Risperidone compared with olanzapine in a naturalistic clinical study: a cost analysis.
Risperidone and olanzapine are thought to have broadly similar clinical effects. This study was designed as a cost analysis study comparing costs and basic clinical outcomes of treatment with risperidone or olanzapine in a naturalistic setting. The U.K. Risperidone Olanzapine Drug Outcomes Studies in Schizophrenia (RODOS-UK) program consisted of a retrospective review of medical notes and prescription charts for 501 patients with schizophrenia or schizoaffective disorder who had been admitted to the hospital for the treatment of psychosis. The main outcome measure was cost of inpatient drug treatment. Clinical outcomes (clinician-assessed and -documented effectiveness, time to discharge) were also evaluated. Data were collected and verified between June and September 2000. Clinical outcomes were similar for risperidone and olanzapine. Clinician-assessed effectiveness was similar for both treatments (78% risperidone, 74% olanzapine; p =.39), but mean time to documented onset of effectiveness was significantly shorter for those treated with risperidone versus olanzapine (17.6 vs. 22.4 days; p =.01). Risperidone-treated patients stayed a mean of 9 fewer days in the hospital compared with olanzapine-treated patients (49 vs. 58 days; p =.007). The possibility that these observed differences were a result of different baseline characteristics could not be entirely discounted. Mean +/- SD doses of risperidone and olanzapine were 5.5 +/- 2.4 mg/day and 14.1 +/- 4.7 mg/day, respectively. The mean daily cost of all inpatient drugs was significantly higher for olanzapine than for risperidone (pound 5.63 vs. pound 3.92; p <.0001). Mean total costs of all inpatient drugs were significantly higher for olanzapine than for risperidone (pound 164 vs. pound 96; p <.0001), which partly reflected the longer mean treatment duration for olanzapine compared with risperidone (44 vs. 37 days). Concomitant antipsychotic use was similar for both groups (66% risperidone, 67% olanzapine). The number of patients documented as experiencing adverse events was not different between groups (22% risperidone, 19% olanzapine; p =.32). Risperidone and olanzapine produced broadly comparable clinical outcome in this cohort of hospitalized patients, but the use of risperidone was associated with significantly lower drug treatment costs.


The lipoprotein receptor LRP1 modulates sphingosine-1-phosphate signaling and is essential for vascular development.
Low density lipoprotein receptor-related protein 1 (LRP1) is indispensable for embryonic development. Comparing different genetically engineered mouse models, we found that expression of Lrp1 is essential in the embryo proper. Loss of LRP1 leads to lethal vascular defects with lack of proper investment with mural cells of both large and small vessels. We further demonstrate that LRP1 modulates Gi-dependent sphingosine-1-phosphate (S1P) signaling and integrates S1P and PDGF-BB signaling pathways, which are both crucial for mural cell recruitment, via its intracellular domain. Loss of LRP1 leads to a lack of S1P-dependent inhibition of RAC1 and loss of constraint of PDGF-BB-induced cell migration. Our studies thus identify LRP1 as a novel player in angiogenesis and in the recruitment and maintenance of mural cells. Moreover, they reveal an unexpected link between lipoprotein receptor and sphingolipid signaling that, in addition to angiogenesis during embryonic development, is of potential importance for other targets of these pathways, such as tumor angiogenesis and inflammatory processes.


Adaptive peripheral immune response increases proliferation of neural precursor cells in the adult hippocampus.
To understand the link between peripheral immune activation and neuronal precursor biology, we investigated the effect of T-cell activation on adult hippocampal neurogenesis in female C57Bl/6 mice. A peripheral adaptive immune response triggered by adjuvant-induced rheumatoid arthritis (2 microg/microl methylated BSA) or staphylococcus enterotoxin B (EC(50) of 0.25 microg/ml per 20 g body weight) was associated with a transient increase in hippocampal precursor cell proliferation and neurogenesis as assessed by immunohistochemistry and confocal microscopy. Both treatments were paralleled by an increase in corticosterone levels in the hippocampus 1- to 2-fold over the physiological amount measured by quantitative radioimmunoassay. In contrast, intraperitoneal administration of the innate immune response activator lipopolysaccaride (EC(50) of 0.5 microg/ml per 20 g body weight) led to a chronic 5-fold increase of hippocampal glucocorticoid levels and a decrease of adult neurogenesis. In vitro exposure of murine neuronal progenitor cells to corticosterone triggered either cell death at high (1.5 nM) or proliferation at low (0.25 nM) concentrations. This effect could be blocked using a viral vector system expressing a transdomain of the glucocorticoid receptor. We suggest an evolutionary relevant communication route for the brain to respond to environmental stressors like inflammation mediated by glucocorticoid levels in the hippocampus.


Matrix metalloproteinase-9-mediated tissue injury overrides the protective effect of matrix metalloproteinase-2 during colitis.
Matrix metalloproteinases (MMP) play an important role in pathogenesis of inflammatory bowel disease (IBD). Two known gelatinases, MMP-2 and MMP-9, are upregulated during IBD. Epithelial-derived MMP-9 is an important mediator of tissue injury in colitis, whereas MMP-2 protects against tissue damage and maintains gut barrier function. It has been suggested that developing strategies to block MMP-9 activity in the gut might be of benefit to IBD. However, given that MMP-2 and MMP-9 are structurally similar, such approaches would also likely inhibit MMP-2. Thus, to gain insight into outcome of inhibiting both MMP-2 and MMP-9, MMP-2(-/-)/MMP-9(-/-) double knockout mice (dKO) lacking both MMP-2 and MMP-9 were used in this study. Three models of murine colitis were used: dextran sodium sulfate (DSS), Salmonella typhimurium (S.T.), and trinitrobenzene sulfonic acid (TNBS). Our data demonstrate that MMP-2 and MMP-9 activities were highly upregulated in wild-type (WT) mice treated with DSS, S.T., or TNBS whereas dKO mice were resistant to the development of colitis. WT mice had extensive inflammation and tissue damage compared with dKO mice as suggested by histological assessment and myeloperoxidase activity. In conclusion, these results suggest an overriding role of MMP-9 in mediating tissue injury compared with the protective role of MMP-2 in development of colitis. Thus inhibition of MMP-9 may be beneficial in treatment of colitis even if resulting in inhibition of MMP-2.


Mesenchymal Stem Cells for Perianal Crohn's Disease.
Perianal fistulizing Crohn's disease (PFCD) is associated with significant morbidity and might negatively impact the quality of life of CD patients. In the last two decades, the management of PFCD has evolved in terms of the multidisciplinary approach involving gastroenterologists and colorectal surgeons. However, the highest fistula healing rates, even combining surgical and anti-TNF agents, reaches 50% of treated patients. More recently, the administration of mesenchymal stem cells (MSCs) have shown notable promising results in the treatment of PFCD. The aim of this review is to describe the rationale and the possible mechanism of action of MSC application for PFCD and the most recent results of randomized clinical trials. Furthermore, the unmet needs of the current administration process and the expected next steps to improve the outcomes will be addressed.


Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis.
Fingolimod (FTY720) is a first-in-class orally bioavailable compound that has shown efficacy in advanced clinical trials for the treatment of multiple sclerosis (MS). In vivo, fingolimod is phosphorylated to form fingolimod-phosphate, which resembles naturally occurring sphingosine 1-phosphate (S1P), an extracellular lipid mediator whose major effects are mediated by cognate G protein-coupled receptors. There are at least 5 S1P receptor subtypes, known as S1P subtypes 1-5 (S1P1-5), 4 of which bind fingolimod-phosphate. These receptors are expressed on a wide range of cells that are involved in many biological processes relevant to MS. S1P1 plays a key role in the immune system, regulating lymphocyte egress from lymphoid tissues into the circulation. Fingolimod-phosphate initially activates lymphocyte S1P1 via high-affinity receptor binding yet subsequently induces S1P1 down-regulation that prevents lymphocyte egress from lymphoid tissues, thereby reducing autoaggressive lymphocyte infiltration into the central nervous system (CNS). S1P receptors are also expressed by many CNS cell types and have been shown to influence cell proliferation, morphology, and migration. Fingolimod crosses the blood-brain barrier and may therefore have direct CNS effects, distinguishing it from immunologically targeted MS therapies. Prophylactic administration of fingolimod to animals with experimental autoimmune encephalitis (EAE), a model of MS, completely prevents development of EAE features, whereas therapeutic administration significantly reduces clinical severity of EAE. Therapeutic efficacy observed in animal studies has been substantiated in phase 2 and 3 trials involving patients with relapsing or relapsing-remitting MS.


Global evolution and paleogeographic distribution of mid-Cretaceous orbitolinids.
Members of the Larger Benthic Foraminiferal (LBF) family Orbitolinidae occurred from the Cretaceous to the Paleogene, however, they were most diverse during the mid-Cretaceous, and dominated the agglutinated LBF assemblages described from limestones of that period. Various orbitolinid species have been used to zone and date lithologies formed in the shallow, warm waters of the Aptian to the early Cenomanian, and many, sometimes inaccurate, generic and sub-generic nomenclatures have been proposed to differentiate the often-subtle morphological changes that orbitolinids exhibit over time. Also, until now, it has not been possible to develop an effective global overview of their evolution and environmental development because descriptions of specimens from Asia have been relatively rare. Following our recent study of over 1800 orbitolinid-rich thin sections of material from 13 outcrops of Langshan limestone, from the Southern Tibetan Plateau, and from the Barito Basin, South Kalimantan, Indonesia, it has been possible to compare the stratigraphic ranges of these orbitolinids with previously described Tethyan and American forms, based on the use of a planktonic zonal (PZ) scheme, itself tied to the most recent chronostratigraphic scale. This has allowed the reconstruction of the phylogenetic and paleogeographic evolution of the orbitolinids from their Valanginian origin in the Tethys. Although the Tethys remained the paleogeographic centre for the orbitolinids, it is inferred here for the first time that a bi-directional paleogeographic migration of some orbitolinid genera occurred from the Tethys to the Americas and also to the Western Pacific region. Our observations and dating suggest that global marine regressions in the Aptian were coincident with, and may well have facilitated, these orbitolinid transoceanic migrations. Migration stopped however after rising sea level in the early Albian appears to have again isolated these provinces from each other. Tectonic forces associated with the subduction of the Farallon Plate and further sea level raises led to the opening of the Western Interior Seaway in North America, which correlates with, and may have been the cause of, the middle Albian (top of PZ Albian 2) extinction of the American orbitolinids. The extinction of the orbitolinids revealed that the Western Pacific province was split into two sub-provinces, with extinction occurring at the end of the early Albian (top of PZ Albian 1) in the Northwest Pacific sub-province, and at the end of the Albian (top of PZ Albian 4) in the subprovince that is today South East Asia (on the margins and west of the Wallace Line). The final near extinction of the orbitolinids occurred at the end of the Cenomanian in the Tethyan province, which coincides with, and may have been caused by, global anoxic oceanic events that correlate with a near-peak Mesozoic eustatic sea level high-stand that led to the overall global collapse of the paleotropical reef ecosystem at that time.


Human Virus Transcriptional Regulators.
Viral genomes encode transcriptional regulators that alter the expression of viral and host genes. Despite an emerging role in human diseases, a thorough annotation of human viral transcriptional regulators (vTRs) is currently lacking, limiting our understanding of their molecular features and functions. Here, we provide a comprehensive catalog of 419 vTRs belonging to 20 different virus families. Using this catalog, we characterize shared and unique cellular genes, proteins, and pathways targeted by particular vTRs and discuss the role of vTRs in human disease pathogenesis. Our study provides a unique and valuable resource for the fields of virology, genomics, and human disease genetics.


Modeling mammary organogenesis from biological first principles: Cells and their physical constraints.
In multicellular organisms, relations among parts and between parts and the whole are contextual and interdependent. These organisms and their cells are ontogenetically linked: an organism starts as a cell that divides producing non-identical cells, which organize in tri-dimensional patterns. These association patterns and cells types change as tissues and organs are formed. This contextuality and circularity makes it difficult to establish detailed cause and effect relationships. Here we propose an approach to overcome these intrinsic difficulties by combining the use of two models; 1) an experimental one that employs 3D culture technology to obtain the structures of the mammary gland, namely, ducts and acini, and 2) a mathematical model based on biological principles. The typical approach for mathematical modeling in biology is to apply mathematical tools and concepts developed originally in physics or computer sciences. Instead, we propose to construct a mathematical model based on proper biological principles. Specifically, we use principles identified as fundamental for the elaboration of a theory of organisms, namely i) the default state of cell proliferation with variation and motility and ii) the principle of organization by closure of constraints. This model has a biological component, the cells, and a physical component, a matrix which contains collagen fibers. Cells display agency and move and proliferate unless constrained; they exert mechanical forces that i) act on collagen fibers and ii) on other cells. As fibers organize, they constrain the cells on their ability to move and to proliferate. The model exhibits a circularity that can be interpreted in terms of closure of constraints. Implementing the mathematical model shows that constraints to the default state are sufficient to explain ductal and acinar formation, and points to a target of future research, namely, to inhibitors of cell proliferation and motility generated by the epithelial cells. The success of this model suggests a step-wise approach whereby additional constraints imposed by the tissue and the organism could be examined in silico and rigorously tested by in vitro and in vivo experiments, in accordance with the organicist perspective we embrace.


Significant photoluminescence enhancement in WS2 monolayers through Na2S treatment.
Tungsten disulfide monolayers have attracted extensive attention in nanoelectronics and optoelectronics applications due to their remarkable electronic and optical properties. High-quality WS2 monolayers with a scalable size and uniform thickness can be synthesized by a chemical vapor deposition method (CVD). However, they commonly contain intrinsic structural defects and different populations of charge carriers, which are responsible for different contributions of excitons, trions, and biexcitons to their photoluminescence (PL) emission. Here, we adopt sodium sulphide (Na2S) solution to chemically treat CVD-grown WS2 monolayers by a simple immersing method. The results show that WS2 monolayers have a significantly enhanced PL emission by a factor of 25-fold and an obvious red-shift of the PL wavelength, resulting from the different excitonic states induced by effective n-type doping after Na2S treatment. This work provides a simple but promising chemical doping route to significantly improve the optical properties of WS2 monolayers and paves the way for the realization of practical WS2 monolayer based optoelectronic applications.


High-speed atomic force microscopy reveals structural dynamics of α-synuclein monomers and dimers.
α-Synuclein (α-syn) is the major component of the intraneuronal inclusions called Lewy bodies, which are the pathological hallmark of Parkinson's disease. α-Syn is capable of self-assembly into many different species, such as soluble oligomers and fibrils. Even though attempts to resolve the structures of the protein have been made, detailed understanding about the structures and their relationship with the different aggregation steps is lacking, which is of interest to provide insights into the pathogenic mechanism of Parkinson's disease. Here we report the structural flexibility of α-syn monomers and dimers in an aqueous solution environment as probed by single-molecule time-lapse high-speed AFM. In addition, we present the molecular basis for the structural transitions using discrete molecular dynamics (DMD) simulations. α-Syn monomers assume a globular conformation, which is capable of forming tail-like protrusions over dozens of seconds. Importantly, a globular monomer can adopt fully extended conformations. Dimers, on the other hand, are less dynamic and show a dumbbell conformation that experiences morphological changes over time. DMD simulations revealed that the α-syn monomer consists of several tightly packed small helices. The tail-like protrusions are also helical with a small β-sheet, acting as a "hinge". Monomers within dimers have a large interfacial interaction area and are stabilized by interactions in the non-amyloid central (NAC) regions. Furthermore, the dimer NAC-region of each α-syn monomer forms a β-rich segment. Moreover, NAC-regions are located in the hydrophobic core of the dimer.


In vitro hemocompatibility on thin ceramic and hydrogel films deposited on polymer substrate performed in arterial flow conditions.
Hydrogel coatings were stabilized by titanium carbonitride a-C:H:Ti:N buffer layers deposited directly onto the polyurethane (PU) substrate beneath a final hydrogel coating. Coatings of a-C:H:Ti:N were deposited using a hybrid method of pulsed laser deposition (PLD) and magnetron sputtering (MS) under high vacuum conditions. The influence of the buffer a-C:H:Ti:N layer on the hydrogel coating was analysed by means of a multi-scale microstructure study. Mechanical tests were performed at an indentation load of 5 mN using Berkovich indenter geometry. Haemocompatible analyses were performed in vitro using a blood flow simulator. The blood-material interaction was analysed under dynamic conditions. The coating fabrication procedure improved the coating stability due to the deposition of the amorphous titanium carbonitride buffer layer.


Spatiotemporal contrast enhancement and feature extraction in the bat auditory midbrain and cortex.
Navigating on the wing in complete darkness is a challenging task for echolocating bats. It requires the detailed analysis of spatial and temporal information gained through echolocation. Thus neural encoding of spatiotemporal echo information is a major function in the bat auditory system. In this study we presented echoes in virtual acoustic space and used a reverse-correlation technique to investigate the spatiotemporal response characteristics of units in the inferior colliculus (IC) and the auditory cortex (AC) of the bat Phyllostomus discolor. Spatiotemporal response maps (STRMs) of IC units revealed an organization of suppressive and excitatory regions that provided pronounced contrast enhancement along both the time and azimuth axes. Most IC units showed either spatially centralized short-latency excitation spatiotemporally imbedded in strong suppression, or the opposite, i.e., central short-latency suppression imbedded in excitation. This complementary arrangement of excitation and suppression was very rarely seen in AC units. In contrast, STRMs in the AC revealed much less suppression, sharper spatiotemporal tuning, and often a special spatiotemporal arrangement of two excitatory regions. Temporal separation of excitatory regions ranged up to 25 ms and was thus in the range of temporal delays occurring in target ranging in bats in a natural situation. Our data indicate that spatiotemporal processing of echo information in the bat auditory midbrain and cortex serves very different purposes: Whereas the spatiotemporal contrast enhancement provided by the IC contributes to echo-feature extraction, the AC reflects the result of this processing in terms of a high selectivity and task-oriented recombination of the extracted features.


Intrapartum and neonatal mortality in primary midwife-led and secondary obstetrician-led care in the Amsterdam region of the Netherlands: A retrospective cohort study.
To compare intrapartum- and neonatal mortality and intervention rates in term women starting labour in primary midwife-led versus secondary obstetrician-led care. Retrospective cohort study. Amsterdam region of the Netherlands. Women with singleton pregnancies who gave birth beyond 37+0 weeks gestation in the years 2005 up to 2008 and lived in the catchment area of the neonatal intensive care units of both academic hospitals in Amsterdam. Women with a primary caesarean section or a pregnancy complicated by antepartum death or major congenital anomalies were excluded. For women in the midwife-led care group, a home or hospital birth could be planned. Analysis of linked data from the national perinatal register, and hospital- and midwifery record data. We assessed (unadjusted) relative risks with confidence intervals. Main outcome measures were incidences of intrapartum and neonatal (<28 days) mortality. Secondary outcomes included incidences of caesarean section and vaginal instrumental delivery. 53,123 women started labour in primary care and 30,166 women in secondary care. Intrapartum and neonatal mortality rates were 37/53,123 (0.70‰) in the primary care group and 24/30,166 (0.80‰) in the secondary care group (relative risk 0.88; 95% CI 0.52-1.46). Women in the primary care group were less likely to deliver by secondary caesarean section (5% versus 16%; RR 0.31; 95% CI 0.30-0.32) or by instrumental delivery (10% versus 13%; RR 0.76; 95% CI 0.73-0.79). We found a low absolute risk of intrapartum and neonatal mortality, with a comparable risk for women who started labour in primary versus secondary care. The intervention rate was significantly lower in women who started labour in primary care. These findings suggest that it is possible to identify a group of women at low risk of complications that can start labour in primary care and have low rates of medical interventions whereas perinatal mortality is low.


Computational methods using genome-wide association studies to predict radiotherapy complications and to identify correlative molecular processes.
The biological cause of clinically observed variability of normal tissue damage following radiotherapy is poorly understood. We hypothesized that machine/statistical learning methods using single nucleotide polymorphism (SNP)-based genome-wide association studies (GWAS) would identify groups of patients of differing complication risk, and furthermore could be used to identify key biological sources of variability. We developed a novel learning algorithm, called pre-conditioned random forest regression (PRFR), to construct polygenic risk models using hundreds of SNPs, thereby capturing genomic features that confer small differential risk. Predictive models were trained and validated on a cohort of 368 prostate cancer patients for two post-radiotherapy clinical endpoints: late rectal bleeding and erectile dysfunction. The proposed method results in better predictive performance compared with existing computational methods. Gene ontology enrichment analysis and protein-protein interaction network analysis are used to identify key biological processes and proteins that were plausible based on other published studies. In conclusion, we confirm that novel machine learning methods can produce large predictive models (hundreds of SNPs), yielding clinically useful risk stratification models, as well as identifying important underlying biological processes in the radiation damage and tissue repair process. The methods are generally applicable to GWAS data and are not specific to radiotherapy endpoints.


Obstacle stepping in children: task acquisition and performance.
The aim of this study was to investigate the locomotor capacity of children during the performance of different lower extremity tasks with increasing difficulty. Two subject groups of children (aged 6-8 and 9-12 years) and adult controls performed several motor tasks from the Zürich Neuromotor Assessment (ZNA) test, as well as a unilateral and bilateral obstacle stepping test during treadmill walking. Performance of ZNA items, changes in foot clearance, and obstacle hits were assessed. Correlations between children's age, ZNA and obstacle measures were calculated. Performance of all motor tasks improved with increasing age. All three groups improved foot clearance during unilateral obstacle stepping, while the younger children achieved a poorer performance level. During bilateral obstacle stepping, only the adult controls and the 9-12 years old children's group further improved foot clearance, while no further improvement occurred in the 6-8 years old children's group. A relationship between items of ZNA and bilateral obstacle stepping was found. It is concluded that children in the mid-childhood range are able to significantly improve performance of a high-precision locomotor task. However, children below 9 years of age have a poorer motor performance compared to older children and adults that becomes more pronounced with increasing complexity of the task. Finally, ZNA tests can improve the prediction of complex adaptive locomotor behaviour compared to calendar age alone.


UK bone conduction hearing device consensus workshop: Narrative summary.
To identify United Kingdom (UK)-specific research priorities in the field of bone conduction hearing devices (BCHDs). Narrative summary of the discussions and outcomes of a UK BCHD research workshop. The workshop was organized on 8 September 2016 under the auspices of the National Institute for Health Research (NIHR) Clinical Research Network (CRN) ENT Specialty group and Royal College of Surgeons (RCS) Clinical Research Initiative. Representatives from a wide range of patient and professional groups from the UK and abroad were invited to attend. Main outcome measures were research priorities and approaches in the field of BCHDs. Key research questions in the field of BCHDs are as follows: (1) What are the existing national BCHD practices? (2) What are the patient information and support needs on BCHDs? (3) Which outcomes should be measured across clinical studies in the field of BCHDs? The workshop suggested the following approaches to address these priorities: (1) a service evaluation of current UK BCHD practice; development of a national registry of BCHDs; (2) qualitative research to understand patient information and support needs; development of patient decision support tools; (3) development of core outcome sets for BCHDs. Building upon the framework of the recent UK Research Agenda for ENT, Hearing and Balance, patients and professionals defined key UK-specific research priorities and approaches in the field of BCHDs. This approach promotes engagement, buy-in, national collaboration and thereby value of future BCHD research.


Idiopathic adhesive capsulitis. A prospective functional outcome study of nonoperative treatment.
Idiopathic adhesive capsulitis is a commonly recognized but poorly understood cause of a painful and stiff shoulder. Although most orthopaedic literature supports treatment with physical therapy and stretching exercises, some studies have demonstrated late pain and functional deficits. The purpose of this study was to evaluate the outcome of patients with idiopathic adhesive capsulitis who were treated with a stretching-exercise program. Seventy-five consecutive patients (seventy-seven shoulders) with phase-II idiopathic adhesive capsulitis were treated with use of a specific four-direction shoulder-stretching exercise program and evaluated prospectively. The initial evaluation included the recording of a detailed medical and orthopaedic history and assessment of pain, range of motion, and function. The outcome evaluation included assessment of pain, range of motion, and function; completion of the Disabilities of the Arm, Shoulder, and Hand (DASH) Questionnaire; and completion of the Short Form-36 (SF-36) Health Survey. The mean duration of follow-up was twenty-two months (range, twelve to forty-one months). One patient died prior to the final evaluation, and three patients were lost to follow-up. Sixty-four (90 percent) of the patients reported a satisfactory outcome. Seven (10 percent) were not satisfied with the outcome, and five (7 percent) underwent manipulation and/or arthroscopic capsular release. The outcomes of the patients who did not have manipulation or capsular release were evaluated. There were significant improvements in the scores for pain at rest (from a mean of 1.57 points before treatment to a mean of 1.16 points at the final evaluation; p < 0.001) and pain with activity (from a mean of 4.12 points before treatment to a mean of 1.33 points at the final evaluation; p < 0.0001). On the average, active forward elevation increased 43 degrees, active external rotation increased 25 degrees, passive internal rotation increased eight vertebral levels, and the glenohumeral rotation arc at 90 degrees of abduction increased 72 degrees (p < 0.00001). The number of "yes" responses to the Simple Shoulder Test increased from a mean of 4.1 (of a possible twelve) to a mean of 10.75 (p < 0.00001). Despite the significant improvements and the high rate of patient satisfaction, there were still significant differences in the pain and motion of the affected shoulder when compared with those of the unaffected, contralateral shoulder (p < 0.00001). At the final outcome evaluation, the DASH scores demonstrated limitations when compared with known population norms, whereas the profiles of the SF-36 were comparable with those of age and gender-matched control populations. Prior treatment with physical therapy and a Workers' Compensation claim or pending litigation were the only variables that were associated with the eventual need for manipulation or capsular release. Male gender and diabetes mellitus were associated with worse motion at the final evaluation. Patients with a greater severity of pain with activity at the initial evaluation had significantly lower DASH scores at the final evaluation, and patients with lower initial scores on the Simple Shoulder Test had comparatively lower scores on the Simple Shoulder Test at the outcome evaluation. The vast majority of patients who have phase-II idiopathic adhesive capsulitis can be successfully treated with a specific four-direction shoulder-stretching exercise program. Although measurable limitations and deficiencies were noted at the outcome evaluation, these appeared to be acceptable to most of the patients and did not affect their general health status. Patients with more severe pain and functional limitations before treatment had relatively worse outcomes. More aggressive treatment such as manipulation or capsular release was rarely necessary, and the efficacy of early use of these treatments should be further studied.


Testosterone and dominance in men.
In men, high levels of endogenous testosterone (T) seem to encourage behavior intended to dominate--to enhance one's status over--other people. Sometimes dominant behavior is aggressive, its apparent intent being to inflict harm on another person, but often dominance is expressed nonaggressively. Sometimes dominant behavior takes the form of antisocial behavior, including rebellion against authority and low breaking. Measurement of T at a single point in time, presumably indicative of a man's basal T level, predicts many of these dominant or antisocial behaviors. T not only affects behavior but also responds to it. The act of competing for dominant status affects male T levels in two ways. First, T rises in the face of a challenge, as if it were an anticipatory response to impending competition. Second, after the competition, T rises in winners and declines in losers. Thus, there is a reciprocity between T and dominance behavior, each affecting the other. We contrast a reciprocal model, in which T level is variable, acting as both a cause and effect of behavior, with a basal model, in which T level is assumed to be a persistent trait that influences behavior. An unusual data set on Air Force veterans, in which data were collected four times over a decade, enables us to compare the basal and reciprocal models as explanations for the relationship between T and divorce. We discuss sociological implications of these models.


Distinct binding and immunogenic properties of the gonococcal homologue of meningococcal factor h binding protein.
Neisseria meningitidis is a leading cause of sepsis and meningitis. The bacterium recruits factor H (fH), a negative regulator of the complement system, to its surface via fH binding protein (fHbp), providing a mechanism to avoid complement-mediated killing. fHbp is an important antigen that elicits protective immunity against the meningococcus and has been divided into three different variant groups, V1, V2 and V3, or families A and B. However, immunisation with fHbp V1 does not result in cross-protection against V2 and V3 and vice versa. Furthermore, high affinity binding of fH could impair immune responses against fHbp. Here, we investigate a homologue of fHbp in Neisseria gonorrhoeae, designated as Gonococcal homologue of fHbp (Ghfp) which we show is a promising vaccine candidate for N. meningitidis. We demonstrate that Gfhp is not expressed on the surface of the gonococcus and, despite its high level of identity with fHbp, does not bind fH. Substitution of only two amino acids in Ghfp is sufficient to confer fH binding, while the corresponding residues in V3 fHbp are essential for high affinity fH binding. Furthermore, immune responses against Ghfp recognise V1, V2 and V3 fHbps expressed by a range of clinical isolates, and have serum bactericidal activity against N. meningitidis expressing fHbps from all variant groups.


Quantitative trait loci associated with different polar metabolites in perennial ryegrass - providing scope for breeding towards increasing certain polar metabolites.
Recent advances in the mapping of biochemical traits have been reported in Lolium perenne. Although the mapped traits, including individual sugars and fatty acids, contribute greatly towards ruminant productivity, organic acids and amino acids have been largely understudied despite their influence on the ruminal microbiome. In this study, we used a targeted gas-chromatography mass spectrometry (GC-MS) approach to profile the levels of 25 polar metabolites from different classes (sugars, amino acids, phenolic acids, organic acids and other nitrogen-containing compounds) present in a L. perenne F2 population consisting of 325 individuals. A quantitative trait (QTL) mapping approach was applied and successfully identified QTLs regulating seven of those polar metabolites (L-serine, L-leucine, glucose, fructose, myo-inositol, citric acid and 2, 3-hydroxypropanoic acid).Two QTL mapping approaches were carried out using SNP markers on about half of the population only and an imputation approach using SNP and DArT markers on the entire population. The imputation approach confirmed the four QTLs found in the SNP-only analysis and identified a further seven QTLs. These results highlight the potential of utilising molecular assisted breeding in perennial ryegrass to modulate a range of biochemical quality traits with downstream effects in livestock productivity and ruminal digestion.


Characteristics of plasma scalds in multilayer dielectric films.
Plasma scalding is one of the most typical laser damage morphologies induced by a nanosecond laser with a wavelength of 1053 nm in HfO(2)/SiO(2) multilayer films. In this paper, the characteristics of plasma scalds are systematically investigated with multiple methods. The scalding behaves as surface discoloration under a microscope. The shape is nearly circular when the laser incidence angle is close to normal incidence and is elliptical at oblique incidence. The nodular-ejection pit is in the center of the scalding region when the laser irradiates at the incidence angle close to normal incidence and in the right of the scalding region when the laser irradiates from left to right at oblique incidence. The maximum damage size of the scalding increases with laser energy. The edge of the scalding is high compared with the unirradiated film surface, and the region tending to the center is concave. Plasma scald is proved to be surface damage. The maximum depth of a scald increases with its size. Tiny pits of nanometer scale can be seen in the scalding film under a scanning electronic microscope at a higher magnification. The absorptions of the surface plasma scalds tend to be approximately the same as the lower absorptions of test sites without laser irradiation. Scalds do not grow during further illumination pulses until 65 J/cm(2). The formation of surface plasma scalding may be related to the occurrence of the laser-supported detonation wave.


Clinically feasible stable isotope technique at a reasonable price: analysis of 13CO2/12CO2-abundance in breath samples with a new isotope selective-nondispersive infrared spectrometer.
Up to now, stable isotope analysis of carbon dioxide in breath samples is carried out with sensitive but very expensive and complex isotope ratio mass spectrometry (IRMS). Aiming at a more widespread application of breath tests in gastroenterological diagnostic routine, we tested a newly developed isotope selective non-dispersive infrared spectrometer (NDIRS) in comparison to IRMS. 13C-urea breath tests were performed in 63 patients as the routine screening method for Helicobacter pylori infection. Breath samples at baseline and (15) 30 min after administration of the test solution containing 13C-urea were analysed both by NDIRS and conventional IRMS. The correlation between the delta values of both devices was linear and in good agreement (r = 0.96; p < 0.0001; Y = 1.01 X -0.94). Comparing the delta over baseline-values, the correlation was Y = 1.11 X -0.36 (r = 0.98; p < 0.0001). Referring to the diagnosis of Helicobacter pylori infection with IRMS we calculated a sensitivity of 95.0% and an unchanged specificity (100%) for NDIR analysis. In conclusion, NDIRS appears a promising, easy to operate, and low cost potential alternative to conventional IRMS thus encouraging further detailed investigation and more widespread application of the noninvasive stable isotope technique in breath tests for gastrointestinal function testing.


Trans-ancestral studies fine map the SLE-susceptibility locus TNFSF4.
We previously established an 80 kb haplotype upstream of TNFSF4 as a susceptibility locus in the autoimmune disease SLE. SLE-associated alleles at this locus are associated with inflammatory disorders, including atherosclerosis and ischaemic stroke. In Europeans, the TNFSF4 causal variants have remained elusive due to strong linkage disequilibrium exhibited by alleles spanning the region. Using a trans-ancestral approach to fine-map the locus, utilising 17,900 SLE and control subjects including Amerindian/Hispanics (1348 cases, 717 controls), African-Americans (AA) (1529, 2048) and better powered cohorts of Europeans and East Asians, we find strong association of risk alleles in all ethnicities; the AA association replicates in African-American Gullah (152,122). The best evidence of association comes from two adjacent markers: rs2205960-T (P=1.71 × 10(-34) , OR=1.43[1.26-1.60]) and rs1234317-T (P=1.16 × 10(-28) , OR=1.38[1.24-1.54]). Inference of fine-scale recombination rates for all populations tested finds the 80 kb risk and non-risk haplotypes in all except African-Americans. In this population the decay of recombination equates to an 11 kb risk haplotype, anchored in the 5' region proximal to TNFSF4 and tagged by rs2205960-T after 1000 Genomes phase 1 (v3) imputation. Conditional regression analyses delineate the 5' risk signal to rs2205960-T and the independent non-risk signal to rs1234314-C. Our case-only and SLE-control cohorts demonstrate robust association of rs2205960-T with autoantibody production. The rs2205960-T is predicted to form part of a decameric motif which binds NF-κBp65 with increased affinity compared to rs2205960-G. ChIP-seq data also indicate NF-κB interaction with the DNA sequence at this position in LCL cells. Our research suggests association of rs2205960-T with SLE across multiple groups and an independent non-risk signal at rs1234314-C. rs2205960-T is associated with autoantibody production and lymphopenia. Our data confirm a global signal at TNFSF4 and a role for the expressed product at multiple stages of lymphocyte dysregulation during SLE pathogenesis. We confirm the validity of trans-ancestral mapping in a complex trait.


Smoking, heart rate, and ischemic stroke: a population-based prospective cohort study among Inner Mongolians in China.
Smoking is a major public health challenge and an important risk factor for cardiovascular diseases. No previous studies have evaluated the association among smoking, heart rate, and ischemic stroke in an Inner Mongolian population. We aim to evaluate the cumulative effect of smoking and heart rate on ischemic stroke incidence in this population. A prospective cohort study from June 2003 through July 2012 was conducted among 2530 people ≥20 years of age from Inner Mongolia, China. We categorized the participants into 4 subgroups according to smoking status and heart rate. Cox proportional hazards models and receiver operating characteristic curves were used to evaluate the association among smoking, heart rate, and ischemic stroke. The multivariate-adjusted hazard ratios (95% confidence intervals) of ischemic stroke incidence for nonsmokers with heart rate ≥80 bpm, smokers with heart rate <80 bpm, and smokers with heart rate ≥80 bpm were 1.42 (0.62-3.28), 2.11 (1.06-4.23), and 2.86 (1.33-6.14), respectively, compared with nonsmokers with heart rate <80 bpm. The area under receiver operating characteristic curve (area under the curve) for a model containing smoking status and heart rate, along with conventional factors (area under the curve=0.755), was significantly (P=0.018) larger than the one containing only conventional factors (area under the curve=0.739). Our study indicated that smoking was an independent risk factor of ischemic stroke, and smokers with faster heart rate had the highest risk of ischemic stroke among Inner Mongolians. These findings suggest that smoking status and heart rate may be valuable in predicting ischemic stroke incidence.


Associations between oxaliplatin-induced peripheral neuropathy and polymorphisms of the ERCC1 and GSTP1 genes.
Oxaliplatin-induced chronic neuropathy is cumulative and dose-limiting; reliable predictors and determination of the mechanism of this toxic effect are needed. We retrospectively studied 51 Japanese adults with colorectal cancer who had received oxaliplatin-based chemotherapy to explore the pharmacogenetic association between oxaliplatin-induced neuropathy and polymorphisms of the excision repair cross-complementation Group 1 (ERCC1) and glutathione-S-transferases pi 1 (GSTP1) genes. For the ERCC1 C118T polymorphism, Grade 1 chronic neuropathy developed earlier in patients with C/T and T/T genotypes (median number of treatment cycles at onset = 6) than in those with the reference C/C genotype (7 cycles; p = 0.0162 by the generalized Wilcoxon test). For the GSTP1 Ile105Val polymorphism, chronic neuropathy developed earlier in patients with the reference Ile/Ile genotype (6 cycles) than in those with Ile/Val and Val/Val genotypes (9 cycles; p = 0.0321). ERCC1 C118T and GSTP1 Ile105Val polymorphisms were not significantly associated with an increased risk of developing Grade 2 or more severe chronic neuropathy. Our results suggest that ERCC1, C118T and GSTP1 Ile105Val polymorphisms are more strongly related to the time until onset of neuropathy than to the grade of neuropathy. Most likely these polymorphisms influence patients' sensitivity to neuropathy.


Apitherapy as a New Approach in Treatment of Palmoplantar Psoriasis.
Apitherapy is the medical use of honey bee products, "honey, propolis, royal jelly, bee wax, and bee venom to relieve human ailments. Propolis is one of the most well-documented products derived from the honeybee and has always played an important role in traditional folk medicine. The aim was to justify the consideration of Aloe Vera as an effective remedy for the treatment of psoriasis. The study follows (857) patients (354 females, 503 males) with a mean age range from (9 - 62) years, affected with moderate to severe psoriasis in palms and foot soles treated by a combination mixture of propolis and Aloe in the form of an ointment (Aloreed) and Beauty reed cream. The treatment duration was for 12 weeks. Results were evaluated by using clinical, histological and statistical parameters. After the 12 - week treatment, we observed an 86% overall response rate from which 62% showed excellent results and 24% showed good results, therefore proving the efficiency in the use of the mixture of propolis 50% and aloe vera 3% as topically applied ointment in the treatment of mild to moderate psoriasis. Patients who have palmoplantar psoriasis, who were treated with a topically applied mixture of propolis (50%) and aloe vera (3%), have shown noteworthy improvement thus proving the efficiency of propolis and aloe vera in the treatment of mild to moderate psoriasis.


Prognostic significance of quantitative bacteremia in septicemic melioidosis.
Pour-plate blood cultures were performed for 418 adult patients with suspected septicemic melioidosis in order to determine the relationship between quantitative bacterial counts in blood and mortality. Of 108 patients whose hemocultures yielded Burkholderia pseudomallei, 53% had < 10 cfu/mL and 24% had > 100 cfu/mL. High blood bacterial counts were more common than reported previously with regard to other gram-negative septicemias and were significantly associated with the development of hypotension (P = .008) and a fatal outcome (P = .0001). The overall mortality was 63% (95% CI, 53%-72%); however, counts of < or = 1 cfu/mL were associated with a mortality of 42% (95% CI, 28%-58%), compared with 96% (95% CI, 80%-100%) with counts of > 100 cfu/mL. Heavy bacteremia (> 50 cfu/mL) is common in septicemic melioidosis and is usually fatal.


Relationships between non-pathological dream-enactment and mirror behaviors.
Dream-enacting behaviors (DEBs) are behavioral expressions of forceful dream images often occurring during sleep-to-wakefulness transitions. We propose that DEBs reflect brain activity underlying social cognition, in particular, motor-affective resonance generated by the mirror neuron system. We developed a Mirror Behavior Questionnaire (MBQ) to assess some dimensions of mirror behaviors and investigated relationships between MBQ scores and DEBs in a large of university undergraduate cohort. MBQ scores were normally distributed and described by a four-factor structure (Empathy/Emotional Contagion, Behavioral Imitation, Sleepiness/Anger Contagion, Motor Skill Imitation). DEB scores correlated positively with MBQ total and factor scores even with social desirability, somnambulism and somniloquy controlled. Emotion-specific DEB items correlated with corresponding emotion-specific MBQ items, especially crying and smiling. Results provide preliminary evidence for cross-state relationships between propensities for dream-enacting and mirror behaviors--especially behaviors involving motor-affective resonance--and our suggestion that motor-affective resonance mediates dream-enactment imagery during sleep and emotional empathy during waking.


Impact of fecal immunochemical test-based screening programs on proximal and distal colorectal cancer surgery rates: A natural multiple-baseline experiment.
Colorectal cancer (CRC) screening programs based on the fecal immunochemical test (FIT) were found to reduce overall CRC surgery rates, but to the authors' knowledge data by subsite are lacking. The objective of the current study was to assess the impact of FIT-based screening on proximal and distal CRC surgical resection rates. The Veneto region in Italy can be subdivided into 3 areas with staggered introduction of FIT-based screening programs: early (2002-2004), intermediate (2005-2007), and late (2008-2009) areas. Time series of proximal and distal CRC surgery were investigated in the 3 populations between 2001 and 2012 by Joinpoint regression analysis and segmented Poisson regression models. The impact of screening was similar in the study populations. Rates of distal CRC surgical resection were stable before screening, increased at the time of screening implementation (rate ratio [RR], 1.25; 95% confidence interval [95% CI], 1.14-1.37), and thereafter declined by 10% annually (RR, 0.90; 95% CI, 0.88-0.92). Rates of proximal CRC surgical resection increased by 4% annually before screening (RR, 1.04; 95% CI, 1.03-1.05) but, after a peak at the time of screening initiation, the trend was reversed. The percentage represented by proximal CRC surgery rose from 28% in 2001 to 41% in 2012. In this natural multiple-baseline experiment, consistent findings across each time series demonstrated that FIT-based screening programs have an impact both on proximal and distal CRC surgery rates. However, underlying preexisting epidemiological trends are leading to a rapidly increasing percentage of proximal CRC.


Androgen receptor gene CAG and GGN repeat polymorphisms in Chilean men with primary severe spermatogenic failure.
There is ample documentation supporting the fact that androgens are required for normal spermatogenesis. A minority of infertile men have abnormal testosterone blood levels or mild androgen receptor mutations. We investigated the androgen receptor CAG and GGN repeat lengths in Chilean men with spermatogenic impairment. We studied 117 secretory azoospermic/oligozoospermic men (93 idiopathic and 24 excryptorchidic), without Y-chromosome microdeletions, and 121 controls with normal spermatogenesis (42 obstructive and 79 normozoospermic men). Peripheral blood was drawn to obtain genomic DNA for polymerase chain reaction and automated sequencing of CAG and GGN repeats. Testicular characterization included hormonal studies, physical evaluation, and seminal and biopsy analysis. The CAG and GGN polymorphism distributions were similar among idiopathic men, excryptorchidic men, and controls and among the different types of spermatogenic impairment. However, the proportion of the CAG 21 allele was significantly increased in idiopathic cases compared to controls (P = .012 by Bonferroni test, odds ratio = 2.99, 95% confidence interval, 1.27-7.0) and the CAG 32 allele only was observed in excryptorchidic patients (P < .0002, Bonferroni test). Idiopathic cases with Sertoli cell-only syndrome showed the highest proportion of the CAG 21 allele (P = .024, χ(2) test). On the other hand, in idiopathic cases and controls the most common GGN allele was 23, followed by 24, but an inverse relation was found among excryptorchidic cases. The joint distribution of CAG and GGN in control, idiopathic, and excryptorchidic groups did not show an association between the 2 allele repeat polymorphisms (P > 0.05, χ(2) test). Our results suggest that the CAG 21 allele seems to increase the risk of idiopathic Sertoli cell-only syndrome. Moreover, the GGN 24 allele could be contributing to deranged androgen receptor function, associated with cryptorchidism and spermatogenic failure.


Repetitive Transcranial Magnetic Stimulation (rTMS) Therapy in Parkinson Disease: A Meta-Analysis.
Several studies have reported repetitive transcranial magnetic stimulation (rTMS) therapy as an effective treatment for the control of motor symptoms in Parkinson disease. The objective of the study is to quantify the overall efficacy of this treatment. Systematic review and meta-analysis. We reviewed the literature on clinical rTMS trials in Parkinson disease since the technique was introduced in 1980. We used the following databases: MEDLINE, Web of Science, Cochrane, and CINAHL. Patients with Parkinson disease who were participating in prospective clinical trials that included an active arm and a control arm and change in motor scores on Unified Parkinson's Disease Rating Scale as the primary outcome. We pooled data from 21 studies that met these criteria. We then analyzed separately the effects of low- and high-frequency rTMS on clinical motor improvements. The overall pooled mean difference between treatment and control groups in the Unified Parkinson's Disease Rating Scale motor score was significant (4.0 points, 95% confidence interval, 1.5, 6.7; P = .005). rTMS therapy was effective when low-frequency stimulation (≤ 1 Hz) was used with a pooled mean difference of 3.3 points (95% confidence interval 1.6, 5.0; P = .005). There was a trend for significance when high-frequency stimulation (≥ 5 Hz) studies were evaluated with a pooled mean difference of 3.9 points (95% confidence interval, -0.7, 8.5; P = .08). rTMS therapy demonstrated benefits at short-term follow-up (immediately after a treatment protocol) with a pooled mean difference of 3.4 points (95% confidence interval, 0.3, 6.6; P = .03) as well as at long-term follow-up (average follow-up 6 weeks) with mean difference of 4.1 points (95% confidence interval, -0.15, 8.4; P = .05). There were insufficient data to statistically analyze the effects of rTMS when we specifically examined bradykinesia, gait, and levodopa-induced dyskinesia using quantitative methods. rTMS therapy in patients with Parkinson disease results in mild-to-moderate motor improvements and has the potential to be used as an adjunct therapy for the treatment of Parkinson disease. Future large, sample studies should be designed to isolate the specific clinical features of Parkinson disease that respond well to rTMS therapy.


Women in mental health nursing: angels or custodians?
Like other 'Cinderella' services mental health nursing has received much less attention from historians than general nursing. However a study of its history can illuminate such issues as the division of labour, gender, images of nursing, professionalisation and unionisation. Drawing on primary historical sources, including hospital archives and contemporaneous reports and journals, the author considers the role of women in mental health nursing, from its origins to the onset of the NHS in 1948. The development of mental health nursing differed substantially from general nursing. It could be argued that the tensions between the two were never more apparent than in the debate surrounding the registration of nursing in the early twentieth century. Female mental health nurses fighting with police in the Radcliff Strike in 1922 portrays a much less famous image in nursing's history than Florence Nightingale with her lamp. The dichotomy between the custodial nature of the Victorian asylum system and the caring ethos espoused by the advocates of 'moral management' created many tensions. Images of nurses as angels, responding to a calling or vocation, sat uneasily with the large numbers of men working in the asylums and the growth of trade unionism in this period, particularly after the foundation of the National Asylum Workers Union in 1910. The periods of industrial unrest in the mental hospitals of the inter-war years saw women members playing an important role; this has important ramifications for mental health nursing today.


The aorta in humans and African great apes, and cardiac output and metabolic levels in human evolution.
Humans have a larger energy budget than great apes, allowing the combination of the metabolically expensive traits that define our life history. This budget is ultimately related to the cardiac output, the product of the blood pumped from the ventricle and the number of heart beats per minute, a measure of the blood available for the whole organism physiological activity. To show the relationship between cardiac output and energy expenditure in hominid evolution, we study a surrogate measure of cardiac output, the aortic root diameter, in humans and great apes. When compared to gorillas and chimpanzees, humans present an increased body mass adjusted aortic root diameter. We also use data from the literature to show that over the human lifespan, cardiac output and total energy expenditure follow almost identical trajectories, with a marked increase during the period of brain growth, and a plateau during most of the adult life. The limited variation of adjusted cardiac output with sex, age and physical activity supports the compensation model of energy expenditure in humans. Finally, we present a first study of cardiac output in the skeleton through the study of the aortic impression in the vertebral bodies of the spine. It is absent in great apes, and present in humans and Neanderthals, large-brained hominins with an extended life cycle. An increased adjusted cardiac output, underlying higher total energy expenditure, would have been a key process in human evolution.


Immunochemical characterisation of antigens and growth inhibition of Fonsecaea pedrosoi by species-specific IgG.
Antigens of Fonsecaea pedrosoi, the most common agent of chromomycosis, were characterised by immunoprecipitation with a rabbit antiserum raised against the cell-protein extract and serum from an infected patient. Thirteen antigens were commonly detected and, as some of these antigens could be iodinated, they may be present in the fungal cell wall. Purified IgG from the rabbit antiserum was shown to produce a 50-60% inhibition of fungal growth. Some of the antigens characterised may be important in relation to the stimulation of protective immunity against chromomycosis.


Comprehension of inferences in discourse processing by adolescents with and without language impairment.
This study investigated inference construction within spoken narratives in adolescents with varying cognitive and language abilities, using W. Kintsch's (1988) construction-integration model as a framework. The role of working memory in inference construction was examined along with language and nonverbal cognition. Participants were 527 eighth-grade students in 4 diagnostic groups: normal language (NL), low cognitive (LC), specific language impairment (SLI), and nonspecific language impairment (NLI). Participants answered premise and inference questions based on adjacent and distant information. Distant inferences were significantly more difficult than were adjacent inferences. When controlling for premise accuracy, the NL group performed significantly better than each of the other groups on distant inferences. The LC group demonstrated significantly higher accuracy on distant inferences than did the NLI group. Regression analyses revealed that performance on a verbal working memory measure predicted unique variance in distant inference accuracy beyond that accounted for by measures of language and nonverbal cognition. Understanding implicit information, particularly when linking distant information, is difficult for adolescents who are deficient in language comprehension, verbal working memory skills, and/or general world knowledge.


JOURNAL CLUB: Is screening MRI indicated for women with a personal history of breast cancer? Analysis based on biopsy results.
American College of Radiology and Society of Breast Imaging guidelines call for routine breast MRI screening only for women with the highest risk profiles for development of breast cancer, suggesting that screening of women at lower risk might result in an increased frequency of false-positive biopsy results. The purpose of this study was to test this assumption by comparing MRI-guided biopsy outcomes of lesions detected at MRI screening of women with a personal history of breast cancer with outcomes among women with genetic or familial high risk. Outcomes of 130 MRI-guided biopsies were analyzed. One group consisted of women with hereditary (genetic or familial) risk, and the other group consisted of women with a personal history of breast cancer. Biopsies were performed with a 9-gauge vacuum-assisted device or surgically after MRI localization. Of 130 MRI-guided biopsies, 20 (15%) yielded malignant histologic findings, 14 (11%) yielded high-risk lesions, and 96 (74%) had benign findings. There was a slightly higher malignancy rate for the personal-risk group (19%) compared with the hereditary-risk group (13.5%). There also was a slightly higher combined rate of malignancy and high-risk lesions (34% vs 22%) with no statistically significant difference (p < 0.25, p < 0.12). Patients in the hereditary-risk group were younger (44 ± 1.2 vs 54 ± 1.7 years; p < 0.001) than those in the personal-risk group. Our preliminary data show no difference between the two risk groups with respect to probability of an MRI-guided biopsy result of malignancy, calling into question the proposed assumption. Further prospective studies of the role of MRI screening combined with MRI-guided biopsy when required for patients with previously treated localized breast cancer may be indicated.


Improvement of DCT-based compression algorithms using Poisson's equation.
We propose two new image compression-decompression methods that reproduce images with better visual fidelity, less blocking artifacts, and better PSNR, particularly in low bit rates, than those processed by the JPEG Baseline method at the same bit rates. The additional computational cost is small, i.e., linearly proportional to the number of pixels in an input image. The first method, the "full mode" polyharmonic local cosine transform (PHLCT), modifies the encoder and decoder parts of the JPEG Baseline method. The goal of the full mode PHLCT is to reduce the code size in the encoding part and reduce the blocking artifacts in the decoder part. The second one, the "partial mode" PHLCT (or PPHLCT for short), modifies only the decoder part, and consequently, accepts the JPEG files, yet decompresses them with higher quality with less blocking artifacts. The key idea behind these algorithms is a decomposition of each image block into a polyharmonic component and a residual. The polyharmonic component in this paper is an approximate solution to Poisson's equation with the Neumann boundary condition, which means that it is a smooth predictor of the original image block only using the image gradient information across the block boundary. Thus, the residual--obtained by removing the polyharmonic component from the original image block--has approximately zero gradient across the block boundary, which gives rise to the fast-decaying DCT coefficients, which, in turn, lead to more efficient compression-decompression algorithms for the same bit rates. We show that the polyharmonic component of each block can be estimated solely by the first column and row of the DCT coefficient matrix of that block and those of its adjacent blocks and can predict an original image data better than some of the other AC prediction methods previously proposed. Our numerical experiments objectively and subjectively demonstrate the superiority of PHLCT over the JPEG Baseline method and the improvement of the JPEG-compressed images when decompressed by PPHLCT.


An intervention to improve interprofessional collaboration and communications: a comparative qualitative study.
Interprofessional communication and collaboration are promoted by policymakers as fundamental building blocks for improving patient safety and meeting the demands of increasingly complex care. This paper reports qualitative findings of an interprofessional intervention designed to improve communication and collaboration between different professions in general internal medicine (GIM) hospital wards in Canada. The intervention promoted self-introduction by role and profession to a collaborating colleague in relation to the shared patient, a question or communication regarding the patient, to be followed by an explicit request for feedback from the partner professional. Implementation and uptake of the intervention were evaluated using qualitative methods, including 90 hours of ethnographic observations and interviews collected in both intervention and comparison wards. Documentary data were also collected and analysed. Fieldnotes and interviews were transcribed and analysed thematically. Our findings suggested that the intervention did not produce the anticipated changes in communication and collaboration between health professionals, and allowed us to identify barriers to the implementation of effective collaboration interventions. Despite initially offering verbal support, senior physicians, nurses, and allied health professionals minimally explained the intervention to their junior colleagues and rarely role-modelled or reiterated support for it. Professional resistances as well as the fast paced, interruptive environment reduced opportunities or incentive to enhance restrictive interprofessional relationships. In a healthcare setting where face-to-face spontaneous interprofessional communication is not hostile but is rare and impersonal, the perceived benefits of improvement are insufficient to implement simple and potentially beneficial communication changes, in the face of habit, and absence of continued senior clinician and management support.


Role of capsule endoscopy in inflammatory bowel disease: where we are and where we are going.
Capsule endoscopy (CE) is an innovative technological breakthrough that for the first time provides a noninvasive method to obtain high-resolution imaging of the entire small bowel. Since its recent inception, the diagnostic utility of CE has become well established for the evaluation of diverse ulcerative and inflammatory disorders of the jejunum and ileum. The incredible resolution of its lens (0.1 mm) detects focal villous edema or atrophy, denuded, as well as ulcerated mucosal lesions missed by other imaging techniques. CE has been shown by meta-analysis to be a more sensitive method to investigate patients for small bowel Crohn's disease, with an incremental yield above 30% versus other imaging modalities. In patients with indeterminate colitis, CE is useful in distinguishing between ulcerative and Crohn's colitis. Among patients with established Crohn's disease, CE may be employed to determine: (1) the extent and severity of small bowel involvement, (2) postoperative recurrence, (3) post-therapy mucosal healing, and (4) whether active small bowel inflammatory lesions exist in the clinical setting of functional bowel disorder. Complications are rare and include capsule retention at stricture sites. The new patency capsule can diminish the risk of the latter problem in at-risk patients. CE can also serve as a guide to sites that require biopsies or dilatation by push or double-balloon enteroscopy. However, other causes of small bowel lesions may mimic Crohn's disease. A standard terminology system has thus been developed, and a CE Crohn's disease severity scoring index is currently undergoing validation studies.


Feedforward inhibitory connections from multiple thalamic cells to multiple regular-spiking cells in layer 4 of the somatosensory cortex.
Thalamocortical (TC) cells in the ventrobasal thalamus make direct excitatory connections with regular-spiking (RS) cells in layer 4 of the somatosensory cortex, but also make disynaptic feedforward inhibitory connections with the RS cells by layer 4 fast-spiking (FS) cells. In this study, we investigated connection rules of the feedforward inhibitory circuit from multiple TC cells to multiple RS cells, at the level of synaptic potentials. Using thalamocortical brain slices of young mice (postnatal days 12-16), we made simultaneous patch-clamp recordings from three adjacent cortical cells (two RS cells and one FS cell), combined with minimal stimulation of presumed single TC fibers. We found that nearly all (97%) of TC fibers, which generated excitatory inputs onto RS cells, also generated divergent excitatory inputs onto adjacent FS cells. Some 44% of TC fibers generated divergent excitatory inputs onto adjacent pairs of RS cells. We then combined the triple patch-clamp recording with multisite (two to three) minimal stimulation of single TC fibers and found that 86% of FS cells received convergent inputs from all of the stimulated TC fibers. We also found that 68% of FS cells generated divergent inhibitory inputs onto adjacent pairs of RS cells. The results indicate that spikes in TC cells, which excite RS cells, also excite adjacent FS cells with high fidelity. The results also indicate that FS cells receive convergent excitatory inputs from multiple TC cells and then send divergent inhibitory outputs to multiple RS cells.


The ERCC6 gene and age-related macular degeneration.
Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in the developed countries and is caused by both environmental and genetic factors. A recent study (Tuo et al., PNAS) reported an association between AMD and a single nucleotide polymorphism (SNP) (rs3793784) in the ERCC6 (NM_000124) gene. The risk allele also increased ERCC6 expression. ERCC6 is involved in DNA repair and mutations in ERCC6 cause Cockayne syndrome (CS). Amongst others, photosensitivity and pigmentary retinopathy are hallmarks of CS. Separate and combined data from three large AMD case-control studies and a prospective population-based study (The Rotterdam Study) were used to analyse the genetic association between ERCC6 and AMD (2682 AMD cases and 3152 controls). We also measured ERCC6 mRNA levels in retinal pigment epithelium (RPE) cells of healthy and early AMD affected human donor eyes. Rs3793784 conferred a small increase in risk for late AMD in the Dutch population (The Rotterdam and AMRO-NL study), but this was not replicated in two non-European studies (AREDS, Columbia University). In addition, the AMRO-NL study revealed no significant association for 9 other variants spanning ERCC6. Finally, we determined that ERCC6 expression in the human RPE did not depend on rs3793784 genotype, but, interestingly, on AMD status: Early AMD-affected donor eyes had a 50% lower ERCC6 expression than healthy donor eyes (P = 0.018). Our meta-analysis of four Caucasian cohorts does not replicate the reported association between SNPs in ERCC6 and AMD. Nevertheless, our findings on ERCC6 expression in the RPE suggest that ERCC6 may be functionally involved in AMD. Combining our data with those of the literature, we hypothesize that the AMD-related reduced transcriptional activity of ERCC6 may be caused by diverse, small and heterogeneous genetic and/or environmental determinants.


AbiV, a novel antiphage abortive infection mechanism on the chromosome of Lactococcus lactis subsp. cremoris MG1363.
Insertional mutagenesis with pGhost9::ISS1 resulted in independent insertions in a 350-bp region of the chromosome of Lactococcus lactis subsp. cremoris MG1363 that conferred phage resistance to the integrants. The orientation and location of the insertions suggested that the phage resistance phenotype was caused by a chromosomal gene turned on by a promoter from the inserted construct. Reverse transcription-PCR analysis confirmed that there were higher levels of transcription of a downstream open reading frame (ORF) in the phage-resistant integrants than in the phage-sensitive strain L. lactis MG1363. This gene was also found to confer phage resistance to L. lactis MG1363 when it was cloned into an expression vector. A subsequent frameshift mutation in the ORF completely eliminated the phage resistance phenotype, confirming that the ORF was necessary for phage resistance. This ORF provided resistance against virulent lactococcal phages belonging to the 936 and c2 species with an efficiency of plaquing of 10(-4), but it did not protect against members of the P335 species. A high level of expression of the ORF did not affect the cellular growth rate. Assays for phage adsorption, DNA ejection, restriction/modification activity, plaque size, phage DNA replication, and cell survival showed that the ORF encoded an abortive infection (Abi) mechanism. Sequence analysis revealed a deduced protein consisting of 201 amino acids which, in its native state, probably forms a dimer in the cytosol. Similarity searches revealed no homology to other phage resistance mechanisms, and thus, this novel Abi mechanism was designated AbiV. The mode of action of AbiV is unknown, but the activity of AbiV prevented cleavage of the replicated phage DNA of 936-like phages.


Clonal tracing of Sox9+ liver progenitors in mouse oval cell injury.
Proliferating ducts, termed "oval cells," have long been thought to be bipotential, that is, produce both biliary ducts and hepatocytes during chronic liver injury. The precursor to oval cells is considered to be a facultative liver stem cell (LSC). Recent lineage tracing experiments indicated that the LSC is SRY-related HMG box transcription factor 9 positive (Sox9(+) ) and can replace the bulk of hepatocyte mass in several settings. However, no clonal relationship between Sox9(+) cells and the two epithelial liver lineages was established. We labeled Sox9(+) mouse liver cells at low density with a multicolor fluorescent confetti reporter. Organoid formation validated the progenitor activity of the labeled population. Sox9(+) cells were traced in multiple oval cell injury models using both histology and fluorescence-activated cell sorting. Surprisingly, only rare clones containing both hepatocytes and oval cells were found in any experiment. Quantitative analysis showed that Sox9(+) cells contributed only minimally (<1%) to the hepatocyte pool, even in classic oval cell injury models. In contrast, clonally marked mature hepatocytes demonstrated the ability to self-renew in all classic mouse oval cell activation injuries. A hepatocyte chimera model to trace hepatocytes and nonparenchymal cells also demonstrated the prevalence of hepatocyte-driven regeneration in mouse oval cell injury models. Sox9(+) ductal progenitor cells give rise to clonal oval cell proliferation and bipotential organoids, but rarely produce hepatocytes in vivo. Hepatocytes themselves are the predominant source of new parenchyma cells in prototypical mouse models of oval cell activation.


Statin therapy in athletes and patients performing regular intense exercise - Position paper from the International Lipid Expert Panel (ILEP).
Acute and chronic physical exercises may enhance the development of statin-related myopathy. In this context, the recent (2019) guidelines of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) for the management of dyslipidemias recommend that, although individuals with dyslipidemia should be advised to engage in regular moderate physical exercise (for at least 30 min daily), physicians should be alerted with regard to myopathy and creatine kinase (CK) elevation in statin-treated sport athletes. However it is worth emphasizing that abovementioned guidelines, previous and recent ESC/EAS consensus papers on adverse effects of statin therapy as well as other previous attempts on this issue, including the ones from the International Lipid Expert Panel (ILEP), give only general recommendations on how to manage patients requiring statin therapy on regular exercises. Therefore, these guidelines in the form of the Position Paper are the first such an attempt to summary existing, often scarce knowledge, and to present this important issue in the form of step-by-step practical recommendations. It is critically important as we might observe more and more individuals on regular exercises/athletes requiring statin therapy due to their cardiovascular risk.


Preparation of developing and adult Drosophila brains and retinae for live imaging.
The Drosophila brain and visual system are widely utilized model systems to study neuronal development, function and degeneration. Here we show three preparations of the brain and visual system that cover the range from the developing eye disc-brain complex in the developing pupae to individual eye and brain dissection from adult flies. All protocols are optimized for the live culture of the preparations. However, we also present the conditions for fixed tissue immunohistochemistry where applicable. Finally, we show live imaging conditions for these preparations using conventional and resonant 4D confocal live imaging in a perfusion chamber. Together, these protocols provide a basis for live imaging on different time scales ranging from functional intracellular assays on the scale of minutes to developmental or degenerative processes on the scale of many hours.


Mapping the Physiological Response of Oenococcus oeni to Ethanol Stress Using an Extended Genome-Scale Metabolic Model.
The effect of ethanol on the metabolism of Oenococcus oeni, the bacterium responsible for the malolactic fermentation (MLF) of wine, is still scarcely understood. Here, we characterized the global metabolic response in O. oeni PSU-1 to increasing ethanol contents, ranging from 0 to 12% (v/v). We first optimized a wine-like, defined culture medium, MaxOeno, to allow sufficient bacterial growth to be able to quantitate different metabolites in batch cultures of O. oeni. Then, taking advantage of the recently reconstructed genome-scale metabolic model iSM454 for O. oeni PSU-1 and the resulting experimental data, we determined the redistribution of intracellular metabolic fluxes, under the different ethanol conditions. Four growth phases were clearly identified during the batch cultivation of O. oeni PSU-1 strain, according to the temporal consumption of malic and citric acids, sugar and amino acids uptake, and biosynthesis rates of metabolic products - biomass, erythritol, mannitol and acetic acid, among others. We showed that, under increasing ethanol conditions, O. oeni favors anabolic reactions related with cell maintenance, as the requirements of NAD(P)+ and ATP increased with ethanol content. Specifically, cultures containing 9 and 12% ethanol required 10 and 17 times more NGAM (non-growth associated maintenance ATP) during phase I, respectively, than cultures without ethanol. MLF and citric acid consumption are vital at high ethanol concentrations, as they are the main source for proton extrusion, allowing higher ATP production by F0F1-ATPase, the main route of ATP synthesis under these conditions. Mannitol and erythritol synthesis are the main sources of NAD(P)+, countervailing for 51-57% of its usage, as predicted by the model. Finally, cysteine shows the fastest specific consumption rate among the amino acids, confirming its key role for bacterial survival under ethanol stress. As a whole, this study provides a global insight into how ethanol content exerts a differential physiological response in O. oeni PSU-1 strain. It will help to design better strategies of nutrient addition to achieve a successful MLF of wine.


The Arcuate Fasciculus and language origins: Disentangling existing conceptions that influence evolutionary accounts.
The Arcuate Fasciculus (AF) is of considerable interdisciplinary interest, because of its major implication in language processing. Theories about language brain evolution are based on anatomical differences in the AF across primates. However, changing methodologies and nomenclatures have resulted in conflicting findings regarding interspecies AF differences: Historical knowledge about the AF originated from human blunt dissections and later from monkey tract-tracing studies. Contemporary tractography studies reinvestigate the fasciculus' morphology, but remain heavily bound to unclear anatomical priors and methodological limitations. First, we aim to disentangle the influences of these three epistemological steps on existing AF conceptions, and to propose a contemporary model to guide future work. Second, considering the influence of various AF conceptions, we discuss four key evolutionary changes that propagated current views about language evolution: 1) frontal terminations, 2) temporal terminations, 3) greater Dorsal- versus Ventral Pathway expansion, 4) lateralisation. We conclude that new data point towards a more shared AF anatomy across primates than previously described. Language evolution theories should incorporate this more continuous AF evolution across primates.


Systematic review of the clinical effectiveness and cost-effectiveness of photodynamic diagnosis and urine biomarkers (FISH, ImmunoCyt, NMP22) and cytology for the detection and follow-up of bladder cancer.
To assess the clinical effectiveness and cost-effectiveness of photodynamic diagnosis (PDD) compared with white light cystoscopy (WLC), and urine biomarkers [fluorescence in situ hybridisation (FISH), ImmunoCyt, NMP22] and cytology for the detection and follow-up of bladder cancer. Major electronic databases including MEDLINE, MEDLINE In-Process, EMBASE, BIOSIS, Science Citation Index, Health Management Information Consortium and the Cochrane Controlled Trials Register were searched until April 2008. A systematic review of the literature was carried out according to standard methods. An economic model was constructed to assess the cost-effectiveness of alternative diagnostic and follow-up strategies for the diagnosis and management of patients with bladder cancer. In total, 27 studies reported PDD test performance. In pooled estimates [95% confidence interval (CI)] for patient-level analysis, PDD had higher sensitivity than WLC [92% (80% to 100%) versus 71% (49% to 93%)] but lower specificity [57% (36% to 79%) versus 72% (47% to 96%)]. Similar results were found for biopsy-level analysis. The median sensitivities (range) of PDD and WLC for detecting lower risk, less aggressive tumours were similar for patient-level detection [92% (20% to 95%) versus 95% (8% to 100%)], but sensitivity was higher for PDD than for WLC for biopsy-level detection [96% (88% to 100%) versus 88% (74% to 100%)]. For more aggressive, higher-risk tumours the median sensitivity of PDD for both patient-level [89% (6% to 100%)] and biopsy-level [99% (54% to 100%)] detection was higher than those of WLC [56% (0% to 100%) and 67% (0% to 100%) respectively]. Four RCTs comparing PDD with WLC reported effectiveness outcomes. PDD use at transurethral resection of bladder tumour resulted in fewer residual tumours at check cystoscopy [relative risk, RR, 0.37 (95% CI 0.20 to 0.69)] and longer recurrence-free survival [RR 1.37 (95% CI 1.18 to 1.59)] compared with WLC. In 71 studies reporting the performance of biomarkers and cytology in detecting bladder cancer, sensitivity (95% CI) was highest for ImmunoCyt [84% (77% to 91%)] and lowest for cytology [44% (38% to 51%)], whereas specificity was highest for cytology [96% (94% to 98%)] and lowest for ImmunoCyt [75% (68% to 83%)]. In the cost-effectiveness analysis the most effective strategy in terms of true positive cases (44) and life-years (11.66) [flexible cystoscopy (CSC) and ImmunoCyt followed by PDD in initial diagnosis and CSC followed by WLC in follow-up] had an incremental cost per life-year of over 270,000 pounds. The least effective strategy [cytology followed by WLC in initial diagnosis (average cost over 20 years 1403 pounds, average life expectancy 11.59)] was most likely to be considered cost-effective when society's willingness to pay was less than 20,000 pounds per life-year. No strategy was cost-effective more than 50% of the time, but four of the eight strategies in the probabilistic sensitivity analysis (three involving a biomarker or PDD) were each associated with a 20% chance of being considered cost-effective. In sensitivity analyses the results were most sensitive to the pretest probability of disease (5% in the base case). The advantages of PDD's higher sensitivity in detecting bladder cancer have to be weighed against the disadvantages of a higher false-positive rate. Taking into account the assumptions made in the model, strategies involving biomarkers and/or PDD provide additional benefits at a cost that society might be willing to pay. Strategies replacing WLC with PDD provide more life-years but it is unclear whether they are worth the extra cost.


Changes in laboratory variables in rheumatoid arthritis patients during a trial of fasting and one-year vegetarian diet.
We have previously reported that significant improvement may be obtained in rheumatoid arthritis patients by fasting followed by a vegetarian diet for one year. The present study was carried out to examine to what extent biochemical and immunological variables changed during the clinical trial of fasting and vegetarian diet. For the patients who were randomised to the vegetarian diet there was a significant decrease in platelet count, leukocyte count, calprotectin, total IgG, IgM rheumatoid factor (RF), C3-activation products, and the complement components C3 and C4 after one month of treatment. None of the measured parameters changed significantly during this period in the group of omnivores. The course of 14 of 15 measured variables favored the vegetarians compared with the omnivores, but the difference was only significant for leukocyte count, IgM RF, and the complement components C3 and C4. Most of the laboratory variables declined considerably in the vegetarians who improved according to clinical variables, indicating a substantial reduction in inflammatory activity. The leukocyte count, however, decreased in the vegetarians irrespective of the clinical results. Thus, the decline in leukocyte count may be attributed to vegetarian diet per se and not to the reduction in disease activity. The results of the present study are in accordance with the findings from the clinical trial, namely that dietary treatment can reduce the disease activity in some patients with rheumatoid arthritis.


Cancer mortality and morbidity among plutonium workers at the Sellafield plant of British Nuclear Fuels.
The mortality of all 14 319 workers employed at the Sellafield plant of British Nuclear Fuels between 1947 and 1975 was studied up to the end of 1992, and cancer incidence was examined from 1971 to 1986, in relation to their exposures to plutonium and to external radiation. The cancer mortality rate was 5% lower than that of England and Wales and 3% less than that of Cumbria. The significant excesses of deaths from cancer of the pleura and thyroid found in an earlier study persist with further follow-up (14 observed, 4.0 expected for pleura; 6 observed, 2.2 expected for thyroid). All of the deaths from pleural cancer were among radiation workers. For neither site was there a significant association between the risk of the cancer and accumulated radiation dose. There were significant deficits of deaths from cancers of mouth and pharynx, liver and gall bladder, and larynx and leukaemia when compared with the national rates. Among all radiation workers, there was a significant positive association between accumulated external radiation dose and mortality from cancers of ill-defined and secondary sites (10-year lag, P = 0.04), leukaemia (no lag, P = 0.03; 2-year lag, P = 0.05), multiple myeloma (20-year lag, P = 0.02), all lymphatic and haematopoietic cancers (20-year lag, P= 0.03) and all causes of death combined (20-year lag, P= 0.008). Among plutonium workers, there were significant excesses of deaths from cancer of the breast (6 observed, 2.6 expected) and ill-defined and secondary cancers (29 observed, 20.1 expected). No significant positive trends were observed between the risk of deaths from cancers of any specific site, or all cancers combined, and cumulative plutonium and external radiation doses. For no cancer site was there a significant excess of cancer registrations compared with rates for England and Wales. Analysis of trends in cancer incidence showed significant increases in risk with cumulative plutonium plus external radiation doses for all lymphatic and haematopoietic neoplasms for 0-, 10- and 20-year lag periods. Taken as a whole, our findings do not suggest that workers at Sellafield who have been exposed to plutonium are at an overall significantly increased risk of cancer compared with other radiation workers.


The Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD) project: Understanding older-age bipolar disorder by combining multiple datasets.
There is a dearth of research about the aging process among individuals with bipolar disorder (BD). One potential strategy to overcome the challenge of interpreting findings from existing limited older-age bipolar disorder (OABD) research studies is to pool or integrate data, taking advantage of potential overlap or similarities in assessment methods and harmonizing or cross-walking measurements where different measurement tools are used to evaluate overlapping construct domains. This report describes the methods and initial start-up activities of a first-ever initiative to create an integrated OABD-focused database, the Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD) project. Building on preliminary work conducted by members of the International Society for Bipolar Disorders OABD taskforce, the GAGE-BD project will be operationalized in four stages intended to ready the dataset for hypothesis-driven analyses, establish a consortium of investigators to guide exploration, and set the stage for prospective investigation using a common dataset that will facilitate a high degree of generalizability. Initial efforts in GAGE-BD have brought together 14 international investigators representing a broad geographic distribution and data on over 1,000 OABD. Start-up efforts include communication and guidance on meeting regulatory requirements, establishing a Steering Committee to guide an incremental analysis strategy, and learning from existing multisite data collaborations and other support resources. The GAGE-BD project aims to advance understanding of associations between age, BD symptoms, medical burden, cognition and functioning across the life span and set the stage for future prospective research that can advance the understanding of OABD.


Evaluation of the Mycobacterium smegmatis and BCG models for the discovery of Mycobacterium tuberculosis inhibitors.
The objective of this study was to measure the efficacy of Mycobacterium smegmatis as a surrogate in vitro model for the detection of compounds which are inhibitory to the growth of Mycobacterium tuberculosis. A chemical screen of the LOPAC library for anti-mycobacterial compounds was performed using M. smegmatis. Parallel screens were conducted with another tuberculosis model, Mycobacterium bovis BCG, and with M. tuberculosis under identical growth conditions and the inhibitors detected across the three species were compared. 50% of compounds that were detected as active against M. tuberculosis were not detected using M. smegmatis compared to 21% of compounds using M. bovis BCG. To examine whether these findings were unique to LOPAC, screens were performed with the NIH Diversity Set and Spectrum Collection. An even higher proportion of M. tuberculosis inhibitors were not detected from the NIH Diversity Set and Spectrum Collection using M. smegmatis compared to M. bovis BCG. These data reveal that a significant proportion of M. tuberculosis inhibitors are missed in library screening with M. smegmatis. The basis of the variation in the inhibitory profiles of M. smegmatis and M. tuberculosis has yet to be fully determined, however, our genomic comparisons indicate that approximately 30% of M. tuberculosis proteins lack conserved orthologues in M. smegmatis compared to 3% being absent in M. bovis BCG. In conclusion, although M. smegmatis offers some technical benefits such as a shorter generation time and negligible risk to laboratory workers, it is significantly less effective in the detection of anti-M. tuberculosis compounds relative to M. bovis BCG. This limitation needs to be taken into consideration when selecting an in vitro screening model for tuberculosis drug discovery.


[Health sector reform in Colombia and its effects on tuberculosis control and immunization programs].
This paper analyzes the effects of health reform in Colombia on public health programs at the local level, particularly the Expanded Program of Immunization (EPI) and the tuberculosis control program. The research was developed in three health districts in two States by analysis of documents, direct observation, and longitudinal follow-up of the transition process. The health districts were unprepared for the change, resulting in insufficient technical skills among staff as well as lack of awareness of important elements in the new system, associated with a reduction in immunization coverage and tuberculosis case detection. Structural problems in the new system included loss of immunization opportunities and lack of examination of tuberculosis contacts. The potentialities of the new system were the local development of a new organizational structure and the improvement of the information system; a limiting factor was exposure of the health system to local political interests. The general conclusion is that the transition period takes far longer than anticipated and requires a much greater information flow to both the local level and the community. There are transitory but also structural maladjustments that require a political response.


High-affinity T cell receptors for adoptive cell transfer.
Adoptive cell transfer (ACT) of engineered T cell receptors (TCRs) for cancer immunotherapy has evolved from simple gene transfer of isolated TCRs to various affinity enhancement techniques that overcome limitations imposed by central and peripheral tolerance on TCR affinity. In the current issue of the JCI, Poncette et al. used mice with human TCRαβ and HLA gene loci to discover CD4+ TCRs of optimal affinity for cancer testis antigen (CTA) NY-ESO-1. They combined this TCR with a previously discovered NY-ESO-1-specific CD8+ TCR in an ACT fibrosarcoma tumor model to demonstrate the importance of T cell help in mediating antitumor responses.


Takete and Maluma in Action: A Cross-Modal Relationship between Gestures and Sounds.
Despite Saussure's famous observation that sound-meaning relationships are in principle arbitrary, we now have a substantial body of evidence that sounds themselves can have meanings, patterns often referred to as "sound symbolism". Previous studies have found that particular sounds can be associated with particular meanings, and also with particular static visual shapes. Less well studied is the association between sounds and dynamic movements. Using a free elicitation method, the current experiment shows that several sound symbolic associations between sounds and dynamic movements exist: (1) front vowels are more likely to be associated with small movements than with large movements; (2) front vowels are more likely to be associated with angular movements than with round movements; (3) obstruents are more likely to be associated with angular movements than with round movements; (4) voiced obstruents are more likely to be associated with large movements than with small movements. All of these results are compatible with the results of the previous studies of sound symbolism using static images or meanings. Overall, the current study supports the hypothesis that particular dynamic motions can be associated with particular sounds. Building on the current results, we discuss a possible practical application of these sound symbolic associations in sports instructions.


Influence of solute carriers on the pharmacokinetics of CYP3A4 probes.
We hypothesized that the assessment of baseline CYP3A4 activity is influenced by probe-specific differences in hepatocellular uptake mechanisms. There was no significant correlation between the erythromycin breath test (ERMBT) parameters and midazolam clearance in 30 cancer patients (R(2) < 0.01), regardless of their CYP3A5 genotype status. In cellular models overexpressing 10 different solute carriers, erythromycin uptake was significantly increased by OATP1A2 (P < 0.005) and OATP1B3 (P < 0.01). Midazolam was not a substrate for any of the tested transporters. In a separate cohort of 119 patients, 6 nonsynonymous variants in the OATP1B3 gene SLCO1B3 were identified. Individuals carrying two copies of the T allele at the 334 locus had a 2.4-fold lower value for ERMBT 1/T(max) (P = 0.001), a measure reflecting more rapid hepatic uptake. These findings suggest that differential affinities for solute carriers should be considered when selecting an appropriate phenotypic probe to allow tailored dosing of pharmaceuticals that are CYP3A4 substrates.