Furosemide versus placebo for fluid overload in intensive care patients-The randomised GODIF trial second version: Statistical analysis plan.
Fluid overload is associated with increased mortality in intensive care unit (ICU) patients. The GODIF trial aims to assess the benefits and harms of fluid removal with furosemide versus placebo in stable adult patients with moderate to severe fluid overload in the ICU. This article describes the detailed statistical analysis plan for the primary results of the second version of the GODIF trial. The GODIF trial is an international, multi-centre, randomised, stratified, blinded, parallel-group, pragmatic clinical trial, allocating 1000 adult ICU patients with moderate to severe fluid overload 1:1 to furosemide versus placebo. The primary outcome is days alive and out of hospital within 90 days post-randomisation. With a power of 90% and an alpha level of 5%, we may reject or detect an improvement of 8%. The primary analyses of all outcomes will be performed in the intention-to-treat population. For the primary outcome, the Kryger Jensen and Lange method will be used to compare the two treatment groups adjusted for stratification variables supplemented with sensitivity analyses in the per-protocol population and with further adjustments for prognostic variables. Secondary outcomes will be analysed with multiple linear regressions, logistic regressions or the Kryger Jensen and Lange method as suitable with adjustment for stratification variables. The GODIF trial data will increase the certainty about the effects of fluid removal using furosemide in adult ICU patients with fluid overload. EudraCT identifier: 2019-004292-40 and ClinicalTrials.org: NCT04180397.


von Willebrand disease and aging: an evolving phenotype.
Because the number of elderly von Willebrand disease (VWD) patients is increasing, the pathophysiology of aging in VWD has become increasingly relevant. To assess age-related changes in von Willebrand factor (VWF) and factor VIII (FVIII) levels and to compare age-related differences in bleeding phenotype between elderly VWD patients and those < 65 years. We also studied co-morbidity in elderly patients. We included VWD patients with VWF levels ≤ 30 U dL(-1) in the nationwide cross-sectional 'Willebrand in the Netherlands' (WiN-) study. Patients reported bleeding episodes and treatment of VWD in the year preceding inclusion and during life. This was compared between VWD patients older (n = 71) and younger (16-64 years, n = 593) than 65 years. In elderly patients, age-related changes in VWF and FVIII levels were studied longitudinally by including all historically measured levels. All medical records were examined for co-morbidity. In elderly type 1 patients, a decade age increase was associated with a 3.5 U dL(-1) (95% CI, -0.6 to 7.6) VWF:Ag increase and 7.1 U dL(-1) (95% CI, 0.7 to 13.4) FVIII:C increase. This increase was not observed in elderly type 2 patients. Elderly type 2 patients reported significantly more bleeding symptoms in the year preceding inclusion than younger patients (16/27, 59% vs. 87/221, 39%; P = 0.048), which was not observed in type 1 VWD. von Willebrand factor parameters and bleeding phenotype evolve with increasing age in VWD. VWF and FVIII levels increase with age in type 1 patients with no mitigation in bleeding phenotype. In type 2 patients VWF parameters do not increase with age and in these patients aging is accompanied by increased bleeding.


Screw epiphysiodesis for ankle valgus.
Progressive ankle valgus is an insidious deformity that may develop during childhood due to a variety of etiologies including neuromuscular disease, skeletal dysplasia, chromosomal anomalies, and clubfoot. This may be concomitant with, or mistaken for, hindfoot valgus. The surgical options for treatment include supramalleolar osteotomy or hemiepiphysiodesis of the medial distal tibial physis. We report the rationale and technique of retarding medial malleolar growth by means of inserting a single 4.5-mm vertical screw. In a population of 31 children (50 feet), we have observed satisfactory improvement of ankle valgus with low morbidity and without permanent physeal closure. This represents a safe, predictable, and effective solution for children who present with progressive and symptomatic ankle valgus.


Xenotropic murine leukemia virus-related virus in monozygotic twins discordant for chronic fatigue syndrome.
A recent report suggested an association between xenotropic murine leukemia virus-related virus (XMRV) and chronic fatigue syndrome (CFS). If confirmed, this would suggest that antiretroviral therapy might benefit patients suffering from CFS. We validated a set of assays for XMRV and evaluated the prevalence of XMRV in a cohort of monozygotic twins discordant for CFS. Stored peripheral blood mononuclear cell (PBMC) samples were tested with 3 separate polymerase chain reaction (PCR) assays (one of which was nested) for XMRV DNA, and serum/plasma was tested for XMRV RNA by reverse transcription (RT)-PCR. None of the PBMC samples from the twins with CFS or their unaffected co-twins was positive for XMRV, by any of the assays. One plasma sample, from an unaffected co-twin, was reproducibly positive by RT-PCR. However, serum from the same day was negative, as was a follow-up plasma sample obtained 2 days after the positive specimen. These data do not support an association of XMRV with CFS.


Is Bilateral Staged Muscle-Sparing Thoracotomy Performed within 1 Week for Lung Hydatid Cysts Safe for Pediatric Patients?
Median sternotomy or staged thoracotomies are generally the preferred surgical treatment options for bilateral lung hydatid cysts. According to literature, it is usually recommended to wait from 3 weeks to 3 months between bilateral staged thoracotomies. The aim of this study is to compare postoperative complications, hospitalization days and morbidity and mortality ratios between unilateral thoracotomy and bilateral staged thoracotomy groups and to evaluate the safety of performing bilateral staged thoracotomy within 1 week for lung hydatid cysts in pediatric patients. In total, 112 patients under the age of 16 years who underwent surgery between 2000 and 2016 because of pulmonary hydatid cysts were included in this study. The patients were classified into two groups as Group 1 (unilateral muscle-sparing thoracotomy) and Group 2 (bilateral staged muscle-sparing thoracotomy applied within 1 week). There were 91 patients in Group 1 and 21 patients in Group 2. No statistically significant differences were detected when both groups were compared by age, gender, perforation rates, follow-up period and postoperative complications. To prevent hydatid cysts complications, the elapsed time between two thoracotomies should be not only long enough to evaluate the postoperative complications but also relatively short to prevent possible complications that may develop in the other lung. In our opinion, a patient follow-up of 3-7 days between thoracotomies is sufficient for the assessment of patients' clinical status and possible complications.


Definition of metabolic syndrome in preadolescent girls.
To compare and contrast proposed definitions of metabolic syndrome in pediatrics, and to determine prevalence of metabolic syndrome in preadolescent females when applying different criteria. A literature review on definitions of metabolic syndrome and cardiovascular "risk factor clustering" in children and adolescents published in the past decade. Pediatric definitions of metabolic syndrome were then applied to a community-based study of 261 black preadolescent females (Girls Health Enrichment MultiSite studies [GEMS]) and a school-based, cross-sectional study of 240 ethnically-diverse preadolescent females (Girls Activity, Movement and Environmental Strategy [GAMES]) who had a baseline physical examination and fasting morning blood sample. Agreement among pediatric definitions of metabolic syndrome was poor. The prevalence of MS and cardiovascular risk factor clustering ranged from 0.4% to 23.0% for GEMS and 2.0% to 24.6% for GAMES with definitions adapted from the National Cholesterol Education Program Adult Treatment Panel III, and 0% to 15.3% for GEMS and 0.4% to 15.8% for GAMES using modified criteria from the World Health Organization. The prevalence of metabolic syndrome in preadolescent girls varies widely because of disagreement among proposed definitions of metabolic syndrome in pediatrics. Further investigation is needed to determine which metabolic factors and their respective cut points should be used to identify children at risk for development of clinical disease.


HomeoDB2: functional expansion of a comparative homeobox gene database for evolutionary developmental biology.
Homeobox gene database (HomeoDB), a manually curated database of homeobox genes and their classification, has been well received since its release in 2008. Here, we report HomeoDB2, an expansion and improvement of the original database that provides greater functionality for the user. HomeoDB2 includes all homeobox loci from 10 animal genomes (human, mouse, chicken, frog, zebrafish, amphioxus, nematode, fruitfly, beetle, honeybee) plus tools for downloading sequences, comparing between species and BLAST searching. HomeoDB2 provides a resource for studying the dynamics of homeobox gene evolution, and is freely accessible at http://homeodb.zoo.ox.ac.uk.


Long-term Outcomes Following Vickers Ligament Release and Growth Modulation for the Treatment of Madelung Deformity.
Madelung deformity arises from a partial distal radial growth disturbance in combination with an abnormal hypertrophic ligament spanning the volar radius and carpus, termed, the Vickers ligament. The purpose of this study is to report long-term clinical and radiographic outcomes following Vickers ligament release and distal radial physiolysis in a population of skeletally immature patients with symptomatic Madelung deformity. Medical records were retrospectively reviewed of patients with Madelung deformity surgically treated between 1994 and 2005. All eligible patients who underwent a Vickers ligament release and distal radial physiolysis were contacted and invited to return to the clinic for follow-up. Six patients (8 wrists) with Madelung deformity underwent Vickers ligament release and distal radial physiolysis. All were white females with a mean age at initial presentation of 11.4 years (10 to 12.8 y). Mean age at the time of initial surgery was 12.0 years (10.0 to 14.5 y). The median follow-up time was 10.6 years (5.8 to 21.9 y) and the average age at last follow-up was 23.1 years (17.5 to 32.2 y). Pain alone or in combination with concerns for deformity was the chief complaint in 6 of 8 of the wrists. At 1 year of clinical follow-up, 7 of 8 wrists were reported to be pain-free, and 6 of the 8 were noted to be completely pain-free at last follow-up. Motion in flexion, extension, pronation, supination, radial, or ulnar deviation was similar between the preoperative status and long-term follow-up. The average preoperative ulnar tilt was 35.1 degrees (SD: 8.5 degrees), average preoperative lunate subsidence was 1.9 degrees (SD: 1.8 degrees), and average preoperative palmar carpal displacement was 21.9 degrees (SD: 2.9 degrees). At the final follow-up, there was a large progression in lunate subsidence, but minimal change in ulnar tilt and palmar carpal displacement. At last clinical follow-up, 2 of the 6 patients had undergone a subsequent procedure including 1 radial dome osteotomy and 1 ulnar shortening osteotomy. In the skeletally immature patient population with Madelung deformity with growth potential remaining, distal radial physiolysis and Vickers ligament release is associated with relief of pain, preservation of motion, and, a reasonable rate of reoperation. This was a therapeutic study. Level II.


Deconstructing the default: cortical subdivision of the default mode/intrinsic system during self-related processing.
Recent brain imaging research has highlighted a new global system of areas termed the Default Mode network (DM), which appears to specialize in intrinsically oriented functions. However, it is still unresolved to what extent this system contains functional subsystems as in the better known sensory and motor cortices. Here, we report that functional subdivisions can be revealed within individual nodes of the DM, such as the Inferior Parietal Lobule (IPL), through the use of different categories of self-oriented tasks. Subjects underwent BOLD fMRI scans during which they were asked to recall self-related positive and negative information in the categories of people and food. These tasks elicited distinct regions of activation within the DM. Importantly, the observed activations were above the activity level in the baseline, no-task condition for these regions. The main subdivision within the DM was observed in the inferior and posterior parietal cortex. Analysis of coherent resting state fluctuations (functional connectivity analysis) revealed that these regions of activation were part of a distinct network of regions within the DM. These results argue against viewing the DM as a unitary system, and are compatible with the notion that, similar to the rest of the cerebral cortex, the DM consists of distinct, functionally specialized subregions.


Leukaemia survival trends in children with Down's syndrome in Great Britain, 1971-2000: a population-based study.
Children with Down's syndrome (DS) who developed leukaemia have had a worse prognosis than other children with leukaemia in the past. In the 1970s and early 1980s, some children with DS who developed leukaemia received fewer cycles of chemotherapy or were advised not to have treatment. In this population-based study, trends in 5-year survival from leukaemia were evaluated for children with and without DS who were diagnosed in Great Britain during 1971-2000 and followed to the end of 2004. For all children, with and without DS, survival has increased dramatically over the 30 year study period. For lymphoid leukaemia, survival in children with DS increased, but remains lower than for other children (5-year survival 59% vs 83% during 1996-2000). For acute non-lymphoblastic leukaemia (ANLL), however, 5-year survival improved substantially for children with DS, from less than 1% in the early 1970s to over 80% in the 1990s. For other children, survival increased from 6% to 64% during the same period. Survival for all children diagnosed with leukaemia has improved during the last three decades. For lymphoid leukaemia, the inferior outcome observed on more recent treatment protocols in children with DS remains an area for concern. For ANLL, the improvement in survival for children with DS is due to a number of factors, namely increased recruitment of these children to clinical trials, changes in clinical practice and important differences in the biology of myeloid leukaemia in young children with DS, resulting in a better response to some chemotherapeutic agents.


High-intensity kayak performance after adaptation to intermittent hypoxia.
Live-high train-low altitude training produces worthwhile gains in performance for endurance athletes, but the benefits of adaptation to various forms of artificial altitude are less clear. To quantify the effects of intermittent hypoxic exposure on kayak performance. In a crossover design with a 6-week washout, we randomized 10 subelite male sprint kayak paddlers to hypoxia or control groups for 3 weeks (5 days/week) of intermittent hypoxic exposure using a nitrogen-filtration device. Each day's exposure consisted of alternately breathing hypoxic and ambient air for 5 minutes each over 1 hour. Performance tests were an incremental step test to estimate peak power, maximal oxygen uptake, exercise economy, and lactate threshold; a 500-m time trial; and 5 x 100-m sprints. All tests were performed on a wind-braked kayak ergometer 7 and 3 days pretreatment and 3 and 10 days posttreatment. Hemoglobin concentration was measured at 1 day pretreatment, 5 and 10 days during treatment, and 3 days after treatment. Relative to control, at 3 days posttreatment the hypoxia group showed the following increases: peak power 6.8% (90% confidence limits, + or - 5.2%), mean repeat sprint power 8.3% (+ or - 6.7%), and hemoglobin concentration 3.6% (+ or - 3.2%). Changes in lactate threshold, mean 500-m power, maximal oxygen uptake, and exercise economy were unclear. Large effects for peak power and mean sprint speed were still present 10 days posthypoxia. These effects of intermittent hypoxic exposure should enhance performance in kayak racing. The effects might be mediated via changes in oxygen transport.


Assessment of Risk of Xerostomia After Whole-Brain Radiation Therapy and Association With Parotid Dose.
Whole-brain radiation therapy (WBRT) delivers a substantial radiation dose to the parotid glands, but the parotid glands are not delineated for avoidance and xerostomia has never been reported as an adverse effect. Minimizing the toxic effects in patients receiving palliative treatments, such as WBRT, is crucial. To assess whether xerostomia is a toxic effect of WBRT. This observational cohort study enrolled patients from November 2, 2015, to March 20, 2018, at 1 academic center (University of North Carolina Hospitals) and 2 affiliated community hospitals (High Point Regional Hospital and University of North Carolina Rex Hospital). Adult patients (n = 100) receiving WBRT for the treatment or prophylaxis of brain metastases were enrolled. Patients who had substantial baseline xerostomia or did not complete WBRT or at least 1 postbaseline questionnaire were prospectively excluded from analysis and follow-up. Patients received 3-dimensional WBRT using opposed lateral fields covering the skull and the C1 or C2 vertebra. Per standard practice, the parotid glands were not prospectively delineated. Patients completed the University of Michigan Xerostomia Questionnaire and a 4-point bother score at baseline, immediately after WBRT, at 1 month, at 3 months, and at 6 months. The primary end point was the 1-month xerostomia score, with a hypothesized worsening score of 10 points from baseline. Of the 100 patients enrolled, 73 (73%) were eligible for analysis and 55 (55%) were evaluable at 1 month. The 73 patients included 43 women (59%) and 30 men (41%) with a median (range) age of 61 (23-88) years. The median volume of parotid receiving at least 20 Gy (V20Gy) was 47%. The mean xerostomia score was 7 points at baseline and was statistically significantly higher at each assessment period, including 21 points immediately after WBRT (95% CI, 16-26; P < .001), 23 points (95% CI, 16-30; P < .001) at 1 month, 21 points (95% CI, 13-28; P < .001) at 3 months, and 14 points (95% CI, 7-21; P = .03) at 6 months. At 1 month, the xerostomia score increased by 20 points or more in 19 patients (35%). The xerostomia score at 1 month was associated with parotid dose as a continuous variable and was 35 points in patients with parotid V20Gy of 47% or greater, compared with only 9 points in patients with parotid V20Gy less than 47% (P < .001). The proportion of patients who self-reported to be bothered quite a bit or bothered very much by xerostomia at 1 month was 50% in those with parotid V20Gy of 47% or greater, compared with only 4% in those with parotid V20Gy less than 47% (P < .001). At 3 months, this difference was 50% vs 0% (P = .001). Xerostomia was not associated with medication use. Clinically significant xerostomia occurred by the end of WBRT, appeared to be persistent, and appeared to be associated with parotid dose. The findings from this study suggest that the parotid glands should be delineated for avoidance to minimize these toxic effects in patients who undergo WBRT and often do not survive long enough for salivary recovery.


Study of the underlying event in top quark pair production in p p collisions at 13 Te .
Measurements of normalized differential cross sections as functions of the multiplicity and kinematic variables of charged-particle tracks from the underlying event in top quark and antiquark pair production are presented. The measurements are performed in proton-proton collisions at a center-of-mass energy of 13 Te , and are based on data collected by the CMS experiment at the LHC in 2016 corresponding to an integrated luminosity of 35.9 fb - 1 . Events containing one electron, one muon, and two jets from the hadronization and fragmentation of b quarks are used. These measurements characterize, for the first time, properties of the underlying event in top quark pair production and show no deviation from the universality hypothesis at energy scales typically above twice the top quark mass.


Pathogenesis and vertical transmission of a transplacental rat cytomegalovirus.
Cytomegalovirus (CMV) congenital infection is the major viral cause of well-documented birth defects in human. Because CMV is species-specific, the main obstacle to developing animal models for congenital infection is the difference in placental architecture, which preludes virus transmission across the placenta. The rat placenta, resembling histologically to that of human, could therefore facilitate the study of CMV congenital infection in human. In this report, we present clear evidences of the transplacental property of a new rat CMV (RCMV), namely ALL-03, which had been isolated from placenta and uterus of the house rat. Our study signifies the detection of infectious virus, virus particles, viral protein and DNA as well as immune response to demonstrate a natural model of acute CMV infection including the immunocompetent and immunocompromised host associated with or without pregnancy. It is characterized by a full range of CMV related clinical signs; lesions and anatomical virus distribution to uterus, placenta, embryo, fetus, neonate, lung, kidney, spleen, liver and salivary gland of the infected rats in addition to the virus-specific seroconversion. The preference of the virus for different organs mimics the situation in immunocompromised man. Most interestingly, the placenta was observed to be involved in the maternofetal infection and hence confirmed the hypothesis that the RCMV strain ALL-03 is capable to cross the placenta and infect the offsprings congenitally. The maternal viremia leading to uterine infection which subsequently infecting to the fetus through the placenta is the most likely phenomenon of CMV vertical transmission in our study.


Tumour markers for prediction of survival and monitoring of remission in small cell lung cancer.
Levels of the tumour markers neurone specific enolase (NSE), lactate dehydrogenase (LDH), chromogranin A (ChrA) and carcinoembryonic antigen (CEA) were measured in serum taken at presentation and during treatment, remission and relapse from 154 patients who received chemotherapy for small cell lung cancer at a single centre over a 6 year period. At presentation NSE was the most frequently elevated marker, being raised in 81% of patients and significantly higher in extensive as opposed to limited disease, as were LDH and ChrA. The response rate to therapy was best correlated with presentation level of ChrA, being 79% for those whose levels were within twice the upper limit of normal and 51% above (P < 0.01). Multivariate regression analysis showed NSE, performance status and albumin at presentation to be the best independent predictors of survival. Patients with NSE below twice the upper limit of normal, Karnofsky performance status of 80 or above and albumin 35 g l-1 or above had a median survival of 15 months with 25% alive at 2 years, whilst those with NSE above twice normal, Karnofsky below 80 and albumin less that 35 g l-1 had all died by 8 months. Changes in marker levels during therapy were of low predictive value for outcome although the finding of rising NSE during chemotherapy after an initial fall correlated with significantly reduced duration of remission. There was a strong inverse correlation between the NSE level at the time of response and duration of remission (P < 0.0001). Prediction of relapse was most reliable with ChrA, 52% of patients having rising levels before clinical evidence of disease recurrence.


Mechanosignaling in bone health, trauma and inflammation.
Mechanosignaling is vital for maintaining the structural integrity of bone under physiologic conditions. These signals activate and suppress multiple signaling cascades regulating bone formation and resorption. Understanding these pathways is of prime importance to exploit their therapeutic potential in disorders associated with bone loss due to disuse, trauma, or disruption of homeostatic mechanisms. In the case of cells of the bone, an impressive amount of data has been generated that provides evidence of a complex mechanism by which mechanical signals can maintain or disrupt cellular homeostasis by driving transcriptional regulation of growth factors, matrix proteins and inflammatory mediators in health and inflammation. Mechanical signals act on cells in a magnitude dependent manner to induce bone deposition or resorption. During health, physiological levels of these signals are essential for maintaining bone strength and architecture, whereas during inflammation, similar signals can curb inflammation by suppressing the nuclear factor kappa B (NF-κB) signaling cascade, while upregulating matrix synthesis via mothers against decapentaplegic homolog and/or Wnt signaling cascades. Contrarily, excessive mechanical forces can induce inflammation via activation of the NF-κB signaling cascade. Given the osteogenic potential of mechanical signals, it is imperative to exploit their therapeutic efficacy for the treatment of bone disorders. Here we review select signaling pathways and mediators stimulated by mechanical signals to modulate the strength and integrity of the bone. Understanding the mechanisms of mechanotransduction and its effects on bone lay the groundwork for development of nonpharmacologic mechanostimulatory approaches for osteodegenerative diseases and optimal bone health.


Vortex wake and flight kinematics of a swift in cruising flight in a wind tunnel.
In this paper we describe the flight characteristics of a swift (Apus apus) in cruising flight at three different flight speeds (8.0, 8.4 and 9.2 m s(-1)) in a low turbulence wind tunnel. The wingbeat kinematics were recorded by high-speed filming and the wake of the bird was visualized by digital particle image velocimetry (DPIV). Certain flight characteristics of the swift differ from those of previously studied species. As the flight speed increases, the angular velocity of the wingbeat remains constant, and so as the wingbeat amplitude increases, the frequency decreases accordingly, as though the flight muscles were contracting at a fixed rate. The wings are also comparatively inflexible and are flexed or retracted rather little during the upstroke. The upstroke is always aerodynamically active and this is reflected in the wake, where shedding of spanwise vorticity occurs throughout the wingbeat. Although the wake superficially resembles those of other birds in cruising flight, with a pair of trailing wingtip vortices connected by spanwise vortices, the continuous shedding of first positive vorticity during the downstroke and then negative vorticity during the upstroke suggests a wing whose circulation is gradually increasing and then decreasing during the wingbeat cycle. The wake (and implied wing aerodynamics) are not well described by discrete vortex loop models, but a new wake-based model, where incremental spanwise and streamwise variations of the wake impulse are integrated over the wingbeat, shows good agreement of the vertical momentum flux with the required weight support. The total drag was also estimated from the wake alone, and the calculated lift:drag ratio of approximately 13 for flapping flight is the highest measured yet for birds.


[Adolphe Quetelet and biopolitics as secularized theology].
The article recaptures the work of an author who has been forgotten by the contemporary social sciences, that is, the Belgium polymath Adolphe Quetelet. Focusing on his main work, Sur l'homme et le développement de ses facultés, ou Essai de physique sociale, the study underscores how the secularization of theological principles within the realm of science was important to the construction of Quetelet's work. His dual engagement in science and politics is pertinent here, as he was the main nineteenth-century force behind the incorporation of statistics as a science essential to the State's ability to govern its people. He also played a relevant role in the realization of the hegemonic political project of modernity, biopolitics, and its influence in the field of biomedicine in the nineteenth and twentieth centuries.


Spatial variation in allometric growth of invasive lionfish has management implications.
Lionfish (Pterois volitans/miles) are an invasive species in the Western Atlantic and the Caribbean. Improving management of invasive lionfish populations requires accurate total biomass estimates, which depend on accurate estimates of allometric growth; sedentary species like lionfish often exhibit high levels of spatial variation in life history characteristics. We reviewed 17 published length-weight relationships for lionfish taken throughout their invasive range and found regional differences that led to significant misestimates when calculating weight from length observations. The spatial pattern we observed is consistent with findings from other studies focused on genetics or length-at-age. Here, the use of ex situ parameter values resulted in total biomass estimates between 76.2% and 140% of true observed biomass, and up to a threefold under- or overestimation of total weight for an individual organism. These findings can have implications for management in terms of predicting effects on local ecosystems, evaluating the effectiveness of removal programs, or estimating biomass available for harvest.


Id: a target of BMP signaling.
Cytokines of the transforming growth factor-beta (TGF-beta) superfamily transduce their signals by activating receptor-regulated Smads (R-Smads). Distinct R-Smads or combinations of R-Smads are activated by TGF-beta, activin, or bone morphogenetic proteins (BMPs). R-Smads activated by BMPs induce expression of Id proteins, which act as inhibitors of differentiation and stimulators of cell growth by inhibiting the function of basic helix-loop-helix transcription factors. In endothelial cells, TGF-beta binds to two distinct type I receptor serine-threonine kinases, ALK-5 and ALK-1; the latter activates the same R-Smads that are activated by BMP and induces synthesis of Id (inhibitor of differentiation or inhibitor of DNA binding) proteins. Growing evidence suggests that Id proteins may play crucial roles in angiogenesis, neurogenesis, and osteogenesis and act as key molecules in regulating biological responses induced by BMPs and TGF-beta.


Convolutional neural network-based reconstruction for acceleration of prostate T2 weighted MR imaging: a retro- and prospective study.
The aim of this study was to develop a deep neural network (DNN)-based parallel imaging reconstruction for highly accelerated 2D turbo spin echo (TSE) data in prostate MRI without quality degradation compared to conventional scans. 155 participant data were acquired for training and testing. Two DNN models were generated according to the number of acquisitions (NAQ) of input images: DNN-N1 for NAQ = 1 and DNN-N2 for NAQ = 2. In the test data, DNN and TSE images were compared by quantitative error metrics. The visual appropriateness of DNN reconstructions on accelerated scans (DNN-N1 and DNN-N2) and conventional scans (TSE-Conv) was assessed for nine parameters by two radiologists. The lesion detection was evaluated at DNNs and TES-Conv by prostate imaging-reporting and data system. The scan time was reduced by 71% at NAQ = 1, and 42% at NAQ = 2. Quantitative evaluation demonstrated the better error metrics of DNN images (29-43% lower NRMSE, 4-13% higher structure similarity index, and 2.8-4.8 dB higher peak signal-to-noise ratio; p < 0.001) than TSE images. In the assessment of the visual appropriateness, both radiologists evaluated that DNN-N2 showed better or comparable performance in all parameters compared to TSE-Conv. In the lesion detection, DNN images showed almost perfect agreement (κ > 0.9) scores with TSE-Conv. DNN-based reconstruction in highly accelerated prostate TSE imaging showed comparable quality to conventional TSE. Our framework reduces the scan time by 42% of conventional prostate TSE imaging without sequence modification, revealing great potential for clinical application.


Diversity-multiplexing tradeoff in mode-division multiplexing.
The capacity of mode-division multiplexing (MDM) systems is limited, for a given outage probability, by mode-dependent loss (MDL) and gain. Modal degrees of freedom may be exploited to increase transmission rate (multiplexing gain) or lower outage probability (diversity gain), but there is a fundamental tradeoff between the achievable multiplexing and diversity gains. In this Letter, we present the diversity-multiplexing tradeoff in MDM systems for the first time, studying the impact of signal-to-noise ratio, MDL, and frequency diversity order on the tradeoff in the strong-mode-coupling regime.


Standardised inventories of spiders (Arachnida, Araneae) of Macaronesia I: The native forests of the Azores (Pico and Terceira islands).
The data presented here come from samples collected as part of two recent research projects (NETBIOME - ISLANDBIODIV and FCT - MACDIV) which aimed at understanding the drivers of community assembly in Macaronesian islands. We applied the sampling protocol COBRA (Conservation Oriented Biodiversity Rapid Assessment, Cardoso 2009) in sixteen 50 m x 50 m native forest plots in the Azorean Islands of Pico (6 plots) and Terceira (10 plots) to assess spider diversity. Through this publication, we contribute to the knowledge of the arachnofauna of the Azores and, more specifically, to that of the islands of Pico and Terceira. The collected samples yielded 8,789 specimens, of which 45% were adults (3,970) belonging to 13 families, 36 species and three morphospecies that have yet to be described. Species of the family Linyphiidae dominated the samples, with 17 species and two morphospecies that have yet to be described (48% of the taxa). Out of the identified (morpho)species, 16 were introduced, 13 Azorean endemic (three of which were undescribed) and seven native (five of them Macaronesian endemics). We report the first record of the introduced species Haplodrassus signifer and Agyneta decora in Pico Island.


Cortical Activation During Shoulder and Finger Movements in Healthy Adults: A Functional Near-Infrared Spectroscopy (fNIRS) Study.
Characterization of cortical activation patterns during movement of the upper extremity in healthy adults is helpful in understanding recovery mechanisms following neurological disorders. This study explores cortical activation patterns associated with movements of the shoulder and fingers in healthy adults using functional near-infrared spectroscopy (fNIRS). Twelve healthy right-handed participants were recruited. Two motor tasks (shoulder abduction and finger extension) with two different trial lengths (10 s and 20 s) were performed in a sitting position at a rate of 0.5 Hz. The hemodynamic response, as indicated by oxy-hemoglobin (HbO) and deoxy-hemoglobin (HbR), over both hemispheres was acquired using a 54-channel fNIRS system. We found a generalized bilateral cortical activation during both motor tasks with greater activation in the contralateral compared to the ipsilateral primary motor cortex. Particularly in the more medial part of the contralateral hemisphere, significant higher activation was found during the shoulder compared to finger movements. Furthermore, cortical activation patterns are affected not only by motor tasks but also by trial lengths. HbO is more sensitive to detect cortical activation during finger movements in longer trials, while HbR is a better surrogate to capture active areas during shoulder movement in shorter trials. Based on these findings, reporting both HbO and HbR is strongly recommended for future fNIRS studies, and trial lengths should be taken into account when designing experiments and explaining results. Our findings demonstrating distinct cortical activation patterns associated with shoulder and finger movements in healthy adults provide a foundation for future research to study recovery mechanisms following neurological disorders.


The Buttermilk Creek complex and the origins of Clovis at the Debra L. Friedkin site, Texas.
Compelling archaeological evidence of an occupation older than Clovis (~12.8 to 13.1 thousand years ago) in North America is present at only a few sites, and the stone tool assemblages from these sites are small and varied. The Debra L. Friedkin site, Texas, contains an assemblage of 15,528 artifacts that define the Buttermilk Creek Complex, which stratigraphically underlies a Clovis assemblage and dates between ~13.2 and 15.5 thousand years ago. The Buttermilk Creek Complex confirms the emerging view that people occupied the Americas before Clovis and provides a large artifact assemblage to explore Clovis origins.


Factors associated with return to work in men and women with work-related traumatic brain injury.
Symptoms that persist subsequent to a work-related traumatic brain injury (wrTBI) influence the ability to return to work (RTW) and indicate areas of functional disability, as classified in the International Classification of Functioning, Disability and Health (ICF) framework. The purpose of this study was to describe the relationship between RTW status and ICF framework domains in men and women with a wrTBI. A retrospective chart review of 209 consecutive workers with TBI (mild TBI: 71.8%; mean age: 40.2 ± 11.1, men: 71.3%) was conducted. Workers were assessed during the chronic post-injury phase, at the neurology service of a large rehabilitation hospital in Ontario, Canada in 2003. Frequency distributions were calculated and chi-square tests performed. At the point of assessment, 78.0% of workers were in receipt of disability benefits, while the remainder had returned to work on a full- or part-time basis. Significant differences were observed in the Body Functions and Structures domain of the ICF model, specifically clinical diagnoses of depression, anxiety, pain disorders; self-perceived cognitive disturbance, and certain psychosocial factors (p < 0.05), between workers who had returned to work and those who had not. When stratified according to sex, these associations remained significant only in men. The factors outlined above should be subject to further TBI research, as indicators for RTW. The lack of significant findings in women warrants further exploration of variables within the physical and social environmental domains of the ICF.


Patellar component resection arthroplasty for the severely compromised patella.
When severe bone loss precludes reimplantation of a new patellar component during revision knee arthroplasty, the treatment options include patellar bone grafting, patellar component resection arthroplasty, and patellectomy. The purpose of this study was to evaluate the clinical and functional results of patellar component resection arthroplasty for the severely compromised patella for which insertion of another patellar component was not possible. Thirty-five knees (31 patients) were treated with patellar component resection arthroplasty for aseptic patellar component failure associated with severely compromised patellar bone stock. Followup averaged 7.9 years (range, 2-18 years). There was a significant improvement in Knee Society pain and function scores. Pain relief was more dramatic than functional improvement. The range of motion also improved significantly and in particular preoperative extensor lag was resolved in the majority of patients. Patients treated with isolated patellar resection arthroplasty were more likely to have continuing pain and require reoperation compared with patients who had concomitant revision of the tibial and femoral components. Correct positioning and the stability of tibial and femoral components should be tested carefully at the time of patellar resection arthroplasty and considered for revision if malpositioned either axially or rotationally.


Association between 8-oxo-7,8-dihydroguanine excretion and risk of lung cancer in a prospective study.
Oxidative damage to guanine (8-oxoGua) is one of the most abundant lesions induced by oxidative stress and documented mutagenic. 8-Oxoguanine DNA glycosylase 1 (OGG1) removes 8-oxoGua from DNA by excision. The urinary excretion of 8-oxoGua is a biomarker of exposure, reflecting the rate of damage in the steady state. The aim of this study was to investigate urinary 8-oxoGua as a risk factor for lung cancer. In a nested case-cohort design we examined associations between urinary excretion of 8-oxoGua and risk of lung cancer as well as potential interaction with the OGG1 Ser326Cys polymorphism in a population-based cohort of 25,717 men and 27,972 women aged 50-64 years with 3-7 years follow-up. We included 260 cases with lung cancer and a subcohort of 263 individuals matched on sex, age, and smoking duration for comparison. Urine collected at entry was analysed for 8-oxoGua by HPLC with electrochemical detection. There was no significant effect of smoking or OGG1 genotype on the excretion of 8-oxoGua. Overall the incidence rate ratio (IRR) (95% confidence interval) of lung cancer was 1.06 (0.97-1.15) per doubling of 8-oxoGua excretion. The association between lung cancer risk and 8-oxoGua excretion was significant among men [IRR: 1.17 (1.03-1.31)], never-smokers [IRR: 9.94 (1.04-94.7)], and former smokers [IRR: 1.19 (1.07-1.33)]. There was no significant interaction with the OGG1 genotype, although the IRR was 1.14 (0.98-1.34) among subjects homozygous for Cys326. The association between urinary 8-oxoGua excretion and lung cancer risk among former and never-smokers suggests that oxidative stress with damage to DNA is important in this group.


Pharmacokinetics of azithromycin in pediatric patients with acute otitis media.
The objective of our study was to characterize the pharmacokinetics of azithromycin after the oral administration of multiple doses in suspension to children with acute otitis media. Thirteen children (ranging in age from 7.5 months to 5 years) received a single oral dose of 10 mg of azithromycin per kg of body weight on day 1 followed by single daily doses of 5 mg/kg on days 2 to 5. Each child fasted overnight before receiving the final dose on day 5. Multiple blood samples were collected after the last dose. Concentrations of azithromycin in serum were measured by a specific high-performance liquid chromatography-mass spectrometry method. The means and standard deviations for the maximum concentration of azithromycin in serum, the time to maximum concentration of azithromycin in serum, the area under the concentration-time curve (from 0 to 24 h), and the elimination half-life were 224 +/- 120 ng/ml, 1.8 +/- 0.4 h, 1,841 +/- 651 ng.h/ml, and 31.6 +/- 6.6 h, respectively. Concentrations in serum (means +/- standard deviations) at 0 h (predose) and at 24, 48, and 72 h after the final dose were 51 +/- 26, 47 +/- 21, 27 +/- 17, and 17 +/- 13 ng/ml, respectively. Thus, the once-daily administration of azithromycin resulted in sustained systemic exposure to the drug. The drug dosage regimen used in this study should lead to tissue drug concentrations exceeding the MICs for common pathogens.


Impact of exploratory biomarkers on the treatment effect of bevacizumab in metastatic breast cancer.
The addition of bevacizumab to cytotoxic chemotherapy has demonstrated a progression-free survival (PFS) benefit in the first-line and second-line treatment of advanced or metastatic breast cancer (MBC). However, the addition of bevacizumab to capecitabine in heavily pretreated MBC patients did not show a PFS benefit (AVF2119g phase III trial). The aim of this study was to evaluate the expression of novel putative biomarkers as predictors of benefit from bevacizumab in retrospective subset analyses of the AVF2119g trial. In the AVF2119g trial, 462 patients with MBC were randomly assigned to receive capecitabine or capecitabine plus bevacizumab. Primary tumor tissue and outcome data were available for 223 patients. Biomarker expression was assessed by in situ hybridization (VEGF-A, VEGF-B, thrombospondin-2 and Flt4) or immunohistochemistry (VEGF-C, PDGF-C, neuropilin-1, delta-like ligand (Dll) 4, Bv8, p53 and thymidine phosphorylase) on formalin-fixed, paraffin-embedded tissue. PFS was associated with these variables in retrospective subset analyses. Patients with low scores for Dll4, VEGF-C, and neuropilin-1 showed trends toward improvement in PFS associated with the addition of bevacizumab to capecitabine (P values = 0.01, 0.05, and 0.07, respectively). These observations were not statistically significant following correction for multiple hypothesis testing. These retrospective subset analyses suggest that expression of Dll4, VEGF-C, and neuropilin-1 may predict benefit from bevacizumab. Such observations are not conclusive but warrant additional testing.


Judicialization 2.0: Understanding right-to-health litigation in real time.
Over the past two decades, debate over the whys, the hows, and the effects of the ever-expanding phenomenon of right-to-health litigation ('judicialization') throughout Latin America have been marked by polarised arguments and limited information. In contrast to claims of judicialization as a positive or negative trend, less attention has been paid to ways to better understand the phenomenon in real time. In this article, we propose a new approach-Judicialization 2.0-that recognises judicialization as an integral part of democratic life. This approach seeks to expand access to information about litigation on access to medicines (and health care generally) in order to better characterise the complexity of the phenomenon and thus inform new research and more robust public discussions. Drawing from our multi-disciplinary perspectives and field experiences in highly judicialized contexts, we thus describe a new multi-source, multi-stakeholder mixed-method approach designed to capture the patterns and heterogeneity of judicialization and understand its medical and socio-political impact in real time, along with its counterfactuals. By facilitating greater data availability and open access, we can drive advancements towards transparent and participatory priority setting, as well as accountability mechanisms that promote quality universal health coverage.


Sexual power and HIV risk, South Africa.
Gender power inequities are believed to play a key role in the HIV epidemic through their effects on women's power in sexual relationships. We hypothesized that lack of sexual power, measured with a four-point relationship control scale and by a woman's experience of forced sex with her most recent partner, would decrease the likelihood of consistent condom use and increase the risk for HIV infection among sexually experienced, 15- to 24-year-old women in South Africa. While limited sexual power was not directly associated with HIV, it was associated with inconsistent condom use: women with low relationship control were 2.10 times more likely to use condoms inconsistently (95% confidence interval [CI] 1.17-3.78), and women experiencing forced sex were 5.77 times more likely to use condoms inconsistently (95% CI 1.86-17.91). Inconsistent condom use was, in turn, significantly associated with HIV infection (adjusted odds ratio 1.58, 95% CI 1.10-2.27).


Breastfeeding and complementary food: randomized trial of community doula home visiting.
Despite recent efforts to increase breastfeeding, young African American mothers continue to breastfeed at low rates, and commonly introduce complementary foods earlier than recommended. This study examines the effects of a community doula home visiting intervention on infant feeding practices among young mothers. Low-income, African American mothers (n = 248) under age 22 years participated in a randomized trial of a community doula intervention. Intervention-group mothers received services from paraprofessional doulas: specialized home visitors trained as childbirth educators and lactation counselors. Doulas provided home visits from pregnancy through 3 months postpartum, and support during childbirth. Control-group mothers received usual prenatal care. Data were obtained from medical records and maternal interviews at birth and 4 months postpartum. Intent-to-treat analyses showed that doula-group mothers attempted breastfeeding at a higher rate than control-group mothers (64% vs 50%; P = .02) and were more likely to breastfeed longer than 6 weeks (29% vs 17%; P = .04), although few mothers still breastfed at 4 months. The intervention also impacted mothers' cereal/solid food introduction (P = .008): fewer doula-group mothers introduced complementary foods before 6 weeks of age (6% vs 18%), while more waited until at least 4 months (21% vs 13%) compared with control-group mothers. Community doulas may be effective in helping young mothers meet breastfeeding and healthy feeding guidelines. The intervention's success may lie in the relationship that develops between doula and mother based on shared cultural background and months of prenatal home visiting, and the doula's presence at the birth, where she supports early breastfeeding experiences.


Genome-wide association study of circulating retinol levels.
Retinol is one of the most biologically active forms of vitamin A and is hypothesized to influence a wide range of human diseases including asthma, cardiovascular disease, infectious diseases and cancer. We conducted a genome-wide association study of 5006 Caucasian individuals drawn from two cohorts of men: the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study and the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. We identified two independent single-nucleotide polymorphisms associated with circulating retinol levels, which are located near the transthyretin (TTR) and retinol binding protein 4 (RBP4) genes which encode major carrier proteins of retinol: rs1667255 (P =2.30× 10(-17)) and rs10882272 (P =6.04× 10(-12)). We replicated the association with rs10882272 in RBP4 in independent samples from the Nurses' Health Study and the Invecchiare in Chianti Study (InCHIANTI) that included 3792 women and 504 men (P =9.49× 10(-5)), but found no association for retinol with rs1667255 in TTR among women, thus suggesting evidence for gender dimorphism (P-interaction=1.31× 10(-5)). Discovery of common genetic variants associated with serum retinol levels may provide further insight into the contribution of retinol and other vitamin A compounds to the development of cancer and other complex diseases.


Neuropeptide Y1 receptor in immune cells regulates inflammation and insulin resistance associated with diet-induced obesity.
Recruitment of activated immune cells into white adipose tissue (WAT) is linked to the development of insulin resistance and obesity, but the mechanism behind this is unclear. Here, we demonstrate that Y1 receptor signaling in immune cells controls inflammation and insulin resistance in obesity. Selective deletion of Y1 receptors in the hematopoietic compartment of mice leads to insulin resistance and inflammation in WAT under high fat-fed conditions. This is accompanied by decreased mRNA expression of the anti-inflammatory marker adiponectin in WAT and an increase of the proinflammatory monocyte chemoattractant protein-1 (MCP-1). In vitro, activated Y1-deficient intraperitoneal macrophages display an increased inflammatory response, with exacerbated secretion of MCP-1 and tumor necrosis factor, whereas addition of neuropeptide Y to wild-type macrophages attenuates the release of these cytokines, this effect being blocked by Y1 but not Y2 receptor antagonism. Importantly, treatment of adipocytes with the supernatant of activated Y1-deficient macrophages causes insulin resistance, as demonstrated by decreased insulin-induced phosphorylation of the insulin receptor and Akt as well as decreased expression of insulin receptor substrate 1. Thus, Y1 signaling in hematopoietic-derived cells such as macrophages is critical for the control of inflammation and insulin resistance in obesity.


Waldenström macroglobulinemia: 2011 update on diagnosis, risk stratification, and management.
Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, and lymphadenopathy. Presence of IgM monoclonal protein associated with 10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. Age, hemoglobin level, platelet count, b2-microglobulin, and monoclonal IgM concentrations are characteristics required for prognosis. Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-based therapy is used in virtually all US patients with WM and can be combined with alkylating agent or purine nucleoside analogue, or both. The preferred Mayo Clinic nonstudy therapeutic induction is rituximab, cyclophosphamide, and dexamethasone. Future stem cell transplantation should be considered in induction therapy selection. Bortezomib, thalidomide, lenalidomide, and bendamustine have all been shown to have activity in WM. Given WM's natural history, reduction of complications will be a priority for future treatment trials.


Treatment of herpes zoster with Clinacanthus nutans (bi phaya yaw) extract.
A randomized, placebo-controlled trial of the efficacy of topical formulation of Clinacanthus nutans (Bi Phaya Yaw) extract was carried out in 51 patients with varicella-zoster virus infection. The study medication was applied five times daily for 7-14 days until the lesions were healed. The number of patients with lesion crusting within 3 days and with lesion healing within 7 days and 10 days were significantly greater in the C. nutans extract-treated group than the placebo group (p < 0.01). Pain scores were reduced more rapidly in the C. nutans extract-treated group than in the placebo group. There were no side effects of the study medication.


Effect of isoprenaline on the plasma concentrations of angiotensin III in rats.
1. A new column-chromatographic method is described for the simple and reproducible determination of the concentration of [des-Asp1]angiotensin II (angiotensin III) in rat plasma. 2. The method uses the different abilities of the ion-exchange resins Dowex 1 (X8) and Bio Rex 70 to bind angiotensin II and angiotensin III. Under the conditions used, Bio Rex 70 binds only angiotensin III. Angiotensin II and its hexapeptide metabolite [des-Asp1,des-Arg2]angiotensin II pass the resin with the effluent. Dowex 1 (X8) binds angiotensin II and the hexapeptide metabolite, whereas it does not extract angiotensin III. It does not separate angiotensin II from the hexapeptide. Therefore the sum of both peptides is expressed as angiotensin II-like activity. The ratio of the concentrations, angiotensin II/hexapeptide, was 5:1. 3. In normal rats the plasma concentration of angiotensin III was 20 fmol/ml (SD 15; n = 8), and angiotensin II-like activity was 60 fmol/ml (SD 35; n = 8). 4. The beta-sympathomimetic amine isoprenaline caused a time- and dose-dependent increase in plasma angiotensin III and angiotensin II-like activities. 5. Under the conditions studied angiotensin III contributed approximately 25% to the total amount of angiotensins in plasma.


Design of adaptive treatment margins for non-negligible measurement uncertainty: application to ultrasound-guided prostate radiation therapy.
Daily imaging during the course of a fractionated radiotherapy treatment has the potential for frequent intervention and therefore effective adaptation of the treatment to the individual patient. The treatment information gained from such images can be analysed and updated daily to obtain a set of patient individualized parameters. However, in many situations, the uncertainty with which these parameters are estimated cannot be neglected. In this work this methodology is applied to the adaptive estimation of setup errors, the derivation of a daily optimal pre-treatment correction strategy, and the daily update of the treatment margins after application of these corrections. For this purpose a dataset of 19 prostate cancer patients was analysed retrospectively. The position of the prostate was measured daily with an optically guided 3D ultrasound localization system. The measurement uncertainty of this system is approximately 2 mm. The algorithm finds the most likely position of the target maximizing an a posteriori probability given the set of measurements. These estimates are used for the optimal corrections applied to the target volume. The results show that the application of the optimal correction strategy allows a reduction in the treatment margins in a systematic way with increasing progression of the treatment. This is not the case using corrections based only on the measured values that do not take the measurement uncertainty into account.


The effects of bisphenol A, benzyl butyl phthalate, and di(2-ethylhexyl) phthalate on estrogen receptor alpha in estrogen receptor-positive cells under hypoxia.
Endocrine-disrupting chemicals (EDCs) are widely used in various consumer goods. Consequently, humans are constantly exposed to EDCs, which is associated with a variety of endocrine-related diseases. In this study, we demonstrated the effects of bisphenol A (BPA), benzyl butyl phthalate (BBP), and di(2-ethylhexyl) phthalate (DEHP) on estrogen receptor alpha (ERα) expression under normoxia and hypoxia. First, we confirmed the effects of EDCs on ER activity using OECD Test Guideline 455. Compared to the 100% activity induced by 1 nM 17-β-estradiol (positive control), BPA and BBP exhibited 50% ERα activation at concentrations of 1.31 μM and 4.8 μM, respectively. In contrast, and consistent with previous reports, DEHP did not activate ERα. ERα is activated and degraded by hypoxia in breast cancer cells. BPA, BBP, and DEHP enhanced ERα-mediated transcriptional activity under hypoxia. All three EDCs decreased ERα protein levels under hypoxia in MCF-7 cells. The transcriptional activity of hypoxia-inducible factor-1 was decreased and secretion of vascular endothelial growth factor (VEGF) was increased by BPA and BBP under hypoxia in MCF-7 cells, but not by DEHP. All three EDCs decreased the ERα protein expression level in Ishikawa human endometrial adenocarcinoma cells, and DEHP caused a weak decrease in VEGF secretion under hypoxia. These results demonstrate down-regulation of ERα by EDCs may influence the pathological state associated with hypoxia.


Social Participation and Navigation (SPAN) program for adolescents with acquired brain injury: Pilot findings.
Our goal was to examine the feasibility and preliminary efficacy of an app-based coaching intervention (Social Participation and Navigation; SPAN) to help survivors of acquired brain injury attain social participation goals. Research Method/Design: This is a nonrandomized pilot trial of SPAN, including 15 adolescents (9 with traumatic brain injury, 6 with brain tumor) between the ages of 14-22. The SPAN intervention consisted of a mobile app to support the development and implementation of social participation goals, weekly video-conference coaching sessions to identify goals and step-by-step action plans, and online didactic materials. Assessments were completed pre- and postintervention. Satisfaction with the intervention, confidence in the adolescents' ability to participate in and plan social activities and manage their emotions and behaviors, and frequency and satisfaction with social participation were assessed via self- and parent-report questionnaires developed for this project. Behavior problems, social competence, and social problems were measured by using the Child Behavior Checklist and the Youth Self-Report. High levels of participant and parent satisfaction were reported. Increases in parent-reported frequency of social participation and teen-reported confidence in their ability to participate and develop social participation goals and plans were observed. A decline in parent-reported total problems, internalizing problems, externalizing problems, and social problems was noted. Results support the feasibility of the program, because participants were able to successfully meet with their coaches and use the app to develop and accomplish social participation goals. Further research will be needed to refine the app and program, particularly when reaching out to populations beyond traumatic brain injury. (PsycINFO Database Record


Estimating grizzly and black bear population abundance and trend in Banff National Park using noninvasive genetic sampling.
We evaluated the potential of two noninvasive genetic sampling methods, hair traps and bear rub surveys, to estimate population abundance and trend of grizzly (Ursus arctos) and black bear (U. americanus) populations in Banff National Park, Alberta, Canada. Using Huggins closed population mark-recapture models, we obtained the first precise abundance estimates for grizzly bears (N= 73.5, 95% CI = 64-94 in 2006; N= 50.4, 95% CI = 49-59 in 2008) and black bears (N= 62.6, 95% CI = 51-89 in 2006; N= 81.8, 95% CI = 72-102 in 2008) in the Bow Valley. Hair traps had high detection rates for female grizzlies, and male and female black bears, but extremely low detection rates for male grizzlies. Conversely, bear rubs had high detection rates for male and female grizzlies, but low rates for black bears. We estimated realized population growth rates, lambda, for grizzly bear males (λ= 0.93, 95% CI = 0.74-1.17) and females (λ= 0.90, 95% CI = 0.67-1.20) using Pradel open population models with three years of bear rub data. Lambda estimates are supported by abundance estimates from combined hair trap/bear rub closed population models and are consistent with a system that is likely driven by high levels of human-caused mortality. Our results suggest that bear rub surveys would provide an efficient and powerful means to inventory and monitor grizzly bear populations in the Central Canadian Rocky Mountains.


The state of the field: from inception to commercialization of metal-organic frameworks.
As chemists and materials scientists, it is our duty to synthesize and utilize materials for a multitude of applications that promote the development of society and the well-being of its citizens. Since the inception of metal-organic frameworks (MOFs), researchers have proposed a variety of design strategies to rationally synthesize new MOF materials, studied their porosity and gas sorption performances, and integrated MOFs onto supports and into devices. Efforts have explored the relevance of MOFs for applications including, but not limited to, heterogeneous catalysis, guest delivery, water capture, destruction of nerve agents, gas storage, and separation. Recently, several start-up companies have undertaken MOF commercialization within industrial sectors. Herein, we provide a brief overview of the state of the MOF field from their design and synthesis to their potential applications, and finally, to their commercialization.


Access to housing as a structural intervention for homeless and unstably housed people living with HIV: rationale, methods, and implementation of the housing and health study.
Homelessness and unstable housing have been associated with HIV risk behavior and poorer health among persons living with HIV/AIDS (PLWHA), yet prior research has not tested causal associations. This paper describes the challenges, methods, and baseline sample of the Housing and Health Study, a longitudinal, multi-site, randomized controlled trial investigating the effects of providing immediate rental housing assistance to PLWHA who were homeless or at severe risk of homelessness. Primary outcomes included HIV disease progression, medical care access and utilization, treatment adherence, mental and physical health, and risks of transmitting HIV. Across three study sites, 630 participants completed baseline sessions and were randomized to receive either immediate rental housing assistance (treatment group) or assistance finding housing according to local standard practice (comparison group). Baseline sessions included a questionnaire, a two-session HIV risk-reduction counseling intervention, and blood sample collection to measure CD4 counts and viral load levels. Three follow-up visits occurred at 6, 12, and 18 months after baseline. Participants were mostly male, Black, unmarried, low-income, and nearly half were between 40 and 49 years old. At 18 months, 84% of the baseline sample was retained. The retention rates demonstrate the feasibility of conducting scientifically rigorous housing research, and the baseline results provide important information regarding characteristics of this understudied population that can inform future HIV prevention and treatment efforts.


Cardiac transplant outcome of patients supported on left ventricular assist device vs. intravenous inotropic therapy.
Although the left ventricular assist device (LVAD) has been increasingly used as a bridge to transplant, its effect on post-transplant outcome is uncertain. We, therefore, designed this study using the Cardiac Transplant Research Database to compare patients supported on an LVAD before transplant with those treated with intravenous inotropic medical therapy. Of the 5,880 patients transplanted between 1990 and 1997, a total of 502 received support from LVADs and 2,514 received intravenous inotropic medical therapy at the time of transplant. Kaplan-Meier analysis showed no significant difference in post-transplant survival between the LVAD and medical-therapy groups (p = 0.09). Results of a multivariate Cox regression analysis were consistent with that of the Kaplan-Meier analysis and did not identify LVAD as a significant risk factor for mortality. The percentage of patients who received LVADs as a function of total transplants increased from 2% in 1990 to 16% in 1997. Furthermore, although the number of extracorporeal LVADs remained relatively constant, the number of intracorporeal LVADs increased over time. Multivariate parametric analysis found that the risk factors for post-transplant death in the LVAD group were extracorporeal LVAD use (p = 0.0004), elevated serum creatinine (p = 0.05), older donor age (p = 0.03), increased donor ischemic time (p < 0.0001), and earlier year of transplant (p = 0.03). Given a limited donor supply, the intracorporeal LVAD helps the sickest patients survive to transplant and provides post-transplant outcome similar to that of patients supported on inotropic medical therapy. Therefore, patients supported on LVADs before transplant may receive the greatest marginal benefit when compared with other transplant candidates.


Protein kinase Cβ is required for lupus development in Sle mice.
To evaluate the requirement for protein kinase Cβ (PKCβ) in the development of lupus in mice, and to explore the potential of targeting PKCβ as a therapeutic strategy in lupus. Congenic mice bearing the disease loci Sle1 or Sle1 and Sle3, which represent different stages of severity in the development of lupus, were crossed with PKCβ-deficient mice. The effect of PKCβ deficiency in lupus development was analyzed. In addition, the effects of the PKCβ-specific inhibitor enzastaurin on the survival of B cells from mice with lupus and human 9G4-positive B cells as well as the in vivo effect of enzastaurin treatment on the development of lupus in Sle mice were investigated. In Sle mice, PKCβ deficiency abrogated lupus-associated phenotypes, including high autoantibody levels, proteinuria, and histologic features of lupus nephritis. Significant decreases in spleen size and in the peritoneal B-1 cell population, reduced numbers of activated CD4 T cells, and normalized CD4:CD8 ratios were observed. PKCβ deficiency induced an anergic B cell phenotype and preferentially inhibited autoreactive plasma cells and autoantibodies in mice with lupus. Inhibition of PKCβ enhanced apoptosis of both B cells from Sle mice and human autoreactive B cells (9G4 positive). Treatment of Sle mice with the PKCβ-specific inhibitor enzastaurin prevented the development of lupus. This study identifies PKCβ as a central mediator of lupus pathogenesis, suggesting that PKCβ represents a promising therapeutic target for the treatment of systemic lupus erythematosus. Moreover, the results indicate the feasibility of using a PKCβ inhibitor for the treatment of lupus.


Identification of Cysteine Ubiquitylation Sites on the Sec23A Protein of the COPII Complex Required for Vesicle Formation from the ER.
COPII is a multiprotein complex that surrounds carrier vesicles budding from the Endoplasmic Reticulum and allows the recruitment of secretory proteins. The Sec23a protein plays a crucial role in the regulation of the dynamics of COPII formation ensuring the proper function of the secretory pathway. Since few evidences suggest that ubiquitylation could have a role in the COPII regulation, the present study was aimed to establish whether the Sec23a component of the vesicular envelope COPII could be ubiquitylated. Sec23a ubiquitylation was revealed by co-immunoprecipitation experiments. Recombinant Sec23a was gel-purified and analyzed by mass spectrometry subjected to trypsin proteolysis. Signature peptides were identified by the presence of Gly-Gly remnants from the C-terminus of the ubiquitin attached to the amino acid residues of the substrate. Recombinant Sec23a proteins bearing mutations in the ubiquitylation sites were used to evaluate the effect of ubiquitylation in the formation of COPII. We identified two cysteine ubiquitylation sites showed at position 432 and 449 of the Sec23a protein sequence. Interestingly, we revealed that the amino acid residues of Sec23a joined to ubiquitin were cysteine instead of the conventional lysine residues. This unconventional ubiquitylation consists of the addition of one single ubiquitin moiety that is not required for Sec23a degradation. Immunofluorescence results showed that Sec23a ubiquitylation might influence COPII formation by modulating Sec23a interaction with the ER membrane. Presumably, this regulation could occur throughout continual ubiquitylation/de-ubiquityliation cycles. Our results suggest a novel regulatory mechanism for the Sec23a function that could be crucial in several pathophysiological events known to alter COPII recycling.


Safety and tolerability of the rivastigmine patch: results of a 28-week open-label extension.
The primary objective of the open-label extension was to evaluate the long-term safety and tolerability of a transdermal rivastigmine patch up to 1 year, as a novel approach to treatment in Alzheimer disease. This was a 28-week extension to a 24-week, double-blind, double-dummy, placebo-controlled, and active-controlled study evaluating rivastigmine patches [9.5 mg/24 h (10 cm2) and 17.4 mg/24 h (20 cm2)] and oral capsules (3 to 6 mg twice-daily). Patients entering the extension were switched directly to 9.5 mg/ 24 h rivastigmine patch and increased to 17.4 mg/24 h patch, irrespective of their double-blind study treatment. Primary measures included safety and tolerability assessments, including adverse events and serious adverse events. Of 1195 patients randomized to treatment, 870 (72.8%) completed the double-blind study and entered the open-label extension. During weeks 1 to 4 of the extension, 9.5 mg/24 h rivastigmine patch was well tolerated overall by patients formerly randomized to rivastigmine capsule or patch groups: < or =2.5% reported nausea and < or =1.9% reported vomiting. No unexpected safety issues arose, and skin tolerability was good; similar to the double-blind study. During the 28-week, open-label extension phase, the patch seemed to be well tolerated with a favorable safety profile.


Point mutations in yeast CBF5 can abolish in vivo pseudouridylation of rRNA.
In budding yeast (Saccharomyces cerevisiae), the majority of box H/ACA small nucleolar RNPs (snoRNPs) have been shown to direct site-specific pseudouridylation of rRNA. Among the known protein components of H/ACA snoRNPs, the essential nucleolar protein Cbf5p is the most likely pseudouridine (Psi) synthase. Cbf5p has considerable sequence similarity to Escherichia coli TruBp, a known Psi synthase, and shares the "KP" and "XLD" conserved sequence motifs found in the catalytic domains of three distinct families of known and putative Psi synthases. To gain additional evidence on the role of Cbf5p in rRNA biosynthesis, we have used in vitro mutagenesis techniques to introduce various alanine substitutions into the putative Psi synthase domain of Cbf5p. Yeast strains expressing these mutated cbf5 genes in a cbf5Delta null background are viable at 25 degrees C but display pronounced cold- and heat-sensitive growth phenotypes. Most of the mutants contain reduced levels of Psi in rRNA at extreme temperatures. Substitution of alanine for an aspartic acid residue in the conserved XLD motif of Cbf5p (mutant cbf5D95A) abolishes in vivo pseudouridylation of rRNA. Some of the mutants are temperature sensitive both for growth and for formation of Psi in the rRNA. In most cases, the impaired growth phenotypes are not relieved by transcription of the rRNA from a polymerase II-driven promoter, indicating the absence of polymerase I-related transcriptional defects. There is little or no abnormal accumulation of pre-rRNAs in these mutants, although preferential inhibition of 18S rRNA synthesis is seen in mutant cbf5D95A, which lacks Psi in rRNA. A subset of mutations in the Psi synthase domain impairs association of the altered Cbf5p proteins with selected box H/ACA snoRNAs, suggesting that the functional catalytic domain is essential for that interaction. Our results provide additional evidence that Cbf5p is the Psi synthase component of box H/ACA snoRNPs and suggest that the pseudouridylation of rRNA, although not absolutely required for cell survival, is essential for the formation of fully functional ribosomes.


Testosterone-mediated regulation of mouse renal cytochrome P-450 isoenzymes.
We have studied the extent to which mouse renal cytochrome P-450 isoenzymes are sexually differentiated, and the factor(s) regulating this dimorphism. Intriguingly, sex differences were not seen in the expression of a single cytochrome P-450 enzyme, but were observed in the expression of all P-450 isoenzymes detectable, encoded by six gene families or sub-families. This effect was mediated by testosterone, which had the capacity to both induce and repress P-450 gene expression, and which was independent of growth hormone. The changes in protein content were mirrored in all but one case by changes in the levels of mRNA, indicating that these genes contain hormone-responsive elements. These findings are consistent with numerous reports of sex differences in the susceptibility of the mouse kidney to the toxic and carcinogenic effects of drugs and environmental chemicals, many of which are metabolized to cytotoxic products by the cytochrome P-450-dependent mono-oxygenases. These data imply that circulating androgen levels will be an important factor in susceptibility of the kidney to toxic or carcinogenic compounds which require metabolic activation.


Bayesian model selection for group studies.
Bayesian model selection (BMS) is a powerful method for determining the most likely among a set of competing hypotheses about the mechanisms that generated observed data. BMS has recently found widespread application in neuroimaging, particularly in the context of dynamic causal modelling (DCM). However, so far, combining BMS results from several subjects has relied on simple (fixed effects) metrics, e.g. the group Bayes factor (GBF), that do not account for group heterogeneity or outliers. In this paper, we compare the GBF with two random effects methods for BMS at the between-subject or group level. These methods provide inference on model-space using a classical and Bayesian perspective respectively. First, a classical (frequentist) approach uses the log model evidence as a subject-specific summary statistic. This enables one to use analysis of variance to test for differences in log-evidences over models, relative to inter-subject differences. We then consider the same problem in Bayesian terms and describe a novel hierarchical model, which is optimised to furnish a probability density on the models themselves. This new variational Bayes method rests on treating the model as a random variable and estimating the parameters of a Dirichlet distribution which describes the probabilities for all models considered. These probabilities then define a multinomial distribution over model space, allowing one to compute how likely it is that a specific model generated the data of a randomly chosen subject as well as the exceedance probability of one model being more likely than any other model. Using empirical and synthetic data, we show that optimising a conditional density of the model probabilities, given the log-evidences for each model over subjects, is more informative and appropriate than both the GBF and frequentist tests of the log-evidences. In particular, we found that the hierarchical Bayesian approach is considerably more robust than either of the other approaches in the presence of outliers. We expect that this new random effects method will prove useful for a wide range of group studies, not only in the context of DCM, but also for other modelling endeavours, e.g. comparing different source reconstruction methods for EEG/MEG or selecting among competing computational models of learning and decision-making.


Loss of bone density with inhaled triamcinolone in Lung Health Study II.
Inhaled glucocorticosteroids (ICS) are commonly prescribed for chronic obstructive pulmonary disease. No adverse effect on bone mineral density (BMD) has been proven. In a randomized double-blind, placebo-controlled trial at seven centers in North America, we recruited 412 current smokers or recent quitters with mild to moderate chronic obstructive pulmonary disease. They used inhaled triamcinolone acetonide, 600 mcg, or placebo, twice daily. We measured femoral neck and lumbar spine BMD at baseline and after 1 and 3 years, and serum osteocalcin at baseline, 3 months, 1 year, and 3 years. After 3 years, BMD at the femoral neck decreased 1.78% more with ICS than with placebo (p < 0.001). More participants in the ICS group experienced 6% or more loss of femoral neck BMD (p = 0.002). Lumbar spine BMD increased in the placebo group by 0.98% but decreased by 0.35% in the ICS group (a difference of 1.33%, p = 0.007). Changes in osteocalcin did not correlate with changes in BMD. Fractures, lost height, or osteoporosis diagnoses were not increased among ICS users compared with placebo users. In summary, the use of inhaled triamcinolone acetonide was associated with loss of BMD at the femoral neck and lumbar spine after 3 years of treatment.


Evolutionary and ecological causes of the latitudinal diversity gradient in hylid frogs: treefrog trees unearth the roots of high tropical diversity.
Why are there more species in the tropics than in temperate regions? In recent years, this long-standing question has been addressed primarily by seeking environmental correlates of diversity. But to understand the ultimate causes of diversity patterns, we must also examine the evolutionary and biogeographic processes that directly change species numbers (i.e., speciation, extinction, and dispersal). With this perspective, we dissect the latitudinal diversity gradient in hylid frogs. We reconstruct a phylogeny for 124 hylid species, estimate divergence times and diversification rates for major clades, reconstruct biogeographic changes, and use ecological niche modeling to identify climatic variables that potentially limit dispersal. We find that hylids originated in tropical South America and spread to temperate regions only recently (leaving limited time for speciation). There is a strong relationship between the species richness of each region and when that region was colonized but not between the latitudinal positions of clades and their rates of diversification. Temperature seasonality seemingly limits dispersal of many tropical clades into temperate regions and shows significant phylogenetic conservatism. Overall, our study illustrates how two general principles (niche conservatism and the time-for-speciation effect) may help explain the latitudinal diversity gradient as well as many other diversity patterns across taxa and regions.


Ethnoveterinary knowledge of farmers in bilingual regions of Switzerland - is there potential to extend veterinary options to reduce antimicrobial use?
In the pre-antibiotic era, a broad spectrum of medicinal plants was used to treat livestock. This knowledge was neglected in European veterinary medicine for decades but kept alive by farmers. Emergence of multidrug resistant bacterial strains requires a severely restricted use of antibiotics in veterinary medicine. We conducted a survey on the ethnoveterinary knowledge of farmers in the bilingual (French and German speaking) Western region of Switzerland, namely the cantons of Fribourg, Neuchâtel and Jura, and in the French speaking part of the canton of Bern. To find out whether differences exist in plants used by farmers in French speaking and bilingual regions of Switzerland as compared to our earlier studies conducted in Switzerland. Additional focus was on plants that are used in diseases which commonly are treated with antimicrobials, on plants used in skin afflictions, and on plants used in animal species such as horses, for which the range of veterinary medicinal products is limited. We conducted in 2015 semistructured interviews with 62 dialog partners, mainly cattle keeping farmers but also 18 horse keeping farmers. Of these, 41 were native French (FNS) and 21 native German speakers (GNS). Detailed information about homemade herbal remedies (plant species, plant part, manufacturing process) and the corresponding use reports (target animal species, category of use, route of administration, dosage, source of knowledge, frequency of use, last time of use and farmers satisfaction) were collected. A total of 345 homemade remedies were reported, of which 240 contained only one plant species (Homemade Single Species Herbal Remedy Reports; HSHR). A total of 289 use reports (UR) were mentioned for the 240 HSHR, and they comprised 77 plant species belonging to 41 botanical families. Of these, 35 plant species were solely reported from FNS, 20 from GNS, and 22 from both. Taking into account earlier ethnoveterinary studies conducted in Switzerland only 10 (FNS) and 6 (GNS) plant species connected with 7% of FNS and GNS UR respectively were "unique" to the respective language group. The majority of the UR (219) was for treatment of cattle, while 38 UR were intended to treat horses. The most UR were for treatment of gastrointestinal and skin diseases. The most frequently mentioned plants were Linum usitatissimum L., Coffea L., Matricaria chamomilla L., Camellia sinensis (L.) Kuntze, and Quercus robur L. for gastrointestinal diseases, and Calendula officinalis L., Hypericum perforatum L. and Sanicula europaea L. for skin afflictions. No clear differences were found between the medicinal plants used by French native speakers and German native speakers. Several of the reported plants seem to be justified to widen the spectrum of veterinary therapeutic options in gastrointestinal and dermatological disorders in cattle and horses, and to reduce, at least to a certain degree, the need for antibiotic treatments. Our findings may help to strengthen the role of medicinal plants in veterinary research and practice, and to consider them as a further measure in official strategies for lowering the use of antibiotics.


Chemotherapy for pain: reversing inflammatory and neuropathic pain with the anticancer agent mithramycin A.
The persistence of inflammatory and neuropathic pain is poorly understood. We investigated a novel therapeutic paradigm by targeting gene networks that sustain or reverse persistent pain states. Our prior observations found that Sp1-like transcription factors drive the expression of TRPV1, a pain receptor, that is blocked in vitro by mithramycin A (MTM), an inhibitor of Sp1-like factors. Here, we investigate the ability of MTM to reverse in vivo models of inflammatory and chemotherapy-induced peripheral neuropathy (CIPN) pain and explore MTM's underlying mechanisms. Mithramycin reversed inflammatory heat hyperalgesia induced by complete Freund adjuvant and cisplatin-induced heat and mechanical hypersensitivity. In addition, MTM reversed both short-term and long-term (1 month) oxaliplatin-induced mechanical and cold hypersensitivity, without the rescue of intraepidermal nerve fiber loss. Mithramycin reversed oxaliplatin-induced cold hypersensitivity and oxaliplatin-induced TRPM8 overexpression in dorsal root ganglion (DRG). Evidence across multiple transcriptomic profiling approaches suggest that MTM reverses inflammatory and neuropathic pain through broad transcriptional and alternative splicing regulatory actions. Mithramycin-dependent changes in gene expression following oxaliplatin treatment were largely opposite to and rarely overlapped with changes in gene expression induced by oxaliplatin alone. Notably, RNAseq analysis revealed MTM rescue of oxaliplatin-induced dysregulation of mitochondrial electron transport chain genes that correlated with in vivo reversal of excess reactive oxygen species in DRG neurons. This finding suggests that the mechanism(s) driving persistent pain states such as CIPN are not fixed but are sustained by ongoing modifiable transcription-dependent processes.


Absence of P-selectin delays fatty streak formation in mice.
P-selectin is expressed on activated endothelium and platelets where it can bind monocytes, neutrophils, stimulated T cells, and platelets. Because recruitment of these cells is critical for atherosclerotic lesion development, we examined whether P-selectin might play a role in atherosclerosis. We intercrossed P-selectin-deficient mice with mice lacking the low density lipoprotein receptor (LDLR) because these mice readily develop atherosclerotic lesions on diets rich in saturated fat and cholesterol. The atherogenic diet stimulated leukocyte rolling in the mesenteric venules of LDLR-deficient mice, and the increase in adhesiveness of the vessels was P-selectin-dependent. Most likely due to the reduced leukocyte interaction with the vessel wall, P-selectin-deficient mice on diet for 8-20 wk formed significantly smaller fatty streaks in the cusp region of the aortae than did P-selectin-positive mice. This difference was more prominent in males. At 37 wk on diet, the lesions in the LDLR-deficient animals progressed to the fibrous plaque stage and were distributed throughout the entire aorta; their size or distribution was no longer dependent on P-selectin. Our results show that P-selectin-mediated adhesion is an important factor in the development of early atherosclerotic lesions, and that adhesion molecules such as P-selectin are involved in the complex process of atherosclerosis.


nNOS gene deletion exacerbates pathological left ventricular remodeling and functional deterioration after myocardial infarction.
The neuronal isoform of nitric oxide synthase (nNOS) has been implicated in the regulation of basal and beta-adrenergic inotropy in normal and chronically infarcted hearts. Furthermore, myocardial nNOS expression and activity increase in failing hearts, raising the possibility that nNOS may influence left ventricular (LV) remodeling progression and functional deterioration after myocardial infarction (MI). We compared LV remodeling at 1, 4, and 8 weeks after MI in nNOS-knockout mice (nNOS(-/-)) and their wild-type (WT) littermates matched for infarct size by using a highly accurate 3-dimensional echocardiographic technique. Basal LV hemodynamics and the inotropic response to dobutamine infusion (4 and 16 ng.g(-1).min(-1)) were also evaluated 8 weeks after MI. Sham-operated nNOS(-/-) mice showed enhanced basal LV contractility (P<0.03 versus WT, as evaluated by preload-recruitable stroke work) but an attenuated inotropic response to dobutamine infusion (P<0.01 versus WT). Both basal and beta-adrenergic LV relaxations were significantly impaired in nNOS(-/-) mice. Survival after MI did not differ between groups. However, nNOS(-/-) mice developed a faster and more severe LV dilation compared with WT mice (P<0.05 for both end-systolic and end-diastolic volume indices). WT mice maintained a positive inotropic response to dobutamine 8 weeks after MI. In contrast, infarcted nNOS(-/-) mice responded to dobutamine with a dramatic fall in LV contractility (P<0.01 for preload-recruitable stroke work). nNOS plays a crucial role in preventing adverse LV remodeling and maintaining myocardial beta-adrenergic reserve after MI. Taken together, our findings suggest that upregulation of myocardial nNOS in infarcted hearts may be an important adaptive mechanism.


Integument colouration in relation to persistent organic pollutants and body condition in arctic breeding black-legged kittiwakes (Rissa tridactyla).
Vertebrates cannot synthetize carotenoids de novo but have to acquire them through their diet. In birds, carotenoids are responsible for the yellow to red colouration of many secondary sexual traits. They are also involved in physiological functions such as immunostimulation and immunoregulation. Consequently, carotenoid-based colouration is very often considered as a reliable signal for health and foraging abilities. Although a few studies have suggested that carotenoid-based coloured traits could be sensitive to environmental pollution such as persistent organic pollutants (POPs) contamination, the relationships between pollutants and colouration remain unclear. Here, we examined the relationships between the colouration of carotenoid-based integuments and individual POP levels in pre-laying female black-legged kittiwakes from very high latitudes. In this area, these arctic seabirds are exposed to high POPs contamination. Additionally, we investigated the relationships between colouration and body condition, a frequently used index of individual quality. We found a negative relationship between POP levels and several components of integument colouration: saturation of eye-ring, gapes and tongue, suggesting that POPs could disrupt colouration of labile integuments in female kittiwakes. In addition, we found that females in better body condition displayed more orange and brighter gapes and tongue than females in poor body condition. These results demonstrate that hue and brightness are sensitive to the current health and nutritional status of female kittiwakes. Overall, our study shows that carotenoid-based colour integuments can be affected by several environmental-driven variables.


FOXO4-dependent upregulation of superoxide dismutase-2 in response to oxidative stress is impaired in spinocerebellar ataxia type 3.
Ataxin-3 (ATXN3), the disease protein in spinocerebellar ataxia type 3 (SCA3), binds to target gene promoters and modulates transcription by interaction with transcriptional regulators. Here, we show that ATXN3 interacts with the forkhead box O (FOXO) transcription factor FOXO4 and activates the FOXO4-dependent transcription of the manganese superoxide dismutase (SOD2) gene. Upon oxidative stress, ATXN3 and FOXO4 translocate to the nucleus, concomitantly bind to the SOD2 gene promoter and increase the expression of the antioxidant enzyme SOD2. Compared with normal ATXN3, mutant ATXN3 has a reduced capability to activate the FOXO4-mediated SOD2 expression and interferes with binding of FOXO4 to the SOD2 gene promoter. These findings are consistent with a downregulation of SOD2 in pontine brain tissue and lymphoblastoid cell (LC) lines of SCA3 patients. In response to oxidative stress, LCs from SCA3 patients show a specific impairment to upregulate SOD2 expression in correlation with a significantly increased formation of reactive oxygen species and cytotoxicity. The impairment to increase the expression of SOD2 under oxidative stress conditions is associated with a significantly reduced binding of FOXO4 to the SOD2 gene promoter in SCA3-LCs. Finally and consistent with a regulatory role of ATXN3 in SOD2 expression, knockdown of endogenous ATXN3 by RNA interference represses the expression of SOD2. These findings support that ATXN3 plays an important role in regulating the FOXO4-dependent antioxidant stress response via SOD2 and suggest that a decreased antioxidative capacity and increased susceptibility towards oxidative stress contributes to neuronal cell death in SCA3.


Physician Parents Attending Work Despite Own Sick Children: A Qualitative Study on Caregiver Presenteeism Among Norwegian Hospital Physicians.
Studies have shown that physicians manifest a clear duty to work, even in the face of personal risk, and despite their own symptoms of ill health; this is termed presenteeism. We lack knowledge on their willingness to attend work when their children are sick or in times of concern for their unborn; this is termed caregiver presenteeism. To gain a comprehensive knowledge on the occurrence of presenteeism among physicians, it is important to include caregiver presenteeism. The aim of this study is to explore the perception and experience with caregiver presenteeism among hospital physicians who are parents or pregnant and to explore its foundations and its consequences. Secondary thematic analysis of semi-structured interviews of hospital physicians (N = 18). Positive and negative dimensions associated with (1) situations with severe pregnancy symptoms or responsibility for sick children; (2) the perceived impact on their work commitments, personal health, and adequate care for own children; (3) accompanying moderators in the organisational structure and professional culture; and (4) proposed approaches to resolve caregiver and work responsibilities simultaneously contributing to caregiver presenteeism. The study underlines the impact of factors in organisational structure, professional culture, and the personal sphere affecting caregiver presenteeism. It appears that targeting factors contributing to attendance pressure in physicians, including those who are pregnant, is particularly important. This includes changing attitudes towards caregiver responsibilities among physician colleagues, department leaders, and physicians themselves, as well as simple cost-efficient organisational interventions in staffing, routines of absence, and work adjustment.


Exercise prescription for patients with type 2 diabetes and pre-diabetes: a position statement from Exercise and Sport Science Australia.
Type 2 diabetes mellitus (T2DM) and pre-diabetic conditions such as impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) are rapidly increasing in prevalence. There is compelling evidence that T2DM is more likely to develop in individuals who are insufficiently active. Exercise training, often in combination with other lifestyle strategies, has beneficial effects on preventing the onset of T2DM and improving glycaemic control in those with pre-diabetes. In addition, exercise training improves cardiovascular risk profile, body composition and cardiorespiratory fitness, all strongly related to better health outcomes. Based on the evidence, it is recommended that patients with T2DM or pre-diabetes accumulate a minimum of 210 min per week of moderate-intensity exercise or 125 min per week of vigorous intensity exercise with no more than two consecutive days without training. Vigorous intensity exercise is more time efficient and may also result in greater benefits in appropriate individuals with consideration of complications and contraindications. It is further recommended that two or more resistance training sessions per week (2-4 sets of 8-10 repetitions) should be included in the total 210 or 125 min of moderate or vigorous exercise, respectively. It is also recommended that, due to the high prevalence and incidence of comorbid conditions in patients with T2DM, exercise training programs should be written and delivered by individuals with appropriate qualifications and experience to recognise and accommodate comorbidities and complications.


Strategies to improve tumor penetration of nanomedicines through nanoparticle design.
Nanoparticles (NPs) have emerged as an effective means to deliver therapeutic drugs for cancer treatment, as they can preferentially accumulate at tumor site through the enhanced permeability and retention effect. Various forms of NPs including liposomes, polymeric micelles, and inorganic particles have been used for therapeutic applications. However, the therapeutic benefits of nanomedicines are suboptimal. Although many possible reasons may account for the compromised therapeutic efficacy, the inefficient tumor penetration can be a vital obstacle. Tumor develops characteristic pathological environment, such as abnormal vasculature, elevated interstitial fluid pressure, and dense extracellular matrix, which intrinsically hinder the transport of nanomedicines in the tumor parenchyma. The physicochemical properties of the NPs such as size, shape, and surface charge have profound effect on tumor penetration. In this review, we will highlight the factors that affect the transport of NPs in solid tumor, and then elaborate on designing strategies to improve NPs' penetration and uniform distribution inside the tumor interstitium. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.