Effects of the ABCB1 c.3435C>T (rs1045642) Polymorphism on Heat Pain Perception in Opioid-Free Adults With Chronic Pain.
The adenosine triphosphate-binding cassette, subfamily B, member 1 gene (ABCB1) encodes P-glycoprotein (P-gp) that influences the intracellular transport of solutes including endogenous opioid peptides. The primary objective of this study was to determine the effects of the ABCB1 polymorphism c.3435C>T (rs10454642) on heat pain (HP) perception in a group of opioid-free adults with chronic pain. Opioid-free adults with chronic pain consecutively admitted to a pain rehabilitation program comprised the study cohort (N = 134). Individuals were genotyped for the c.3435C>T (rs10454642) polymorphism. The polymorphism was analyzed with nonparametric tests using a dominant (cytosine-cytosine [CC] versus cytosine-thymine [CT] + thymine-thymine [TT]) and recessive (CC + CT versus TT) model of allele effects. Quantitative sensory testing was performed using the Computer Aided Sensory Evaluator IV system. The distribution of genotypes was 22% (N = 29) for CC, 45% (N = 60) for CT, and 33% (N = 45) for TT (Hardy-Weinberg, P > .1). A significant association was observed between the recessive model and HP threshold. Standardized values of HP threshold were significantly greater in the TT group than the CC + CT group (median difference, -0.77; 95% confidence interval [CI], -1.49 to -0.23; P = .005), and the effect size estimate was small (Cliff delta = 0.30). In the dominant model, no significant difference in HP threshold was observed between the CC and CT + TT groups (median difference, -0.45; 95% CI, -1.15 to 0.00; P = .108). These results posit that the efflux of endogenous opioid peptides is reduced in individuals with the TT genotype due to lower expression of P-gp, which, in turn, results in higher HP threshold. This study contributes to the emerging understanding of how the ABCB1 c.3435C>T polymorphism contributes to pain perception in opioid-free adults with chronic pain and provides the foundation for investigating the potential effects of this polymorphism on the clinical course of chronic pain.


Arm-edge conditions in plasmonic folded dipole nanoantennas.
Silver folded dipoles consisting of two parallel nanowires may operate as efficient transmitting and receiving nanoantennas in the optical domain in both cases of silver-nanowire-terminated arm-edges and open-terminated arm-edges, in contrast to their conventional radio-frequency (RF) counterparts that only operate efficiently when they are short-wire-terminated arm-edges. The mode decomposition analysis with the equivalent circuit reveals that the difference of the wave numbers between the common and the differential modes allows this feature for the optical folded dipole nanoantenna under both arm-edge conditions. The analysis also estimates the efficiency of the folded dipoles via the equivalent radius of nanowires for the common mode. These folded nanostructures may exhibit the enhanced efficiency with the maintained radiation patterns, where the efficiency of folded dipoles is the same as that of the effective single dipole at resonance.


A Crucial Caste Regulation Gene Detected by Comparing Termites and Sister Group Cockroaches.
Sterile castes are a defining criterion of eusociality; investigating their evolutionary origins can critically advance theory. In termites, the soldier caste is regarded as the first acquired permanently sterile caste. Previous studies showed that juvenile hormone (JH) is the primary factor inducing soldier differentiation, and treatment of workers with artificial JH can generate presoldier differentiation. It follows that a shift from a typical hemimetabolous JH response might be required for soldier formation during the course of termite evolution within the cockroach clade. To address this possibility, analysis of the role of JH and its signaling pathway was performed in the termite Zootermopsis nevadensis and compared with the wood roach Cryptocercus punctulatus, a member of the sister group of termites. Treatment with a JH analog (JHA) induced a nymphal molt in C. punctulatus RNA interference (RNAi) of JH receptor Methoprene tolerant (Met) was then performed, and it inhibited the presoldier molt in Z. nevadensis and the nymphal molt in C. punctulatus Knockdown of Met in both species inhibited expression of 20-hydroxyecdysone (20E; the active form of ecdysone) synthesis genes. However, in Z. nevadensis, several 20E signaling genes were specifically inhibited by Met RNAi. Consequently, RNAi of these genes were performed in JHA-treated termite individuals. Knockdown of 20E signaling and nuclear receptor gene, Hormone receptor 39 (HR39/FTZ-F1β) resulted in newly molted individuals with normal worker phenotypes. This is the first report of the JH-Met signaling feature in termites and Cryptocercus JH-dependent molting activation is shared by both taxa and mediation between JH receptor and 20E signalings for soldier morphogenesis is specific to termites.


Establishing the role of pre-implantation genetic diagnosis with human leucocyte antigen typing: what place do "saviour siblings" have in paediatric transplantation?
Not all children in need of a haematopoietic stem cell transplant have a suitable relative or unrelated donor available. Recently, in vitro fertilisation (IVF) with pre-implantation genetic diagnosis (PGD) for human leucocyte antigen (HLA) tissue typing has been used to selectively transfer an IVF embryo in order to produce a child who may provide umbilical cord blood for transplantation to an ill sibling. Such children are sometimes called "saviour siblings". To examine the published clinical and epidemiological evidence relevant to the use of this technology, with the aim of clarifying those situations where IVF and PGD for HLA typing should be discussed with parents of an ill child. A critical analysis of published literature on comparative studies of umbilical cord blood versus other sources of stem cells for transplantation; comparative studies of matched unrelated donor versus matched related donor transplantation; and the likelihood of finding an unrelated stem cell donor. IVF and PGD for HLA typing is only applicable when transplantation is non-urgent and parents are of reproductive age. Discussions regarding this technology may be appropriate where no suitable related or unrelated donor is available for a child requiring a transplant, or where no suitable related donor is available and transplantation is only likely to be entertained with a matched sibling donor. Discussion may also be considered in the management of any child lacking a matched related donor who requires a non-urgent transplant or may require a transplant in the future.


Clinical amyloid imaging in Alzheimer's disease.
The hypothesis that amyloid deposition is the leading cause of Alzheimer's disease (AD) is supported by findings in transgenic animal models and forms the basis of clinical trials of anti-amyloid agents. According to this theory, amyloid deposition causes severe damage to neurons many years before onset of dementia via a cascade of several downstream effects. This hypothesis has, however, not yet been directly tested in human beings because of the very limited possibility of diagnosing amyloid deposition in vivo, which until recently required either brain biopsy or PET imaging with an on-site cyclotron and radiochemistry laboratory. Moreover, a clinical diagnosis of AD requires that patients have dementia, at which stage any effective treatment aimed at reducing amyloid deposition will probably be too late. The amyloid imaging tracers flutemetamol, florbetapir, and florbetaben labelled with (18)F have been developed for PET; they can be produced commercially at central cyclotron sites and subsequently delivered to clinical PET scanning facilities. These tracers are currently undergoing formal clinical trials to establish whether they can be used to accurately image fibrillary amyloid and to distinguish patients with AD from normal controls and those with other diseases that cause dementia. They might also be used as biomarkers to predict development of AD before onset of dementia and to assess the effect of anti-amyloid therapy. Negative amyloid scans indicate absence of AD with a high level of accuracy, but healthy elderly volunteers might have positive amyloid scans, so their predictive value in isolation is less clear. Close association of in-vivo amyloid imaging results with post-mortem histopathological findings was shown with florbetapir in a phase 3 study. WHERE NEXT?: Therapeutic studies of anti-amyloid agents that include amyloid tracers as biomarkers are expected to be useful for drug development and to clarify the relation between amyloid removal and clinical effects. Once the (18)F tracers become available for diagnostic use, large-scale longitudinal studies will be needed to clarify their prognostic and diagnostic power in relation to age, risk factors, and AD subtypes. Ultimately, these tracers will hopefully clarify the pathophysiological role of amyloid in AD and contribute to development of new treatments.


Identification of Policy Priorities to Address the Burden of Smokeless Tobacco in Pakistan: A Multimethod Analysis.
We assessed the magnitude of smokeless tobacco (ST) use in Pakistan and identified policy gaps to help ascertain short-, medium-, and long-term priorities. We then elicited stakeholders' views as to which of these identified priorities are most important. In a multimethod study, we: analyzed Global Tobacco Surveillance System data sets to estimate ST consumption and disease burden; conducted a documentary review to identify gaps in policies to control ST in comparison with smoking; elicited stakeholders' views in an interactive workshop to identify a set of policy options available to address ST burden in Pakistan; and ranked policy priorities using a postevent survey. Among all tobacco users in Pakistan (n = 24 million), one-third of men and two-thirds of women consume ST. In 2017, its use led to an estimated 18 711 deaths due to cancer and ischemic heart disease. Compared to smoking, policies to control ST lag behind significantly. Priority areas for ST policies included: banning ST sale to and by minors, advocacy campaigns, introduction of licensing, levying taxes on ST, and standardizing ST packaging. A clear commitment to close cooperation between state actors and stakeholder groups is needed to create a climate of support and information for effective policy making. Smokeless tobacco control in Pakistan should focus on four key policy instruments: legislation, education, fiscal policies, and quit support. More research into the effectiveness of such policies is also needed. A number of opportunities to improve ST regulation in Pakistan were identified. Among these, immediate priorities include banning ST sale to and by minors, mobilizing advocacy campaign, introduction of licensing through the 1958 Tobacco Vendors Act, levying taxes on ST, and standardizing ST packaging.


The potential of Raman spectroscopy for characterisation of the fatty acid unsaturation of salmon.
Raman spectroscopy has been evaluated for characterisation of the degree of fatty acid unsaturation (iodine value) of salmon (Salmo salar). The Norwegian Quality Cuts from 50 salmon samples were obtained, and the samples provided an iodine value range of 147.8-170.0 g I2/100 g fat, reflecting a normal variation of farmed salmon. Raman measurements were performed both on different spots of the intact salmon muscle, on ground salmon samples as well as on oil extracts, and partial least squares regression (PLSR) was utilised for calibration. The oil spectra provided better iodine value predictions than the other data sets, and a correlation coefficient of 0.87 with a root mean square error of cross-validation of 2.5 g I2/100 g fat was achieved using only one PLSR component. The ground samples provided comparable results, but at least two PLSR components were needed. Higher prediction errors were obtained from Raman spectra of intact salmon muscle, and this may partly be explained by sampling uncertainties in the relation between Raman measurements and reference analysis. All PLSR models obtained were based on chemically sound regression coefficients, and thus information regarding fatty acid unsaturation is readily available from Raman spectra even in systems with high contents of protein and water. The accuracy, the robustness and the low complexity of the PLSR models obtained suggest Raman spectroscopy as a promising method for rapid in-process control of the degree of unsaturation in salmon samples.


Indigenous knowledge for disaster risk reduction: An African perspective.
Indigenous knowledge is valuable knowledge that has helped local communities all over the world survive for generations. This knowledge originates from the interaction between members of the community and the environment in which they live. Although much has been written about indigenous knowledge, its documentation in the area of disaster risk reduction and climate change in Africa has been very limited. The wealth of this knowledge has not been well-recognised in the disaster risk reduction field, as policy-makers still rely on mitigation strategies based on scientific knowledge. Colonialism and lack of proper documentation of indigenous knowledge are some of the contributing factors to this. Ignoring the importance of understanding adaptive strategies of the local people has led to failed projects. Understanding how local people in Africa have managed to survive and adapt for generations, before the arrival of Western education, may be the key to developing sustainable policies to mitigate future challenges. Literature used in this article, obtained from the books, papers and publications of various experts in the fields of disaster risk reduction, climate change, indigenous knowledge and adaptation, highlight the need for more interest to be shown in indigenous knowledge, especially in the developing country context. This would lead to better strategies which originate from the community level but would aim for overall sustainable development in Africa.


Cutaneous markers of photo-damage and risk of Basal cell carcinoma of the skin: a meta-analysis.
Epidemiologic research has shown that cutaneous markers of photo-damage are associated with risk of basal cell carcinoma (BCC). However, there has been no previous attempt to calculate pooled risk estimates. We conducted a systematic review and meta-analysis after extracting relevant studies published up to January 2013 from five electronic databases. Eligible studies were those that permitted quantitative assessment of the association between histologically confirmed BCC and actinic keratoses, solar elastosis, solar lentigines, or telangiectasia. Seven eligible studies were identified and summary odds ratios (ORs) were calculated using both random and quality effects models. Having more than ten actinic keratoses was most strongly associated with BCC, conferring up to a fivefold increase in risk (OR: 4.97; 95% CI: 3.26-7.58). Other factors, including solar elastosis, solar lentigines, and telangiectasia had weaker but positive associations with BCC with ORs around 1.5. Markers of chronic photo-damage are positively associated with BCC. The presence of actinic keratoses was the most strongly associated with BCC of the markers examined. This work highlights the relatively modest association between markers of chronic ultraviolet exposure and BCC.


Evaluation of the impact of telementoring using ECHO© technology on healthcare professionals' knowledge and self-efficacy in assessing and managing pain for people with advanced dementia nearing the end of life.
Pain assessment and management in advanced and end-stage dementia are challenging; patients are at risk of under-diagnosis, under-assessment and under-treatment. Previous research has highlighted the importance of needs-driven training and development in this area for physicians, nurses and healthcare assistants (HCAs) across specialties, disciplines and care settings. This study used teleconferencing technology to connect healthcare professionals across multiple settings and disciplines in real-time clinics, based on the Project ECHO© model. This paper reports the evaluation of the clinics by physicians, nurses and HCAs, including their knowledge and self-efficacy in pain assessment and management for patients with advanced and end-stage dementia. A mixed method evaluation comprising quantitative survey of self-reported knowledge and self-efficacy pre- and post-ECHO clinic participation, and qualitative exploration of experiences of the clinics using focus group interviews. A census approach to sampling was undertaken. Pre- and post-ECHO evaluations were administered electronically using Survey Monkey software. Mann-Whitney U tests were used to explore differences in knowledge and self-efficacy scores pre- and post-ECHO clinic participation. Statistical significance was set a-priori at p = 0.05. Focus groups were video- and audio-recorded, transcribed verbatim and analysed using Braun & Clarke's model of thematic analysis. Eighteen healthcare professionals [HCPs] (physicians [n = 7], nurses [n = 10], HCA [n = 1]) and twenty HCPs (physicians [n = 10], nurses [n = 10]) completed pre- and post-ECHO evaluations respectively, reporting improvements in knowledge and self-efficacy on participation in ECHO clinics and perceived utility of the clinics. Seven HCPs (physicians [n = 2], nurses [n = 5]) participated in two focus groups. Four themes emerged: knowledge and skills development and dissemination; protected time; areas for improvement; and the future of ECHO. Telementoring clinics for HCP education and training in pain assessment and management in advanced and end-stage dementia demonstrate a positive impact on knowledge and self-efficacy of HCPs and highlight the value of a cross-specialty network of practice which spans across disciplines/HCP types, care settings and geographical areas. Further development of ECHO services in this and in other clinical areas, shows significant potential to support delivery of high-quality care to complex patient populations.


Clustering analysis of water distribution systems: identifying critical components and community impacts.
Large water distribution systems (WDSs) are networks with both topological and behavioural complexity. Thereby, it is usually difficult to identify the key features of the properties of the system, and subsequently all the critical components within the system for a given purpose of design or control. One way is, however, to more explicitly visualize the network structure and interactions between components by dividing a WDS into a number of clusters (subsystems). Accordingly, this paper introduces a clustering strategy that decomposes WDSs into clusters with stronger internal connections than external connections. The detected cluster layout is very similar to the community structure of the served urban area. As WDSs may expand along with urban development in a community-by-community manner, the correspondingly formed distribution clusters may reveal some crucial configurations of WDSs. For verification, the method is applied to identify all the critical links during firefighting for the vulnerability analysis of a real-world WDS. Moreover, both the most critical pipes and clusters are addressed, given the consequences of pipe failure. Compared with the enumeration method, the method used in this study identifies the same group of the most critical components, and provides similar criticality prioritizations of them in a more computationally efficient time.


Computational modeling of extracellular mechanotransduction.
Mechanotransduction may occur through numerous mechanisms, including potentially through autocrine signaling in a dynamically changing extracellular space. We developed a computational model to analyze how alterations in the geometry of an epithelial lateral intercellular space (LIS) affect the concentrations of constitutively shed ligands inside and below the LIS. The model employs the finite element method to solve for the concentration of ligands based on the governing ligand diffusion-convection equations inside and outside of the LIS, and assumes idealized parallel plate geometry and an impermeable tight junction at the apical surface. Using the model, we examined the temporal relationship between geometric changes and ligand concentration, and the dependence of this relationship on system characteristics such as ligand diffusivity, shedding rate, and rate of deformation. Our results reveal how the kinetics of mechanical deformation can be translated into varying rates of ligand accumulation, a potentially important mechanism for cellular discrimination of varying rate-mechanical processes. Furthermore, our results demonstrate that rapid changes in LIS geometry can transiently increase ligand concentrations in underlying media or tissues, suggesting a mechanism for communication of mechanical state between epithelial and subepithelial cells. These results underscore both the plausibility and complexity of the proposed extracellular mechanotransduction mechanism.


Computational investigation of subject-specific cerebrospinal fluid flow in the third ventricle and aqueduct of Sylvius.
The cerebrospinal fluid flow in the third ventricle of the brain and the aqueduct of Sylvius was studied using computational fluid dynamics (CFD) based on subject-specific boundary conditions derived from magnetic resonance imaging (MRI) scans. The flow domain geometry was reconstructed from anatomical MRI scans by manual image segmentation. The movement of the domain boundary was derived from MRI brain motion scans. Velocimetric MRI scans were used to reconstruct the velocity field at the inferior end of the aqueduct of Sylvius based on the theory of pulsatile flow in pipes. A constant pressure boundary condition was assigned at the foramina of Monro. Three main flow features were observed: a fluid jet emerging from the aqueduct of Sylvius, a moderately mobile recirculation zone above the jet and a mobile recirculation below the jet. The flow in the entire domain was laminar with a maximum Reynolds number of 340 in the aqueduct. The findings demonstrate that by combining MRI scans and CFD simulations, subject-specific detailed quantitative information of the flow field in the third ventricle and the aqueduct of Sylvius can be obtained.


A case report of infective endocarditis in a 10-year-old girl.
Infective endocarditis is a rare disease in children, and it can result in significant morbidity and mortality. The epidemiology of infective endocarditis in children has shifted in recent years with less rheumatic heart disease, more congenital heart disease survival, and increased use of central venous catheters in children with chronic illness. Less commonly, infective endocarditis occurs in children with no preexisting cardiac disease or other known risk factors. We present a "case of" 10 year-old girl with no known cardiac disease or any other risk factors who was diagnosed with infective endocarditis according to modified Duke criteria. Blood cultures grew haemophilus parainfluenza. She had prolonged fever for 2 weeks after starting antibiotics, even though her blood culture became sterile 48 hours after treatment. We emphasize the importance of maintaining high index of suspicion for endocarditis in febrile children, even those without cardiac anomalies or other apparent risk factors.


Evaluation of renal artery stenosis with dynamic gadolinium-enhanced MR angiography.
The purpose of this study was to compare dynamic gadolinium-enhanced three-dimensional spoiled gradient-recalled MR angiography with conventional arteriography in the evaluation of proximal renal artery stenosis (RAS). MR angiography and conventional arteriographic examinations of 30 patients evaluated for RAS were analyzed retrospectively. Three-dimensional MR angiography was performed with an RF spoiled gradient-recalled imaging sequence acquired during the dynamic i.v. injection of gadolinium (0.2-0.3 mmol/kg), MR data and conventional arteriograms were independently evaluated for the number and location of renal arteries and the degree and location of stenoses. The patients had a mean age of 70 years old and a mean serum creatinine level of 2.9 mg/dl, reflecting a population in whom atherosclerotic RAS was the primary concern. Gadolinium-enhanced MR angiography revealed 100% of main renal arteries. For RAS of 50% or greater occlusion, the technique was 100% sensitive and 71% specific; the negative predictive value was 100%. The technique was 100% sensitive and 71% specific for RAS of 75% or greater occlusion. Dynamic gadolinium-enhanced three-dimensional spoiled gradient-recalled MR angiography has a high sensitivity for revealing proximal RAS and is a quick and reliable technique for obtaining helpful anatomic information.


Poor Reliability of Wrist Blood Pressure Self-Measurement at Home: A Population-Based Study.
The reliability of blood pressure measurement with wrist devices, which has not previously been assessed under real-life circumstances in general population, is dependent on correct positioning of the wrist device at heart level. We determined whether an error was present when blood pressure was self-measured at the wrist in 721 unselected subjects from the general population. After training, blood pressure was measured in the office and self-measured at home with an upper-arm device (the UA-767 Plus) and a wrist device (the UB-542, not provided with a position sensor). The upper-arm-wrist blood pressure difference detected in the office was used as the reference measurement. The discrepancy between office and home differences was the home measurement error. In the office, systolic blood pressure was 2.5% lower at wrist than at arm (P=0.002), whereas at home, systolic and diastolic blood pressures were higher at wrist than at arm (+5.6% and +5.4%, respectively; P<0.0001 for both); 621 subjects had home measurement error of at least ±5 mm Hg and 455 of at least ±10 mm Hg (bad measurers). In multivariable linear regression, a lower cognitive pattern independently determined both the systolic and the diastolic home measurement error and a longer forearm the systolic error only. This was confirmed by logistic regression having bad measurers as dependent variable. The use of wrist devices for home self-measurement, therefore, leads to frequent detection of falsely elevated blood pressure values likely because of a poor memory and rendition of the instructions, leading to the wrong position of the wrist.


Circle drawing does not exhibit auditory-motor synchronization.
Differences in timing control processes between tapping and circle drawing have been extensively documented during continuation timing. Differences between event and emergent control processes have also been documented for synchronization timing using emergent tasks that have minimal event-related information. However, it is not known whether the original circle-drawing task also behaves differently than tapping during synchronization. In this experiment, 10 participants performed a table-tapping and a continuous circle-drawing task to an auditory metronome. Synchronization performance was assessed via the value and variability of asynchronies. Synchronization was substantially more difficult in circle drawing than in tapping. Participants drawing timed circles exhibited drift in synchronization error and did not maintain a consistent phase relationship with the metronome. An analysis of temporal anchoring revealed that timing to the timing target was not more accurate than timing to other locations on the circle trajectory. The authors conclude that participants were not able to synchronize movement with metronome tones in the circle-drawing task despite other findings that cyclical tasks do exhibit auditory motor synchronization, because the circle-drawing task is unique and absent of event and cycle position information.


Quartz crystal microbalance with dissipation as a biosensing platform to evaluate cell-surface interactions of osteoblast cells.
Quartz crystal microbalance with dissipation (QCM-D) is one of the powerful techniques, which allow real time, quantitative and noninvasive analysis of the interaction of different cell types with various modified surfaces. In this study, the dynamic adhesion behavior of human fetal osteoblastic bone (hfOB) cell lines was first monitored on untreated and hydrophilically treated gold sensor surfaces as reference substrates. Adhesion was also observed under light microscopy to facilitate the evaluation. Cells increased their surface contact area and spread more on hydrophilic surfaces, and showed distinct profile with an increased rigidity at the interfacial layer, which is assigned to extracellular matrix remodeling. Further, the adhesion strength and kinetics were characterized on cell adhesive (poly-l-lysine and fibronectin) and repellent (bovine serum albumin) surfaces. The overall results indicated that protein-mediated specific interactions contributed mostly to the dissipation changes (ΔD) or acoustic ratio (ΔD/Δf). Finally, the potential of QCM-D to distinguish healthy and cancerous cells were evaluated by comparing the results of hfOB cells with that of SaOS-2 (osteosarcoma) cancerous cells. Cancerous cells interacted more strongly and showed more viscoelastic characteristic than the healthy cells.


Systemic onset juvenile idiopathic arthritis with macrophage activation syndrome and coronary artery dilatation misdiagnosed as Kawasaki disease.
Systemic onset juvenile idiopathic arthritis (SoJIA) is characterized by arthritis, fever and visceral organ involvement including hepatosplenomegaly, lympadenopathy and serositis. This is a case of SoJIA misdiagnosed as Kawasaki disease (KD) and developed machrophage activation syndrome (MAS) secondary to Ebstein-Barr virus (EBV) infection. It is presented to point out the conditions that may come along. First of all, SoJIA should be kept in mind while making the differential diagnosis of coronary arterial ectasias and dilatations usually seen in vasculitic diseases like KD. Second, as a very fatal complication MAS should always be considered while following a patient with the diagnosis of SoJIA. Infections like EBV may be the potential triggers for development of MAS especially in immunesupressed patients.


Descriptive Analysis of a Baseline Concussion Battery Among U.S. Service Academy Members: Results from the Concussion Assessment, Research, and Education (CARE) Consortium.
The prevalence and possible long-term consequences of concussion remain an increasing concern to the U.S. military, particularly as it pertains to maintaining a medically ready force. Baseline testing is being used both in the civilian and military domains to assess concussion injury and recovery. Accurate interpretation of these baseline assessments requires one to consider other influencing factors not related to concussion. To date, there is limited understanding, especially within the military, of what factors influence normative test performance. Given the significant physical and mental demands placed on service academy members (SAM), and their relatively high risk for concussion, it is important to describe demographics and normative profile of SAMs. Furthermore, the absence of available baseline normative data on female and non-varsity SAMs makes interpretation of post-injury assessments challenging. Understanding how individuals perform at baseline, given their unique individual characteristics (e.g., concussion history, sex, competition level), will inform post-concussion assessment and management. Thus, the primary aim of this manuscript is to characterize the SAM population and determine normative values on a concussion baseline testing battery. All data were collected as part of the Concussion Assessment, Research and Education (CARE) Consortium. The baseline test battery included a post-concussion symptom checklist (Sport Concussion Assessment Tool (SCAT), psychological health screening inventory (Brief Symptom Inventory (BSI-18) and neurocognitive evaluation (ImPACT), Balance Error Scoring System (BESS), and Standardized Assessment of Concussion (SAC). Linear regression models were used to examine differences across sexes, competition levels, and varsity contact levels while controlling for academy, freshman status, race, and previous concussion. Zero inflated negative binomial models estimated symptom scores due to the high frequency of zero scores. Significant, but small, sex effects were observed on the ImPACT visual memory task. While, females performed worse than males (p < 0.0001, pη2 = 0.01), these differences were small and not larger than the effects of the covariates. A similar pattern was observed for competition level on the SAC. There was a small, but significant difference across competition level. SAMs participating in varsity athletics did significantly worse on the SAC compared to SAMs participating in club or intramural athletics (all p's < 0.001, η2 = 0.01). When examining symptom reporting, males were more than two times as likely to report zero symptoms on the SCAT or BSI-18. Intramural SAMs had the highest number of symptoms and severity compared to varsity SAMs (p < 0.0001, Cohen's d < 0.2). Contact level was not associated with SCAT or BSI-18 symptoms among varsity SAMs. Notably, the significant differences across competition level on SCAT and BSI-18 were sub-clinical and had small effect sizes. The current analyses provide the first baseline concussion battery normative data among SAMs. While statistically significant differences may be observed on baseline tests, the effect sizes for competition and contact levels are very small, indicating that differences are likely not clinically meaningful at baseline. Identifying baseline differences and significant covariates is important for future concussion-related analyses to inform concussion evaluations for all athlete levels.


Enhancement of experimental colon cancer by genistein.
Several phytochemicals and micronutrients that are present in fruits and vegetables are known to exert cancer chemopreventive effects in several organs, including the colon. Among them, the soybean isoflavonoid genistein received much attention due to its potential anticarcinogenic, antiproliferative effects and its potential role in several signal transduction pathways. The present study was designed to investigate the effect of genistein on azoxymethane (AOM)-induced colon carcinogenesis and to study its modulatory role on the levels of activity of 8-isoprostane, cyclooxygenase (COX), and 15-hydroxyprostaglandin F2alpha dehydrogenase (15-PGDH) in the colonic mucosa and colon tumors of male F344 rats. At 5 weeks of age, groups of male F344 rats were fed control (AIN-76A) diet or a diet containing 250 ppm genistein. Beginning 2 weeks later, all animals except those in the vehicle-treated groups were given weekly s.c. injections of AOM (15 mg/kg body weight) for 2 successive weeks. All rats were continued on their respective dietary regimen for 52 weeks after AOM treatment and were then sacrificed. Colon tumors were evaluated histopathologically. Colonic mucosae and tumors were analyzed for COX, 15-PGDH, and 8-isoprostane levels. Administration of genistein significantly increased noninvasive and total adenocarcinoma multiplicity (P < 0.01) in the colon, compared to the control diet, but it had no effect on the colon adenocarcinoma incidence nor on the multiplicity of invasive adenocarcinoma (P > 0.05). Also, genistein significantly inhibited the 15-PGDH activity (>35%) and levels of 8-iosoprostane (50%) in colonic mucosa and in tumors. In contrast, genistein had no significant effect on the COX synthetic activity, as measured by the rate of formation of prostaglandins and thromboxane B2 from [14C]arachidonic acid. The results of this investigation emphasize that the biological effects of genistein may be organ specific, inhibiting cancer development in some sites yet showing no effect or an enhancing effect on the tumorigenesis at other sites, such as the colon. The inhibition of 8-isoprostane levels by genistein indicates its possible antioxidant potential, which is independent of the observed colon tumor enhancement, yet this agent may also possess several biological effects that overshadow its antioxidant potential. The exact mechanism(s) of colon tumor enhancement by genistein remain to be elucidated; it is likely that its colon tumor-enhancing effects may, at least in part, be related to inhibition of prostaglandin catabolic enzyme activities.


Racial variation in the clinical and economic burden of skeletal-related events among elderly men with stage IV metastatic prostate cancer.
Prostate cancer (PCa) outcomes vary widely among African American (AA) and non-Hispanic White (NHW) men. The authors investigated racial variation in the incidence of skeletal-related events (SREs) and SRE-related healthcare costs among AA and NHW men, a topic that has received limited attention in the literature. AA and NHW men diagnosed with metastatic PCa were identified from the linked Surveillance, Epidemiology and End Results-Medicare dataset. The sample included 6455 men with metastatic PCa, including 5420 NHW men and 1035 AA men. Approximately 16% experienced SREs during follow-up. AA men were less likely to experience SREs compared with NHW men, controlling for individual characteristics (adjusted odds ratio: 0.79; 95% CI: 0.66- 0.94). The SRE-specific costs were US$35,725 (US$22,190-US$49,260) among AA men and US$25,896 (US$21,669-US$30,123) among NHW men. Although AA men were less likely to experience SREs, there were substantial costs attributable to the treatment of SREs among AA men.


Comparing the American and European diagnostic guidelines for cystic fibrosis: same disease, different language?
The American and European cystic fibrosis (CF) guidelines recommend different diagnostic criteria. This study assessed diagnostic concordance between these recommendations. Subjects with single organ manifestations suggestive of CF (chronic sinopulmonary disease (RESP), chronic/recurrent pancreatitis (PANC) or obstructive azoospermia (AZOOSP)) were prospectively evaluated by sweat test, nasal potential difference and genotyping. Concordance in diagnostic outcomes between the two algorithms was measured using observed agreement and κ statistics. A total of 208 subjects were evaluated. Observed agreement was 84.8% and level of agreement was excellent (κ=0.87) between the American and European recommendations. The RESP phenotype was associated with the highest degree of concordance (observed agreement ≥90%, κ=0.92) compared with the PANC (observed agreement 86%, κ=0.65) and AZOOSP (observed agreement 80%, κ=0.87) phenotypes. Incorporation of nasal potential difference into the American algorithm failed to improve the overall degree of concordance (good agreement level; κ=0.75); the level of agreement was unchanged in RESP and PANC subjects, but reduced in AZOOSP subjects (from excellent to good). Extensive genotyping had limited clinical utility in the diagnosis of CF in both algorithms. Despite inconsistencies between the American and European diagnostic recommendations, concordance in diagnostic outcomes among subjects presenting with single organ manifestations of CF was good to excellent. These diagnostic guidelines provide guidance and promote rigorous evaluation for the diagnosis of CF but neither guideline should be regarded as dogma.


Renal catabolism of recombinant human soluble CD4 after intravenous administration to male Sprague-Dawley rats.
Recombinant soluble CD4 (sT4; mol. wt. 45,000) has been studied extensively in Sprague-Dawley rats, and substantial renal processing has been indicated. In rats and monkeys, renal filtration and precipitation of sT4 in the distal nephron caused tubular cast nephropathy. Intravenous pharmacokinetics in the rat demonstrated that sT4 plasma clearance exceeded the glomerular filtration rate. In an effort to determine quantitatively the extent to which kidney and other tissues were responsible for sT4 catabolism, sT4 was labeled with trace amounts of dilactitol-[125I]tyramine and administered intravenously to Sprague-Dawley rats (1 mg/kg). Dilactitol-tyramine accumulates in lysosomes at the site of protein degradation. It has been used primarily to demonstrate hepatic catabolism of endogenous proteins. Blood samples were drawn for pharmacokinetic analysis, and selected tissues were removed to assess radiolabel distribution. Comparison of pharmacokinetic parameters derived from total plasma radiolabel and functional ELISA were not significantly different. Thus, covalent modification of sT4 with dilactitol-tyramine did not appreciably change the rate of clearance. From 3 to 24 hr after intravenous administration, 81.5 +/- 0.1% of the total administered radioactivity was found in the kidney. Approximately 8-13% of the administered dose was recovered in the liver. Macroscopic autoradiography of the kidney demonstrated accumulation of radiolabel in the cortex. Light microscopic autoradiography of the kidney following intravenous administration of directly radioiodinated sT4 confirmed cortical processing, because radiolabel was located primarily in epithelial cells of P1 and P2 segments of the proximal tubule after low intravenous doses (0.4-4 mg/kg). At 40 mg/kg, distal tubules and cortical collecting ducts were labeled as well. Thus, sT4 was filtered by the glomerulus, reabsorbed in the proximal tubule, and degraded in the lysosomal compartment.


Antiviral treatment for chronic hepatitis C in patients with human immunodeficiency virus.
Antiviral treatment for chronic hepatitis C may be less effective if patients are co-infected with human immunodeficiency virus (HIV). To assess the benefits and harms of antiviral treatment for chronic hepatitis C in patients with HIV. Trials were identified through manual and electronic searches in The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded. The last search was May 2009. Randomised trials comparing at least 12 weeks of any anti-HCV treatment versus another treatment regimen or no treatment. Included patients had chronic hepatitis C and stable HIV irrespective of previous antiviral therapy. Data extraction and assessment of risk of bias were done in duplicate. Analysis was by intention-to-treat. Fourteen trials were included. None of the included 2269 patients were previously treated for chronic hepatitis C. Peginterferon (either 2a, 180 microgram, or 2b, 1.5 microgram/kg, once weekly) plus ribavirin was more effective in achieving end of treatment and sustained virological response compared with interferon plus ribavirin (5 trials, 1340 patients) or peginterferon (2 trials, 714 patients). The benefit of peginterferon plus ribavirin was seen irrespective of HCV genotype although patients with genotype 1 or 4 had lower response rates (27%) than patients with genotype 2 or 3 (56%). The remaining trials compared different treatment regimens in patients who were treatment naive or had no virological response after three months of treatment, but overall they had not enough power to show any effect of increasing the dose of interferon or adding both amantadine or ribavirin. The overall mortality was 23/2111 patients with no significant differences between treatment regimens. Treatment increased the risk of adverse events including anaemia and flu-like symptoms, and several serious adverse events occurred including fatal lactic acidosis, liver failure, and suicide due to depression. Peginterferon plus ribavirin may be considered a treatment for patients with chronic hepatitis C and stable HIV who have not received treatment for hepatitis C as the intervention may clear the blood of HCV RNA. Supporting evidence comes mainly from the analysis of this non-validated surrogate outcome assessed in comparisons against other antiviral treatments. There is no evidence on treatment of patients who have relapsed or did not respond to previous therapy. Careful monitoring of adverse events is warranted.


Clinical and electrographic findings in epileptic vertigo and dizziness: a systematic review.
Seizures can cause vestibular symptoms, even without obvious epileptic features. We sought to characterize epileptic vertigo or dizziness (EVD) to improve differentiation from nonepileptic causes, particularly when vestibular symptoms are the sole manifestation. We conducted a systematic review with electronic (Medline) and manual search for English-language studies (1955-2014). Two independent reviewers selected studies. Study/patient characteristics were abstracted. We defined 3 study population types: (1) seizures, some experiencing vertigo/dizziness (disease cohort); (2) vertigo/dizziness, some due to seizures (symptom cohort); (3) vertigo/dizziness due to seizures in all patients (EVD-only cohort). We identified 84 studies describing 11,354 patients (disease cohort = 8,129; symptom cohort = 2,965; EVD-only cohort = 260). Among 1,055 EVD patients in whom a distinction could be made, non-isolated EVD was present in 8.5%, isolated EVD in 0.8%. Thorough diagnostic workups (ictal EEG, vestibular testing, and brain MRI to exclude other causes) were rare (<0.1%). Ictal EEG was reported in 487 (4.3%), formal neuro-otologic assessment in 1,107 (9.7%). Localized EEG abnormalities (n = 350) were most frequently temporal (79.8%) and uncommonly parietal (11.8%). Duration of episodic vestibular symptoms varied, but was very brief (<30 seconds) in 69.6% of isolated EVD and 6.9% of non-isolated EVD. Non-isolated EVD is much more prevalent than isolated EVD, which appears to be rare. Diagnostic evaluations for EVD are often incomplete. EVD is primarily associated with temporal lobe seizures; whether this reflects greater epidemiologic prevalence of temporal lobe seizures or a tighter association with dizziness/vertigo presentations than with other brain regions remains unknown. Consistent with clinical wisdom, isolated EVD spells often last just seconds, although many patients experience longer spells.


Metabolizable energy content of refined glycerin and its effects on growth performance and carcass and pork quality characteristics of finishing pigs.
Two studies were conducted with refined glycerin (97.7 and 97.5% glycerin for studies I and II, respectively) to determine ME content and effects on growth performance and carcass and pork quality measures of finishing pigs. An energy balance study using 24 barrows (21.5 ± 0.6 kg initial BW) determined the apparent ME content of glycerin using a generalized randomized block design with 2 dietary treatments: 1) control (99.85% corn + vitamins and minerals) and 2) glycerin (30% of corn in the control diet replaced with glycerin). A 7-d adaptation was followed by a 5-d collection period for feces and urine. The energy content of diets, feces, and urine was determined by bomb calorimetry. The DE of the glycerin diet was greater (P < 0.01) than that of the control diet (4,298 vs. 3,902 kcal/kg of DM); however, the ME content of the 2 diets was similar (3,820 vs. 3,723 kcal/kg of DM). The ME of refined glycerin (estimated by difference) was 3,584 kcal/kg of DM. A growth study was conducted with 128 gilts housed in groups of 4 and reared from 92.5 ± 0.24 kg of BW for a 28-d period, using a split-plot design with a 4 × 2 factorial arrangement of treatments: 1) dietary glycerin level (0, 5, 10, and 15%) and 2) preslaughter handling (gentle vs. intense). The handling treatment was included to simulate the range in handling intensities that are likely to be experienced in practice. At the end of the 28-d period, one-half of the pens on study were slaughtered and used for carcass and pork quality evaluation with 2 pigs from each pen being subjected to each of the preslaughter handling treatments. There were no interactions (P > 0.05) between dietary glycerin and preslaughter handling treatment. Dietary glycerin had no effect (P > 0.05) on growth performance, carcass measures, or meat quality. There were no differences (P > 0.05) between the gentle and intense handling treatments for carcass or pork quality measures. In conclusion, feeding glycerin to finishing pigs at up to 15% of the diet had no negative effect on growth performance or carcass and pork quality characteristics.


Search for pair-produced dijet resonances in four-jet final states in pp collisions at sqrt[s] = 7 TeV.
A search for the pair production of a heavy, narrow resonance decaying into two jets has been performed using events collected in sqrt[s] = 7 TeV pp collisions with the CMS detector at the LHC. The data sample corresponds to an integrated luminosity of 5.0 fb(-1). Events are selected with at least four jets and two dijet combinations with similar dijet mass. No resonances are found in the dijet mass spectrum. The upper limit at 95% confidence level on the product of the resonance pair production cross section, the branching fractions into dijets, and the acceptance varies from 0.22 to 0.005 pb, for resonance masses between 250 and 1200 GeV. Pair-produced colorons decaying into qq are excluded for coloron masses between 250 and 740 GeV.


Pharmacological activation of IKr in models of long QT Type 2 risks overcorrection of repolarization.
Current treatment for congenital long QT syndrome Type 2 (cLQTS2), an electrical disorder that increases the risk of life-threatening cardiac arrhythmias, is aimed at reducing the incidence of arrhythmia triggers (beta-blockers) or terminating the arrhythmia after onset (implantable cardioverter-defibrillator). An alternative strategy is to target the underlying disease mechanism, which is reduced rapid delayed rectifier current (IKr) passed by Kv11.1 channels. Small molecule activators of Kv11.1 have been identified but the extent to which these can restore normal cardiac signalling in cLQTS2 backgrounds remains unclear. Here, we examined the ability of ICA-105574, an activator of Kv11.1 that impairs transition to the inactivated state, to restore function to heterozygous Kv11.1 channels containing either inactivation enhanced (T618S, N633S) or expression deficient (A422T) mutations. ICA-105574 effectively restored Kv11.1 current from heterozygous inactivation enhanced or expression defective mutant channels in heterologous expression systems. In a human-induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model of cLQTS2 containing the expression defective Kv11.1 mutant A422T, cardiac repolarization, estimated from the duration of calcium transients in isolated cells and the rate corrected field potential duration (FPDc) in culture monolayers of cells, was significantly prolonged. The Kv11.1 activator ICA-105574 was able to reverse the prolonged repolarization in a concentration-dependent manner. However, at higher doses, ICA-105574 produced a shortening of the FPDc compared to controls. In vitro and in silico analysis suggests that this overcorrection occurs as a result of a temporal redistribution of the peak IKr to much earlier in the plateau phase of the action potential, which results in early repolarization. Kv11.1 activators, which target the primary disease mechanism, provide a possible treatment option for cLQTS2, with the caveat that there may be a risk of overcorrection that could itself be pro-arrhythmic.


Association between breaks in sitting time and adiposity in Australian toddlers: Results from the GET-UP! study.
In youth, research on the health benefits of breaking up sitting time is inconsistent. Our aim was to explore the association between the number of breaks in sitting time and adiposity in Australian toddlers. This study comprised 266 toddlers (52% boys), aged 19.6 ± 4.2 months from the GET-UP! Study, Australia. Body mass index (BMI) was calculated and z-scores by age and sex were computed for waist circumference (WC). Participants were classified as overweight according to the WHO criteria for BMI. For WC, participants with a z-score≥1SD were considered overweight. Sitting time was assessed with activPALs during childcare hours and participants were classified by tertiles of the number of breaks/h in sitting time: <26 breaks/h; 26-39 breaks/h, and >39 breaks/h. Logistic regression assessed odds ratios for non-overweight (BMI or waist circumference categories) by number of breaks in sitting time/h, controlling for age, sex, and socioeconomic status. The number of breaks in sitting time significantly predicted a lower weight status (non-overweight) according to WC values (P for trend = 0.032) after adjustments. Breaking up sitting time was positively associated with toddlers' waist circumference. Future studies are needed to determine whether breaking up sitting time is a protective for cardiometabolic health in toddlers.


Mechanism of inhibition of renin secretion by increased left atrial pressure.
Experiments were designed to elucidate the mechanism of the failure of systemic hypotension to stimulate renin release in the presence of elevated left heart pressure. We conducted a series of graded ascending aortic and suprarenal cuff inflations in dogs with bilateral renal denervation (n = 5). The renal perfusion pressure (RPP) was reduced by 10, 20, and 30% of control by inflation of either cuff. Comparison of the renin response with inflation of the ascending aortic to the suprarenal cuff revealed a clear increase in the threshold required to elicit a renin response to graded reduction of RPP after inflation of the ascending aortic cuff. These results may be explained by differential effects of the two maneuvers on left heart pressure. Left atrial pressure increased during inflation of the ascending aortic cuff but did not change during inflation of the suprarenal cuff. Since the kidneys were denervated, the shift in threshold must be caused by a humoral substance(s). In conclusion, our findings suggest that the efferent pathway of potent inhibition of renin release from the left heart is mediated, at least partially, by a humoral substance.


Improvement of system capacitance via weavable superelastic biscrolled yarn supercapacitors.
Yarn-based supercapacitors having improved performance are needed for existing and emerging wearable applications. Here, we report weavable carbon nanotube yarn supercapacitors having high performance because of high loadings of rapidly accessible charge storage particles (above 90 wt% MnO2). The yarn electrodes are made by a biscrolling process that traps host MnO2 nanoparticles within the galleries of helically scrolled carbon nanotube sheets, which provide strength and electrical conductivity. Despite the high loading of brittle metal oxide particles, the biscrolled solid-state yarn supercapacitors are flexible and can be made elastically stretchable (up to 30% strain) by over-twisting to produce yarn coiling. The maximum areal capacitance of the yarn electrodes were up to 100 times higher than for previously reported fibres or yarn supercapacitors. Similarly, the energy density of complete, solid-state supercapacitors made from biscrolled yarn electrodes with gel electrolyte coating were significantly higher than for previously reported fibre or yarn supercapacitors.


Preventing recurrence of thromboembolic events through coordinated treatment in the District of Columbia.
PROTECT DC examines whether stroke navigators can improve cardiovascular risk factors in urban underserved individuals newly hospitalized for stroke or ischemic attack. Within one-year of hospital discharge, up to one-third of patients no longer adhere to secondary prevention behaviors. Adherence rates are lower in minority-underserved groups, contributing to health disparities. In-hospital programs increase use of stroke prevention therapies but may not be as successful in underserved individuals. In these groups, low literacy, limited healthcare access, and sparse community resources may reduce adherence. Lay community health workers (navigators) improve adherence in other illnesses through education and assisting in overcoming barriers to achieving desired health behaviors and obtaining needed healthcare services. PROTECT DC is a Phase II, single-blind, randomized, controlled trial comparing in-hospital education plus stroke navigators to usual care. Atherogenic ischemic stroke and transient ischemic attack survivors are recruited from Washington, DC hospitals. Navigators meet with participants during the index hospitalization, perform home visits, and meet by phone. They focus on stroke education, medication compliance, and overcoming practical barriers to adherence. The interventions are driven by the theories of reasoned action and planned behavior. The primary dependent measure is a summary score of four objective measures of stroke risk factor control: systolic blood pressure, low-density lipoprotein, hemoglobin Hb A1C, and antiplatelet agent pill counts. Secondary outcomes include stroke knowledge, exercise, dietary modification, and smoking cessation. PROTECT DC will determine whether a Phase III trial of stroke navigation for urban underserved individuals to improve adherence to secondary stroke prevention behaviors is warranted.


In vivo and in vitro characterization of specific hyporeactivity to skin xenografts in mixed xenogeneically reconstituted mice (B10 + F344 rat----B10).
Mixed xenogeneically reconstituted mice (F344 rat + C57BL/10Sn----C57BL/10Sn), which specifically retain F344 tail skin xenografts, were studied for the specificity of such hyporeactivity and for in vitro reactivity and immunocompetence. Survival of mixed reconstituted animals was excellent, without evidence for graft vs. host disease. Donor-type tail skin grafts were specifically prolonged (mean survival time = 80 d) in comparison with normal controls and syngeneically reconstituted animals. In vitro, such animals manifested specific hyporeactivity by mixed lymphocyte reaction and cell-mediated lympholysis to F344 rat and B10 cells, with normal response to third-party rat (Wistar-Furth) and mouse (B10.BR). Examination of lymphoid tissues with a fluorescence-activated cell sorter revealed low levels, if any, of donor-type cells detectable. This system offers a model for investigation of xenogeneic transplantation tolerance.


Cancer cell-derived IL-1α induces CCL22 and the recruitment of regulatory T cells.
In cancer patients, immunosuppression through regulatory T cells (Treg) is a crucial component of tumor immune evasion and contributes to disease progression. Tumor-infiltrating Treg in particular suppress local effector T cell responses and are associated with poor prognosis in tumors such as human pancreatic cancer or hepatocellular carcinoma (HCC). The chemokine CCL22 is known to recruit Treg into the tumor tissue and many types of human tumors are known to express high levels of CCL22. The mechanisms leading to intratumoral secretion of CCL22 are so far unknown. We demonstrate here that intratumoral CCL22 is induced in tumor-infiltrating immune cells through cancer cell-derived interleukin-1 (IL-1α). In pancreatic cancer and HCC, CCL22 is produced by intratumoral dendritic cells, while the cancer cells themselves do not secrete CCL22 in vitro and in vivo. Incubation of human peripheral blood mononuclear cells (PBMC) or murine splenocytes with tumor cells or tumor cell supernatants strongly induced CCL22 secretion in vitro. Tumor cell supernatants contained IL-1 and CCL22 induction in PBMC could be specifically prevented by the IL-1 receptor antagonist anakinra or by transfection of tumor cell lines with IL-1 siRNA, leading to a suppression of Treg migration. In conclusion, we identify here tumor cell-derived IL-1α as a major inducer of the Treg attracting chemokine CCL22 in human cancer cells. Therapeutic blockade of the IL-1 pathway could represent a promising strategy to inhibit tumor-induced immunosuppression.


The association of stillbirth with placental abnormalities in growth-restricted and normally grown fetuses.
Stillbirth, defined as foetal death ≥20 weeks' gestation, is associated with poor foetal growth and is often attributed to placental abnormalities, which are also associated with poor foetal growth. Evaluating inter-relationships between placental abnormalities, poor foetal growth, and stillbirth may improve our understanding of the underlying mechanisms for some causes of stillbirth. Our primary objective was to determine whether poor foetal growth, operationalised as small for gestational age (SGA), mediates the relationship between placental abnormalities and stillbirth. We used data from the Stillbirth Collaborative Research Network study, a population-based case-control study conducted from 2006-2008. Our analysis included 266 stillbirths and 1135 livebirths. We evaluated associations of stillbirth with five types of placental characteristics (developmental disorders, maternal and foetal inflammatory responses, and maternal and foetal circulatory disorders) and examined mediation of these relationships by SGA. We also assessed exposure-mediator interaction. Models were adjusted for maternal age, race/ethnicity, education, body mass index, parity, and smoking status. All five placental abnormalities were more prevalent in cases than controls. After adjustment for potential confounders, maternal inflammatory response (odds ratio [OR] 2.58, 95% confidence interval [CI] 1.77, 3.75), maternal circulatory disorders OR 4.14, 95% CI 2.93, 5.84, and foetal circulatory disorders OR 4.58, 95% CI 3.11, 6.74 were strongly associated with stillbirth, and the relationships did not appear to be mediated by SGA status. Associations for developmental disorders and foetal inflammatory response diverged for SGA and non-SGA births, and strong associations were only observed when SGA was not present. Foetal growth did not mediate the relationships between placental abnormalities and stillbirth. The relationships of stillbirth with maternal and foetal circulatory disorders and maternal inflammatory response appear to be independent of poor foetal growth, while developmental disorders and foetal inflammatory response likely interact with foetal growth to affect stillbirth risk.


Effect of growth hormone-releasing factor-44 upon release of concurrently synthesized hormone by perifused rat pituitary tissue.
We previously reported the differential stimulation of stored and newly synthesized rat (r)GH release by human GH-releasing factor-44 (hGRF-44). Those studies were performed over a 3-h period in a static in vitro incubation system. The present experiments focus on hGRF-44 effects upon release of new hormone (synthesized during tissue stimulation by the secretagogue) and were performed in in vitro perifusion to study the time course of the response. A double label ([14C], [3H]), immunoprecipitation protocol defined hormone release in relation to time of synthesis: intracellular stores of hormone were prelabeled with [14C]; subsequent exposure of prelabeled tissue to continuous concurrent [3H]leucine and 3 nM hGRF-44 defined newly synthesized hormone and associated it with the secretagogue. In a parallel set of experiments, 1 mM (Bu)2cAMP was substituted for hGRF-44. Prolonged exposure to hGRF-44 in perifusion stimulated an initial surge of stored [14C]rGH release which was followed by a rate of [14C]rGH release which declined rapidly but remained suprabasal. [14C]rGH release in response to (Bu)2cAMP was also biphasic, but the initial surge was delayed and the later stimulatory period was better sustained in comparison to responses to hGRF-44. Stimulation of stored [14C] rPRL release by hGRF-44 was observed in perifusion, confirming our observation in the static system. Release of newly synthesized, 3H-labeled rGH was immediately stimulated by either hGRF-44 or (Bu)2cAMP, and that stimulation was maintained throughout exposure to either secretagogue. In contrast, whereas newly synthesized [3H]rPRL release was stimulated by (Bu)2cAMP, its release in response to hGRF-44 resembled that in control experiments. No effect upon hormone synthesis was observed during the 3h of exposure to hGRF-44. In conclusion, these experiments confirm that hGRF-44 differentially stimulates release of both newly synthesized and stored rGH, and demonstrate differential dynamics in the response as well. Specifically, hGRF-44 stimulation of new rGH release is sustained while its effect on stored hormone simultaneously wanes. Further, when expressed as a percent of intracellular hormone available for release, new hormone is released more than 10 times faster than stored hormone. These observations argue for the existence of separate intracellular paths along which newly synthesized and stored hormone are released by the somatotroph. Finally, these data confirm that hGRF-44 stimulates release of stored rPRL without altering release of newly synthesized rPRL.


Current Management of Talar Fractures.
Talar fractures are some of the most challenging injuries that orthopaedic traumatologists manage. The current knowledge of functional alterations with regard to malreduction of talar fractures is well established. Decision making with regard to timing, approach, and implant selection as well as strategies to help achieve accurate restoration of talar anatomy substantially affect outcomes and must be carefully considered. Perfect anatomic talar reconstruction should always be attempted, and orthopaedic surgeons should have a strong working knowledge of the vascular, three-dimensional, and radiographic anatomy of the talus before performing talar surgery. Almost the entire talus is surgically accessible via several approaches, all of which surgeons should be clinically familiar with to optimize reduction and fixation and safely preserve the soft-tissue envelope. Furthermore, surgeons must appreciate the plantarmedial vascular area of the talus, which must be avoided during dissection. The complication rates in patients who have talar fractures are high, particularly in those who have talar neck and talar body fractures; therefore, patients should be counseled on their expected outcome, with a specific discussion on the risk of osteonecrosis and subtalar arthritis.


Progress in bio-inspired sacrificial bonds in artificial polymeric materials.
Mimicking natural structures has been highly pursued in the fabrication of synthetic polymeric materials due to its potential in breaking the bottlenecks in mechanical properties and extending the applications of polymeric materials. Recently, it has been revealed that the energy dissipating mechanisms via sacrificial bonds are among the important factors which account for strong and tough attributes of natural materials. Great progress in synthesis of polymeric materials consisting of sacrificial bonds has been achieved. The present review aims at (1) summarizing progress in the mechanics and chemistry of sacrificial bond bearing polymers, (2) describing the mechanisms of sacrificial bonds in strengthening/toughening polymers based on studies by single-molecule force spectroscopy, chromophore incorporation and constitutive laws, (3) presenting synthesis methods for sacrificial bonding including dual-crosslink, dual/multiple-network, and sacrificial interfaces, (4) discussing the important advances in engineering sacrificial bonding into hydrogels, biomimetic structures and elastomers, and (5) suggesting future works on molecular simulation, viscoelasticity, construction of sacrificial interfaces and sacrificial bonds with high dissociative temperature. It is hoped that this review will provide guidance for further development of sacrificial bonding strategies in polymeric materials.


Cancer risk in women prenatally exposed to diethylstilbestrol.
Prenatal diethylstilbestrol (DES) exposure is associated with excess risks of clear cell adenocarcinoma (CCA), and breast cancer in older women. Whether overall cancer risk is also elevated is unclear. Total and site-specific cancer risks were evaluated in the DES Combined Cohort Follow-up Study using age- and calendar-year specific standardized incidence rate ratios (SIR), and age-adjusted incidence rate ratios (RR) comparing DES exposed and unexposed women. A total of 143 and 49 cancer cases occurred in 97,831 and 34,810 person-years among the exposed and unexposed, respectively. There was no overall excess risk among exposed women when compared with external rates (SIR 1.01; 95% confidence interval [CI] 0.86-1.2). The overall RR comparing exposed with unexposed women was 1.32 (95% CI 0.94-1.8). Breast cancer risk was elevated only among women over 40 years (RR 1.83; 95% CI 1.1-3.2). The CCA SIR among exposed women was nearly 40, and the estimated attack rate through age 39 was 1.6/1,000 women. CCA incidence decreased by over 80% after age 25 when compared with 20-24 years. Excluding CCA and breast cancer, the overall RR was 1.21 (95% CI 0.74-2.0). DES was not associated with excess risks of either endometrial or ovarian cancer. These data suggest that the DES associated increase in CCA incidence remains elevated through the reproductive years. There was no consistent evidence of risk excesses for cancers other than CCA, and breast cancer in older women. Given that the population is still young, continued follow-up is necessary to assess the overall carcinogenic impact of prenatal DES exposure.


Memetic algorithms for continuous optimisation based on local search chains.
Memetic algorithms with continuous local search methods have arisen as effective tools to address the difficulty of obtaining reliable solutions of high precision for complex continuous optimisation problems. There exists a group of continuous local search algorithms that stand out as exceptional local search optimisers. However, on some occasions, they may become very expensive, because of the way they exploit local information to guide the search process. In this paper, they are called intensive continuous local search methods. Given the potential of this type of local optimisation methods, it is interesting to build prospective memetic algorithm models with them. This paper presents the concept of local search chain as a springboard to design memetic algorithm approaches that can effectively use intense continuous local search methods as local search operators. Local search chain concerns the idea that, at one stage, the local search operator may continue the operation of a previous invocation, starting from the final configuration (initial solution, strategy parameter values, internal variables, etc.) reached by this one. The proposed memetic algorithm favours the formation of local search chains during the memetic algorithm run with the aim of concentrating local tuning in search regions showing promise. In order to study the performance of the new memetic algorithm model, an instance is implemented with CMA-ES as an intense local search method. The benefits of the proposal in comparison to other kinds of memetic algorithms and evolutionary algorithms proposed in the literature to deal with continuous optimisation problems are experimentally shown. Concretely, the empirical study reveals a clear superiority when tackling high-dimensional problems.


Pneumo-concha dilatans: middle concha growing in anterior and lateral directions.
Aeration of the concha is called concha bullosa regardless of the amount and location of the aeration. Middle concha pneumatization is very frequent, and its incidence rate according to the literature is between 14% and 53.6%. Various types of middle concha such as pneumatized, paradoxical, bifurcate, trifurcate, secondary, and accessory have been defined; however, the most frequently observed variation is the pneumatization of the middle concha. In our case, a male patient presented to our clinic with complaints about difficulty breathing through the nose and decrease in the olfaction. The endoscopic examination showed that his right middle concha had grown enough to extend toward the front of the lower concha, and the left middle and lower meatuses were infested by polyps. The paranasal computed tomographic scan of the patient showed that the left middle concha had maxillary sinus invasion at an amount that was enough to fill 25% of the maxillary sinus. In this case presentation, the middle concha pneumatization presenting with maxillary sinus invasion, which we believe is the first case in the literature, is presented as accompanied by the literature.


Frequent co-expression of miRNA-5p and -3p species and cross-targeting in induced pluripotent stem cells.
A miRNA precursor generally gives rise to one major miRNA species derived from the 5' arm, and are called miRNA-5p. However, more recent studies have shown co-expression of miRNA-5p and -3p, albeit in different concentrations, in cancer cells targeting different sets of transcripts. Co-expression and regulation of the -5p and -3p miRNA species in stem cells, particularly in the reprogramming process, have not been studied. In this work, we investigated co-expression and regulation of miRNA-5p and -3p species in human induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs) and embryonic stem cells (ESC) using a nanoliter-scale real-time PCR microarray platform that included 1,036 miRNAs. In comparing iPSC and ESC, only 32 miRNAs were found to be differentially expressed, in agreement of the ESC-like nature of iPSC. In the analysis of reprogramming process in iPSCs, 261 miRNAs were found to be differentially expressed compared with the parental MSC and pre-adipose tissue, indicating significant miRNA alternations in the reprogramming process. In iPSC reprogrammed from MSC, there were 88 miRNAs (33.7%), or 44 co-expressed 5p/3p pairs, clearly indicating frequent co-expression of both miRNA species on reprogramming. Of these, 40 pairs were either co-up- or co-downregulated indicating concerted 5p/3p regulation. The 5p/3p species of only 4 pairs were regulated in reverse directions. Furthermore, some 5p/3p species of the same miRNAs were found to target the same transcript and the same miRNA may cross-target different transcripts of proteins of the G1/S transition of the cell cycle; 5p/3p co-targeting was confirmed in stem-loop RT-PCR. The observed cross- and co-regulation by paired miRNA species suggests a fail-proof scheme of miRNA regulation in iPSC, which may be important to iPSC pluripotency.


Pressure-induced syneretic response in rhesus monkey lenses.
To investigate the effect of pressure on the freezable and nonfreezable water content of the lens. Excised rhesus monkey lenses in tissue culture media were subjected to three different hydrostatic pressures (2 atm, 1 atm, and 0.03 atm) for 24 hours. Then while still under the experimental pressure, the vessels were cooled in dry ice-acetone until the lenses were frozen. While the lenses were kept frozen, nuclear and cortical samples were dissected, enclosed in a sample pan, and weighed. Differential scanning calorimetry (DSC) measurements were performed between -30 degrees C and 30 degrees C. Total water content of each lens sample was obtained by thermogravimetric analysis at 105 degrees C. The nonfreezable water content was obtained by subtracting the freezable water content calculated from the DSC data from the total water content. The total water content of the lenses did not change significantly as a function of pressure applied. This was true both for cortical and for nuclear sections. The freezable water content increased as the pressure decreased both in cortex and nucleus. Similarly, the freezable water/nonfreezable water ratio also decreased with increasing pressure. External hydrostatic pressure would generate an influx of water into the lens. To alleviate this diluting tendency and to prevent turbidity as a result of dilution, the lens must effect an osmotic pressure change equivalent to the applied pressure. Change in the osmotic pressure is caused by changing the activity of the water (i.e., converting free water to bound water). This is a reversible and energetically the least expensive response. The release of bound water from the hydration layers of macromolecules and its conversion to free water in condensed systems are known as syneresis. In the lens decreasing pressures induce syneresis as demonstrated by the increase in freezable water content and the freezable water/nonfreezable water ratio. Such a response may be operative also in accommodating lenses.


Age-Dependent Relationship Between Plasma Aβ40 and Aβ42 and Total Tau Levels in Cognitively Normal Subjects.
Both amyloid plaques and neurofibrillary tangles are pathological hallmarks in the brains of patients with Alzheimer's disease (AD). However, the constituents of these hallmarks, amyloid beta (Aβ) 40, Aβ42, and total Tau (t-Tau), have been detected in the blood of cognitively normal subjects by using an immunomagnetic reduction (IMR) assay. Whether these levels are age-dependent is not known, and their interrelation remains undefined. We determined the levels of these biomarkers in cognitively normal subjects of different age groups. A total of 391 cognitively normal subjects aged 23-91 were enrolled from hospitals in Asia, Europe, and North America. Healthy cognition was evaluated by NIA-AA guidelines to exclude subjects with mild cognitive impairment (MCI) and AD and by cognitive assessment using the Mini Mental State Examination and Clinical Dementia Rating (CDR). We examined the effect of age on plasma levels of Aβ40, Aβ42, and t-Tau and the relationship between these biomarkers during aging. Additionally, we explored age-related reference intervals for each biomarker. Plasma t-Tau and Aβ42 levels had modest but significant correlations with chronological age (r = 0.127, p = 0.0120 for t-Tau; r = -0.126, p = 0.0128 for Aβ42), ranging from ages 23 to 91. Significant positive correlations were detected between Aβ42 and t-Tau in the groups aged 50 years and older, with Rho values ranging from 0.249 to 0.474. Significant negative correlations were detected between Aβ40 and t-Tau from age 40 to 91 (r ranged from -0.293 to -0.582) and between Aβ40 and Aβ42 in the age groups of 30-39 (r = -0.562, p = 0.0235), 50-59 (r = -0.261, p = 0.0142), 60-69 (r = -0.303, p = 0.0004), and 80-91 (r = 0.459, p = 0.0083). We also provided age-related reference intervals for each biomarker. In this multicenter study, age had weak but significant effects on the levels of Aβ42 and t-Tau in plasma. However, the age group defined by decade revealed the emergence of a relationship between Aβ40, Aβ42, and t-Tau in the 6th and 7th decades. Validation of our findings in a large-scale and longitudinal study is warranted.


The Effect of Interventional Pain Management on Treating Postherpetic Neuralgia.
Herpes zoster (HZ) is identified to induce postherpetic neuralgia (PHN) which is difficult to cure. PHN-related pain brings patients not only physical discomfort but also mental depression and anxiety. Currently, the main purpose of PHN treatment is to reduce patients' pain. Now treatment combining some international pain management and drug therapy has come up. This study aims to evaluate the effect of interventional management through meta-analysis. Interventional pain management was defined as a direct strategy on nerve through physical or chemical method. Drug therapy was always regarded as control. Potentially relevant articles were searched in PubMed, EMBASE, and the Cochrane Library through key words by consensus. Pain severity was evaluated by a validated visual analog scale (VAS). Moreover, the weighted mean difference was used to calculate pain intensity. Some trails recorded the efficiency rate and odds ratio was used to calculate the effectiveness. Statistical heterogeneity was measured by the value of I 2, and when statistical I 2 > 50%, subgroup analysis was used to seek for the source of heterogeneity. Pulsed radiofrequency (PRF) combined with medication reduced the VAS scores at 1, 2, 4, and 8 weeks after treatment. The nerve block combined with medication reduced VAS scores at 8 weeks after treatment, but there is no difference between the results of medication alone at 1, 2, and 4 weeks after treatment. The interventional mean of PRF combined with medication has a good effect on PHN. The effect of nerve block combined with medication on PHN seems to be the same as that of medication alone. Besides, a long period with high-quality randomized controlled trial should be done to verify the results.


Search for neutral Higgs bosons of the minimal supersymmetric standard model decaying to tau pairs in pp collisions at square root of s = 1.96 TeV.
We present a search for neutral supersymmetric Higgs bosons decaying to tau pairs produced in pp collisions at square root of s = 1.96 TeV. The data, corresponding to 310 pb(-1) integrated luminosity, were collected with the Collider Detector at Fermilab in run II of the Tevatron. No significant excess above the standard model backgrounds is observed. We set exclusion limits on the production cross section times branching fraction to tau pairs for Higgs boson masses in the range from 90 to 250 GeV/c2.


Non-thermal modulation of sudomotor function during static exercise and the impact of intensity and muscle-mass recruitment.
Aim: Static muscle activation elicits intensity-dependent, non-thermal sweating that is presumably controlled by feedforward (central command) mechanisms. However, it is currently unknown how the size of the recruited muscle mass interacts with that mechanism. To investigate the possible muscle-size dependency of that non-thermal sweating, the recruitment of two muscle groups of significantly different size was investigated in individuals within whom steady-state thermal sweating had been established and clamped. Methods: Fourteen passively heated subjects (climate chamber and water-perfusion garment) performed 60-s, static handgrip and knee-extension activations at 30% and 50% of maximal voluntary force, plus a handgrip at 40% intensity (143.4 N) and a third knee extension at the same absolute force. Local sweating from four body segments (averaged to represent whole-body sudomotor activity), three deep-body and eight skin temperatures, heart rates and perceptions of physical effort were measured continuously, and analyzed over the final 30 s of exercise. Results: In the presence of thermal clamping and low-level, steady-state sweating, static muscle activation resulted in exercise-intensity dependent changes in the whole-body sudomotor response during these handgrip and knee-extension actions (P < 0.05). However, there was no evidence of a dependency on the size of the recruited muscle mass (P > 0.05), yet both dependencies were apparent for heart rate, and partially evident for the sensations of physical effort. Conclusion: These observations represent the first evidence that exercise-related sudomotor feedforward is not influenced by the size of the activated muscle mass, but is instead primarily dictated by the intensity of the exercise itself.


A high association with cone dystrophy in Fundus albipunctatus caused by mutations of the RDH5 gene.
To analyze the RDH5 gene in patients with fundus albipunctatus with and without cone dystrophy and to determine whether the disease is stationary or progressive and whether the cone dystrophy is a part of fundus albipunctatus or a separate disease. Fourteen patients from 12 separate Japanese families with fundus albipunctatus were examined. Six of the patients from 6 families also had a cone dystrophy. Genomic DNA was extracted from leukocytes of the peripheral blood, and exons 2, 3, 4, and 5 of the RDH5 gene were amplified by polymerase chain reaction and were directly sequenced. A complete ophthalmic examination was performed including best-corrected visual acuity, slit-lamp examination, indirect ophthalmoscopy, fundus photography, and electroretinography. In all the patients, either a homozygous mutation or compound heterozygous mutations in the RDH5 gene were identified. The identified mutations were nucleotide position (nt) 103 G to A (Gly35Ser), nt 319 G to C (Gly107Arg), nt 394 G to A (Val132Met), nt 719 G insertion (frame shift), nt 839 G to A (Arg280His), nt 841 T to C (Tyr281His), and nt 928 C to GAAG (Leu310 to GluVal). All these mutations except the Arg280His were new. The nt 928 C to GAAG mutation was detected in patients with and without cone dystrophy. Cone dystrophy was most frequently seen in patients over 40 years old. Fundus albipunctatus either with or without cone dystrophy is caused by mutations of the RDH5 gene. Cone dystrophy is frequently observed in elderly patients with fundus albipunctatus. The conclusion was reached that the mutations of the RDH5 gene caused a progressive cone dystrophy as well as night blindness.


Outpatient physicians' satisfaction with discharge summaries and perceived need for an electronic discharge summary.
Deficits in information transfer between inpatient and outpatient physicians are common and potentially dangerous. To evaluate satisfaction with current discharge summaries, perceptions of preventable adverse events related to suboptimal information transfer, and the perceived need for the electronic discharge summary we plan to design. : Survey of Department of Medicine physicians with an outpatient practice. Satisfaction with timeliness and quality of discharge summaries was assessed using a 5-point Likert scale. Respondents estimated the number of patients with preventable adverse events related to suboptimal information transfer at discharge. Of the 416 eligible respondents, 226 completed the survey (54%). Only 19% of the participants were satisfied or very satisfied with timeliness, and only 32% were satisfied or very satisfied with the quality of discharge summaries. Overall, 41% believed that at least 1 of their patients hospitalized in the previous 6 months had experienced a preventable adverse event related to poor transfer of information at discharge. Physicians were not satisfied with the timeliness or quality of discharge summaries. Physicians indicated that suboptimal transfer of information at hospital discharge contributed to preventable adverse events.


Clinical evidence on the effects of saffron (Crocus sativus L.) on cardiovascular risk factors: A systematic review meta-analysis.
Cardiovascular disease is a one of most common causes of mortality around the world. This meta-analysis aims to summarize and conclude the clinical evidence regarding the use of saffron and its constituents, in particular crocin, on cardiovascular risk factors. A systematic review was conducted with PubMed, Scopus, Web of Science, Cochrane library and Google Scholar up to 24 May 2018. Randomized controlled trials (RCTs) that assessed the clinical effects of saffron and/or its constituents on blood lipid profile, glycemic parameters, blood pressure and anthropometric indices in human subjects were included. Eleven publication from ten studies comprising 622 participants included in quantitative analysis. Pooling of results showed significant effect of saffron on diastolic blood pressure (-1.24 mmHg; 95% CI: -1.51 to -0.96; I2 = 0%), body weight (-1.29 kg; 95% CI: -2.14 to -0.44; I2 = 70%) and waist circumstance (-1.68 cm; 95% CI: -3.31 to -0.04; I2 = 51%). When subgroup analysis was performed based on quality of studies, a significant reduction in fasting plasma glucose levels was observed in subgroup with high quality studies (-10.14 mg/dl; 95% CI: -13.80 to -6.48; I2 = 0%). Meta-analysis did not reveal any significant change in lipid profile, fasting insulin, systolic blood pressure and body mass index following saffron consumption. Present meta-analysis suggests that saffron might be beneficial in several outcomes related with cardiovascular disease. However, further RCTs with long term intervention with different dose of administration are needed.


Concentration and isotopic composition of carbon and sulfur in apollo 11 lunar samples.
The concentration of carbon and sulfur in six samples ranged between 20 to 200 and 650 to 2300 parts per million, respectively. Carbon was present in gaseous, volatilizable, and nonvolatile forms, and terrestrial contaminants were recognized. Sulfur appeared to exist only as acid-volatile sulfide. The bulk fines contain a high concentration of carbon and a low concentration of sulfur. They are always enriched in the heavier isotope carbon-13 or sulfur-34. The fine-grained basaltic rocks show the reverse relation; lowest carbon, highest sulfide concentrations, and no apparent enrichment in heavy isotopes. The breccias are of intermediate composition.


Red foxes (Vulpes vulpes) and wild dogs (dingoes (Canis lupus dingo) and dingo/domestic dog hybrids), as sylvatic hosts for Australian Taenia hydatigena and Taenia ovis.
Foxes (n = 499), shot during vertebrate pest control programs, were collected in various sites in the Australian Capital Territory (ACT), New South Wales (NSW) and Western Australia (WA). Wild dogs (dingoes (Canis lupus dingo) and their hybrids with domestic dogs) (n = 52) captured also as part of vertebrate pest control programs were collected from several sites in the ACT and NSW. The intestine from each fox and wild dog was collected, and all Taenia tapeworms identified morphologically were collected and identified to species based on the DNA sequence of the small subunit of the mitochondrial ribosomal RNA (rrnS) gene. Taenia species were recovered from 6.0% of the ACT/NSW foxes, 5.1% of WA foxes and 46.1% of ACT/NSW wild dogs. Taenia ovis was recovered from two foxes, 1/80 from Jugiong, NSW and 1/102 from Katanning, WA. We confirm from rrnS sequences the presence of T. ovis in cysts from hearts and diaphragms and T aenia hydatigena in cysts from livers of sheep in Australia. T. ovis was not recovered from any of the wild dogs examined but T. hydatigena were recovered from 4(8.3%) wild dogs and a single fox. With foxes identified as a definitive host for T. ovis in Australia, new control strategies to stop transmission of T. ovis to sheep need to be adopted.


Tandem amplification of the vanM gene cluster drives vancomycin resistance in vancomycin-variable enterococci.
Vancomycin-variable enterococci (VVE) are a potential risk factor for vancomycin resistance gene dissemination and clinical treatment failure. vanM has emerged as a new prevalent resistance determinant among clinical enterococci in China. A total of 54 vancomycin-susceptible enterococci (VSE) isolates carrying incomplete vanM gene clusters were isolated in our previous study. To determine the potential of vanM-carrying VSE to develop vancomycin resistance and investigate the mechanism of alteration of the resistance phenotype. Fifty-four vanM-positive VSE strains were induced in vitro by culturing in increasing concentrations of vancomycin. Genetic changes between three parent VVE strains and their resistant variants were analysed using Illumina and long-read sequencing technologies, quantitative PCR and Southern blot hybridization. Changes in expression level were determined by quantitative RT-PCR. Twenty-five of the 54 VSE strains carrying vanM became resistant upon vancomycin exposure. A significant increase in vanM copy number was observed ranging from 5.28 to 127.64 copies per cell in induced resistant VVE strains. The vanM transposon was identified as tandem repeats with IS1216E between them, and occurred in either the plasmid or the chromosome of resistant VVE cells. In addition, an increase in vanM expression was observed after resistance conversion in VVE. This study identified tandem amplification of the vanM gene cluster as a new mechanism for vancomycin resistance in VVE strains, offering a competitive advantage for VVE under antibiotic pressure.


Identification of Francisella tularensis subsp. tularensis A1 and A2 infections by real-time polymerase chain reaction.
Francisella tularensis subsp. tularensis (type A) is subdivided into clades A1 and A2. Human tularemia infections caused by A1 and A2 differ with respect to clinical outcome; A1 infections are associated with a higher case fatality rate. In this study, we develop and evaluate TaqMan polymerase chain reaction (PCR) assays for identification of A1 and A2. Both assays were shown to be specific to either A1 or A2, with sensitivities of 10 genomic equivalents. Real-time PCR results for identification of A1 and A2 were in complete agreement with results obtained by pulsed field gel electrophoresis analysis or conventional PCR when specimens from sporadic tularemia cases and a tularemia outbreak involving both A1 and A2 were tested. In addition, outbreak samples not previously typed to the clade level could be classified as A1 or A2. The assays described here provide new diagnostic tools with a level of sensitivity not previously available for identification of A1 and A2 infections.


Functional in vivo MHC class II loading by endogenously synthesized glycoprotein during viral infection.
MHC class II presentation of antigenic peptides derived from soluble proteins is usually preceded by antigenic uptake via (nonreceptor-mediated) endocytosis by professional APCs, followed by processing in endosomal compartments. Although in vitro alternative pathways for MHC class II loading have been described for certain intracellularly synthesized proteins, the importance of these pathways has not been assessed in vivo. We have shown previously that endogenously produced membrane-associated glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), a noncytopathic virus, can be presented in vitro on MHC class II molecules in the absence of the invariant chain (Ii), whereas the cytosolic LCMV nucleoprotein (LCMV-NP) failed to be presented under the same conditions. Taking advantage of this system, we analyzed presentation of LCMV-GP and LCMV-NP in vivo in Ii-deficient mice and followed the induced Th cell and B cell responses. At early time points after LCMV infection of li-deficient mice, we found in vivo MHC class II loading exclusively by the endogenously synthesized LCMV-GP, whereas no MHC class II loading by LCMV-NP could be detected. As a direct consequence, LCMV-specific Th cells exhibited initially only LCMV-GP specificity. In contrast, both LCMV-GP- and LCMV-NP-derived epitopes were presented in comparable amounts on APCs upon LCMV infection of normal mice, and LCMV-GP- as well as LCMV-NP-specific Th cells were comparably induced in vivo. Thus, cell internal MHC class II loading pathways are functional in vivo and may become dominant if the usual Ag presentation pathways are hampered.


5-HT1B receptors modulate release of [3H]dopamine from rat striatal synaptosomes.
The effect of the selective r5-HT1B agonist 3-(1,2,5,6-tetrahydro)-4-pyridil-5-pyrrolo [3,2-b] pyril-5-one (CP93,129) on the K(+)-evoked overflow of [3H]dopamine was studied in rat striatal synaptosomes loaded with [3H]dopamine. The aim of the study was to investigate the participation of 5-HT1B receptors in the serotonergic modulation of striatal dopaminergic transmission. The Ca2(+)-dependent, tetrodotoxin-resistant K(+)-evoked overflow of [3H]dopamine was inhibited by CP93,129 (0.01-100 microM) in a concentration-dependent manner (IC50=1.8 microM; maximal inhibition by 35.5% of control). [+/-]8-OH-DPAT, a 5-HT(1A) receptor agonist, [+/-]DOI, a 5-HT2 receptor agonist, and 2-methyl-5-hydroxytryptamine, a 5-HT3 receptor agonist, at concentrations ranging from 0.01 microM to 100 microM did not show any significant effect. Neither ketanserin (1 microM and 5 microM), a selective 5-HT2/5-HT1D receptor antagonist, nor ondansetron (1 microM), a 5-HT3 receptor antagonist, changed the inhibitory effect of CP93,129. SB224289, GR55562, GR127935, isamoltane and metergoline, selective and non-selective 5-HT1B receptor antagonists, in contrast, used at a concentration of 1 microM, antagonized the inhibitory effect of CP93,129 (3 microM and 10 microM). SB224289, a selective 5-HT1B receptor antagonist, inhibited the effect of CP93,129 in a concentration-dependent manner; the calculated K(i) value was 1.8 nM. Our results indicate that in rat striatal axon terminals the K(+)-evoked release of dopamine is regulated by the presynaptic 5-HT1B heteroreceptors.


Late effects of high-dose adjuvant chemotherapy on white and gray matter in breast cancer survivors: converging results from multimodal magnetic resonance imaging.
The neural substrate underlying cognitive impairments after chemotherapy is largely unknown. Here, we investigated very late (>9 years) effects of adjuvant high-dose chemotherapy on brain white and gray matter in primary breast cancer survivors (n = 17) with multimodal magnetic resonance imaging (MRI). A group of breast cancer survivors who did not receive chemotherapy was scanned for comparison (n = 15). Neuropsychological tests demonstrated cognitive impairments in the chemotherapy group. Diffusion tensor imaging (DTI) with tract-based spatial statistics showed that chemotherapy was associated with focal changes in DTI values indicative for reduced white matter integrity. Single voxel proton MR spectroscopy (1H-MRS) in the left centrum semiovale (white matter) showed a reduction of N-acetylasparate/creatine indicative of axonal injury. Voxel-based morphometry demonstrated a reduction of gray matter volume that overlapped with fMRI hypoactivation (as reported in a previous publication) in posterior parietal areas and colocalized with DTI abnormalities. Also, DTI correlated with 1H-MRS only in the chemotherapy group. These results converge to suggest that high-dose adjuvant chemotherapy for breast cancer is associated with long-term injury to white matter, presumably reflecting a combination of axonal degeneration and demyelination, and damage to gray matter with associated functional deficits. Hormonal treatment with tamoxifen may also have contributed to the observed effects, although results from other studies indicate that it is unlikely that tamoxifen is solely or largely responsible. Using this multimodality approach we provide for the first time insight into the neural substrate underlying cognitive impairments following systemic administration of cytotoxic agents many years after treatment.