Physician and practice characteristics associated with the early utilization of new prescription drugs.
Prescription of new drugs contributes to substantial increases in annual drug expenditures. A small proportion of physicians appear to be early users of new prescription drugs and little is known about their characteristics. To estimate the initial utilization rate of new prescription drugs among physicians, and the physician and practice characteristics associated with early use. Cumulative prospective assessment over a 5 year period (1989-1994) of new drug utilization rates in a randomly selected cohort of Quebec physicians. 1661 physicians and 669,867 elderly patients. Prescribing rate of 20 new drugs, in 6 therapeutic categories, to elderly patients in the first 6 months after inclusion in the Quebec formulary. The 20 new drugs were prescribed by 1.3-22.3% of physicians, and there was an 8 to 17-fold difference in new drug utilization rates among prescribers. Characteristics associated with higher rates of utilization differed for general practitioners and specialists. Male general practitioners, and physicians graduating from the most recently established medical school in the province, had higher rates of new drug utilization, whereas recent graduation was only associated with higher utilization rates among specialists. Practice volume was associated with higher rates of utilization among GPs. For both GPs and specialists, having a high proportion of elderly in one's practice and a rural or remote practice location was associated with lower utilization rates. Physician sex, specialty, medical school, years since graduation, practice location, volume, and relative proportion of elderly in the physician's practice influence the utilization of new drugs.


Hierarchical optical ring interconnection (HORN): scalable interconnection network for multiprocessors and multicomputers.
A new interconnection network for massively parallel computing is introduced. This network is called a hierarchal optical ring interconnection (HORN). The HORN consists of a single-hop, scalable, constant-degree, strictly nonblocking, fault-tolerant interconnection topology that uses wavelength-division multiple access to provide better utilization of the terahertz bandwidth offered by optics. The proposed optical network integrates the attractive features of hierarchical ring interconnections, e.g., a simple node interface, a constant node degree, better support for the locality of reference, and fault tolerance, with the advantages of optics. The HORN topology is presented, its architectural properties are analyzed, and an optical design methodology for it is described. Furthermore, a brief feasibility study of the HORN is conducted. The study shows that the topology is highly amenable to optical implementation with commercially available optical elements.


Opiate-dependent adolescents in Ireland: a descriptive study at treatment entry.
To describe the drug history and co-existing psycho-social problems among under-19 year olds accessing treatment for opiate dependency, including methadone maintenance, and examine for any gender differences. A descriptive study of under-19 years assessed at the largest drug treatment clinic in Dublin, Ireland, between October 2000 and September 2006. Data was obtained through review of case notes, assessment questionnaires and urine drug screens. Eighty-six young people were included. Their mean age was 16.8 years. Forty-six (54%) were female. Only 26 (30%) reported an intact family of origin. Twenty-three (27%) had been in care. Mean age for first use of any illicit drug was 12.4 years, and for heroin was 14.8 years. The mean age of leaving school was 14.4 years; 42 (49%) first tried heroin after leaving school. Forty-one (48%) had a history of homelessness. Forty-four (51%) had previously injected; 26 (30%) were currently injecting. Fifty-six (65%) had not been screened for blood-borne diseases; twenty-one (24%) subsequently tested positive for hepatitis C. Thirty-eight (48%) had previous convictions; 33 (38%) were facing charges. Forty-five (52%) had previously seen a psychiatrist; nine (11%) had received inpatient psychiatric treatment. Boys were more likely to leave school early, have a substance-abusing sibling, and to have a past conviction. Girls were more likely to have a partner, and have taken a deliberate overdose. This study highlights the multiple and complex needs of teenagers abusing opiates. Services seeking to meet their needs will require a broad range of interventions and excellent interagency co-operation.


Evaluation of a communication skills course for second-year medical students.
A five-year evaluation and redesign of the communication skills component of the Introduction to Clinical Medicine course was undertaken at the State University of New York Health Science Center at Syracuse College of Medicine. The objectives of the evaluation were to determine the effectiveness of the component in teaching communication skills, identify areas of the component in need of change, and monitor the effectiveness of previous changes. In the first three years, the evaluation focused on the students' perceptions of the importance of communication skills in their training as physicians. Based on the evaluations for those three years, the component was modified substantially. One of the changes was the introduction in years four and five of simulated patients for practicing interviewing skills. The evaluations in years four and five focused on the effectiveness of using the simulated patients and the students' perceptions of how well the course objectives were met.


A phase II study of bevacizumab and high-dose interleukin-2 in patients with metastatic renal cell carcinoma: a Cytokine Working Group (CWG) study.
Overexpression of vascular endothelial growth factor in renal cell carcinoma (RCC) leads to angiogenesis, tumor progression, and inhibition of immune function. We conducted the first phase II study to estimate the efficacy and safety of bevacizumab with high-dose interleukin-2 (IL-2) therapy in patients with metastatic RCC. Eligible patients had predominantly clear cell metastatic RCC, measurable disease, a Karnofsky Performance Status of ≥80%, and adequate end-organ function. IL-2 (600,000 IU/kg) was infused intravenously every 8 hours (maximum 28 doses) during two 5-day cycles on days 1 and 15 of each 84-day course. Bevacizumab (10 mg/kg) was infused intravenously every 2 weeks beginning 2 weeks before initiating IL-2. Fifty of 51 eligible patients from 8 centers were enrolled. Median progression-free survival (PFS) was 11.2 months (90% confidence interval, 5.7-17.7), and 2-year PFS was 18% (90% confidence interval, 8%-27%). Responses included 4 complete (8%) and 11 partial (22%) responses. Toxicities did not exceed those expected from each agent alone. Combining IL-2 plus bevacizumab is feasible, with a response rate and PFS at least as high as reported previously for the single agents. The regimen did not appear to enhance the rate of durable major responses over that of IL-2 alone.


Nudging physicians and patients with autopend clinical decision support to improve diabetes management.
To determine the impact on routine glycated hemoglobin (A1C) laboratory test completion of incorporating an autopend laboratory order functionality into clinical decision support, which (1) routed provider alerts to a separate electronic folder, (2) automatically populated preauthorization forms, and (3) linked the timing and content of electronic patient health maintenance topic (HMT) reminders to the provider authorization. Observational pre-post study from November 2011 (1 year before autopend) through June 2014 (1.5 years after). The study included HMT reminders concerning an A1C test for patients with type 1 or type 2 diabetes (N = 15,630 HMT reminders; 8792 patients) in a large multispecialty ambulatory healthcare system. A Cox proportional hazard model, adjusted for patient and provider demographics, estimated the likelihood of laboratory test completion based on 3 HMT reminder characteristics: preautopend versus postautopend period, read versus unread, and the patient's time to reading. In the postautopend period, the median time for patients to read reminders decreased (1 vs 3 days; P <.001) and the median time to complete laboratory tests decreased (40 vs 48 days; P <.001). Comparing preautopend HMT reminders with a similar time to reading, the likelihood of A1C laboratory test completion increased after autopend by between 21.1% (hazard ratio [HR], 1.211; P = .050), when time to reading was 57 days, and 33.9% (HR, 1.339; P = .003), when time to reading was 0 days. This result included 68% of the reminders. There was no statistical difference in A1C laboratory test completion for unread reminders in the preautopend versus postautopend period. Automated patient-centered decision support can improve guideline-concordant monitoring of A1C among patients with diabetes, particularly among patients who read reminders in a timely fashion.


Probiotics as an Adjuvant Therapy in Major Depressive Disorder.
Major depressive disorder is a common, debilitating psychiatric disorder, which originates from the interaction of susceptibility genes and noxious environmental events, in particular stressful events. It has been shown that dysregulation of hypothalamus-pituitary-adrenal (HPA) axis, imbalance between anti- and pro-inflammatory cytokines, depletion of neurotransmitters (serotonin, norepinephrine and/or dopamine) in the central nervous system, altered glutamatergic and GABAergic transmission have an important role in the pathogenesis of depression. Due to numerous diverse biological events included in the pathophysiology of depression a large number of antidepressant drugs exerting distinct pharmacological effects have been developed. Nevertheless, clinical needs are still not solved. Relatively new research strategies advanced the understanding of psychiatric illness and their connections with disturbances in gastrointestinal tract. The existence of bidirectional communication between the brain and the gut has been proven, and an increasing body of evidence supports the hypothesis that cognitive and emotional processes are influenced through the brain-gut axis. On the other hand, microbiome may influence brain function and even behavior giving to the specific microorganisms a psychobiotic potential. In this review we discuss the possibilities of classical antidepressant drug treatment being supported with the psychobiotics/probiotic bacteria in patients suffering from major depressive disorder.


Long-term survival of high-risk pediatric patients with primitive neuroectodermal tumors treated with antineoplastons A10 and AS2-1.
Primitive neuroectodermal tumors (PNETs) are usually successfully treated with craniospinal radiation and chemotherapy; however, difficulties with standard treatment can be encountered in very young children, in adult patients at high risk of complication from standard treatment, and in patients with recurrent tumors. Thirteen children, either with recurrent disease or high risk, were treated in phase II studies with antineoplastons (ANP). The median age of patients was 5 years, 7 months (range, 1-11). Medulloblastoma was diagnosed in 8 patients, pineoblastoma in 3 patients, and other PNET in 2 patients. Previous treatments included surgery in 12 patients (1 had biopsy only, suboccipital craniotomy), chemotherapy in 6 patients, and radiation therapy in 6 patients. Six patients had not received prior chemotherapy or radiation. The treatment consisted of intravenous infusions of 2 formulations of ANP, A10 and AS2-1, and was administered for an average of 20 months. The average dosage of A10 was 10.3 g/kg/d and of AS2-1 was 0.38 g/kg/d. Complete response was accomplished in 23%, partial response in 8%, stable disease in 31%, and progressive disease in 38% of cases. Six patients (46%) survived more than 5 years from initiation of ANP; 5 were not treated earlier with radiation therapy or chemotherapy. The serious side effects included single occurrences of fever, granulocytopenia, and anemia. The study is ongoing and accruing additional patients. The percentage of patients' response is lower than for standard treatment of favorable PNET, but long-term survival in poor-risk cases and reduced toxicity makes ANP promising for very young children, patients at high risk of complication of standard therapy, and patients with recurrent tumors.


Impact of Haptic Cues and an Active Ankle Exoskeleton on Gait Characteristics.
This study examined the interaction of gait-synchronized vibrotactile cues with an active ankle exoskeleton that provides plantarflexion assistance. An exoskeleton that augments gait may support collaboration through feedback to the user about the state of the exoskeleton or characteristics of the task. Participants (N = 16) were provided combinations of torque assistance and vibrotactile cues at pre-specified time points in late swing and early stance while walking on a self-paced treadmill. Participants were either given explicit instructions (N = 8) or were allowed to freely interpret (N=8) how to coordinate with cues. For the free interpretation group, the data support an 8% increase in stride length and 14% increase in speed with exoskeleton torque across cue timing, as well as a 5% increase in stride length and 7% increase in speed with only vibrotactile cues. When given explicit instructions, participants modulated speed according to cue timing-increasing speed by 17% at cues in late swing and decreasing speed 11% at cues in early stance compared to no cue when exoskeleton torque was off. When torque was on, participants with explicit instructions had reduced changes in speed. These findings support that the presence of torque mitigates how cues were used and highlights the importance of explicit instructions for haptic cuing. Interpreting cues while walking with an exoskeleton may increase cognitive load, influencing overall human-exoskeleton performance for novice users. Interactions between haptic feedback and exoskeleton use during gait can inform future feedback designs to support coordination between users and exoskeletons.


Treatment of Epileptic Encephalopathies.
Epileptic encephalopathies represent the most severe epilepsies, with onset in infancy and childhood and seizures continuing in adulthood in most cases. New genetic causes are being identified at a rapid rate. Treatment is challenging and the overall outcome remains poor. Available targeted treatments, based on the precision medicine approach, are currently few. To provide an overview of the treatment of epileptic encephalopathies with known genetic determinants, including established treatment, anecdotal reports of specific treatment, and potential tailored precision medicine strategies. Genes known to be associated to epileptic encephalopathy were selected. Genes where the association was uncertain or with no reports of details on treatment, were not included. Although some of the genes included are associated with multiple epilepsy phenotypes or other organ involvement, we have mainly focused on the epileptic encephalopathies and their antiepileptic treatments. Most epileptic encephalopathies show genotypic and phenotypic heterogeneity. The treatment of seizures is difficult in most cases. The available evidence may provide some guidance for treatment: for example, ACTH seems to be effective in controlling infantile spams in a number of genetic epileptic encephalopathies. There are potentially effective tailored precision medicine strategies available for some of the encephalopathies, and therapies with currently unexplained effectiveness in others. Understanding the effect of the mutation is crucial for targeted treatment. There is a broad range of disease mechanisms underlying epileptic encephalopathies, and this makes the application of targeted treatments challenging. However, there is evidence that tailored treatment could significantly improve epilepsy treatment and prognosis.


Tumor necrosis factor-alpha induced by hepatitis B virus core mediating the immune response for hepatitis B viral clearance in mice model.
Persistent hepatitis B viral (HBV) infection results in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). An efficient control of virus infections requires the coordinated actions of both innate and adaptive immune responses. In order to define the role of innate immunity effectors against HBV, viral clearance was studied in a panel of immunodeficient mouse strains by the hydrodynamic injection approach. Our results demonstrate that HBV viral clearance is not changed in IFN-α/β receptor (IFNAR), RIG-I, MDA5, MYD88, NLRP3, ASC, and IL-1R knock-out mice, indicating that these innate immunity effectors are not required for HBV clearance. In contrast, HBV persists in the absence of tumor necrosis factor-alpha (TNF-α) or in mice treated with the soluble TNF receptor blocker, Etanercept. In these mice, there was an increase in PD-1-expressing CD8+ T-cells and an increase of serum HBV DNA, HBV core, and surface antigen expression as well as viral replication within the liver. Furthermore, the induction of TNF-α in clearing HBV is dependent on the HBV core, and TNF blockage eliminated HBV core-induced viral clearance effects. Finally, the intra-hepatic leukocytes (IHLs), but not the hepatocytes, are the cell source responsible for TNF-α production induced by HBcAg. These results provide evidences for TNF-α mediated innate immune mechanisms in HBV clearance and explain the mechanism of HBV reactivation during therapy with TNF blockage agents.


Sex differences in deterioration of sleep properties associated with aging: a 12-year longitudinal cohort study.
The sleep patterns of humans are greatly influenced by age and sex and have various effects on overall health as they change continuously during the lifespan. We investigated age-dependent changes in sleep properties and their relation to sex in middle-aged individuals. We analyzed data from 2,640 participants (mean age of 49.8 ± 6.8 years at baseline, 50.6% women) in the Korean Genome and Epidemiology Study, which assessed sleep habits using the Pittsburgh Sleep Quality Index and other clinical characteristics. We analyzed the sleep habit changes that occurred between baseline and a follow-up point (mean interval: 12.00 ± 0.16 years). Associations of age and sex with 9 sleep characteristics were evaluated. Age was associated with most of the sleep characteristics cross-sectionally and longitudinally (P < .05), except for the time in bed at baseline (P = .455) and change in sleep duration (P = .561). Compared with men, women had higher Pittsburgh Sleep Quality Index scores, shorter time in bed, shorter sleep duration, and longer latency at baseline (P ≤ .001). Longitudinal deterioration in Pittsburgh Sleep Quality Index score, habitual sleep efficiency, duration, and latency was more prominent in women (P < .001). The sex differences in these longitudinal sleep changes were mainly noticeable before age 60 years (P < .05). Worsening of Pittsburgh Sleep Quality Index scores, habitual sleep efficiency, and latency was most evident in perimenopausal women. Men presented with greater advancement of chronotype (P = .006), with the peak sex-related difference occurring when they were in their late 40s (P = .048). Aging is associated with substantial deterioration in sleep quantity and quality as well as chronotype advancement, with the degree and timing of these changes differing by sex.


Frequency discretization in dielectrophoretic assisted cell sorting arrays to isolate neural cells.
We present an automated dielectrophoretic assisted cell sorting (DACS) device for dielectric characterization and isolation of neural cells. Dielectrophoretic (DEP) principles are often used to develop cell sorting techniques. Here we report the first statistically significant neuronal sorting using DACS to enrich neurons from a heterogeneous population of mouse derived neural stem/progenitor cells (NSPCs) and neurons. We also study the dielectric dispersions within a heterogeneous cell population using a Monte-Carlo (MC) simulation. This simulation model explains the trapping behavior of populations as a function of frequency and predicts sorting efficiencies. The platform consists of a DEP electrode array with three multiplexed trapping regions that can be independently activated at different frequencies. A novel microfluidic manifold enables cell sorting by trapping and collecting cells at discrete frequency bands rather than single frequencies. The device is used to first determine the percentage of cells trapped at these frequency bands. With this characterization and the MC simulation we choose the optimal parameters for neuronal sorting. Cell sorting experiments presented achieve a 1.4-fold neuronal enrichment as predicted by our model.


Dental anxiety levels in British servicemen and women.
The objectives of the study were to determine: 1, the level of dental anxiety in British Service personnel; 2 whether there was a difference in dental anxiety levels across the three Services; and, 3, the relationship between number of operational tours and level of dental anxiety. Cross sectional questionnaire survey of individuals attending 3 Armed Services dental treatment centres in the UK. The questionnaires were completed between February 2008 and April 2009. 50 patients each from the Royal Navy, Army and Royal Air Force, selected consecutively from those attending the centres for treatment. There was a 100% response rate. Dental fear as assessed by the Dental Fear Survey (DFS) and scores on a scale of fear of dental injections. 27% of the Armed Services experienced severe dental anxiety: a level similar to that found in the general population. There was no difference in the level of dental anxiety or fear of dental injections across the three Armed Services. There was no relationship between number of operational tours undertaken and level of dental anxiety. Dental anxiety is found amongst members of the British Armed Services at levels similar to that in the general population. This represents a challenge for service provision, particularly in operational settings.


Chevrel Phase Mo6 T8 (T = S, Se) as Electrodes for Advanced Energy Storage.
With the large-scale applications of electric vehicles in recent years, future batteries are required to be higher in power and possess higher energy densities, be more environmental friendly, and have longer cycling life, lower cost, and greater safety than current batteries. Therefore, to develop alternative electrode materials for advanced batteries is an important research direction. Recently, the Chevrel phase Mo6 T8 (T = S, Se) has attracted increasing attention as electrode candidate for advanced batteries, including monovalent (e.g., lithium and sodium) and multivalent (e.g., magnesium, zinc and aluminum) ion batteries. Benefiting from its unique open crystal structure, the Chevrel phase Mo6 T8 cannot only ensure rapid ion transport, but also retain the structure stability during electrochemical reactions. Although the history of the research on Mo6 T8 as electrodes for advanced batteries is short, there has been significant progress on the design and fabrication of Mo6 T8 for various advanced batteries as above mentioned. An overview of the recent progress on Mo6 T8 electrodes applied in advanced batteries is provided, including synthesis methods and diverse structures for Mo6 T8 , and electrochemical mechanism and performance of Mo6 T8 . Additionally, a briefly conclusion on the significant progress, obvious drawbacks, emerging challenges and some perspectives on the research of Mo6 T8 for advanced batteries in the near future is provided.


Efficacy and safety of mu-opioid antagonists in the treatment of opioid-induced bowel dysfunction: systematic review and meta-analysis of randomized controlled trials.
Opioid-induced bowel dysfunction (OBD) is characterized by constipation, incomplete evacuation, bloating, and increased gastric reflux. OBD occurs both acutely and chronically, in multiple disease states, resulting in increased morbidity and reduced quality of life. To compare the efficacy and safety of traditional and peripherally active opioid antagonists vs conventional interventions for OBD. We searched MEDLINE, the Cochrane Central Register of Controlled Trials and EMBASE. Additional reports were identified from the reference lists of retrieved articles. Studies were included if they were randomized controlled trials that investigated the efficacy of mu-opioid antagonists for OBD. Data were extracted by two independent investigators and included demographic variables, diagnoses, interventions, efficacy, and adverse events. Twenty-two articles met inclusion criteria and provided data on 2,352 opioid antagonist-treated patients. The opioid antagonist investigated was alvimopan (eight studies), methylnaltrexone (six), naloxone (seven), and nalbuphine (one). Meta-analysis demonstrated that methylnaltrexone and alvimopan are efficacious in reversing opioid-induced increased gastrointestinal transit time and constipation, and that alvimopan is safe and efficacious in treating postoperative ileus. The incidence of adverse events with opioid antagonists was similar to placebo and generally reported as mild-to-moderate. Insufficient evidence exists for the safety or efficacy of naloxone or nalbuphine in the treatment of OBD. Long-term efficacy and safety of any of the opioid antagonists is unknown, as is the incidence or nature of rare adverse events. Alvimopan and methylnaltrexone both show promise in treating OBD, but further data will be required to fully assess their place in therapy.


Crystallographic structure of an intact IgG1 monoclonal antibody.
The structure of an intact monoclonal antibody for phenobarbital, subclass IgG1, has been determined to 3.2 A resolution by X-ray crystallography. The molecule was visualized in a monoclinic unit cell having an entire immunoglobulin as the asymmetric unit. The two Fab segments, both with elbow angles of 155 degrees , were related by a rotation of 179.7 degrees plus a translation along the approximate dyad of 9 A. This is the first observation of such an Fab translation in a structurally defined antibody. The approximate 2-fold of the Fc was independent of that relating Fabs, making an angle of 107 degrees with the Fab dyad. The angle between long axes of the Fabs was 115 degrees, the most acute angle yet observed, yielding a distorted Y shaped molecule. This is in contrast to the distorted T shape of the only other intact IgG (2a) whose complete structure is known. Primary lattice interactions arise through formation of VH antiparallel beta ribbons whose strands are contributed by pseudo dyad related H2, and by L3 hypervariable loops from neighboring molecules. While one CH2 domain was mobile, Fabs and three domains of the Fc were well defined, as were hinge polypeptides connecting Fabs to the Fc, and the covalently attached oligosaccharides. Direct interactions are observed between hinge polypeptides, the glycosylated loop of one CH2 domain, and the oligosaccharide. Lattice interactions clearly influence, perhaps even determine the overall conformation of the antibody observed in this crystal. Comparison of this IgG1 with previously determined intact antibody structures extends the conformational range arising from segmental flexibility.


Rationale and design of a randomized controlled trial of allogeneic mesenchymal stem cells in patients with nonischemic cardiomyopathy.
This article describes an ongoing study investigating the safety and efficacy of ischemia-tolerant mesenchymal stem cell (MSC) therapy in patients with nonischemic heart failure and dysfunctional viable myocardium without scarring. This study will follow principles of the previously described mechanistic translational-phase concept whereby the effect of the study agent on laboratory and imaging markers of cardiac structure and function will be tested in a small homogenous cohort with the goal to enhance the understanding of the effect of interventions on cardiac remodeling and performance. This single-blind, placebo-controlled, crossover, multicenter, randomized study will assess the safety, tolerability, and preliminary efficacy of a single intravenous (i.v.) dose of allogeneic ischemia-tolerant MSCs in individuals with heart failure of nonischemic cause, ejection fraction 40% or less, and dysfunctional viable myocardium who have been receiving guideline-directed medical therapy. Eligible patients will have no evidence of baseline replacement scarring on delayed-enhancement cardiac magnetic resonance (CMR). Approximately 20 patients will be randomized in a 1 : 1 ratio to receive an i.v. infusion of ischemia-tolerant MSCs or placebo. At 90 days, the two groups will undergo crossover and received the alternative treatment. The primary endpoint is safety, as evaluated through at least 1-year post-MSC infusion. Additional efficacy endpoints will include measures of cardiac structure and function, as evaluated by serial cine-CMR and transthoracic echocardiography at 90 and 180 days post-initial infusion. This pilot study will explore the safety and effects on cardiac structure and function of i.v. injection of ischemia-tolerant MSCs in a small homogenous cohort of nonischemic heart failure patients with reduced ejection fraction and absent replacement scarring on CMR. This study also represents a prospective mechanistic translational-phase study using baseline and serial CMR imaging in heart failure patients and serves as a potential model for design of future heart failure trials (ClinicalTrials.gov identifier: NCT02467387).


Asthma control test and pediatric asthma quality of life questionnaire association in children with poor asthma control.
The aim of this study was to evaluate the association between Pediatric Asthma Quality of Life Questionnaire (PAQLQ) and Asthma Control Test (ACT) in patients with poor asthma control. Children between 7-17 years of age with diagnosis of persistent asthma who are not on daily inhaler corticosteroid therapy were involved. At enrollment, sociodemographic and asthmatic characteristics were investigated and pulmonary function test (PFT), ACT and PAQLQ were administered. Patients were reevaluated following six week regular inhaler therapy and ACT, PAQLQ and PFT were performed. Out of 77 patients, 35 (45%) were female. The mean age was 11.62 ± 2.35 years. Following 6 weeks daily inhaler therapy, the scores of ACT, all the parameters of PAQLQ and all the parameters of PFT except FEV1/FVC were significantly increased (p < 0.05). There was a significant correlation between ACT and PAQLQ scores (r < 0.5, p=0.001). In conclusion, there is a correlation between ACT and PAQLQ.


Soft hydrated sliding interfaces as complex fluids.
Hydrogel surfaces are biomimics for sensing and mobility systems in the body such as the eyes and large joints due to their important characteristics of flexibility, permeability, and integrated aqueous component. Recent studies have shown polymer concentration gradients resulting in a less dense region in the top micrometers of the surface. Under shear, this gradient is hypothesized to drive lubrication behavior due to its rheological similarity to a semi-dilute polymer solution. In this work we map 3 distinct lubricating regimes between a polyacrylamide surface and an aluminum annulus using stepped-velocity tribo-rheometry over 5 decades of sliding speed in increasing and decreasing steps. These regimes, characterized by weakly or strongly time-dependent response and thixotropy-like hysteresis, provide the skeleton of a lubrication curve for hydrogel-against-hard material interfaces and support hypotheses of polymer mechanics-driven lubrication. Tribo-rheometry is particularly suited to uncover the lubrication mechanisms of complex interfaces such as are formed with hydrated hydrogel surfaces and biological surfaces.


Gentamicin-intercalated smectite as a new therapeutic option for Helicobacter pylori eradication.
Novel antibacterial strategies against Helicobacter pylori are needed because H. pylori strains are acquiring resistance to antibiotics. We evaluated the efficacy of gentamicin-intercalated smectite hybrid (S-GEN)-based treatment regimens in a murine model of H. pylori infection. Two groups of 10 rats were administered either smectite or S-GEN to measure coverage of the gastric mucosa. To evaluate anti-H. pylori efficacy, mice were divided into eight groups of 10 mice each given different treatments, and H. pylori eradication was assessed by a Campylobacter-like organism (CLO) test and H. pylori PCR of the gastric mucosa, and H. pylori antigen and H. pylori PCR analysis of mouse faeces. The levels of proinflammatory cytokines were examined. S-GEN was retained in the gastric mucosal layer with a >60% distribution ratio for up to 1 h, and the S-GEN-based triple regimen decreased bacterial burden in vivo compared with that of untreated mice or mice treated with other regimens. The cure rates in the CLO test and H. pylori PCR from gastric mucosa were 70%, 60%, 80%, 50%, 60% and 60% in Groups III-VIII, respectively. Those for H. pylori PCR in the faeces of mice were 90% and 100% in Group III with standard therapy and Group V with triple therapy including S-GEN, respectively. S-GEN triple therapy also reduced the levels of proinflammatory cytokines. These results suggest that S-GEN is a promising and effective therapeutic agent for the treatment of H. pylori infection.


Treatment of Felty's syndrome with the haemopoietic growth factor granulocyte colony-stimulating factor (G-CSF).
Felty's syndrome (FS) (rheumatoid arthritis with neutropenia and splenomegaly) has a poor prognosis, largely because of the high risk of severe infection. Granulocyte colony-stimulating factor (G-CSF) is an emerging treatment for chronic neutropenia. We prospectively monitored its use in eight patients with recurrent infections or who required joint surgery. Significant side-effects were documented in five, including nausea, malaise, generalized joint pains, and in one patient, a vasculitic skin rash. In two patients treatment had to be stopped, and in these cases G-CSF had been started at full vial dosage (300 micrograms/ml filgrastim or 263 micrograms/ml lenograstim) alternate days or daily. G-CSF treatment was continued in three patients by restarting at reduced dose, and changing the proprietary formulation. G-CSF raised the neutrophil count, reduced severe infection, and allowed surgery to be performed. A combined clinical and laboratory index suggested that long-term treatment (up to 3.5 years) did not exacerbate the arthritis. Once on established treatment, it may be possible to use smaller weekly doses of G-CSF to maintain the same clinical benefit. One of the three patients whose FS was associated with a large granular T-cell lymphocytosis showed a reduction in this subset of lymphocytes during G-CSF treatment.


Cardiac signatures of personality.
There are well-established relations between personality and the heart, as evidenced by associations between negative emotions on the one hand, and coronary heart disease or chronic heart failure on the other. However, there are substantial gaps in our knowledge about relations between the heart and personality in healthy individuals. Here, we investigated whether amplitude patterns of the electrocardiogram (ECG) correlate with neurotisicm, extraversion, agreeableness, warmth, positive emotion, and tender-mindedness as measured with the Neuroticism-Extraversion-Openness (NEO) personality inventory. Specifically, we investigated (a) whether a cardiac amplitude measure that was previously reported to be related to flattened affectivity (referred to as Eκ values) would explain variance of NEO scores, and (b) whether correlations can be found between NEO scores and amplitudes of the ECG. NEO scores and rest ECGs were obtained from 425 healthy individuals. Neuroticism and positive emotion significantly differed between individuals with high and low Eκ values. In addition, stepwise cross-validated regressions indicated correlations between ECG amplitudes and (a) agreeableness, as well as (b) positive emotion. These results are the first to demonstrate that ECG amplitude patterns provide information about the personality of an individual as measured with NEO personality scales and facets. These findings open new perspectives for a more efficient personality assessment using cardiac measures, as well as for more efficient risk-stratification and pre-clinical diagnosis of individuals at risk for cardiac, affective and psychosomatic disorders.


The analysis of visual motion: a comparison of neuronal and psychophysical performance.
We compared the ability of psychophysical observers and single cortical neurons to discriminate weak motion signals in a stochastic visual display. All data were obtained from rhesus monkeys trained to perform a direction discrimination task near psychophysical threshold. The conditions for such a comparison were ideal in that both psychophysical and physiological data were obtained in the same animals, on the same sets of trials, and using the same visual display. In addition, the psychophysical task was tailored in each experiment to the physiological properties of the neuron under study; the visual display was matched to each neuron's preference for size, speed, and direction of motion. Under these conditions, the sensitivity of most MT neurons was very similar to the psychophysical sensitivity of the animal observers. In fact, the responses of single neurons typically provided a satisfactory account of both absolute psychophysical threshold and the shape of the psychometric function relating performance to the strength of the motion signal. Thus, psychophysical decisions in our task are likely to be based upon a relatively small number of neural signals. These signals could be carried by a small number of neurons if the responses of the pooled neurons are statistically independent. Alternatively, the signals may be carried by a much larger pool of neurons if their responses are partially intercorrelated.


Impact of TGF-β inhibition during acute exercise on Achilles tendon extracellular matrix.
The purpose of this study was to evaluate the role of TGF-β1 in regulating tendon extracellular matrix after acute exercise. Wistar rats exercised (n = 15) on a treadmill for four consecutive days (60 min/day) or maintained normal cage activity. After each exercise bout, the peritendinous space of each Achilles tendon was injected with a TGF-β1 receptor inhibitor or sham. Independent of group, tendons injected with inhibitor exhibited ~50% lower Smad 3 (Ser423/425) (P < 0.05) and 2.5-fold greater ERK1/2 phosphorylation (P < 0.05) when compared with sham (P < 0.05). Injection of the inhibitor did not alter collagen content in either group (P > 0.05). In exercised rats, hydroxylyslpyridinoline content and collagen III expression were lower (P < 0.05) in tendons injected with inhibitor when compared with sham. In nonexercised rats, collagen I and lysyl oxidase (LOX) expression was lower (P < 0.05) in tendons injected with inhibitor when compared with sham. Decorin expression was not altered by inhibitor in either group (P > 0.05). On the basis of evaluation of hematoxylin and eosin (H&E) stained cross sections, cell numbers were not altered by inhibitor treatment in either group (P > 0.05). Evaluation of H&E-stained sections revealed no effect of inhibitor on collagen fibril morphology. In contrast, scores for regional variation in cellularity decreased in exercised rats (P < 0.05). No differences in fiber arrangement, structure, and nuclei form were noted in either group (P > 0.05). Our findings suggest that TGF-β1 signaling is necessary for the regulation of tendon cross-link formation, as well as collagen and LOX gene transcription in an exercise-dependent manner.


Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial.
Ipilimumab is a fully human monoclonal antibody that binds cytotoxic T-lymphocyte antigen 4 to enhance antitumour immunity. Our aim was to assess the use of ipilimumab after radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel chemotherapy. We did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8 Gy in one fraction) followed by either ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Non-progressing patients could continue to receive ipilimumab at 10 mg/kg or placebo as maintenance therapy every 3 months until disease progression, unacceptable toxic effect, or death. Patients were randomly assigned to either treatment group via a minimisation algorithm, and stratified by Eastern Cooperative Oncology Group performance status, alkaline phosphatase concentration, haemoglobin concentration, and investigator site. Patients and investigators were masked to treatment allocation. The primary endpoint was overall survival, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00861614. From May 26, 2009, to Feb 15, 2012, 799 patients were randomly assigned (399 to ipilimumab and 400 to placebo), all of whom were included in the intention-to-treat analysis. Median overall survival was 11·2 months (95% CI 9·5-12·7) with ipilimumab and 10·0 months (8·3-11·0) with placebo (hazard ratio [HR] 0·85, 0·72-1·00; p=0·053). However, the assessment of the proportional hazards assumption showed that it was violated (p=0·0031). A piecewise hazard model showed that the HR changed over time: the HR for 0-5 months was 1·46 (95% CI 1·10-1·95), for 5-12 months was 0·65 (0·50-0·85), and beyond 12 months was 0·60 (0·43-0·86). The most common grade 3-4 adverse events were immune-related, occurring in 101 (26%) patients in the ipilimumab group and 11 (3%) of patients in the placebo group. The most frequent grade 3-4 adverse events included diarrhoea (64 [16%] of 393 patients in the ipilimumab group vs seven [2%] of 396 in the placebo group), fatigue (40 [11%] vs 35 [9%]), anaemia (40 [10%] vs 43 [11%]), and colitis (18 [5%] vs 0). Four (1%) deaths occurred because of toxic effects of the study drug, all in the ipilimumab group. Although there was no significant difference between the ipilimumab group and the placebo group in terms of overall survival in the primary analysis, there were signs of activity with the drug that warrant further investigation. Bristol-Myers Squibb.


What is the incidence of Barrett's and gastric metaplasia in esophageal atresia/tracheoesophageal fistula (EA/TEF) patients?
Aim of the study was to document the incidence of gastric and intestinal metaplasia (Barrett's esophagus) in a closely followed group with EA/TEF, determine the efficacy of pH probe studies in diagnosing reflux and, moreover, to determine the lag period between the development of gastroesophageal reflux disease (GERD) and metaplasia. Patients who underwent EA/TEF correction were followed up over an 18-year period (1990-2009) with regular pH probe and endoscopy investigations. Biopsies were performed at 3 year intervals to evaluate for metaplastic changes in the esophageal epithelium. The interval between esophageal atresia correction and the development of erosive esophagitis, gastric metaplasia and Barrett's esophagus was determined. The development of complicated GERD was statistically correlated to age at detection. 51 patients (28 male) underwent EA/TEF correction during the study period. The ages of the children followed up ranged from 7 months to 19 years. There were 5 Type A, 44 Type C and 2 Type D fistulas. 37 patients (5 Type A, 31 Type C, 1 Type D) had documented reflux and 14 did not. 17 (46%) of the patients with reflux underwent an anti-reflux operation. 4 of the 17 underwent 2 or more anti-reflux procedures. 21 patients had pH probe studies positive for reflux, 3 had negative pH probe studies after an anti-reflux operation. 18 of the 37 patients with reflux (about 50%) needed esophageal dilatation for either anastamotic or non-anastamotic strictures. Only 4/14 (28.5%) patients without reflux underwent dilatations and only in their first year of life (p=NS). 15 patients had mucosal abnormalities in endoscopic biopsies. 8 patients had gastric metaplasia and 1 patient had Barrett's esophagus. The mean age in the group with metaplasia (gastric and intestinal) was 13 years, which was significantly different from the mean age of the group (5.2 years) without mucosal changes (p<0.001). 2 patients with normal pH probe studies had metaplasia on biopsies. Metaplasia arises in about 15% of patients with EA/TEF. The lag time to developing metaplasia from the time of initial surgical correction is about 10 years. Endoscopy and biopsies are the best way of detecting mucosal changes.