Evaluating Localization Accuracy of Automated Driving Systems.
Automated driving systems are in need of accurate localization, i.e., achieving accuracies below 0.1 m at confidence levels above 95%. Although during the last decade numerous localization techniques have been proposed, a common methodology to validate their accuracies in relation to a ground-truth dataset is missing so far. This work aims at closing this gap by evaluating four different methods for validating localization accuracies of a vehicle's position trajectory to different ground truths: (1) a static driving-path, (2) the lane-centerline of a high-definition (HD) map with validated accuracy, (3) localized vehicle body overlaps of the lane-boundaries of a HD map, and (4) longitudinal accuracy at stop points. The methods are evaluated using two localization test datasets, one acquired by an automated vehicle following a static driving path, being additionally equipped with roof-mounted localization systems, and a second dataset acquired from manually-driven connected vehicles. Results show the broad applicability of the approach for evaluating localization accuracy and reveal the pros and cons of the different methods and ground truths. Results also show the feasibility of achieving localization accuracies below 0.1 m at confidence levels up to 99.9% for high-quality localization systems, while at the same time demonstrate that such accuracies are still challenging to achieve.


MTCH2/MIMP is a major facilitator of tBID recruitment to mitochondria.
The BH3-only BID protein (BH3-interacting domain death agonist) has a critical function in the death-receptor pathway in the liver by triggering mitochondrial outer membrane permeabilization (MOMP). Here we show that MTCH2/MIMP (mitochondrial carrier homologue 2/Met-induced mitochondrial protein), a novel truncated BID (tBID)-interacting protein, is a surface-exposed outer mitochondrial membrane protein that facilitates the recruitment of tBID to mitochondria. Knockout of MTCH2/MIMP in embryonic stem cells and in mouse embryonic fibroblasts hinders the recruitment of tBID to mitochondria, the activation of Bax/Bak, MOMP, and apoptosis. Moreover, conditional knockout of MTCH2/MIMP in the liver decreases the sensitivity of mice to Fas-induced hepatocellular apoptosis and prevents the recruitment of tBID to liver mitochondria both in vivo and in vitro. In contrast, MTCH2/MIMP deletion had no effect on apoptosis induced by other pro-apoptotic Bcl-2 family members and no detectable effect on the outer membrane lipid composition. These loss-of-function models indicate that MTCH2/MIMP has a critical function in liver apoptosis by regulating the recruitment of tBID to mitochondria.


Transgenic rearranged T cell receptor gene inhibits lymphadenopathy and accumulation of CD4-CD8-B220+ T cells in lpr/lpr mice.
The lpr gene in homozygous form induces development of CD4-CD8-B220+ T cells and lymphadenopathy in MRL and C57BL/6 mice. Although the propensity for excessive production of T cells is related to an intrinsic T cell defect, a thymus is also required because neonatal thymectomy eliminates lymphadenopathy. Recent evidence suggests that excessive production and release of autoreactive T cells from the thymus of lpr/lpr mice might lead to downregulation of CD4 and CD8 as a "fail safe" tolerance mechanism that occurs during late thymic or post-thymic development. To test this hypothesis, T cell receptor (TCR) transgenic mice that produce large numbers of immature thymocytes recognizing the H-2Db and male H-Y antigens were backcrossed with C57BL/6-lpr/lpr mice and MRL-lpr/lpr mice. It was predicted that Db male lpr/lpr mice would produce large numbers of autoreactive T cells during early thymic development that would lead to an accelerated lymphoproliferative disease. In contrast, Db female lpr/lpr mice would produce large numbers of Db H-Y-reactive T cells, but might not develop lymphadenopathy because the male H-Y antigen would not be present. Unexpectedly, there was complete elimination of lymphadenopathy in both male and female TCR transgenic lpr/lpr mice. The elimination of lymphadenopathy was not due to a failure of thymic maturation since the thymus of H-2Db female lpr/lpr mice contained nearly normal numbers of mature thymocytes. Elimination of lymphadenopathy was also not due to a lack of autoreactive T cells in the peripheral lymph nodes (LN) since there was an increased syngeneic mixed lymphocyte proliferative response of LNT cells from transgenic lpr/lpr compared with +/+ mice in vitro. Hypergammaglobulinemia and autoantibody production in the transgenic lpr/lpr was present at levels comparable with or higher than control nontransgenic lpr/lpr mice, suggesting a dissociation of autoantibody production from the lymphoproliferative disease in the TCR transgenic mice. Conversely, the development of lymphadenopathy and production of CD4-CD8-B220+ T cells appear to be intimately linked, as both were completely eliminated in T cells expressing the transgenic TCR. We propose that lymphoproliferation and production of CD4-CD8-6B2+ T cells in lpr/lpr mice is related to decreased expression of the TCR, and providing the T cells with a rearranged TCR transgene overcomes this defect.


Time Constraints Do Not Limit Group Size in Arboreal Guenons but Do Explain Community Size and Distribution Patterns.
To understand how species will respond to environmental changes, it is important to know how those changes will affect the ecological stress that animals experience. Time constraints can be used as indicators of ecological stress. Here we test whether time constraints can help us understand group sizes, distribution patterns, and community sizes of forest guenons (Cercopithecus/Allochrocebus). Forest guenons typically live in small to medium sized one-male-multifemale groups and often live in communities with multiple forest guenon species. We developed a time-budget model using published data on time budgets, diets, body sizes, climate, and group sizes to predict maximum ecologically tolerable group and community sizes of forest guenons across 202 sub-Saharan African locations. The model correctly predicted presence/absence at 83% of these locations. Feeding-foraging time (an indicator of competition) limited group sizes, while resting and moving time constraints shaped guenon biogeography. Predicted group sizes were greater than observed group sizes but comparable to community sizes, suggesting community sizes are set by competition among guenon individuals irrespective of species. We conclude that time constraints and intraspecific competition are unlikely to be the main determinants of relatively small group sizes in forest guenons. Body mass was negatively correlated with moving time, which may give larger bodied species an advantage over smaller bodied species under future conditions when greater fragmentation of forests is likely to lead to increased moving time. Resting time heavily depended on leaf consumption and is likely to increase under future climatic conditions when leaf quality is expected to decrease.


Transcriptional regulation and specification of neural stem cells.
With the discovery two decades ago that the adult brain contains neural stem cells (NSCs) capable of producing new neurons, a great deal of research has been undertaken to manipulate these cells to repair the damaged nervous system. Much progress has been made in understanding what regulates adult neural stem cell specification, proliferation and differentiation but much remains to be determined. Lessons can be learned from understanding how embryonic neural stem cells produce the exquisitely complicated organ that is the adult mammalian nervous system. This review will highlight the role of transcriptional regulation of mammalian neural stem cells during embryonic development and compare these to the adult neural stem cell/neural precursor cell (NPC) niches of the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the hippocampal dentate gyrus. Normal physiological NSC/NPC regulation will be explored, as well as their regulation and responses following neural injury and disease. Finally, transcriptional regulation of the endogenous NSC/NPCs will be compared and contrasted with embryonic stem/induced pluripotent stem (ES/iPS) cell-derived NSC/NPCs. Recapitulation of the embryonic sequence of transcriptional events in neural stem cell development into specific neuronal or glial lineages improves directed differentiation of ES/iPS cells and may be useful for activation and specification of endogenous adult neural stem cells for therapeutic purposes.


Patterning of dopaminergic neurotransmitter identity among Caenorhabditis elegans ray sensory neurons by a TGFbeta family signaling pathway and a Hox gene.
We have investigated the mechanism that patterns dopamine expression among Caenorhabditis elegans male ray sensory neurons. Dopamine is expressed by the A-type sensory neurons in three out of the nine pairs of rays. We used expression of a tyrosine hydroxylase reporter transgene as well as direct assays for dopamine to study the genetic requirements for adoption of the dopaminergic cell fate. In loss-of-function mutants affecting a TGFbeta family signaling pathway, the DBL-1 pathway, dopaminergic identity is adopted irregularly by a wider subset of the rays. Ectopic expression of the pathway ligand, DBL-1, from a heat-shock-driven transgene results in adoption of dopaminergic identity by rays 3-9; rays 1 and 2 are refractory. The rays are therefore prepatterned with respect to their competence to be induced by a DBL-1 pathway signal. Temperature-shift experiments with a temperature-sensitive type II receptor mutant, as well as heat-shock induction experiments, show that the DBL-1 pathway acts during an interval that extends from two to one cell generation before ray neurons are born and begin to differentiate. In a mutant of the AbdominalB class Hox gene egl-5, rays that normally express EGL-5 do not adopt dopaminergic fate and cannot be induced to express DA when DBL-1 is provided by a heat-shock-driven dbl-1 transgene. Therefore, egl-5 is required for making a subset of rays capable of adopting dopaminergic identity, while the function of the DBL-1 pathway signal is to pattern the realization of this capability.


Ecological and evolutionary drivers of range size in Coenagrion damselflies.
Geographic range size is a key ecological and evolutionary characteristic of a species, yet the causal basis of variation in range size among species remains largely unresolved. One major reason for this is that several ecological and evolutionary traits may jointly shape species' differences in range size. We here present an integrated study of the contribution of ecological (dispersal capacity, body size and latitudinal position) and macroevolutionary (species' age) traits in shaping variation in species' range size in Coenagrion damselflies. We reconstructed the phylogenetic tree of this genus to account for evolutionary history when assessing the contribution of the ecological traits and to evaluate the role of the macroevolutionary trait (species' age). The genus invaded the Nearctic twice independently from the Palearctic, yet this was not associated with the evolution of larger range sizes or dispersal capacity. Body size and species' age did not explain variation in range size. There is higher flight ability (as measured by wing aspect ratio) at higher latitudes. Species with a larger wing aspect ratio had a larger range size, also after correcting for phylogeny, suggesting a role for dispersal capacity in shaping the species' ranges. More northern species had a larger species' range, consistent with Rapoport's rule, possibly related to niche width. Our results underscore the importance of integrating macroecology and macroevolution when explaining range size variation among species.


Society of Dermatology Hospitalists supportive care guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults.
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening conditions with high morbidity and mortality. Supportive care management of SJS/TEN is highly variable. A systematic review of the literature was performed by dermatologists, ophthalmologists, intensivists, and gynecologists with expertise in SJS/TEN to generate statements for supportive care guideline development. Members of the Society of Dermatology Hospitalists with expertise in SJS/TEN were invited to participate in a modified, online Delphi-consensus. Participants were administered 9-point Likert scale questionnaires regarding 135 statements. The RAND/UCLA Appropriateness Method was used to evaluate and select proposed statements for guideline inclusion; statements with median ratings of 6.5 to 9 and a disagreement index of ≤1 were included in the guideline. For the final round, the guidelines were appraised by all of the participants. Included are an evidence-based discussion and recommendations for hospital setting and care team, wound care, ocular care, oral care, urogenital care, pain management, infection surveillance, fluid and electrolyte management, nutrition and stress ulcer prophylaxis, airway management, and anticoagulation in adult patients with SJS/TEN.


From genes to function: the next challenge to understanding multiple sclerosis.
Susceptibility to multiple sclerosis is jointly determined by genetic and environmental factors, and progress has been made in defining some of these genetic associations, as well as their possible interactions with the environment. However, definitive proof for the involvement of specific genetic determinants in the disease will only come from studies that examine their functional roles in disease pathogenesis. New and combined approaches are needed to analyse the complexity of gene regulation and the functional contribution of each genetic determinant to disease susceptibility or pathophysiology. These studies should proceed in parallel with the use of genetically defined human populations to explore how both genetic and environmental factors affect the function of the pathways in individuals with and without disease, and how these determine the inherited risk of multiple sclerosis.


Using classical test theory, item response theory, and Rasch measurement theory to evaluate patient-reported outcome measures: a comparison of worked examples.
To provide comparisons and a worked example of item- and scale-level evaluations based on three psychometric methods used in patient-reported outcome development-classical test theory (CTT), item response theory (IRT), and Rasch measurement theory (RMT)-in an analysis of the National Eye Institute Visual Functioning Questionnaire (VFQ-25). Baseline VFQ-25 data from 240 participants with diabetic macular edema from a randomized, double-masked, multicenter clinical trial were used to evaluate the VFQ at the total score level. CTT, RMT, and IRT evaluations were conducted, and results were assessed in a head-to-head comparison. Results were similar across the three methods, with IRT and RMT providing more detailed diagnostic information on how to improve the scale. CTT led to the identification of two problematic items that threaten the validity of the overall scale score, sets of redundant items, and skewed response categories. IRT and RMT additionally identified poor fit for one item, many locally dependent items, poor targeting, and disordering of over half the response categories. Selection of a psychometric approach depends on many factors. Researchers should justify their evaluation method and consider the intended audience. If the instrument is being developed for descriptive purposes and on a restricted budget, a cursory examination of the CTT-based psychometric properties may be all that is possible. In a high-stakes situation, such as the development of a patient-reported outcome instrument for consideration in pharmaceutical labeling, however, a thorough psychometric evaluation including IRT or RMT should be considered, with final item-level decisions made on the basis of both quantitative and qualitative results.


The utility of multivariate outlier detection techniques for data quality evaluation in large studies: an application within the ONDRI project.
Large and complex studies are now routine, and quality assurance and quality control (QC) procedures ensure reliable results and conclusions. Standard procedures may comprise manual verification and double entry, but these labour-intensive methods often leave errors undetected. Outlier detection uses a data-driven approach to identify patterns exhibited by the majority of the data and highlights data points that deviate from these patterns. Univariate methods consider each variable independently, so observations that appear odd only when two or more variables are considered simultaneously remain undetected. We propose a data quality evaluation process that emphasizes the use of multivariate outlier detection for identifying errors, and show that univariate approaches alone are insufficient. Further, we establish an iterative process that uses multiple multivariate approaches, communication between teams, and visualization for other large-scale projects to follow. We illustrate this process with preliminary neuropsychology and gait data for the vascular cognitive impairment cohort from the Ontario Neurodegenerative Disease Research Initiative, a multi-cohort observational study that aims to characterize biomarkers within and between five neurodegenerative diseases. Each dataset was evaluated four times: with and without covariate adjustment using two validated multivariate methods - Minimum Covariance Determinant (MCD) and Candès' Robust Principal Component Analysis (RPCA) - and results were assessed in relation to two univariate methods. Outlying participants identified by multiple multivariate analyses were compiled and communicated to the data teams for verification. Of 161 and 148 participants in the neuropsychology and gait data, 44 and 43 were flagged by one or both multivariate methods and errors were identified for 8 and 5 participants, respectively. MCD identified all participants with errors, while RPCA identified 6/8 and 3/5 for the neuropsychology and gait data, respectively. Both outperformed univariate approaches. Adjusting for covariates had a minor effect on the participants identified as outliers, though did affect error detection. Manual QC procedures are insufficient for large studies as many errors remain undetected. In these data, the MCD outperforms the RPCA for identifying errors, and both are more successful than univariate approaches. Therefore, data-driven multivariate outlier techniques are essential tools for QC as data become more complex.


Betaine transport in the gill of a marine mussel, Mytilus californianus.
The integumental epithelium of Mytilus californianus gill accumulates amino acids directly from seawater against chemical gradients exceeding 10(7) to 1. In the present report, we confirm the presence of betaine in Mytilus tissue and identify a transport process in the gill for this organic osmolyte. Betaine content of gill tissue from animals acclimated to 100% seawater (980 mosM) was 45 mmol/kg wet wt, similar to that of taurine (53 mmol/kg). The kinetics of betaine uptake were adequately described by the Michaelis-Menten equation, with a Kt of 6 microM and Jmax of 7 mumol.g-1.h-1. Betaine transport was inhibited by L-proline and related structural analogues, and by alanine. L-Proline transport, which involves both high- and low-affinity pathways, was partially inhibited by betaine. The low-affinity proline pathway transports lysine. Betaine and L-lysine showed no reciprocal inhibitory interactions. This pattern of structural specificity suggested that betaine transport in the gill is confined to the alanine-proline pathway. Uptake of 0.5 microM betaine into gills was inhibited by 97% when Na+ in seawater was replaced with Li+. Activation of betaine transport in the gill was a near-linear function of the external Na+ concentration up through 100% artificial seawater (ASW, 425 mM Na+). Acute exposure of the gill to 60% ASW inhibited betaine uptake by 83%. Maintenance of normal osmotic concentration (980 mosM, by addition of mannitol to 60% ASW) reduced inhibition to 31%, similar to the level predicted from the availability of Na+.(ABSTRACT TRUNCATED AT 250 WORDS)


[Restoration of depressed immune responses by PSK in C3H/He mice bearing the syngeneic X5563 tumor].
PSK is a protein-bound polysaccharide prepared from cultured mycelium of Coriolus versicolor. The effects of PSK on immunologic responsiveness were investigated in C3H/He mice bearing syngeneic X5563 tumor. The results were as follows. elayed foot pad reaction and antibody-forming capacity to sheep erythrocytes were depressed in tumor bearing mice, and such depression was prevented by oral or intraperitoneal administration of PSK. In vitro cytotoxic activity of splenic lymphocytes against the tumor was augmented by PSK administration. Antitumor effect was augmented by combination of PSK and X-irradiation. Delayed foot pad reaction to sheep erythrocytes was suppressed in normal C3H/He mice given immunosuppressive substance obtained from tumor-bearing mice, and the depressed reaction recovered to the normal level following PSK administration. These results show that PSK is effective in the syngeneic murine tumor system.


Statins Dose-Dependently Exert Significant Chemopreventive Effects Against Various Cancers in Chronic Obstructive Pulmonary Disease Patients: A Population-Based Cohort Study.
PURPOSE: Chronic obstructive pulmonary disease (COPD) is associated with an increased cancer risk. We evaluated the chemopreventive effect of statins against all cancers in COPD patients and identified the statin with the strongest chemopreventive effect. PATIENTS AND METHODS: All patients diagnosed with COPD at health care facilities in Taiwan (n = 116,017) from January 1, 2001, to December 31, 2012, were recruited. Each patient was followed to assess the following protective and risk factors for all cancers: age; sex; comorbidities (diabetes, hypertension, dyslipidemia) and the Charlson comorbidity index [CCI]); urbanization level; monthly income; and nonstatin drug use. The index date of statins use was the date of COPD confirmation. Propensity scores (PSs) were derived using a logistic regression model to estimate the effect of statins by considering the covariates predicting intervention (statins) receipt. To examine the dose-response relationship, we categorized statin use into four groups in each cohort (<28 [statin nonusers], 28-90, 91-365, and >365 cumulative defined daily dose). RESULTS: After PS adjustment for age, sex, CCI, diabetes, hypertension, dyslipidemia, urbanization level, and monthly income, we analyzed the all-cancer risk. The adjusted hazard ratios (aHRs) for the all-cancer risk were lower among statin users than among statin nonusers (aHR = 0.46, 95% confidence interval: 0.43 to 0.50). The aHRs for the all-cancer risk were lower among patients using rosuvastatin, simvastatin, atorvastatin, pravastatin, and fluvastatin than among statin nonusers (aHRs = 0.42, 0.55, 0.59, 0.66, and 0.78, respectively). Sensitivity analysis indicated that statins dose-dependently reduced the all-cancer risk. CONCLUSION: Statins dose-dependently exert a significant chemopreventive effect against various cancers in COPD patients. In particular, rosuvastatin has the strongest chemopreventive effect.


Endoscopic endonasal access to the jugular foramen: defining the surgical approach.
Introduction The endoscopic endonasal approach to the parapharyngeal space (PPS) and jugular foramen is not well defined. We sought to systematically define the important landmarks and limitations of this new surgical technique using an endoscopic transmaxillary transpterygoid corridor. Methods Endoscopic dissection was performed in both sides of two latex-injected cadaver heads. Left-sided dissections were facilitated by the addition of a sublabial maxillary antrostomy. The pterygopalatine fossa, infratemporal fossa, and PPS were sequentially dissected and the endoscopic perspective was examined. Measurements were obtained from the surgical orifices to the upper cervical internal carotid artery (ICA) and internal jugular vein (IJV). Results Successful access to the PPS and jugular foramen was achieved in each dissection. The lateral pterygoid plate, mandibular branch of the trigeminal nerve, middle meningeal artery, levator veli palatini muscle, Eustachian tube, and stylopharyngeal fascia were identified as landmarks for the upper cervical ICA and the IJV. The mean distance from the nasal sill was markedly greater than from an ipsilateral sublabial antrostomy. Conclusion The endoscopic endonasal approach can provide adequate access to the PPS, carotid sheath, and jugular foramen. Multiple landmarks are useful to guide the dissection within these deep spaces and may facilitate the clinical application of this approach.


Long-wave infrared imaging for non-invasive beehive population assessment.
Long-wave infrared imaging is used for non-invasive assessment of the internal population of honey bee colonies. The radiometrically calibrated camera signal is related to the number of frames that are populated by bees inside each hive. This enables rapid measurement of population without opening the hive, which disturbs the bees and can endanger the queen. The best results are obtained just before sunrise, when there is maximum thermal contrast between the hive and the background. This technique can be important for bee hive monitoring or for applications requiring frequent hive assessment, such as the use of bees for detecting chemicals or explosives.


Single molecule simulations in complex geometries with embedded dynamic one-dimensional structures.
Stochastic models of reaction-diffusion systems are important for the study of biochemical reaction networks where species are present in low copy numbers or if reactions are highly diffusion limited. In living cells many such systems include reactions and transport on one-dimensional structures, such as DNA and microtubules. The cytoskeleton is a dynamic structure where individual fibers move, grow, and shrink. In this paper we present a simulation algorithm that combines single molecule simulations in three-dimensional space with single molecule simulations on one-dimensional structures of arbitrary shape. Molecules diffuse and react with each other in space, they associate with and dissociate from one-dimensional structures as well as diffuse and react with each other on the one-dimensional structure. A general curve embedded in space can be approximated by a piecewise linear curve to arbitrary accuracy. The resulting algorithm is hence very flexible. Molecules bound to a curve can move by pure diffusion or via active transport, and the curve can move in space as well as grow and shrink. The flexibility and accuracy of the algorithm is demonstrated in five numerical examples.


A new coupling agent for composite materials: 4-methacryloxyethyl trimellitic anhydride.
Composite materials were made by sedimention of ceramic powders in methyl methacrylate which was then polymerized by gamma-irradiation. Inclusion of 4-methacryloxyethyl trimellitic anhydride (4-META) generally was found to result in an increase in Knoop hardness number, Young's modulus, and transverse strength. Most emphasis was placed on transverse strength which was found to be increased by ca. 30% by inclusion of 4-META (5 wt %) in composites made with silanated LiAlSiO4. However an abrupt decrease in strength was found for composites with greater than ca. 83 wt % silanated LiAlSiO4. This was shown by fractography to be due to increased porosity and dewetting at the higher filler contents. Fractography also indicated that inclusion of 4-META results in a more coherent polymeric matrix. Further evidence for greater coherence was obtained by showing that 4-META confers resistance to disintegration by chloroform.


Sevoflurane Post-Conditioning Ameliorates Neuronal Deficits and Axon Demyelination After Neonatal Hypoxic Ischemic Brain Injury: Role of Microglia/Macrophage.
Microglia/macrophages have been identified to be highly polarized after ischemia. Interestingly, the polarization of these microglia/macrophages varies immensely under differing disease conditions. Post-conditioning using sevoflurane, a volatile anesthetic, could provide long-term neuroprotection to neonatal rats after hypoxic-ischemic brain injury (HIBI). Thus, the current study aimed at investigating the effects of sevoflurane post-conditioning (SPC) on microglia/macrophage polarization after HIBI induction in neonatal rats. Additionally, we aimed at identifying the underpinning mechanisms specifically related to autophagy and lysosomal protease enzyme, cathepsin B. To develop a HIBI model, 7-day-old Sprague-Dawley rats underwent left common carotid artery ligation followed by 2 h of hypoxia. The role of microglia/macrophages in the neuroprotection conferred by SPC was examined by left-side intra-cerebroventricular injection with adenovirus vector carrying catB-GFP or rapamycin. The number of interleukin (IL)-1β+ cells, cathepsin B+ cells, light chain 3B positive (LC3B+) cells among ionized calcium binding adaptor molecule 1(Iba1+)cells to investigate microglia polarization, neuronal apoptosis to assess neuronal death in the acute phase were tested at 24 h after HIBI. Behavioral tests including suspension test, Morris water maze tests were performed to investigate the long-term effects of SPC, at 21 to 34 days post HIBI. Nissl staining and myelin basic protein (MBP) immunostaining to assess the long-term neuronal and myelin damage were performed at 34 days after HIBI. Based on the obtained results post HIBI, we observed the cells that were positive for IL-1β, cathepsin B, and LC3B among Iba1 positive cell population in the hippocampus were significantly decreased after SPC treatment. SPC significantly attenuated the HIBI-induced increase in neuronal apoptosis, improved long-term cognitive function, and attenuated HI-induced decrease of Nissl-positive cells and MBP expression. However, these trends were reversed by injection of adenovirus vector carrying catB-GFP and rapamycin. SPC attenuated microglia polarization towards neurotoxic phenotypes, alleviates neuronal death and axon demyelination after HIBI in neonatal rats by regulating microglia autophagy and cathepsin B expression, and therefore provided long-term cognitive, learning and memory protection.


Medical-grade footwear: the impact of fit and comfort.
Pressure-related skin lesions on the digits are a significant cause of discomfort. Most foot pain related to ill-fitting shoes occurs in the forefoot and digital areas. Pain has been associated with poor shoe fit, reduced toe box volume, as well as contour and shape of the shoe Off-the-shelf medical-grade footwear is designed as an intervention for chronic lesions on the digits. These shoes are designed with a flexible neoprene fabric upper that is thought to reduce pressure on the forefoot and reduce discomfort associated with ill-fitting shoes. The aim of this study was to investigate the effect of an off-the-shelf, medical-grade shoe on dorsal digital pressure and perceived comfort when compared to participant's own preferred shoe. Thirty participants (18 females, 12 males) scored their perceived comfort whilst wearing each footwear style using a visual analog comfort scale. Dorsal digital and interdigital pressures were measured in using the WalkinSense® in-shoe pressure system. Sensors were placed on predetermined anatomical landmarks on the digits. Participants were randomly assigned the test shoe and their own shoe. Once wearing the shoe, the participants walked across a 6 m walkway and pressure data from each sensor was collected and processed to obtain peak pressure, time to peak pressure and contact time. Participants scored the test shoe with higher comfort points than their own footwear. Overall peak pressure, pressure time integral and contact time decreased, whilst the time taken to reach peak pressure increased across all anatomical landmarks whilst wearing the test shoe. Statistically significant changes were observed for all of the measured variables relating to pressure on the medial border of the first metatarsophalangeal joint. The test shoe provided greater comfort and reduced the amount of pressure on the forefoot. The medical-grade footwear therefore, is a viable alternative to custom made prescription footwear and is more suitable than a regular everyday shoe when treating digital lesions associated with pressure.


Physiotherapy treatment of sexual pain disorders.
Physiotherapists provide treatment to restore function, improve mobility, relieve pain, and prevent or limit permanent physical disabilities of patients suffering from injuries or disease. Women with vulvar pain, dyspareunia, or vaginismus have limited ability to function sexually and often present with musculoskeletal and neurological findings appropriately addressed by a trained physiotherapist. Although pelvic floor surface electromyography (sEMG) biofeedback has been studied, the inclusion of physiotherapy in the team approach to treating women with sexual pain disorders is a relatively recent advancement, and its exact role is not widely understood by doctors, mental health professionals, or laypersons. This article will examine the supportive and often primary role of the physiotherapist in the overlapping conditions of vaginismus and dyspareunia.


Anopheles larval abundance and diversity in three rice agro-village complexes Mwea irrigation scheme, central Kenya.
The diversity and abundance of Anopheles larvae has significant influence on the resulting adult mosquito population and hence the dynamics of malaria transmission. Studies were conducted to examine larval habitat dynamics and ecological factors affecting survivorship of aquatic stages of malaria vectors in three agro-ecological settings in Mwea, Kenya. Three villages were selected based on rice husbandry and water management practices. Aquatic habitats in the 3 villages representing planned rice cultivation (Mbui Njeru), unplanned rice cultivation (Kiamachiri) and non-irrigated (Murinduko) agro-ecosystems were sampled every 2 weeks to generate stage-specific estimates of mosquito larval densities, relative abundance and diversity. Records of distance to the nearest homestead, vegetation coverage, surface debris, turbidity, habitat stability, habitat type, rice growth stage, number of rice tillers and percent Azolla cover were taken for each habitat. Captures of early, late instars and pupae accounted for 78.2%, 10.9% and 10.8% of the total Anopheles immatures sampled (n = 29,252), respectively. There were significant differences in larval abundance between 3 agro-ecosystems. The village with 'planned' rice cultivation had relatively lower Anopheles larval densities compared to the villages where 'unplanned' or non-irrigated. Similarly, species composition and richness was higher in the two villages with either 'unplanned' or limited rice cultivation, an indication of the importance of land use patterns on diversity of larval habitat types. Rice fields and associated canals were the most productive habitat types while water pools and puddles were important for short periods during the rainy season. Multiple logistic regression analysis showed that presence of other invertebrates, percentage Azolla cover, distance to nearest homestead, depth and water turbidity were the best predictors for Anopheles mosquito larval abundance. These results suggest that agricultural practices have significant influence on mosquito species diversity and abundance and that certain habitat characteristics favor production of malaria vectors. These factors should be considered when implementing larval control strategies which should be targeted based on habitat productivity and water management.


Nonconscious activation of an elderly stereotype and speed of driving.
Under the guise of evaluating a head-up display in a driving simulator, 11 participants (5 men), ages 21 to 35 years, completed scrambled-sentence tasks (while waiting at stop signs) designed to prime an elderly stereotype. Each driver completed both the Elderly Stereotype and Control conditions with order counterbalanced across participants. Further, order of presentation of word sets for each trial was random. Driving speed and driving time between stop signs in the Elderly Stereotype condition were compared to the Control condition in which nonspecific age words were substituted for elderly stereotyped words. Participants showed lower maximum speed and longer driving time in the Elderly Stereotype condition than in the Control condition, even though participants reported no awareness of the theme in the experimental condition.


Traditional medicine used in childbirth and for childhood diarrhoea in Nigeria's Cross River State: interviews with traditional practitioners and a statewide cross-sectional study.
Examine factors associated with use of traditional medicine during childbirth and in management of childhood diarrhoea. Cross-sectional cluster survey, household interviews in a stratified last stage random sample of 90 census enumeration areas; unstructured interviews with traditional doctors. Oil-rich Cross River State in south-eastern Nigeria has 3.5 million residents, most of whom depend on a subsistence agriculture economy. 8089 women aged 15-49 years in 7685 households reported on the health of 11,305 children aged 0-36 months in July-August 2011. Traditional medicine used at childbirth and for management of childhood diarrhoea; covariates included access to Western medicine and education, economic conditions, engagement with the modern state and family relations. Cluster-adjusted analysis relied on the Mantel-Haenszel procedure and Mantel extension. 24.1% (1371/5686) of women reported using traditional medicine at childbirth; these women had less education, accessed antenatal care less, experienced more family violence and were less likely to have birth certificates for their children. 11.3% (615/5425) of young children with diarrhoea were taken to traditional medical practitioners; these children were less likely to receive BCG, to have birth certificates, to live in households with a more educated head, or to use fuel other than charcoal for cooking. Education showed a gradient with decreasing use of traditional medicine for childbirth (χ(2) 135.2) and for childhood diarrhoea (χ(2) 77.2). Use of traditional medicine is associated with several factors related to cultural transition and to health status, with formal education playing a prominent role. Any assessment of the effectiveness of traditional medicine should anticipate confounding by these factors, which are widely recognised to affect health in their own right.


Tetrahydronaphthalene lignan compounds as potent anti-HIV type 1 agents.
Anti-HIV-1 activity of tetrahydronaphthalene (THN) derivatives of lignan compounds was studied. THN derivatives prevented cell death caused by HIV-1 infection in MT-4 cells. They also inhibited giant cell formation by HIV-1 in Sup-T1 cells, and p24 production in HIV-1-infected H9 cells. The 50% effective concentration (ED50) of the most active compound, 1737 [5,6,7-trimethoxy-4-(3,4,5-trimethoxyphenyl)-1,3,3a,4,9,9a-hexahydron aphtho[2,3-c]thiophene], for inhibition of the cytopathic effects of HIV-1 infection ranged from 0.15 to 0.8 microM. The 50% cytotoxic concentration (CC50) of compound 1737 measured by the viability of MT-4 cells was 58 microM, indicating a selective index (CC50/ED50) of 70-400. Substitution of the phenyl ring with other structures markedly decreased cytotoxicity but did not affect the antiviral activity of the compounds. This resulted in compounds with a high selective index. One such compound was 1738 [7-methoxy5,6-methylenedioxy-4-(4-benzyloxy-3-methoxyphenyl)1,3,3a ,4,9,9a-hexahydronaphtho[2,3-c]thiophene], with a selective index higher than 770. The time-of-addition experiment indicated that these compounds acted at or near the reverse transcription step of the HIV-1 life cycle. THN derivatives inhibited HIV-1 reverse transcriptase (RT) in vitro at a concentration of 1 microM. Resistant viruses selected in the presence of THN derivatives showed some degree of cross-resistance to other nonnucleoside RT inhibitors, but not to the nucleoside RT inhibitor, AZT. THN derivatives failed to inhibit replication of pyridinone- and nevirapine-resistant HIV strains. However, compound 1737 inhibited replication of a TIBO-resistant strain more effectively than the wild-type HIV-1. Consistent with this result, compound 1737 also inhibited TIBO-resistant RT more effectively than the wild-type RT in vitro. These results suggested that THN derivatives interact with RT in a manner similar to but slightly different from that of other nonnucleoside HIV-1 RT inhibitors.


Invited review: The anti-inflammatory properties of dairy lipids.
Dairy product consumption is often associated with negative effects because of its naturally high levels of saturated fatty acids. However, recent research has shown that dairy lipids possess putative bioactivity against chronic inflammation. Inflammation triggers the onset of several chronic diseases, including cardiovascular disease, type 2 diabetes mellitus, obesity, and cancer. This review discusses the anti-inflammatory properties of dairy lipids found in milk, yogurt, and cheese, and it examines them in relation to their implications for human health: their protective effects and their role in pathology. We also consider the effect of lipid profile alteration in dairy products-by using ruminant dietary strategies to enrich the milk, or by lipid fortification in the products. We critically review the in vivo, in vitro, ex vivo, and epidemiological studies associated with these dairy lipids and their role in various inflammatory conditions. Finally, we discuss some suggestions for future research in the study of bioactive lipids and dairy products, with reference to the novel field of metabolomics and epidemiological studies.


Aerobic oxidation catalysis with stable radicals.
Selective oxidation reactions are challenging when carried out on an industrial scale. Many traditional methods are undesirable from an environmental or safety point of view. There is a need to develop sustainable catalytic approaches that use molecular oxygen as the terminal oxidant. This review will discuss the use of stable radicals (primarily nitroxyl radicals) in aerobic oxidation catalysis. We will discuss the important advances that have occurred in recent years, highlighting the catalytic performance, mechanistic insights and the expanding synthetic utility of these catalytic systems.


Induction of bystander T cell proliferation by viruses and type I interferon in vivo.
T cell proliferation in vivo is presumed to reflect a T cell receptor (TCR)-mediated polyclonal response directed to various environmental antigens. However, the massive proliferation of T cells seen in viral infections is suggestive of a bystander reaction driven by cytokines instead of the TCR. In mice, T cell proliferation in viral infections preferentially affected the CD44hi subset of CD8+ cells and was mimicked by injection of polyinosinic-polycytidylic acid [poly(I:C)], an inducer of type I interferon (IFN I), and also by purified IFN I; such proliferation was not associated with up-regulation of CD69 or CD25 expression, which implies that TCR signaling was not involved. IFN I [poly(I:C)]-stimulated CD8+ cells survived for prolonged periods in vivo and displayed the same phenotype as did long-lived antigen-specific CD8+ cells. IFN I also potentiated the clonal expansion and survival of CD8+ cells responding to specific antigen. Production of IFN I may thus play an important role in the generation and maintenance of specific memory.


Fully Dispersed Rh Ensemble Catalyst To Enhance Low-Temperature Activity.
Minimizing the use of precious metal catalysts is important in many applications. Single-atom catalysts (SACs) have received much attention because all of the metal atoms can be used for surface reactions. However, SACs cannot catalyze some important reactions that require ensemble sites. Here, Rh catalysts were prepared by treating 2 wt % Rh/CeO2 hydrothermally at 750 °C for 25 h. Nearly 100% dispersion was obtained, but the surface Rh atoms were not isolated (denoted as ENS). They catalyzed the oxidation of C3H6 or C3H8 at low temperatures, but these oxidations did not occur on the Rh SAC. When the simultaneous oxidation of CO, C3H6, and C3H8 was performed, the T20 (temperature at conversion 20%) for CO oxidation increased significantly from 40 °C for sole CO oxidation to 180 °C on SAC due to the competitive adsorption of hydrocarbons. However, T20 increased much less on ENS, from 60 to 100 °C. ENS exhibited superior activity for low-temperature oxidation. During hydrothermal treatment for 25 h, the Rh size initially increased from 2.3 to 6.7 nm then decreased to 0.9 nm. The surface hydroxyl groups formed on the catalyst surface help detach Rh atoms from Rh clusters, while preventing the reaggregation of dispersed Rh atoms into Rh clusters. This fully dispersed catalyst would have maximum atom-efficiency while catalyzing various surface reactions.


Evaluating risk factors and possible mediation effects in posttraumatic depression and posttraumatic stress disorder comorbidity.
On September 11, 2001 (9/11), attacks on the World Trade Center (WTC) killed 341 Fire Department of the City of New York (FDNY) firefighters and injured hundreds more. Previous WTC-related studies reported high rates of comorbid depression and posttraumatic stress disorder (PTSD), identifying disability retirement, alcohol use, and early arrival at the WTC site as correlates. However, those studies did not evaluate risk factors that could have mediated the observed comorbidity. We identified unique risk factors for each condition in an effort to better understand comorbidity. We screened retired WTC-exposed firefighters using self-administered questionnaires including the Center for Epidemiologic Studies Depression Scale, the Post Traumatic Stress Disorder Checklist, and the Alcohol Use Disorders Identification Test. We performed regression analyses to compare independent predictors of elevated depression and PTSD risk, and also tested a mediation hypothesis. From December 2005 to July 2007, 23% and 22% of 1,915 retirees screened positive for elevated depression and PTSD risk, respectively, with comorbidity > 70%. Controlling for comorbidity, we identified unique risk factors for (1) depression: problem alcohol use and (2) PTSD: early arrival at the WTC site. Our data support the premise that PTSD and depression are different responses to trauma with unique risk factors. The data also suggest a hypothesis that PTSD mediates the relationship between early WTC arrival and depression, while depression mediates the relationship between alcohol use and PTSD, a more complex relationship than shown in previous studies. Clinicians should consider these factors when evaluating patients for depression and PTSD.


Purification and properties of dihydrofolate reductase from cultured mammalian cells.
Dihydrofolate reductase was purified quickly and simply from small quantities of cultured mammalian cells by affinity chromatography. On gel electrophoresis of the purified enzyme, multiple bands of activity resulted from enzyme-buffer interaction at low but not high buffer concentration. A Ferguson plot (Ferguson, 1964) showed that this heterogeneity was due to a charge difference with no alteration in the size of the enzyme. Stimulation of enzyme activity by KCl, urea and p-hydroxymercuribenzoate, and inhibition by methotrexate and trimethoprim, showed only minor differences between the various enzymes.


Estimation of physical activity levels using cell phone questionnaires: a comparison with accelerometry for evaluation of between-subject and within-subject variations.
Physical activity promotes health and longevity. Further elaboration of the role of physical activity for human health in epidemiological studies on large samples requires accurate methods that are easy to use, cheap, and possible to repeat. The use of telecommunication technologies such as cell phones is highly interesting in this respect. In an earlier report, we showed that physical activity level (PAL) assessed using a cell phone procedure agreed well with corresponding estimates obtained using the doubly labeled water method. However, our earlier study indicated high within-subject variation in relation to between-subject variations in PAL using cell phones, but we could not assess if this was a true variation of PAL or an artifact of the cell phone technique. Our objective was to compare within- and between-subject variations in PAL by means of cell phones with corresponding estimates using an accelerometer. In addition, we compared the agreement of daily PAL values obtained using the cell phone questionnaire with corresponding data obtained using an accelerometer. PAL was measured both with the cell phone questionnaire and with a triaxial accelerometer daily during a 2-week study period in 21 healthy Swedish women (20 to 45 years of age and BMI from 17.7 kg/m² to 33.6 kg/m²). The results were evaluated by fitting linear mixed effect models and descriptive statistics and graphs. With the accelerometer, 57% (95% confidence interval [CI] 40%-66%) of the variation was within subjects, while with the cell phone, within-subject variation was 76% (95% CI 59%-83%). The day-to-day variations in PAL observed using the cell phone questions agreed well with the corresponding accelerometer results. Both the cell phone questionnaire and the accelerometer showed high within-subject variations. Furthermore, day-to-day variations in PAL within subjects assessed using the cell phone agreed well with corresponding accelerometer values. Consequently, our cell phone questionnaire is a promising tool for assessing levels of physical activity. The tool may be useful for large-scale prospective studies.


Knowledge-based generalization of metabolic networks: a practical study.
The complex process of genome-scale metabolic network reconstruction involves semi-automatic reaction inference, analysis, and refinement through curation by human experts. Unfortunately, decisions by experts are hampered by the complexity of the network, which can mask errors in the inferred network. In order to aid an expert in making sense out of the thousands of reactions in the organism's metabolism, we developed a method for knowledge-based generalization that provides a higher-level view of the network, highlighting the particularities and essential structure, while hiding the details. In this study, we show the application of this generalization method to 1,286 metabolic networks of organisms in Path2Models that describe fatty acid metabolism. We compare the generalised networks and show that we successfully highlight the aspects that are important for their curation and comparison.


Enhancement of Thermal Boundary Conductance of Metal-Polymer System.
In organic electronics, thermal management is a challenge, as most organic materials conduct heat poorly. As these devices become smaller, thermal transport is increasingly limited by organic-inorganic interfaces, for example that between a metal and a polymer. However, the mechanisms of heat transport at these interfaces are not well understood. In this work, we compare three types of metal-polymer interfaces. Polymethyl methacrylate (PMMA) films of different thicknesses (1-15 nm) were spin-coated on silicon substrates and covered with an 80 nm gold film either directly, or over an interface layer of 2 nm of an adhesion promoting metal-either titanium or nickel. We use the frequency-domain thermoreflectance (FDTR) technique to measure the effective thermal conductivity of the polymer film and then extract the metal-polymer thermal boundary conductance (TBC) with a thermal resistance circuit model. We found that the titanium layer increased the TBC by a factor of 2, from 59 × 106 W·m-2·K-1 to 115 × 106 W·m-2·K-1, while the nickel layer increased TBC to 139 × 106 W·m-2·K-1. These results shed light on possible strategies to improve heat transport in organic electronic systems.


Effects of bambuterol and terbutaline on isolated rat's tracheal smooth muscle.
Terbutaline (Bricanyl) and its prodrug Bambuterol (Bambec) are highly potent beta(2)-adrenoceptor agonists often used in asthma patients. Terbutaline in the form of inhaled short-acting bronchodilator relieves asthmatic symptoms. However, the effects of bambuterol given intratracheally have rarely been explored. To verify the effect of bambuterol and terbutaline, which act on the tracheal smooth muscle directly in vitro, we used our preparation to test the effects of bambuterol on isolated rat's tracheal smooth muscle compared with terbutaline. The following assessments of bambuterol and terbutaline were performed: (1) effect on tracheal smooth muscle resting tension; (2) effect on contraction caused by 10(-6) M methacholine as a parasympathetic mimetic; (3) effect of the drugs on electrically induced tracheal smooth muscle contractions. The results indicated that adding bambuterol induced a significant further contraction to 10(-6) M methacholine-induced contraction when the preparation was increased to 10(-4) M. But terbutaline elicited a relaxation response at a dose of 10(-6) M or more. Both bambuterol and terbutaline could inhibit electrical field stimulation (EFS) induced spike contraction. Terbutaline had an anti-cholinergic effect that could relieve asthmatic symptoms. But the effect of bambuterol acting on tracheal smooth muscle directly was controversial.


Drosophila neuroblast asymmetric cell division: recent advances and implications for stem cell biology.
Asymmetric cell division is an evolutionarily conserved mechanism widely used to generate cellular diversity during development. Drosophila neuroblasts have been a useful model system for studying the molecular mechanisms of asymmetric cell division. In this minireview, we focus on recent progress in understanding the role of heterotrimeric G proteins and their regulators in asymmetric spindle geometry, as well as the role of an Inscuteable-independent microtubule pathway in asymmetric localization of proteins in neuroblasts. We also discuss issues of progenitor proliferation and differentiation associated with asymmetric cell division and their broader implications for stem cell biology.


Development of a complex intervention to promote appropriate prescribing and medication intensification in poorly controlled type 2 diabetes mellitus in Irish general practice.
Poorly controlled type 2 diabetes mellitus (T2DM) can be seen as failure to meet recommended targets for management of key risk factors including glycaemic control, blood pressure and lipids. Poor control of risk factors is associated with significant morbidity, mortality and healthcare costs. Failure to intensify medications for patients with poor control of T2DM when indicated is called clinical inertia and is one contributory factor to poor control of T2DM. We aimed to develop a theory and evidence-based complex intervention to improve appropriate prescribing and medication intensification in poorly controlled T2DM in Irish general practice. The first stage of the Medical Research Council Framework for developing and evaluating complex interventions was utilised. To identify current evidence, we performed a systematic review to examine the effectiveness of interventions targeting patients with poorly controlled T2DM in community settings. The Behaviour Change Wheel theoretical approach was used to identify suitable intervention functions. Workshops, simulation, collaborations with academic partners and observation of physicians were utilised to operationalise the intervention functions and design the elements of the complex intervention. Our systematic review highlighted that professional-based interventions, potentially through clinical decision support systems, could address poorly controlled T2DM. Appropriate intensification of anti-glycaemic and cardiovascular medications, by general practitioners (GPs), for adults with poorly controlled T2DM was identified as the key behaviour to address clinical inertia. Psychological capability was the key driver of the behaviour, which needed to change, suggesting five key intervention functions (education, training, enablement, environmental restructuring and incentivisation) and nine key behaviour change techniques, which were operationalised into a complex intervention. The intervention has three components: (a) a training program/academic detailing of target GPs, (b) a remote finder tool to help GPs identify patients with poor control of T2DM in their practice and (c) A web-based clinical decision support system. This paper describes a multifaceted process including an exploration of current evidence and a thorough theoretical understanding of the predictors of the behaviour resulting in the design of a complex intervention to promote the implementation of evidence-based guidelines, through appropriate prescribing and medication intensification in poorly controlled T2DM.


Fever and Skin Involvement at Diagnosis Predicting the Intractable Langerhans Cell Histiocytosis: 40 Case-Series in a Single Center.
Langerhans cell histiocytosis (LCH) occurs as a clonal disease with enigmatic immune responses. LCH patients occasionally present with fever, although the significance remains elusive. We investigated the predicting factors for developing intractable disease of refractory and/or reactivated LCH. In total, 40 pediatric LCH patients managed in Kyushu University from 1998 to 2014 were enrolled. The medical records were analyzed retrospectively. Sixteen patients suffered from multisystem (MS) LCH involving risk organs (ROs) (n=4) or not (n=12). In total, 24 patients had single-system LCH affecting bone (multi n=8, single n=13), skin (n=2), or lymph node lesions (n=1). Eight patients had the intractable disease of 7 MS or 1 multibone LCH. Two patients died from MS LCH with or without RO involvement. Ten patients showed persistent fever (>38°C) at onset. Intractable cases had fever, RO and skin involvement, leukocytosis, coagulopathy, microcytic anemia, higher levels of soluble interleukin-2 receptor and C-reactive protein, more frequently at diagnosis. Multivariate analysis indicated that fever and skin lesions at diagnosis were independently associated with the intractability (odds ratio: fever, 35.5; 95% confidence interval, 3.0-1229.1; skin lesions, 24.6; 95% confidence interval, 1.9-868.7). Initial fever and skin involvement might predict the development of intractable and fatal-risk LCH even without the RO involvement.


Quantification of vestibular-induced eye movements in zebrafish larvae.
Vestibular reflexes coordinate movements or sensory input with changes in body or head position. Vestibular-evoked responses that involve the extraocular muscles include the vestibulo-ocular reflex (VOR), a compensatory eye movement to stabilize retinal images. Although an angular VOR attributable to semicircular canal stimulation was reported to be absent in free-swimming zebrafish larvae, recent studies reveal that vestibular-induced eye movements can be evoked in zebrafish larvae by both static tilts and dynamic rotations that tilt the head with respect to gravity. We have determined herein the basis of sensitivity of the larval eye movements with respect to vestibular stimulus, developmental stage, and sensory receptors of the inner ear. For our experiments, video recordings of larvae rotated sinusoidally at 0.25 Hz were analyzed to quantitate eye movements under infrared illumination. We observed a robust response that appeared as early as 72 hours post fertilization (hpf), which increased in amplitude over time. Unlike rotation about an earth horizontal axis, rotation about an earth vertical axis at 0.25 Hz did not evoke eye movements. Moreover, vestibular-induced responses were absent in mutant cdh23 larvae and larvae lacking anterior otoliths. Our results provide evidence for a functional vestibulo-oculomotor circuit in 72 hpf zebrafish larvae that relies upon sensory input from anterior/utricular otolith organs.


Patient- and hospital-level predictors of vancomycin-resistant Enterococcus (VRE) bacteremia in Ontario, Canada.
Data are limited on risk factors for vancomycin-resistant Enterococcus (VRE) bacteremia. All patients with a confirmed VRE bacteremia in Ontario, Canada, between January 2009 and December 2013 were linked to provincial healthcare administrative data sources and frequency matched to 3 controls based on age, sex, and aggregated diagnosis group. Associations between predictors and VRE bacteremia were estimated by generalized estimating equations and summarized using odds ratios (ORs) and corresponding 95% confidence intervals (CIs). In total, 217 cases and 651 controls were examined. In adjusted analyses, patient-level predictors included bone marrow transplant (OR 106.99 [95% CI 12.19-939.26]); solid organ transplant (OR 17.17 [95% CI 4.95-59.54]); any cancer (OR 8.64 [95% CI 3.88-19.21]); intensive care unit (ICU) admission (OR 6.81 [95% CI 3.53-13.13]); heart disease (OR 5.27 [95% CI 2.00-13.90]); and longer length of stay (OR 1.07 per day [95% CI 1.06-1.09]). Hospital-level predictors included hospital size (per increase in 100 beds (OR 1.26 [95% CI 1.07-1.48]) and teaching hospitals (OR 3.87 [95% CI 1.85-8.08]). Patients with a bone marrow transplant, solid organ transplant, cancer, or who are admitted to the ICU are at highest risk of VRE bacteremia, particularly at large hospitals and teaching hospitals.


Bevacizumab and rapamycin can decrease corneal opacity and apoptotic keratocyte number following photorefractive keratectomy.
We investigated the effects of bevacizumab and rapamycin on central corneal opacity and apoptotic keratocyte number after photorefractive keratectomy (PRK) followed by ultraviolet B (UV-B) irradiation. A total of 60 right eyes of Sprague-Dawley rats in four groups (n = 15 each) underwent PRK ablation to 80 μm with a 3-mm zone. Sponges soaked with 0.02% mitomycin C (MMC), 2.5% bevacizumab, 0.01% rapamycin, and balanced saline solution were applied for 2 minutes to these eyes in the MMC, bevacizumab, rapamycin, and control groups, respectively. At 3 weeks after PRK, all right eyes were exposed to 100 mJ/cm(2) UV-B irradiation. Biomicroscopy was used to determine the amount of haze, and TUNEL staining for apoptosis and histology were performed at 3, 6, and 12 weeks. Contrary to the results at 3 weeks, central corneal haze, and apoptotic keratocyte and keratocyte number decreased significantly in the MMC, bevacizumab, and rapamycin groups compared to the control group, and the keratocyte number was lower in the MMC group than the bevacizumab and rapamycin groups at 6 weeks (all P < 0.05). At 12 weeks, the apoptotic keratocyte number was lower in the MMC, bevacizumab, and rapamycin groups than the control group, and the keratocyte number was significantly lower in the MMC than the rapamycin and control groups (all P < 0.05). Intraoperative bevacizumab and rapamycin administration decreases central corneal haze and apoptotic keratocyte number after PRK. Bevacizumab and rapamycin may be safe alternatives to MMC during refractive surgery to prevent postoperative corneal opacity less affecting the keratocyte number.


Sensitivity-enhanced, common-mode-compensated Mach-Zehnder fiber-optic sensor circuit with electro-optic feedback.
A Mach-Zehnder fiber-optic sensor circuit incorporating an optical compensation circuit to reduce errors from common-mode perturbations and electro-optic feedback to enhance measurand sensitivity is proposed and demonstrated. Experimental results show that the phase bias and the feedback constant can be adjusted to yield an operating region with negligible sensitivity to common-mode perturbations and a measurand sensitivity an order of magnitude above that expected from an equivalent conventional Mach-Zehnder sensor, in good agreement with theory.


First Report of Powdery Mildew Caused by Erysiphe cruciferarum on Brassica campestris var. pekinensis, B. carinata, Eruca sativa, E. vesicaria in Australia and on B. rapa and B. oleracea var. capitata in Western Australia.
Inspection of field plantings of diverse cruciferous species, mainly oilseed varieties sown for agronomic assessment at Crawley, (31.99°S, 115.82°E), Western Australia, in September 2012, indicated the occurrence of extensive leaf and stem colonization by powdery mildew at the late flowering stage, with whitish patches 3 to 4 cm in length on stems of Brassica campestris var. pekinensis, B. carinata, B. oleracea var. capitata, B. rapa, Eruca sativa, and E. vesicaria. These patches coalesced to form a dense, white, powdery layer. Infected leaves showed signs of early senescence. Pathogenicity was demonstrated from transferring field inoculum from the most susceptible variety by pressing diseased leaves onto leaves of the six potted plant species, and incubating plants in a moist chamber for 48 hours post-inoculation (hpi) in an air-conditioned glasshouse approximating 25°C. Signs of powdery mildew were evident by 7 days post-inoculation (dpi), and well developed symptoms by 10 dpi and as observed in the field. Uninoculated control plants did not develop powdery mildew. On all inoculated species, abundant conidia typical of those produced by Erysiphe cruciferarum were observed, matching the descriptions of conidia given by Purnell and Sivanesan (3), with cylindrical conidia typically borne singly or in short chains. Mycelia were amphigenous, in patches, often spreading to become effused. Conidiophores were 3 to 4 cells, unbranched, and foot cells cylindrical. Across all host species, conidia were mostly produced singly with overall mean measured lengths 19.7 to 35.4 μm (mean 26.9 μm), and measured widths 7.1 to 12.9 μm (mean 9.7 μm), from measurements taken on 200 conidia for each of the six different species. Spore sizes measured approximated those found for E. cruciferarum by Kaur et al. (1) on B. juncea in Western Australia (viz. 21.2 to 35.4 × 8.8 to 15.9 μm), but were smaller than those reported by Purnell and Sivanesan (3) (viz. 30 to 40 × 12 to 16 μm) or by Koike and Saenz (1) (viz. 35 to 50 × 12 to 21 μm). We confirmed a length-to-width ratio >2 (mean range 2.7 to 2.8 across all six species) as found by both Purnell and Sivanesan (3) and Koike and Saenz (2). Amplification of the internal transcribed spacer (ITS)1 and (ITS)2 regions flanking the 5.8S rRNA gene was carried out with universal primers ITS1 and ITS4 and PCR products from E. cruciferarum from B. oleracea var. capitata and B. rapa sequenced. BLAST analyses to compare sequences with those in GenBank showed a >99% nucleotide identity for E. cruciferarum. In Western Australia, E. cruciferarum has been recorded on B. napus var. napobrassica since 1971 (4), B. napus since 1986 (4), and on B. juncea since 2008 (1). In other regions of Australia, E. cruciferarum has been recorded on B. campestris, B. oleracea var. capitata, B. oleracea var. acephala, B. napus, B. napus var. naprobrassica, and B. rapa var. rapa. To the best of our knowledge, this is the first record of E. cruciferarum on B. campestris var. pekinensis, B. carinata, E. sativa, and E. vesicaria in Australia and on B. rapa and B. oleracea var. capitata in Western Australia. Powdery mildew epidemics on other brassicas in Western Australia are generally sporadic and it remains to be seen what the impact of this disease will be on these new host species. References: (1) P. Kaur et al. Plant Dis. 92:650, 2008. (2) S. T. Koike and G. S. Saenz. Plant Dis. 81:1093, 1997. (3) T. J. Purnell and A. Sivanesan. No. 251 in IMI Descriptions of Fungi and Bacteria, 1970. (4) R. G. Shivas. J. Royal Soc. West. Aust. 72:1, 1989.


Tumor necrosis factor-alpha antagonist etanercept decreases blood pressure and protects the kidney in a mouse model of systemic lupus erythematosus.
Chronic inflammation has been implicated in the pathology of hypertension; however, the role for specific cytokines remains unclear. We tested whether tumor necrosis factor-α blockade with etanercept (Etan) reduces mean arterial pressure in a female mouse model of systemic lupus erythematosus (SLE). SLE is a chronic inflammatory disorder with prevalent hypertension. Thirty-week-old SLE (NZBWF1) and control mice (NZW/LacJ) received Etan (0.8 mg/kg SC weekly) for 4 weeks or vehicle. Mean arterial pressure (in millimeters of mercury) was increased in SLE mice (150±5 versus 113±5 in controls; P<0.05) and was lower in Etan-treated SLE mice (132±3) but not controls (117±5). Albuminuria (in micrograms per milligram of creatinine) was elevated in SLE mice (28 742±9032 versus 1075±883; P<0.05) and was lower in Etan-treated SLE mice (8154±3899) but not control animals (783±226). Glomerulosclerosis (in percentage of glomeruli) was evident in SLE mice (2.5±1.6 versus 0.0±0.0 in controls; P<0.05) and was ameliorated in Etan-treated SLE mice (0.1±0.1). Renal cortex CD68(+) cell staining (in percentage of area) was elevated in SLE mice (4.75±0.80 versus 0.79±0.12 in controls; P<0.05) and was lower in Etan-treated SLE mice (2.28±0.32) but not controls (1.43±0.25). Renal cortex NADPH oxidase activity (relative light units per milligram of protein) was higher in SLE mice compared with controls (10 718±1276 versus 7584±229; P<0.05) and lowered in Etan-treated SLE mice (6645±490). Renal cortex nuclear factor κB (phosphorylated and nonphosphorylated) was increased in SLE mice compared with controls and lower in Etan-treated SLE mice. These data suggest that TNF-α mechanistically contributes to the development of hypertension in a chronic inflammatory disease through increased renal nuclear factor κB, oxidative stress, and inflammation.


Clinical Utility of the Nonstructural 1 Antigen Rapid Diagnostic Test in the Management of Dengue in Returning Travelers With Fever.
Rapid diagnostic test (RDT) detecting the nonstructural 1 (NS1) antigen is increasingly used for dengue diagnosis in endemic and nonendemic settings, but its clinical utility has not been studied in travel clinic practice. From August 2012 to July 2016, travelers returning from the tropics with fever were evaluated in the Institute of Tropical Medicine (Antwerp, Belgium) with the routine use of NS1 antigen RDT that provided results within 1 hour. We determined the diagnostic performance, assessed the management of patients with a positive RDT result, and compared it with that of historical cases of dengue diagnosed from 2000 to 2006, when only antibody detection assays were available. Of 335 travelers evaluated for fever, 54 (16%) were diagnosed with dengue, including 1 severe case. Nonstructural 1 antigen RDT was performed in 308 patients. It was truly positive in 43 of 52 tested dengue cases and falsely positive in only 1 of the 256 nondengue cases; therefore, sensitivity was 82.7% (95% confidence interval [CI], 74.4%-93.0%) and specificity was 99.6% (95% CI, 98.8%-100%). Only 3 (7%) of the 43 febrile travelers "immediately" diagnosed by RDT were admitted, and only 2 (5%) were given empirical antibacterial treatment, without adverse outcome. Admission and antibiotic prescription rates were significantly higher in the historical cases (n = 43) diagnosed by antibody detection (33%, P = .006 and 26%, P = .014, respectively), although the frequency of severe dengue was similar. In our practice, the diagnostic performance of NS1 antigen RDT substantially contributed in withholding unnecessary hospitalization and antibiotherapy in dengue patients.


Surgical and systemic management of endometrial cancer: an international survey.
To ascertain the spectrum of clinical management of endometrial carcinoma (EC) the largest international survey was conducted to evaluate and identify differences worldwide. After validation of a 15-item questionnaire regarding surgical and adjuvant treatment of EC in Germany, an English-adapted questionnaire was put online and posted to all the major gynecological cancer Societies worldwide for further distribution commencing in 2010 and continued for 26 months. A total of 618 Institutions around the world participated: Central Europe (CE), Southern Europe (SE), Northern Europe (NE), Asia and USA/Canada/UK. Both a therapeutic and staging value was attributed to systematic pelvic and paraaortic lymph node dissection (LND) in CE (74.6%) and in Asia (67.2%), as opposed to USA/UK where LND was mainly for staging purposes (53.5%; p < 0.001). LND was performed up to the renal veins in CE in 86.8%, in Asia in 80.8%, in USA/UK in 51.2% and in SE in 45.1% (p < 0.001) of cases. In advanced disease, centers from Asia were treated most with adjuvant chemotherapy alone (93.6%), as opposed to centers in SE, CE and UK/USA that employed combination chemo-radiotherapy in 90.9% (p < 0.001) of cases. Paclitaxel/carboplatin was mostly used followed by doxorubicin/cisplatin (75 vs. 23.3%; p < 0.001). In total, 94% of all participants supported the concept of treating EC patients within appropriate clinical trials. There is broad range in both the surgical and adjuvant treatment of EC across different countries. Large-scale multicenter prospective trials are warranted to establish consistent, evidence-based guidelines to optimize treatment worldwide.


Melatonin regulation of biliary functions.
The intrahepatic biliary epithelium is a three-dimensional tubular system lined by cholangiocytes, epithelial cells that in addition to modify ductal bile are also the targets of vanishing bile duct syndromes (i.e., cholangiopathies) such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) that are characterized by the damage/proliferation of cholangiocytes. Cholangiocyte proliferation is critical for the maintenance of the biliary mass and secretory function during the pathogenesis of cholangiopathies. Proliferating cholangiocytes serve as a neuroendocrine compartment during the progression of cholangiopathies, and as such secrete and respond to hormones, neurotransmitters and neuropeptides contributing to the autocrine and paracrine pathways that regulate biliary homeostasis. The focus of this review is to summarize the recent findings related to the role of melatonin in the modulation of biliary functions and liver damage in response to a number of insults. We first provide a general background on the general function of cholangiocytes including their anatomic characteristics, their innervation and vascularization as well the role of these cells on secretory and proliferation events. After a background on the synthesis and regulation of melatonin and its role on the maintenance of circadian rhythm, we will describe the specific effects of melatonin on biliary functions and liver damage. After a summary of the topics discussed, we provide a paragraph on the future perspectives related to melatonin and liver functions.


A phase I study of veliparib in combination with metronomic cyclophosphamide in adults with refractory solid tumors and lymphomas.
Oral administration of the alkylating agent cyclophosphamide at low doses, metronomic dosing, is well tolerated, with efficacy in multiple tumor types. PARP inhibition potentiates effects of cyclophosphamide in preclinical models. We conducted a phase I trial of the PARP inhibitor veliparib and metronomic cyclophosphamide in patients with refractory solid tumors and lymphoid malignancies. Objectives were to establish the safety and maximum tolerated dose (MTD) of the combination; characterize veliparib pharmacokinetics (PK); measure poly(ADP-ribose) (PAR), a product of PARP, in tumor biopsies and peripheral blood mononuclear cells (PBMC); and measure the DNA-damage marker γH2AX in PBMCs and circulating tumor cells (CTC). Cyclophosphamide was administered once daily in 21-day cycles in combination with veliparib administered once daily for 7, 14, or 21 days. Thirty-five patients were enrolled. The study treatment was well tolerated, and the MTD was established as veliparib 60 mg with cyclophosphamide 50 mg given once daily. Seven patients had partial responses; an additional six patients had disease stabilization for at least six cycles. PAR was significantly decreased in PBMCs (by at least 50%) and tumor biopsies (by at least 80%) across dose levels (DL); γH2AX levels were increased in CTCs from seven of nine patients evaluated after drug administration. The combination of veliparib with metronomic cyclophosphamide is well tolerated and shows promising activity in a subset of patients with BRCA mutations. A phase II trial of the combination compared with single-agent cyclophosphamide is ongoing in BRCA-positive ovarian cancer, triple-negative breast cancer, and low-grade lymphoma.


Ascertainment of intimate partner violence using two abuse measurement frameworks.
To estimate prevalence of intimate partner violence (IPV) according to two abuse ascertainment tools, and agreement between the tools. 2504 women randomly selected from a health maintenance organization were asked about IPV exposure in their most recent intimate relationship using five questions on physical and sexual abuse, and fear due to partner's threats and controlling behavior from the Behavioral Risk Factor Surveillance Survey (BRFSS) and 10 questions from the Women's Experience with Battering (WEB) scale. IPV prevalence was estimated according to the BRFSS and WEB, and the proportion of women who were WEB+/BRFSS+, WEB-/BRFSS-, WEB-/BRFSS+, and WEB+/BRFSS-. In their most recent relationship, 14.7% of women reported abuse of any type on the BRFSS versus 7.0% on the WEB scale. In direct comparisons of the WEB and BRFSS questions, a higher percentage of abused women reported any IPV on the five BRFSS questions (88.4%) compared to the 10 WEB questions (42.0%). However, both the BRFSS and WEB identified some women as abused that would have been missed by the other instrument. Intimate partner violence prevalence depends on how women are asked about abuse. Resources permitting, more than one abuse ascertainment strategy (for example, both the BRFSS and WEB questions) should be tried in order to broadly identify as many women as possible who interpret themselves as abused.


TMPRSS2, a SARS-CoV-2 internalization protease is downregulated in head and neck cancer patients.
SARS-coronavirus-2 enters host cells through binding of the Spike protein to ACE2 receptor and subsequent S priming by the TMPRSS2 protease. We aim to assess differences in both ACE2 and TMPRSS2 expression in normal tissues from oral cavity, pharynx, larynx and lung tissues as well as neoplastic tissues from the same areas. The study has been conducted using the TCGA and the Regina Elena Institute databases and validated by experimental model in HNSCC cells. We also included data from one COVID19 patient who went under surgery for HNSCC. TMPRSS2 expression in HNSCC was significantly reduced compared to the normal tissues. It was more evident in women than in men, in TP53 mutated versus wild TP53 tumors, in HPV negative patients compared to HPV positive counterparts. Functionally, we modeled the multivariate effect of TP53, HPV, and other inherent variables on TMPRSS2. All variables had a statistically significant independent effect on TMPRSS2. In particular, in tumor tissues, HPV negative, TP53 mutated status and elevated TP53-dependent Myc-target genes were associated with low TMPRSS2 expression. The further analysis of both TCGA and our institutional HNSCC datasets identified a signature anti-correlated to TMPRSS2. As proof-of-principle we also validated the anti-correlation between microRNAs and TMPRSS2 expression in a SARS-CoV-2 positive HNSCC patient tissues Finally, we did not find TMPRSS2 promoter methylation. Collectively, these findings suggest that tumoral tissues, herein exemplified by HNSCC and lung cancers might be more resistant to SARS-CoV-2 infection due to reduced expression of TMPRSS2. These observations may help to better assess the frailty of SARS-CoV-2 positive cancer patients.


Aleuritic (9,10,16-trihydroxypalmitic) acid self-assembly on mica.
Aleuritic (9,10,16-trihydroxypalmitic) acid self-assembly on mica from solution has been studied using AFM, ATR-FTIR and MD simulations. The goal of this study is to define the role of hydroxyl groups in the interaction between molecules as reference data to understand the mechanism of formation of synthetic and natural biopolyesters from polyhydroxylated long chain carboxylic acids. In a confined structure, such as the one imposed by a vertically self-assembled layer on mica, aleuritic acid has a tendency to adopt a monolayer configuration ruled by the lateral interactions between molecules via the two secondary hydroxyl groups. This (2D) growth competes with the multilayer formation (3D), which is conditioned by the terminal primary hydroxyl group. As the self-assembly spatial constraint is relaxed, MD has shown that the structure tends to become an amorphous and crosslinked phase that can be characterized by topographic and friction force AFM data.


The MetJ regulon in gammaproteobacteria determined by comparative genomics methods.
Whole-genome sequencing of bacteria has proceeded at an exponential pace but annotation validation has lagged behind. For instance, the MetJ regulon, which controls methionine biosynthesis and transport, has been studied almost exclusively in E. coli and Salmonella, but homologs of MetJ exist in a variety of other species. These include some that are pathogenic (e.g. Yersinia) and some that are important for environmental remediation (e.g. Shewanella) but many of which have not been extensively characterized in the literature. We have determined the likely composition of the MetJ regulon in all species which have MetJ homologs using bioinformatics techniques. We show that the core genes known from E. coli are consistently regulated in other species, and we identify previously unknown members of the regulon. These include the cobalamin transporter, btuB; all the genes involved in the methionine salvage pathway; as well as several enzymes and transporters of unknown specificity. The MetJ regulon is present and functional in five orders of gammaproteobacteria: Enterobacteriales, Pasteurellales, Vibrionales, Aeromonadales and Alteromonadales. New regulatory activity for MetJ was identified in the genomic data and verified experimentally. This strategy should be applicable for the elucidation of regulatory pathways in other systems by using the extensive sequencing data currently being generated.


Investigation into the relationship between cord blood adiponectin levels and aortic intima media thickness in healthy, term neonates.
Adiponectin has important anti-inflammatory and anti-atherogenic effects. Although adiponectin and atherosclerosis correlate inversely in children and adults, we have little information regarding this relationship in neonates. We measured cord blood adiponectin levels and abdominal aortic intima media thickness (aIMT) in 80 healthy, term neonates and investigated the relationship between adiponectin and total cholesterol (TC), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), and triglyceride, and their relationships to infant anthropometry and gender. Mean birth weight, length, head circumference and aIMT values for male neonates were statistically significantly higher than those for female neonates. Adiponectin levels were not significantly different with respect to gender. In correlation analysis, the mean adiponectin level correlated positively with TC, HDL-C and LDL-C levels and birth weight, length and head circumference. There was no significant correlation between aIMT and any other parameters. The cord blood adiponectin and aIMT values reported here for the first time, represent reference values in the early neonatal period. The positive correlations between adiponectin levels and birth weight, length and head circumference, and TC, HDL-C and LDL-C indicate that further studies are required to demonstrate the exact relationship and clinical importance of adiponectin metabolism during the neonatal period.


The effect of replacing dietary saturated fat with polyunsaturated or monounsaturated fat on plasma lipids in free-living young adults.
To examine, in free-living adults eating self-selected diets, the effects on plasma cholesterol of substituting saturated fat rich foods with either n-6 polyunsaturated or monounsaturated fat rich foods while at the same time adhering to a total fat intake of 30-33% of dietary energy. Two randomised crossover trials. General community. Volunteer sample of healthy free-living nutrition students at the University of Otago. Trial I, n=29; and trial II, n=42. In trials I and II participants were asked to follow for 2(1/2) weeks a diet high in saturated fat yet with a total fat content that conformed to nutrition recommendations (30-33% energy). During the 2(1/2) week comparison diet, saturated fat rich foods were replaced with foods rich in n-6 polyunsaturated fats (trial I) whereas in trial II the replacement foods were rich in monounsaturated fats. Participants were asked to maintain a total fat intake of 30-33% of energy on all diets. Energy and nutrient intakes, plasma triglyceride fatty acids, and plasma cholesterol. When replacing saturated fat with either n-6 polyunsaturated fat or monounsaturated fat, total fat intakes decreased by 2.9% energy and 5.1% energy, respectively. Replacing saturated fat with n-6 polyunsaturated fat (trial I) lowered plasma total cholesterol by 19% [from 4.87 (0.88) to 3.94 (0.92) mmol/l, mean (s.d.)], low density lipoprotein cholesterol by 22% [from 2.87 (0.75) to 2.24 (0.67) mmol/l], and high density lipoprotein cholesterol by 14% [from 1.39 (0.36) to 1.19 (0.34) mmol/l], whereas replacing saturated fat with monounsaturated fat (trial II) decreased total cholesterol by 12%, low density lipoprotein cholesterol by 15%, and high density lipoprotein cholesterol by 4%, respectively. The change in the ratio of total to high density lipoprotein cholesterol was similar during trial I and trial II. Young adults are very responsive to dietary-induced changes in plasma cholesterol even when an isocaloric replacement of saturated fat with n-6 polyunsaturated or monounsaturated fat is not achieved. Replacing saturated fat with either n-6 polyunsaturated or monounsaturated fat is equally efficacious at reducing the total to high density lipoprotein cholesterol ratio. University of Otago, Meadow Lea Ltd.


The influence of health insurance plans on the long term outcome of patients with acute myocardial infarction.
Little is known, especially in our country, about the influence of health insurance plans on the long term outcome of patients after acute myocardial infarction (AMI). To assess the outcome of patients with AMI who are covered by the National Health System (SUS) or other health insurance plans. We analyzed 1,588 patients with AMI (mean age of 63.3 + 12.9 years, 71.7% male) who were included prospectively into a specific database and followed up for up to 7.55 years. Of this total, 1,003 were placed in the "SUS" group and 585 in the "other insurance plans" group. We applied chi-square, log-rank and Cox (stepwise) to the different statistical analyses. The long term multivariate model with mortality as a dependent variable included 18 independent variables. In-hospital mortality rates in the "other insurance plans" and "SUS" groups were 11.4% and 10.3%, respectively (p = 0.5); in the long term, survival chances in the groups were respectively, 70.4% + 2.9 and 56.4% + 4.0 (p = 0.001, hazard-ratio = 1.43, or a 43% higher chance of death in the "SUS" group). In the adjusted model, the 'SUS' group had a significantly higher chance of death (a 36% higher chance, p = 0.005). Surgical revascularization and angioplasty improved the prognosis of these patients, whereas age and previous history of infarction, diabetes or heart failure worsened the prognosis. Relative to patients with other insurance plans, SUS users present similar mortality rates during hospital stay, but their prognosis is worse in the long term, thus reinforcing the need for additional efforts to improve the care provided to these patients after hospital discharge.


Local anatomy around terminal ureter related to the anterior leaf of the vesicouterine ligament in radical hysterectomy.
Radical hysterectomy is performed for invasive cervical cancer. In this surgery, separation of the anterior leaf and posterior leaves of the vesicouterine ligament (VUL) is important. We studied the local anatomy of the anterior leaf of the VUL, especially the branches of the umbilical artery from the view point of surgery and cadaver dissection. We observed the cervicovesical blood vessels and the connective tissue layer continued from umbilical artery and searched for the origin of the cervicovesical blood vessels in radical hysterectomy. We also dissected a formalin-fixed female cadaver, and observed the same points. After separation of the connective tissue of urinary bladder from the cervical fascia, we could discern the outline of the distal ureter near the ureterovesical junction. We separate the connective tissue of the so-called anterior leaf of the VUL enwrapping the ureter gently, and then the ureter with the connective tissue is completely rolled out laterally. We identified a cervicovesical vessel crossing over the ureter. We looked for the central side of the cervicovesical vessel and found that cervicovesical vessel was a branch of the superior vesical artery. And, during cadaver dissection, we found that the connective tissue and the branches of the superior vesical artery were similarly observed. We found the precise anatomy of the connective tissue layer from umbilical artery to urinary bladder and the superior vesical artery. Our procedure based on the precise anatomy obtained in this study is reasonable anatomically as a method for separation of the vesicouterine ligament during radical hysterectomy.


Reoperation for persistent or recurrent secondary hyperparathyroidism.
Secondary hyperparathyroidism is a common acquired disorder seen in chronic renal failure. Its pathophysiology is mainly due to hyperphosphatemia and vitamin D deficiency and resistance. When medical treatment fails, subtotal and total parathyroidectomy with autotransplantation are the standard procedures, although both are associated with high recurrence rates. 4 patients experienced persistence and 9 relapse. The first 4 were subjected to reoperation after 6 months for the persistence of symptoms due to the finding of a supernumerary adenomatous gland while the remaining patients at the reoperation showed in 5 cases 2 more glands in over thymic position, and 4 an hyperplasia of the residual glandular tissue. A classic cervicotomy was sufficient to remove the residual parathyroid in patients with persistent hyperparathyroidism. For cases of recurrent hyperparathyroidism it was enough a medial approach and sometimes lateral for the complete excision of the hyperplastic tissue. The advent of the intraoperative technique of parathyroid hormone dosage allowed a better performance of the surgical technique for the last 3 patients undergoing reoperation. After reoperation all patients had immediate regression of clinical symptoms with normalization of serum calcium and PTH levels. On the basis of these considerations, diagnostic imaging has a not negligible role because during the first intervention helps to have an idea of the possible location of the glands and thus to avoid the risk of recurrence and relapse due to ectopic or supernumerary tissue.


Inhibition of tumor cell kinetics and serum insulin growth factor I levels by octreotide in colorectal cancer patients.
Octreotide was shown to inhibit the growth of colon cancer and to reduce serum concentrations of tumor growth factors such as insulin-like growth factor I (IGF-I) and epidermal growth factor (EGF) in vitro and in animal models. Effects of octreotide on tumor cell kinetics and serum concentration of IGF-I and EGF in patients with colorectal cancer were evaluated. Seventy-five patients with colorectal cancer were randomized to receive octreotide (200 micrograms daily) in the 2 weeks before surgery or the usual medications. Samples of tumor tissue were taken at endoscopy and at surgery. [3H]Thymidine labeling index and flow cytometry were used to assess the S-phase fraction. In octreotide-treated patients, plasma levels of IGF-I, EGF, and growth hormone were assessed before and after treatment. There was a statistically significant reduction in the mean percentage of the S-phase fraction as a result of octreotide treatment measured by both [3H]thymidine labeling index (P = 0.001) and flow cytometry (P = 0.001). No reduction in the percentage of the S-phase fraction was observed in the control group patients. Serum values of IGF-I were significantly reduced by octreotide, whereas EGF and growth hormone levels were not affected. Octreotide reduces the proliferative activity of tumor cells and the serum IGF-I levels in patients with colorectal cancer. This activity may have a role in the treatment of colorectal cancer.


Nuclear miR-30b-5p suppresses TFEB-mediated lysosomal biogenesis and autophagy.
Lysosome is a crucial organelle in charge of degrading proteins and damaged organelles to maintain cellular homeostasis. Transcription factor EB (TFEB) is the master transcription factor regulating lysosomal biogenesis and autophagy. Under external stimuli such as starvation, dephosphorylated TFEB transports into the nucleus to specifically recognize and bind to the coordinated lysosomal expression and regulation (CLEAR) elements at the promotors of autophagy and lysosomal biogenesis-related genes. The function of TFEB in the nucleus is fine regulated but the molecular mechanism is not fully elucidated. In this study, we discovered that miR-30b-5p, a small RNA which is known to regulate a series of genes through posttranscriptional regulation in the cytoplasm, was translocated into the nucleus, bound to the CLEAR elements, suppressed the transcription of TFEB-dependent downstream genes, and further inhibited the lysosomal biogenesis and the autophagic flux; meanwhile, knocking out the endogenous miR-30b-5p by CRISPR/Cas9 technique significantly increased the TFEB-mediated transactivation, resulting in the increased expression of autophagy and lysosomal biogenesis-related genes. Overexpressing miR-30b-5p in mice livers showed a decrease in lysosomal biogenesis and autophagy. These in vitro and in vivo data indicate that miR-30b-5p may inhibit the TFEB-dependent transactivation by binding to the CLEAR elements in the nucleus to regulate the lysosomal biogenesis and autophagy. This novel mechanism of nuclear miRNA regulating gene transcription is conducive to further elucidating the roles of miRNAs in the lysosomal physiological functions and helps to understand the pathogenesis of abnormal autophagy-related diseases.


Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction.
Despite suggestive early findings on the therapeutic use of hallucinogens in the treatment of substance use disorders, rigorous follow-up has not been conducted. To determine the safety and feasibility of psilocybin as an adjunct to tobacco smoking cessation treatment we conducted an open-label pilot study administering moderate (20 mg/70 kg) and high (30 mg/70 kg) doses of psilocybin within a structured 15-week smoking cessation treatment protocol. Participants were 15 psychiatrically healthy nicotine-dependent smokers (10 males; mean age of 51 years), with a mean of six previous lifetime quit attempts, and smoking a mean of 19 cigarettes per day for a mean of 31 years at intake. Biomarkers assessing smoking status, and self-report measures of smoking behavior demonstrated that 12 of 15 participants (80%) showed seven-day point prevalence abstinence at 6-month follow-up. The observed smoking cessation rate substantially exceeds rates commonly reported for other behavioral and/or pharmacological therapies (typically <35%). Although the open-label design does not allow for definitive conclusions regarding the efficacy of psilocybin, these findings suggest psilocybin may be a potentially efficacious adjunct to current smoking cessation treatment models. The present study illustrates a framework for future research on the efficacy and mechanisms of hallucinogen-facilitated treatment of addiction.