First Report of Catharanthus mosaic virus in Mandevilla in the United States.
Mandevilla (Apocynaceae) is an ornamental tropical vine popular for its bright and attractive flowers. During 2012 to 2013, 12 Mandevilla sp. samples from Minnesota and Florida nurseries were submitted for analysis at the University of Minnesota Plant Disease Clinic. Plants showed mosaic symptoms, leaf deformation, premature leaf senescence, and vine dieback. Filamentous virus particles with modal lengths 700 to 900 nm were observed by transmission electron microscopy (TEM) in partially purified preparations from symptomatic leaves. Partially purified virions were obtained using 30% sucrose cushion centrifuged at 109,000 gmax for 2 h at 10°C (5). No other virus particles were observed in these samples, nor were any observed in non-symptomatic samples. One sample was submitted as potted plant (Mandevilla 'Sunmandeho' Sun Parasol Giant White) and was kept under greenhouse conditions for subsequent analyses. Total RNA (Qiagen) was extracted from this sample, and Potyvirus was detected using the universal primers Poty S (5'-GGN AAY AAY AGY GGN CAR CC-3') and PV1 (5'-20(T)V-3') (1) by reverse transcription (RT)-PCR (3). The amplified product was the expected ~1.7-kb, corresponding to the partial nuclear inclusion body gene, the coat protein (CP) gene, and the 3' end untranslated region. The RT-PCR amplicon was cloned (NEB) and sequenced, and the 1,720-bp consensus sequence was deposited in GenBank (Accession No. KM243928). NCBI BLAST analysis at the nucleotide level revealed highest identity (83%) with an isolate of Catharanthus mosaic virus (CatMV) from Brazil (Accession No. DQ365928). Pairwise analysis of the predicted 256 amino acid CP revealed 91% identity with the CatMV Brazilian isolate (ABI94824) and 68% or less identity with other potyviruses. Two potyviruses are usually considered the same species if their CP amino acid sequences are greater than 80% identical (2). Serological analysis of the infected sample Mandevilla 'Sunmandeho' Sun Parasol Giant White using a CatMV specific antiserum (4) resulted in positive indirect ELISA reactions. CatMV has been previously reported in periwinkle (Catharanthus roseus) in Brazil (4). Based on the analyses by TEM, RT-PCR, nucleotide and amino acid sequence identities, and serological reactivity, we identify this virus as a U.S. Mandevilla isolate of CatMV. To our knowledge, this is the first report of Catharanthus mosaic virus both in the United States and in Mandevilla. References: (1) J. Chen et al. Arch Virol. 146:757, 2001. (2) A. Gibbs and K. Ohshima. Ann. Rev. Phytopathol. 48:205, 2010. (3) R. L. Jordan et al. Acta Hortic. 901:159, 2011. (4) S. C. Maciell et al. Sci. Agric. Piracicaba, Brazil. 68:687, 2011. (5) D. Mollov et al. Arch Virol. 158:1917, 2013.


An electrophysiological study of the effects of orthographic neighborhood size on printed word perception.
In two experiments participants read words and pseudowords that belonged to either large or small lexical neighborhoods while event-related brain potentials (ERPs) were recorded from their scalps. In Experiment 1, participants made speeded lexical decisions to all items, while in Experiment 2 they engaged in a go/no-go semantic categorization task in which the critical items did not require an overt behavioral response. In both experiments, words and pseudowords produced a consistent pattern of ERP effects: items with many lexical neighbors (large neighborhoods) generated larger N400s than similar items with relatively fewer lexical neighbors (small neighborhoods). Reaction time (RT, Experiment 1), on the other hand, showed a different pattern consistent with previous behavioral studies. While words tended to produce a facilitation in RT for larger neighborhoods, pseudowords produced an inhibition effect. The findings are discussed in terms of recent theories of word recognition and the functional significance of the N400.


Challenges encountered and lessons learnt from venous injuries at Sri Lankan combat theatres.
The objective of this study was to characterise the spectrum of peripheral venous injury in the Sri Lankan war theatres, including categorisation of anatomic patterns, mechanism and management of casualties, including short-term results of surgical repair of traumatic venous injuries versus ligation. In addition, the effects and outcome of combined arterial and venous injuries versus arterial injury alone are compared. All adults with extremity vascular injuries admitted to a military base hospital during an 8-month period were prospectively recorded and those with a venous injury were analysed. A total of 123 vascular injuries were recorded in the study period, of which 70 had a venous injury, combined with an arterial injury in 58 (83%) and in isolation in 12 (17%). There were 43 transections, 26 lateral tears and a single through and through penetrating injury. Twenty-five (36%) vein injures were repaired and 45 ligated. Only six popliteal veins were repaired in 21 lower limbs that underwent arterial revascularisation. In the combined arterial/venous injuries group 13 primary amputations were performed and five delayed amputations were necessary. There were no amputations in the isolated venous injury group. There were three deaths (4.3%), 18 infections with four cultures positive for pseudomonas species, five arterial graft thromboses were recorded. There were significantly more blood transfusions and concomitant skeletal injuries, resulting in more amputations, in combined arterial and venous injuries in comparison with arterial injury alone (all p values<0.05). In an ideal setting, venous injuries should be repaired when possible and tolerated by the patient in order to ameliorate the risk of thrombotic and infectious complications. An aggressive use of shunting, fasciotomies and venous repair in wartime limb injuries at echelon structured care may prevent preventable limb loss in these challenging case scenarios.


Heritability of life satisfaction in adults: a twin-family study.
Subjective well-being (SWB) can be partitioned into the components life satisfaction and affect. Research on factors influencing these components of well-being has mainly focused on environmental characteristics. The aim of this study was to investigate the relative contribution of genes and environment to individual differences in life satisfaction in a large sample of Dutch twins and their singleton siblings. Life satisfaction of 5668 subjects registered with The Netherlands Twin Registry (NTR) was measured with a Dutch version of the self-reported Satisfaction with Life Scale. An extended twin design was used to obtain correlations in life satisfaction scores for monozygotic twins, dizygotic twins and sibling pairs and to estimate the contribution of genes and environment to the variation in life satisfaction. No differences between males and females were found in the mean level of life satisfaction. Broad-sense heritability was 38%. Non-additive genetic factors explained all or most of the genetic influences. The remaining 62% of the variance in life satisfaction could be attributed to unique environmental factors, both persistent and transitory, plus measurement error. Individual differences in life satisfaction are determined in part by genetic factors that are largely or entirely non-additive in nature.


Altered central alpha 2-adrenoceptor sensitivity in panic disorder.
The possibility that a disorder of brain alpha 2-adrenoceptor sensitivity might contribute to the etiology of panic disorder was examined using a challenge paradigm with the alpha 2-adrenoceptor agonist clonidine. The cardiovascular, psychological, and endocrine actions of 1.5-microgram/kg clonidine hydrochloride given intravenously were assessed in 16 patients and compared with age- and sex-matched controls. Patients with panic disorder showed an increased fall in blood pressure and decreased sedative and endocrine responses as compared with controls. These results suggest that there may be subsensitivity of some, and supersensitivity of other, brain alpha 2-adrenoceptors in panic disorder. In view of the increased cardiovascular responses seen in the present study and other reports of increased responses to the alpha 2-adrenoceptor antagonist yohimbine, there may exist an increased lability (decreased damping) of cardiovascular control mechanisms in panic disorder. Such a dysfunction could contribute to the symptoms of panic attacks, such as dizziness, palpitations, and faintness.


Antiplatelet loading improves behavioral outcome in a rabbit model of stroke.
No approved acute therapy exists for thousands of patients with ischemic stroke who present ineligible for thrombolytics. The purpose of this proof-of-concept study was to evaluate the efficacy of acute antiplatelet loading on stroke outcome in the rabbit small clot embolic model. Sixty male New Zealand white rabbits were embolized via small clots into the middle cerebral artery. Two hours later, animals were treated with (1) aspirin (5 mg/kg; n=20); (2) usual dual antiplatelet loading (aspirin 10 mg/kg+clopidogrel 10 mg/kg; n=20); or (3) high-dose dual antiplatelet loading (aspirin 10 mg/kg+clopidogrel 30 mg/kg; n=20). The coprimary outcomes were as follows: (1) platelet inhibition and (2) behavioral outcome as measured by the P50 (milligrams of clot that leads to neurological dysfunction in 50% of animals in a group). There was a significant difference in 3-hour arachidonic acid and ADP (P<0.011); 6-hour collagen and ADP (P<0.01, P<0.01); and 24-hour collagen, arachidonic acid, and ADP (P=0.02, P<0.01, P<0.01) platelet inhibition. The behavioral outcome was significantly better in the usual dual antiplatelet loading versus aspirin group (P=0.02). This study suggests that usual dual antiplatelet loading is clinically beneficial in a validated model of acute stroke. Study of usual dual antiplatelet loading in acute stroke is warranted to provide treatment to stroke victims ineligible for current therapies.


Longitudinal cognitive decline in the AIBL cohort: The role of APOE ε4 status.
The ε4 polymorphism of the APOE gene confers a substantially increased risk of developing Alzheimer's disease. However, the influence of the ε4 allele on age-related cognitive functioning is more contentious. Previously, we demonstrated relatively little evidence for a role of the ε4 allele on baseline cognitive performance in older adults in the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing (Foster et al., 2013). We here investigated whether the APOE ε4 allele influenced cognitive status over time when the AIBL cohort was studied longitudinally over a 3-year period. The AIBL neuropsychological test battery was administered at baseline, after 18 months and again after 36 months. Participants comprised 764 Healthy Controls and 131 Mild Cognitively Impaired individuals enrolled in the AIBL Study of Ageing. We compared individuals within each group with and without an ε4 allele. Healthy Controls with an ε4 allele manifested a modest acceleration in cognitive decline over 36 months on measures of verbal episodic memory. By contrast, Mild Cognitively Impaired individuals with an ε4 allele showed increased cognitive decline across a range of cognitive tasks, putatively reflecting early cognitive signs of Alzheimer's disease. Given the long prodromal period that has been noted in late onset Alzheimer's disease, we suggest that these findings are consistent with a prodromal account rather than a phenotypic account of ε4-related cognitive ageing.


Descending adrenergic input to the primate spinal cord and its possible role in modulation of spinothalamic cells.
The present study focuses on 3 different aspects of the descending adrenergic system in the primate: (1) the distribution of adrenergic fibers and terminals in the spinal cord, (2) the source of this input and (3) the possible physiological effects of this system on spinal nociceptive processing. Antibodies to the enzyme phenylethanolamine-N-methyltransferase (PNMT) were employed to map the distribution of epinephrine-containing axonal profiles in the primate spinal cord. Smooth longitudinally oriented fibers were localized to the outer edge of the lateral funiculus. PNMT-containing axonal enlargements were distributed to the superficial dorsal horn, intermediate gray matter and the region surrounding the central canal at all spinal cord levels. PNMT-immunostained profiles were also observed in the intermediolateral cell column. A double labeling study employing retrograde transport of HRP from the spinal cord and PNMT immunohistochemistry identified a small population of HRP-PNMT-labeled neurons in the 'C1' region at the levels of the medulla and ponto-medullary junction. Thus, these cells are a probable source of adrenergic input to the spinal cord. Electrophysiological studies demonstrated that iontophoresis of epinephrine onto identified primate spinothalamic tract neurons in the lumbar dorsal horn resulted in inhibition of the glutamate-induced firing of these cells. The data from these studies support the hypothesis that adrenergic (PNMT-containing) cells in the caudal brainstem project to all levels of the cord and may contribute to descending modulation of nociceptive processing at these levels.


Uncertainty-Adjusted Translation for Preference-Sensitive Decision Support.
In Multi-Criteria Decision Analysis-based decision support for person-centred care, the person's quantitative preferences (as criterion weightings) are combined with quantified evidence and expert assessments (as option performance ratings on all criteria) to produce a personalised quantified opinion (as a set of expected value option scores). In our current decision support tools, we use the best available (central point) estimates for option performance ratings. The uncertainty surrounding the performance rating estimates, routinely reported by researchers as intervals around the means, are ignored. While defensible, this paper responds to questioning of this disregard. Apart from the inappropriate 'inverse variance' method, we find no attempt to integrate parameter uncertainty into decision analyses, simply an emphasis on reporting it fully, leaving decision makers unsupported in the burden of dealing with the separated outputs - e.g. Means and Credible Intervals. The paper suggests that uncertainty can be brought within Multi-Criteria Decision Analysis-based decision support by treating the means and uncertainties of all outcomes and process considerations as separate criteria, having them traded-off in an individually preference-sensitive manner at the point of decision. An empirical proof of method via an online example on bone health medications is provided, involving six options, two considerations and four criteria.


A highly selective dual-therapeutic nanosystem for simultaneous anticancer and antiangiogenesis therapy.
The rational design of highly selective and cancer-targeted nanodrug delivery systems with attractive anticancer activities is urgently needed for future exploration and translational application of nanomedicine. As angiogenesis and tumor growth could be mutually enhanced, dual therapeutic nanomedicine with simultaneous antiangiogenesis and anticancer activities is practical for cancer therapy. Therefore, herein we have rationally designed functionalized mesoporous silica nanoparticles (MSNs) to realize the dual therapy of tumor growth and angiogenesis based on the biochemical similarity of membranes of cancer cells and angiogenic cells. This nanosystem demonstrates high selectivity in vivo against cancer cells with high integrin expression levels in two-tumor bearing models, and could simultaneously inhibit cancer cell growth and disrupt tumor neovasculature, thus achieving satisfactory in vivo anticancer efficacy. Interestingly, the nanosystem triggers ROS overproduction in both cancer and human umbilical vein endothelial cells, which activates various downstream signaling pathways to regulate cell cycle arrest and apoptosis. Moreover, the nanosystem also effectively reduces the toxic side effects of loaded drugs to normal tissues and prolongs blood circulation in vivo. Therefore, this study provides a simple approach for facile manufacture of a potent nanodrug delivery system that could achieve dual therapy of tumor growth and angiogenesis.


Systematic identification of latent disease-gene associations from PubMed articles.
Recent scientific advances have accumulated a tremendous amount of biomedical knowledge providing novel insights into the relationship between molecular and cellular processes and diseases. Literature mining is one of the commonly used methods to retrieve and extract information from scientific publications for understanding these associations. However, due to large data volume and complicated associations with noises, the interpretability of such association data for semantic knowledge discovery is challenging. In this study, we describe an integrative computational framework aiming to expedite the discovery of latent disease mechanisms by dissecting 146,245 disease-gene associations from over 25 million of PubMed indexed articles. We take advantage of both Latent Dirichlet Allocation (LDA) modeling and network-based analysis for their capabilities of detecting latent associations and reducing noises for large volume data respectively. Our results demonstrate that (1) the LDA-based modeling is able to group similar diseases into disease topics; (2) the disease-specific association networks follow the scale-free network property; (3) certain subnetwork patterns were enriched in the disease-specific association networks; and (4) genes were enriched in topic-specific biological processes. Our approach offers promising opportunities for latent disease-gene knowledge discovery in biomedical research.


Novel TRAF1-ALK fusion identified by deep RNA sequencing of anaplastic large cell lymphoma.
Chromosomal translocations leading to expression of abnormal fusion proteins play a major role in the pathogenesis of various hematologic malignancies. The recent development of high-throughput, "deep" sequencing has allowed discovery of novel translocations leading to a rapid increase in understanding these diseases. Translocations involving the anaplastic lymphoma kinase (ALK) gene leading to ALK fusion proteins originally were discovered in anaplastic large cell lymphomas (ALCLs). Among ALCLs, NPM1-ALK fusions are most common and lead to nuclear localization of the fusion protein. Here, we present a 50-year-old male with ALCL demonstrating cytoplasmic ALK immunoreactivity only, suggesting the presence of a non-NPM1 fusion partner. We performed deep RNA sequencing of tumor tissue from this patient and identified a novel transcript fusing Exon 6 of TRAF1 to Exon 20 of ALK. The TRAF1-ALK fusion transcript was confirmed at the mRNA level by Sanger sequencing and the fusion protein was visualized by Western blot. The discovery of this TRAF1-ALK fusion expands the diversity of known ALK fusion partners and highlights the power of deep sequencing for fusion transcript discovery. © 2013 Wiley Periodicals, Inc.


68Ga-Sienna+ for PET-MRI Guided Sentinel Lymph Node Biopsy: Synthesis and Preclinical Evaluation in a Metastatic Breast Cancer Model.
Sentinel lymph node biopsy (SLNB) is commonly performed in cancers that metastasise via the lymphatic system. It involves excision and histology of sentinel lymph nodes (SLNs) and presents two main challenges: (i) sensitive whole-body localisation of SLNs, and (ii) lack of pre-operative knowledge of their metastatic status, resulting in a high number (>70%) of healthy SLN excisions. To improve SLNB, whole-body imaging could improve detection and potentially prevent unnecessary surgery by identifying healthy and metastatic SLNs. In this context, radiolabelled SPIOs and PET-MRI could find applications to locate SLNs with high sensitivity at the whole-body level (using PET) and guide high-resolution MRI to evaluate their metastatic status. Here we evaluate this approach by synthesising a GMP-compatible 68Ga-SPIO (68Ga-Sienna+) followed by PET-MR imaging and histology studies in a metastatic breast cancer mouse model. Methods. A clinically approved SPIO for SLN localisation (Sienna+) was radiolabelled with 68Ga without a chelator. Radiochemical stability was tested in human serum. In vitro cell uptake was compared between 3E.Δ.NT breast cancer cells, expressing the hNIS reporter gene, and macrophage cell lines (J774A.1; RAW264.7.GFP). NSG-mice were inoculated with 3E.Δ.NT cells. Left axillary SLN metastasis was monitored by hNIS/SPECT-CT and compared to the healthy right axillary SLN. 68Ga-Sienna+ was injected into front paws and followed by PET-MRI. Imaging results were confirmed by histology. Results.68Ga-Sienna+ was produced in high radiochemical purity (>93%) without the need for purification and was stable in vitro. In vitro uptake of 68Ga-Sienna+ in macrophage cells (J774A.1) was significantly higher (12 ± 1%) than in cancer cells (2.0 ± 0.1%; P < 0.001). SPECT-CT confirmed metastasis in the left axillary SLNs of tumour mice. In PET, significantly higher 68Ga-Sienna+ uptake was measured in healthy axillary SLNs (2.2 ± 0.9 %ID/mL), than in metastatic SLNs (1.1 ± 0.2 %ID/mL; P = 0.006). In MRI, 68Ga-Sienna+ uptake in healthy SLNs was observed by decreased MR signal in T2/T2*-weighted sequences, whereas fully metastatic SLNs appeared unchanged. Conclusion.68Ga-Sienna+ in combination with PET-MRI can locate and distinguish healthy from metastatic SLNs and could be a useful preoperative imaging tool to guide SLN biopsy and prevent unnecessary excisions.


Upregulation of vascular endothelial growth factor by cobalt chloride-simulated hypoxia is mediated by persistent induction of cyclooxygenase-2 in a metastatic human prostate cancer cell line.
Upregulation of vascular endothelial growth factor (VEGF) expression induced by hypoxia is crucial event leading to neovascularization. Cyclooxygenase-2, an inducible enzyme that catalyzes the formation of prostaglandins (PGs) from arachidonic acid, has been demonstrated to be induced by hypoxia and play role in angiogenesis and metastasis. To investigate the potential effect of COX-2 on hypoxia-induced VEGF expression in prostate cancer. We examined the relationship between COX-2 expression and VEGF induction in response to cobalt chloride (CoCl2)-simulated hypoxia in three human prostate cancer cell lines with differing biological phenotypes. Northern blotting and ELISA revealed that all three tested cell lines constitutively expressed VEGF mRNA, and secreted VEGF protein to different degrees (LNCaP > PC-3 > PC3ML). However, these cell lines differed in the ability to produce VEGF in the presence of CoCl2-simulated hypoxia. CoCl2 treatment resulted in 40% and 75% increases in VEGF mRNA, and 50% and 95% in protein secretion by LNCaP and PC-3 cell lines, respectively. In contrast, PC-3ML cell line, a PC-3 subline with highly invasive, metastatic phenotype, exhibits a dramatic upregulation of VEGF, 5.6-fold in mRNA and 6.3-fold in protein secretion after treatment with CoCl2. The upregulation of VEGF in PC-3ML cells is accompanied by a persistent induction of COX-2 mRNA (6.5-fold) and protein (5-fold). Whereas COX-2 expression is only transiently induced in PC-3 cells and not affected by CoCl2 in LNCaP cells. Moreover, the increases in VEGF mRNA and protein secretion induced by CoCl2 in PC-3ML cells were significantly suppressed following exposure to NS398, a selective COX-2 inhibitor. Finally, the effect of COX-2 inhibition on CoCl2-induced VEGF production was reversed by the treatment with exogenous PGE2. Our data demonstrate that VEGF induction by cobalt chloride-simulated hypoxia is maintained by a concomitant, persistent induction of COX-2 expression and sustained elevation of PGE2 synthesis in a human metastatic prostate cancer cell line, and suggest that COX-2 activity, reflected by PGE2 production, is involved in hypoxia-induced VEGF expression, and thus, modulates prostatic tumor angiogenesis.


Ca(2+)-dependent regulation of vascular smooth-muscle caldesmon by S.100 and related smooth-muscle proteins.
1. We have investigated the ability of bovine brain S.100, and of three related proteins from sheep aorta smooth muscle, to confer Ca(2+)-sensitivity on thin filaments reconstituted from smooth-muscle actin, tropomyosin and caldesmon. 2. At 37 degrees C in pH 7.0 buffer containing 120 mM-KCl, approximately stoichiometric amounts of S.100 reversed caldesmon's inhibition of the activation of myosin MgATPase by smooth-muscle actin-tropomyosin. The [S.100] which reversed by 50% the inhibition by caldesmon (the E.C.50) was 2.5 microM when [caldesmon] = 2-3 microM in the assay mixture. When [KCl] was decreased to 70 mM, E.C.50 = 11.5 microM; at 25 degrees C in 70 mM-KCl, up to 20 microM-S.100 had no effect. When skeletal-muscle actin rather than smooth-muscle actin was used to reconstitute thin filaments, 20 microM-S.100 did reverse inhibition by caldesmon, at 25 degrees C in buffer containing 70 mM-KCl. This dependence on conditions is also characteristic of the calmodulin-caldesmon interaction. 3. These results suggested that S.100 or a related protein might interact with caldesmon in smooth muscle. We therefore attempted to prepare such a protein from sheep aorta. Three proteins were purified: an Mr-17,000 protein (yield 16 mg/kg), an abundant Mr-11,000 protein (yield 48 mg/kg), and an Mr-9000 protein (yield 4 mg/kg). Neither of the last two low-Mr proteins had any effect on activation of myosin MgATPase by reconstituted thin filaments. The protein of Mr 17,000 had Ca(2+)-sensitizing activity, and behaved exactly like brain calmodulin in the assay system.


Multicilin promotes centriole assembly and ciliogenesis during multiciliate cell differentiation.
Multiciliate cells function prominently in the respiratory system, brain ependyma and female reproductive tract to produce vigorous fluid flow along epithelial surfaces. These specialized cells form during development when epithelial progenitors undergo an unusual form of ciliogenesis, in which they assemble and project hundreds of motile cilia. Notch inhibits multiciliate cell formation in diverse epithelia, but how progenitors overcome lateral inhibition and initiate multiciliate cell differentiation is unknown. Here we identify a coiled-coil protein, termed multicilin, which is regulated by Notch and highly expressed in developing epithelia where multiciliate cells form. Inhibiting multicilin function specifically blocks multiciliate cell formation in Xenopus skin and kidney, whereas ectopic expression induces the differentiation of multiciliate cells in ectopic locations. Multicilin localizes to the nucleus, where it directly activates the expression of genes required for multiciliate cell formation, including foxj1 and genes mediating centriole assembly. Multicilin is also necessary and sufficient to promote multiciliate cell differentiation in mouse airway epithelial cultures. These findings indicate that multicilin initiates multiciliate cell differentiation in diverse tissues, by coordinately promoting the transcriptional changes required for motile ciliogenesis and centriole assembly.


Panel-integration of natural light and the related system of light guiding and illumination.
This Letter proposes an idea of a natural light illumination system by using a light collecting panel. The light collecting panel is coupled with a light guide followed by a specifically designed lens to achieve uniform illumination on a target screen. To assess the system specification, we build a primary model in three-dimensional modeling software and make ray tracing simulation based on a Monte Carlo algorithm. The simulation results show a relatively high efficiency of 41.41% for the entire system and achieve a high uniformity of more than 0.8 within the circular illumination area.


Higher Physical Activity Is Related to Lower Neck Adiposity in Young Men, but to Higher Neck Adiposity in Young Women: An Exploratory Study.
The role of lifestyle behaviors on neck adipose tissue (NAT), a fat depot that appears to be involved in the pathogenesis of different cardiometabolic diseases and in inflammatory status, is unknown. In this cross-sectional and exploratory study, the authors examined the relationship between sedentary time and physical activity (PA) with neck adiposity in young adults. A total of 134 subjects (69% women, 23 ± 2 years) were enrolled. The time spent in sedentary behavior and PA of different intensity were objectively measured for 7 consecutive days (24 hr/day), using a wrist (nondominant)-worn accelerometer. The NAT volume was assessed using computed tomography, and the compartmental (subcutaneous, intermuscular, and perivertebral) and total NAT volumes were determined at the level of vertebra C5. Anthropometric indicators and body composition (by dual-energy X-ray absorptiometry) were determined. The time spent in light physical activity and moderate physical activity (MPA) and the overall PA were inversely associated with the intermuscular NAT volume in men, as were the MPA and overall PA with total NAT volume (all ps ≤ .04). Sedentary time was directly related to the total NAT volume (p = .04). An opposite trend was observed in women, finding a direct relationship of MPA with the subcutaneous NAT; of light physical activity, MPA, and overall PA with the perivertebral NAT; and of light physical activity with total NAT volumes (all ps ≤ .05). The observed associations were weak, and after adjusting for multiplicity, the results became nonsignificant (p > .05). These findings suggest that the specific characteristics of PA (time and intensity) might have sex-dependent implications in the accumulation of NAT.


Recommendations for the Reporting of Harms in Manuscripts on Clinical Trials Assessing Osteoarthritis Drugs: A Consensus Statement from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO).
There is strong evidence of under-reporting of harms in manuscripts on randomized controlled trials (RCTs) compared with the volume of raw data retrieved from these trials. Many guidelines have been developed to tackle this, but they have failed to address some important issues that would allow for standardization and transparency. As a consequence, harms reporting in manuscripts remains suboptimal. The European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) aimed to deliver accurate recommendations for better reporting of harms in clinical trials manuscripts on anti-osteoarthritis (OA) drugs. These could help to better inform clinicians on harms recorded in RCTs and further help researchers conducting meta-analyses. Using the outcomes of several systematic reviews on the safety of anti-OA drugs, we summarized the ways in which harms have been reported in OA RCT manuscripts to date. Next, we drafted some recommendations and initiated a modified Delphi process that involved a panel of clinicians and clinical researchers to build an expert consensus on recommendations from the ESCEO for the reporting of harms in future manuscripts on RCTs assessing anti-OA drugs. These recommendations emphasize that all treatment-emergent adverse events (AEs) should always be taken into account for harms reporting, with no frequency threshold, and describe how specific AEs should be reported; they also provide a list of the most relevant organ systems to be considered according to each class of drug for reporting of harms within the results section of a manuscript. Irrespective of the drug, the ESCEO recommends that total, severe and serious AEs and withdrawals due to AEs should always be reported; guidance on the reporting of specific events pertaining to each category is provided. The ESCEO also recommends the reporting of information on drug effect on biological parameters, with specific guidance. These recommendations may contribute to improve transparency in the field of safety of anti-OA medications. Pharmaceutical companies developing drugs for OA, and researchers conducting clinical trials, are encouraged to comply with them when reporting harms-related results in manuscripts on RCTs. The ESCEO also encourages journals to refer to the ESCEO recommendations in their instructions to authors for the publication of manuscripts on trials of anti-OA medications.


Effects of alteplase on survival after ischaemic stroke (IST-3): 3 year follow-up of a randomised, controlled, open-label trial.
The effect of alteplase on patient survival after ischaemic stroke is the subject of debate. We report the effect of intravenous alteplase on long-term survival after ischaemic stroke of participants in the Third International Stroke Trial (IST-3). In IST-3, done at 156 hospitals in 12 countries (Australia, Europe, and the UK), participants (aged >18 years) were randomly assigned with a telephone voice-activated or web-based system in a 1:1 ratio to treatment with intravenous 0·9 mg/kg alteplase plus standard care or standard care alone within 6 h of ischaemic stroke. We followed up participants in the UK and Scandinavia (Sweden and Norway) for survival up to 3 years after randomisation using data from national registries and compared survival in the two groups with proportional hazards survival analysis, adjusting for key prognostic variables. IST-3 is registered with the ISRCTN registry, number ISRCTN25765518. Between May 5, 2000, and July 27, 2011, 3035 participants were enrolled in IST-3. Of these, 1948 (64%) of 3035 participants were scheduled for analysis of 3 year survival, and 1946 (>99%) of these were included in the analysis (967 [50%] in the alteplase plus standard care group and 979 [50%] in the standard care alone group). By 3 years after randomisation, 453 (47%) of 967 participants in the alteplase plus standard care group and 494 (50%) of 979 in the standard care alone group had died (risk difference 3·6% [95% CI -0·8 to 8·1]). Participants allocated to alteplase had a significantly higher hazard of death during the first 7 days (99 [10%] of 967 died in the alteplase plus standard care group vs 65 [7%] of 979 in the standard care alone group; hazard ratio 1·52 [95% CI 1·11-2·08]; p=0·004) and a significantly lower hazard of death between 8 days and 3 years (354 [41%] of 868 vs 429 [47%] of 914; 0·78 [0·68-0·90]; p=0·007). Alteplase treatment within 6 h after ischaemic stroke was associated with a small, non-significant reduction in risk of death at 3 years, but among individuals who survived the acute phase, treatment was associated with a significant increase in long-term survival. These results are reassuring for clinicians who have expressed concerns about the effect of alteplase on survival. Heart and Stroke Scotland, UK Medical Research Council, Health Foundation UK, Stroke Association UK, Research Council of Norway, AFA Insurance, Swedish Heart Lung Fund, Foundation of Marianne and Marcus Wallenberg, Polish Ministry of Science and Education, Australian Heart Foundation, Australian National Health and Medical Research Council, Swiss National Research Foundation, Swiss Heart Foundation, Assessorato alla Sanita (Regione dell'Umbria), and Danube University.


[Energy expenditure of adults in the city of Niterói, state of Rio de Janeiro: nutrition, Physical activity and Health Survey--PNAFS].
The accurate assessment of energy expenditure (EE) and of the physical activity level (PAL) is important for establishing the energy requirements (ER) of populations. Little is known about these variables in the Brazilian population. The purpose of the present study was to assess EE and PAL in the adult population (> 20 years) of Niterói, RJ. An adapted version of the MOSPA time-budget questionnaire was used to assess the duration of the daily activities of the subjects. The energy cost of the activities was obtained from the table published by FAO in 2004, expressed as multiples of the basal metabolic rate (BMR) measured by indirect calorimetry. Total daily EE (TDEE) was calculated as the sum of EE of all activities of a typical daily routine. TDEE was higher in males than in females (2382.0 + 38.0 and 1987.1 + 22.9 kcal.day-1 respectively) but women showed higher PAL values (1.70 + 0.02 and 1.75 + 0.01 respectively). ER estimated using a PAL of 1.40 was the best predictor of EE of the population in all nutritional status categories, particularly for males. In conclusion, it seems prudent to use lower PAL values when estimating the ER of the adult population of Niterói. It is also evident that more data on the energy cost of activities must be generated for establishing the ER of the Brazilian population.


Navier-Stokes Equations Do Not Describe the Smallest Scales of Turbulence in Gases.
In turbulent flows, kinetic energy is transferred from the largest scales to progressively smaller scales, until it is ultimately converted into heat. The Navier-Stokes equations are almost universally used to study this process. Here, by comparing with molecular-gas-dynamics simulations, we show that the Navier-Stokes equations do not describe turbulent gas flows in the dissipation range because they neglect thermal fluctuations. We investigate decaying turbulence produced by the Taylor-Green vortex and find that in the dissipation range the molecular-gas-dynamics spectra grow quadratically with wave number due to thermal fluctuations, in agreement with previous predictions, while the Navier-Stokes spectra decay exponentially. Furthermore, the transition to quadratic growth occurs at a length scale much larger than the gas molecular mean free path, namely in a regime that the Navier-Stokes equations are widely believed to describe. In fact, our results suggest that the Navier-Stokes equations are not guaranteed to describe the smallest scales of gas turbulence for any positive Knudsen number.


Evaluating spatial surveillance: detection of known outbreaks in real data.
Since the anthrax attacks of October 2001 and the SARS outbreaks of recent years, there has been an increasing interest in developing surveillance systems to aid in the early detection of such illness. Systems have been established which do this is by monitoring primary health-care visits, pharmacy sales, absenteeism records, and other non-traditional sources of data. While many resources have been invested in establishing such systems, relatively little effort has as yet been expended in evaluating their performance. One way to evaluate a given surveillance system is to compare the signals it generates with known outbreaks identified in other systems. In public health practice, for example, public health departments investigate reports of illness and sometimes track hospital admissions. Comparison of new systems with extant systems cannot generate estimates of test characteristics such as sensitivity and specificity, since the actual number of positives and negatives cannot be known. However, the comparison can reveal whether a new or proposed system's signals match outbreaks detected by the existing system. This could help support or reject the new system as an alternative or complement to the extant system. We propose three methods to test the null hypothesis that the new system does not signal true outbreaks more often than would be expected by chance. The methods differ in the restrictiveness of the assumptions required. Each test may detect weaknesses in the new system, depending on the distribution of outbreaks and can be used to construct confidence limits on the agreement between the new system's signals and the outbreaks, given the distribution of the signals. They can be used to assess whether the new system works in that it detects the outbreaks better than chance would suggest and can also determine if the new systems' signals are generated earlier than an extant system.


Clinical and financial burdens of secondary level care in a public sector antiretroviral roll-out setting (G. F. Jooste Hospital).
Antiretroviral therapy (ART) is being extended across South Africa. While efforts have been made to assess the costs of providing ART via accredited service points, little information is available on its downstream costs, particularly in public secondary level hospitals. To determine the cost of care for inpatients and outpatients at a dedicated antiretroviral referral unit treating and caring for antiretroviral-related conditions in a South African peri-urban setting; to identify key epidemiological cost drivers; and to examine the associated clinical and outcome data. A prospective costing study on 48 outpatients and 25 inpatients was conducted from a health system perspective. Incremental economic costs and clinical data were collected from primary sources at G. F. Jooste Hospital, Cape Town, over a 1-month period (March 2005). Incremental cost per outpatient was R1 280, and per inpatient R5 802. Costs were dominated by medical staff costs (62% inpatient and 58% outpatient, respectively). Infections predominated among diagnoses and costs--55% and 67% respectively for inpatients, and 49% and 54% respectively for outpatients. Most inpatients and outpatients were judged by attending physicians to have improved or stabilised as a result of treatment (52% and 59% respectively). The costs of providing secondary level care for patients on or immediately preceding ART initiation can be significant and should be included in the government's strategic planning: (i) so that the service can be expanded to meet current and future needs; and (ii) to avoid crowding out other secondary level health services.


Gender differences in reading and writing achievement: Evidence from the National Assessment of Educational Progress (NAEP).
A frequently observed research finding is that females outperform males on tasks of verbal and language abilities, but there is considerable variability in effect sizes from sample to sample. The gold standard for evaluating gender differences in cognitive ability is to recruit a large, demographically representative sample. We examined 3 decades of U.S. student achievement in reading and writing from the National Assessment of Educational Progress to determine the magnitude of gender differences (N = 3.9 million), and whether these were declining over time as claimed by Feingold (1988). Examination of effect sizes found a developmental progression from initially small gender differences in Grade 4 toward larger effects as students progress through schooling. Differences for reading were small-to-medium (d = -.32 by Grade 12), and medium-sized for writing (d = -.55 by Grade 12) and were stable over the historical time. Additionally, there were pronounced imbalances in gender ratios at the lower left and upper right tails of the ability spectrum. These results are interpreted in the context of Hyde's (2005) gender similarities hypothesis, which holds that most psychological gender differences are only small or trivial in size. Language and verbal abilities represent one exception to the general rule of gender similarities, and we discuss the educational implications of these findings. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Developmental trajectory of social influence integration into perceptual decisions in children.
The opinions of others have a profound influence on decision making in adults. The impact of social influence appears to change during childhood, but the underlying mechanisms and their development remain unclear. We tested 125 neurotypical children between the ages of 6 and 14 years on a perceptual decision task about 3D-motion figures under informational social influence. In these children, a systematic bias in favor of the response of another person emerged at around 12 years of age, regardless of whether the other person was an age-matched peer or an adult. Drift diffusion modeling indicated that this social influence effect in neurotypical children was due to changes in the integration of sensory information, rather than solely a change in decision behavior. When we tested a smaller cohort of 30 age- and IQ-matched autistic children on the same task, we found some early decision bias to social influence, but no evidence for the development of systematic integration of social influence into sensory processing for any age group. Our results suggest that by the early teens, typical neurodevelopment allows social influence to systematically bias perceptual processes in a visual task previously linked to the dorsal visual stream. That the same bias did not appear to emerge in autistic adolescents in this study may explain some of their difficulties in social interactions.


A missense mutation in TUBD1 is associated with high juvenile mortality in Braunvieh and Fleckvieh cattle.
Haplotypes with reduced or missing homozygosity may harbor deleterious alleles that compromise juvenile survival. A scan for homozygous haplotype deficiency revealed a short segment on bovine chromosome 19 (Braunvieh haplotype 2, BH2) that was associated with high juvenile mortality in Braunvieh cattle. However, the molecular genetic underpinnings and the pathophysiology of BH2 remain to be elucidated. The frequency of BH2 was 6.5 % in 8,446 Braunvieh animals from the national bovine genome databases. Both perinatal and juvenile mortality of BH2 homozygous calves were higher than the average in Braunvieh cattle resulting in a depletion of BH2 homozygous adult animals (P = 9.3x10(-12)). The analysis of whole-genome sequence data from 54 Braunvieh animals uncovered a missense mutation in TUBD1 (rs383232842, p.H210R) that was compatible with recessive inheritance of BH2. The availability of sequence data of 236 animals from diverse bovine populations revealed that the missense mutation also segregated at a low frequency (1.7 %) in the Fleckvieh breed. A validation study in 37,314 Fleckvieh animals confirmed high juvenile mortality of homozygous calves (P = 2.2x10(-15)). Our findings show that the putative disease allele is located on an ancestral haplotype that segregates in Braunvieh and Fleckvieh cattle. To unravel the pathophysiology of BH2, six homozygous animals were examined at the animal clinic. Clinical and pathological findings revealed that homozygous calves suffered from chronic airway disease possibly resulting from defective cilia in the respiratory tract. A missense mutation in TUBD1 is associated with high perinatal and juvenile mortality in Braunvieh and Fleckvieh cattle. The mutation is located on a common haplotype likely originating from an ancient ancestor of Braunvieh and Fleckvieh cattle. Our findings demonstrate for the first time that deleterious alleles may segregate across closed cattle breeds without recent admixture. Homozygous calves suffer from chronic airway disease resulting in poor growth performance and high juvenile mortality. The respiratory manifestations resemble key features of diseases resulting from impaired function of airway cilia.


The localized requirements for a gene affecting segmentation in Drosophila: analysis of larvae mosaic for runt.
The runt gene is required in a developing Drosophila embryo for proper segmentation. Mutant embryos fail to hatch but secrete a larval cuticle in which pattern defects are apparent. In runt embryos, there are pattern deletions spaced at two segment intervals along the antero-posterior axis of the animal. The deleted regions are replaced by mirror-image duplications of the remaining regions. This paper investigates the localized requirements for runt+ activity by analyzing the segmentation patterns in larval genetic mosaics. This analysis is aided by the faintoid and shavenbaby mutations which affect larval cuticle morphology without affecting segmentation. These two mutations serve as markers of the regions of larval cuticle secreted by genetically runt cells. The analysis of the runt mosaic patterns indicates the effects of the gene on segmentation are primarily cell autonomous. This includes both the pattern deletions and the associated mirror-image duplications. This indicates the mirror-image duplications are not due to regeneration but result from a more direct effect of runt on patterning in the embryo. The mosaic patterns also reveal other aspects of the process of pattern formation in the larval epidermis. Based on these results a model is presented for the generation of the larval pattern.


Antioxidant, anti-inflammatory and anti-fibrotic effects of Boswellia serrate gum resin in CCl4-induced hepatotoxicity.
The present study aims to investigate the potential antioxidant, anti-inflammatory and anti-fibrotic effects of Boswellia serrate (BS) gum resin against carbon tetrachloride (CCl4)-induced liver damage. Four groups consisting of eight rats each were designated: Group I, normal healthy control; group II, CCl4-induced liver fibrosis; group III, CCl4-induced liver fibrosis followed by BS treatment daily for two weeks; and group IV, CCl4-induced liver fibrosis followed by silymarin treatment daily for two weeks. Expression of tumor necrosis factor-α (TNF-α) and nuclear factor κB (NF-κB), interleukin-6 (IL-6), transforming growth factor-β (TGF-β) and cyclooxygenase-2 (COX-2) were assessed, in addition to histopathological and fibrotic changes in liver tissues isolated from the rats. BS significantly ameliorated CCl4-induced increases in serum aspartate (AST) and alanine transaminase (ALT) levels, reduced lactate dehydrogenase (LDH) activities in addition to restoring total bilirubin, triglyceride and albumin levels. BS treatment also alleviated oxidative stress and improved total antioxidant capacity in the liver, and reduced the expression of TNF-α, NF-κB, TGF-β, IL-6 and COX-2. On a histopathological level, BS treatment also exhibited antifibrotic activity. In conclusion, these findings suggest that BS contains potentially hepatoprotective effects against CCl4-induced liver injury via its antioxidant, anti-inflammatory and antifibrotic characteristics.


Immunohistochemical analysis of inflammatory limbal conjunctiva adjacent to Mooren's ulcer.
To examine the characteristics of infiltrating cells in conjunctival tissues adjacent to the peripheral corneal ulcers of Mooren's ulcer. This study involved four eyes of four patients with Mooren's ulcer and who were considered to be in need of surgical treatment. The patients' resected conjunctival tissues were embedded and frozen. The tissue sections were then subjected to H&E and immunohistochemical staining. The stained sections were observed and the characteristics of the infiltrating cells in the conjunctival tissues were pathologically examined. In all patients, infiltration of inflammatory cells was observed in the submucosal connective tissue of the conjunctiva. Immunohistochemical analysis revealed inflammatory cell infiltration into the submucosal layer of the conjunctiva that was mainly composed of CD3-positive and CD45RO-positive cells. Some of these cells also showed positive reactivity with CD4, yet very few cells showed positive reactivity with CD8. In addition, infiltration of the cells indicating CD68 positivity was frequent in a few cases. In the four Mooren's ulcer cases, infiltrating cells in the submucosa of the conjunctival tissues adjacent to the ulcerative cornea were found to be mainly composed of helper T lymphocytes and macrophages. Our results show that helper T cells and macrophages contribute to the pathogenesis of Mooren's ulcer.


Antenatal screening for Down syndrome with special considerations in the Puerto Rican population.
Down syndrome is the most studied chromosomal abnormality, and the risk of having a child with Down syndrome increases as maternal age increases. The prevalence of Down syndrome has been increasing in the last decade because more women older than 35 years of age are having children. In recent decades, the rate of identification of fetal anomalies in the uterus has substantially increased. Diagnostically speaking, serious concerns yet remain within the obstetrical community regarding who should be recommended for invasive procedures. The FASTER, SURUSS, and BUN studies have attempted to address this issue. In the United States, the quadruple screen for Down syndrome (hcG, AFP, estriol, and inhibin-A) is the most commonly used test today. During the first trimester, the nuchal translucency measurement combined with serum markers hcG and PAPP-A (pregnancy-associated plasma protein-A) results in high detection rates and low false-positive rates. For Down syndrome screening, new methods of evaluation have been proposed; among these are integrated, sequential, and contingent modalities. Different trials have demonstrated that first-trimester screening for Down syndrome is very effective, but all conclude that combining screening during both trimesters allows for lower false-positive values and higher detection rates. In Puerto Rico, in spite of the fact that a large proportion of the population undergoes serum screening, the rate of Down syndrome live births remains steady. One important aspect that appears to limit prenatal diagnosis of Down syndrome in our population is a poor acceptance rate of diagnostic testing techniques such as amniocentesis. Also, a limited efficiency in the implementation of these screening methods as well as their diagnostic success has been observed for our patient population.


A cross-associative neural network for SVD of non-squared data matrix in signal processing.
This paper proposes a cross-associative neural network (CANN) for singular value decomposition (SVD) of a non-squared data matrix in signal processing, in order to improve the convergence speed and avoid the potential instability of the deterministic networks associated with the cross-correlation neural-network models. We study the global asymptotic stability of the network for tracking all the singular components, and show that the selection of its learning rate in the iterative algorithm is independent of the singular value distribution of a non-squared matrix. The performances of CANN are shown via simulations.


Treatment of carcinoma of the sigmoid colon and upper rectum. A comparison of local segmental resection and left hemicolectomy.
We report a retrospective study of 107 cases of carcinoma of the sigmoid colon and upper rectum treated for primary cure at the University of California at Los Angeles Hospital between 1955 and 1970. Excluded from this analysis were patients treated by abdominoperineal resection, local excision, fulguration, or abdominoperineal pull-through procedures. Ninety-one patients were treated by local segmental resection and 16 by left hemicolectomy. Both groups were similar in regard to patient age and general health, lesion size, location, and pathological Duke's classification. Five-year survival was 70.3% after local segmental resection and 56.3% after left hemicolectomy. Hospital mortality was 1% after the former and 6.2% after the latter. Rate of recurrence after local segmental resection was 41% of that seen after left hemicolectomy, while complications were one-third as great. The present results after local segmental resection are comparable to the results reported in the literature when hemicolectomy was the procedure used. The data presented suggest that local segmental resection is an effective cancer operation for carcinoma of the sigmoid and upper rectum, and is fraught with a lesser morbidity and mortality than a radical left hemicolectomy.


The Effectiveness and Mechanism of Toona sinensis Extract Inhibit Attachment of Pandemic Influenza A (H1N1) Virus.
TSL-1 is a fraction of the aqueous extract from the tender leaf of Toona sinensis Roem, a nutritious vegetable. The pandemic influenza A (H1N1) virus is a recently described, rapidly contagious respiratory pathogen which can cause acute respiratory distress syndrome (ARDS) and poses a major public health threat. In this study, we found that TSL-1 inhibited viral yields on MDCK plaque formation by pandemic influenza A (H1N1) virus on infected A549 cells with high selectivity index. Meanwhile, TSL-1 also suppressed viral genome loads in infected A549 cells, quantified by qRT-PCR. This study further demonstrated that TSL-1 inhibited pandemic influenza A (H1N1) virus activity through preventing attachment of A549 cells but not penetration. TSL-1 inhibited viral attachment through significant downregulation of adhesion molecules and chemokines (VCAM-1, ICAM-1, E-selectin, IL-8, and fractalkine) compared to Amantadine. Our results suggest that TSL-1 may be used as an alternative treatment and prophylaxis against pandemic influenza A (H1N1) virus.


Interleukin 13 inhibits human immunodeficiency virus type 1 production in primary blood-derived human macrophages in vitro.
The mechanisms by which cellular immunity maintains the asymptomatic state after human immunodeficiency virus type 1 (HIV-1) infection are poorly understood. CD4+ T lymphocytes play a complex role in regulating anti-HIV effector pathways, including activation of macrophages, which are themselves implicated in clinical latency and pathogenesis of symptomatic acquired immune deficiency syndrome. We have found that a newly identified T helper type 2 lymphokine, interleukin 13 (IL-13), inhibits HIV-1ADA and Ba-L replication in primary tissue culture-derived macrophages but not in peripheral blood lymphocytes. Viral production in cells was measured by viral protein (p24) and reverse transcriptase levels, while entry was assessed by proviral DNA analysis at timed intervals after infection. Inhibition by IL-13 was dose and time dependent and not mediated through altered viral entry, reverse transcription, or viral release. IL-13 is therefore a candidate cytokine for the suppression of HIV infection within monocytes and macrophages in vivo.


Histone Demethylation and Toll-like Receptor 8-Dependent Cross-Talk in Monocytes Promotes Transdifferentiation of Fibroblasts in Systemic Sclerosis Via Fra-2.
To investigate whether epigenetic changes can modulate monocytes to produce tissue inhibitor of metalloproteinases 1 (TIMP-1) via Fra-2 (an activator protein 1 [AP-1] family member), a novel downstream mediator that promotes fibrogenesis. AP-1 transcription factors and TIMP-1 expression were measured in monocytes from systemic sclerosis (SSc) patients and healthy controls. Involvement of Fra-2 in the regulation of TIMP-1 following treatment with Toll-like receptor 8 (TLR-8) agonist was investigated using a luciferase activity assay and chromatin immunoprecipitation (ChIP) analysis. Expression of TIMP-1 and Fra-2 was determined in response to TLR-8 treatment and to different histone modifications, including 3'-deazaneplanocin (DZNep) and apicidin. Fibroblasts from healthy controls were cocultured with DZNep plus TLR-8-treated healthy control monocytes. Up-regulation of Fra-2 was detected in bleomycin-challenged mice and in skin biopsy samples from SSc patients. Enhanced expression of Fra-2 and TIMP-1 was correlated in SSc monocytes (P = 0.021). The expression of Fra-1 was significantly reduced (P = 0.037) in SSc monocytes. Inhibiting AP-1 activity reduced TIMP-1 production in TLR-8-stimulated monocytes from healthy controls and SSc patients. ChIP experiments revealed binding of Fra-2 to the TIMP-1 promoter. Stimulation with DZNep plus TLR-8 enhanced Fra-2 and TIMP-1 expression in healthy control monocytes, whereas TLR-8 plus apicidin repressed Fra-2 and TIMP-1 expression. Finally, healthy control monocytes treated with DZNep plus TLR-8 induced strong production of α-smooth muscle actin in dermal fibroblasts, which was inhibited by TIMP-1-blocking antibody. These data demonstrate a novel role of histone demethylation induced by DZNep on Fra-2-mediated TIMP-1 production by monocytes in the presence of TLR-8 agonist. This consequently orchestrates the transdifferentiation of fibroblasts, a key event in the pathogenesis of SSc.


DEEPScreen: high performance drug-target interaction prediction with convolutional neural networks using 2-D structural compound representations.
The identification of physical interactions between drug candidate compounds and target biomolecules is an important process in drug discovery. Since conventional screening procedures are expensive and time consuming, computational approaches are employed to provide aid by automatically predicting novel drug-target interactions (DTIs). In this study, we propose a large-scale DTI prediction system, DEEPScreen, for early stage drug discovery, using deep convolutional neural networks. One of the main advantages of DEEPScreen is employing readily available 2-D structural representations of compounds at the input level instead of conventional descriptors that display limited performance. DEEPScreen learns complex features inherently from the 2-D representations, thus producing highly accurate predictions. The DEEPScreen system was trained for 704 target proteins (using curated bioactivity data) and finalized with rigorous hyper-parameter optimization tests. We compared the performance of DEEPScreen against the state-of-the-art on multiple benchmark datasets to indicate the effectiveness of the proposed approach and verified selected novel predictions through molecular docking analysis and literature-based validation. Finally, JAK proteins that were predicted by DEEPScreen as new targets of a well-known drug cladribine were experimentally demonstrated in vitro on cancer cells through STAT3 phosphorylation, which is the downstream effector protein. The DEEPScreen system can be exploited in the fields of drug discovery and repurposing for in silico screening of the chemogenomic space, to provide novel DTIs which can be experimentally pursued. The source code, trained "ready-to-use" prediction models, all datasets and the results of this study are available at ; https://github.com/cansyl/DEEPscreen.


Use of a digital phantom developed by QIBA for harmonizing SUVs obtained from the state-of-the-art SPECT/CT systems: a multicenter study.
Although quantitative analysis using standardized uptake value (SUV) becomes realistic in clinical single-photon emission computed tomography/computed tomography (SPECT/CT) imaging, reconstruction parameter settings can deliver different quantitative results among different SPECT/CT systems. This study aims to propose a use of the digital reference object (DRO), which is a National Electrical Manufacturers Association (NEMA) phantom-like object developed by the Quantitative Imaging Biomarker Alliance (QIBA) fluorodeoxyglucose-positron emission tomography technical committee, for the purpose of harmonizing SUVs in Tc-99m SPECT/CT imaging. The NEMA body phantom with determined Tc-99m concentration was scanned with the four state-of-the-art SPECT/CT systems. SPECT data were reconstructed using different numbers of the product of subset and iteration numbers (SI) and the width of 3D Gaussian filter (3DGF). The mean (SUVmean), maximal (SUVmax), and peak (SUVpeak) SUVs for six hot spheres (10, 13, 17, 22, 28, and 37 mm) were measured after converting SPECT count into SUV using Becquerel calibration factor. DRO smoothed by 3DGF with a FWHM of 17 mm (DRO17 mm) was generated, and the corresponding SUVs were measured. The reconstruction condition to yield the lowest root mean square error (RMSE) of SUVmeans for all the spheres between DRO17 mm and actual phantom images was determined as the harmonized condition for each SPECT/CT scanner. Then, inter-scanner variability in all quantitative metrics was measured before (i.e., according to the manufacturers' recommendation or the policies of their own departments) and after harmonization. RMSE was lowest in the following reconstruction conditions: SI of 100 and 3DGF of 13 mm for Brightview XCT, SI of 160 and 3DGF of 3 pixels for Discovery NM/CT, SI of 60 and 3DGF of 2 pixels for Infinia, and SI of 140 and 3DGF of 15 mm for Symbia. In pre-harmonized conditions, coefficient of variations (COVs) among the SPECT/CT systems were greater than 10% for all quantitative metrics in three of the spheres, SUVmax and SUVmean, in one of the spheres. In contrast, all metrics except SUVmax in the 17-mm sphere yielded less than 10% of COVs after harmonization. Our proposed method clearly reduced inter-scanner variability in SUVs. A digital phantom developed by QIBA would be useful for harmonizing SUVs in multicenter trials using SPECT/CT.


Cost Effectiveness of Malignant Pleural Effusion with Indwelling Catheter: Systematic Review.
Background: The current cost of treatment of malignant pleural effusion (MPE) with an indwelling pleural catheter (IPC) is unclear. Objective: We propose a review of the scientific evidence on the cost and effectiveness of this therapeutic option. Methods: Systematic review of the literature on the cost and effectiveness of the treatment of MPE by IPC, according to the PRISMA methodology and quality according to the scientific guidelines. Results: A total of 4 articles, 152 patients, and 159 IPCs were included. The use of IPC was associated with improvement in symptoms and quality of life. The most common complications were infections (empyema in 20.9% of patients and cellulitis in 17.3%); 9% of cases were hospitalized due to complications, and <2% required subsequent procedures. The average cost of IPC (set/drainage bottles) ranged from €2,025.6 to €1,200.5 if it was placed on an outpatient basis, €1,100 if survival was <6 weeks, and €4,028 in patients with mesothelioma. Complications increased the cost, and taking into account follow-up visits, additional tests, and days of admission for complications, the cost was >€5,000. Compared with pleurodesis, the cost of IPC was significantly lower when patient survival was <14 weeks, but not when survival was longer or home care was required. Conclusions: The use of IPC is associated with good control of MPE and seldom requires many subsequent procedures; however, it is also associated with a certain rate of complications, which may increase costs. However, ambulatory management may help reduce costs, which are directly related to the type of tumor, the duration of survival, and the need for specialized treatment.


Health and Welfare in Dutch Organic Laying Hens.
From 2007-2008, data on animal health and welfare and farm management during rearing and laying periods were collected from 49 flocks of organic laying hens in the Netherlands. Our aim was to investigate how organic egg farms performed in terms of animal health and welfare and which farm factors affected this performance. The flocks in our study were kept on farms with 34 to 25,000 hens (average 9,300 hens). Seventy-one percent of the flocks consisted of 'silver hybrids': white hens that lay brown eggs. Fifty-five percent of the flocks were kept in floor-based housing and 45% of the flocks in aviaries. No relation was found between the amount of time spent outdoors during the laying period and mortality at 60 weeks. Flocks that used their outdoor run more intensively had better feather scores. In 40% of the flocks there was mortality caused by predators. The average feed intake was 129 g/day at 30 weeks and 133 g/day at 60 weeks of age. The average percentage of mislaid eggs decreased from three at 30 weeks to two at 60 weeks. The average mortality was 7.8% at 60 weeks. Twenty-five percent of the flocks were not treated for worms in their first 50 weeks. Flubenol(©) was applied to the flocks that were treated. Ten percent of the flocks followed Flubenol(©) instructions for use and were wormed five or more times. The other 65% percent were treated irregularly between one and four times. Sixty-eight percent of the flocks showed little or no feather damage, 24% showed moderate damage and 8% showed severe damage. The feather score was better if the hens used the free-range area more intensely, the laying percentage at 60 weeks was higher, and if they were allowed to go outside sooner after arrival on the laying farm. In 69% of the flocks, hens had peck wounds in the vent area: on average this was 18% of the hens. Keel bone deformations were found in all flocks, on average in 21% of the birds. In 78% of the flocks, an average of 13% of the hens had foot-sole wounds, mostly a small crust. Combs were darker in flocks that used the range area more intensively. More fearful flocks had lighter combs. We conclude that organic farms are potentially more animal friendly than other poultry systems based on the animal welfare benefits of the free range areas. However, we also observed mortality rates, internal parasites, keel bone deformities, and foot sole lesions on organic farms that were comparable to or worse than in other husbandry systems. It is unclear whether these 'remaining' problems can be attributed to housing or if they are the result of keeping high productive genotypes in an artificial environment. Organic farms use the same high productive genotypes as other husbandry systems.


What causes breast cancer? A systematic review of causal attributions among breast cancer survivors and how these compare to expert-endorsed risk factors.
The aim of this paper was to review published research that analyzed causal attributions for breast cancer among women previously diagnosed with breast cancer. These attributions were compared with risk factors identified by published scientific evidence in order to determine the level of agreement between cancer survivors' attributions and expert opinion. A comprehensive search for articles, published between 1982 and 2012, reporting studies on causal attributions for breast cancer among patients and survivors was undertaken. Of 5,135 potentially relevant articles, 22 studies met the inclusion criteria. Two additional articles were sourced from reference lists of included studies. Results indicated a consistent belief among survivors that their own breast cancer could be attributed to family history, environmental factors, stress, fate, or chance. Lifestyle factors were less frequently identified, despite expert health information highlighting the importance of these factors in controlling and modifying cancer risk. This review demonstrated that misperceptions about the contribution of modifiable lifestyle factors to the risk of breast cancer have remained largely unchanged over the past 30 years. The findings of this review indicate that beliefs about the causes of breast cancer among affected women are not always consistent with the judgement of experts. Breast cancer survivors did not regularly identify causal factors supported by expert consensus such as age, physical inactivity, breast density, alcohol consumption, and reproductive history. Further research examining psychological predictors of attributions and the impact of cancer prevention messages on adjustment and well-being of cancer survivors is warranted.


Localization of tumour necrosis factor-alpha (TNF-alpha) and its receptors in normal and psoriatic skin: epidermal cells express the 55-kD but not the 75-kD TNF receptor.
The distribution of TNF-alpha, p55 TNF receptor (TNF-R) and p75 TNF-R in normal skin and uninvolved and lesional skin from psoriasis patients has been investigated, using specific mono- and polyclonal antibodies. In normal skin, and uninvolved and lesional skin from psoriasis patients, p55 TNF-R is associated with epidermal keratinocytes and a network of upper dermal dendritic cells. This suggests that the actions of TNF-alpha on epidermal cells in vivo are mediated by binding to the p55 TNF-R. In lesional psoriasis skin, there was staining of the parakeratotic stratum corneum and increased expression of p55 TNF-R in association with upper dermal blood vessels. Staining for p75 TNF-R in normal skin was restricted to eccrine sweat ducts and dermal dendritic cells, and was absent from the epidermis. In lesional psoriasis skin, there was staining for p75 TNF-R in association with upper dermal blood vessels and perivascular infiltrating cells. TNF-alpha in normal skin was predominantly localized to the basal cell layers of the epidermis, and was seen in association with eccrine ducts and sebaceous glands. In lesional psoriasis skin, and to a lesser extent in uninvolved psoriasis skin, TNF-alpha was distributed throughout the epidermis, and was also specifically localized to upper dermal blood vessels. Up-regulation of TNF-alpha, p55 TNF-R and p75 TNF-R on dermal blood vessels in psoriasis may play an important role in the pathogenesis of this condition by promoting cutaneous recruitment of inflammatory cells.


Intrinsic and extrinsic factors drive ontogeny of early-life at-sea behaviour in a marine top predator.
Young animals must learn to forage effectively to survive the transition from parental provisioning to independent feeding. Rapid development of successful foraging strategies is particularly important for capital breeders that do not receive parental guidance after weaning. The intrinsic and extrinsic drivers of variation in ontogeny of foraging are poorly understood for many species. Grey seals (Halichoerus grypus) are typical capital breeders; pups are abandoned on the natal site after a brief suckling phase, and must develop foraging skills without external input. We collected location and dive data from recently-weaned grey seal pups from two regions of the United Kingdom (the North Sea and the Celtic and Irish Seas) using animal-borne telemetry devices during their first months of independence at sea. Dive duration, depth, bottom time, and benthic diving increased over the first 40 days. The shape and magnitude of changes differed between regions. Females consistently had longer bottom times, and in the Celtic and Irish Seas they used shallower water than males. Regional sex differences suggest that extrinsic factors, such as water depth, contribute to behavioural sexual segregation. We recommend that conservation strategies consider movements of young naïve animals in addition to those of adults to account for developmental behavioural changes.


Coffee consumption and liver cancer risk in Japan: a meta-analysis of six prospective cohort studies.
Previous epidemiological studies have shown that coffee consumption may reduce liver cancer risk. The present study aimed to summarize the evidence for this association in the Japanese population by performing a meta-analysis of the results of relevant cohort studies conducted in Japan. We searched studies published prior to September 1, 2018 in PubMed. Extracted data were analyzed using a random effects model. A total of six cohort studies from five publications were included in the final analysis. The pooled estimate of relative risk with 95% confidence interval (CI) for the group with highest coffee consumption was 0.50 (95% CI: 0.38-0.66, p < 0.001) compared with non-coffee drinkers or those who almost never drink coffee. No evidence of publication bias was observed (p for Begg's test = 0.85). This meta-analysis suggested that coffee consumption among Japanese people has a significant role in preventing liver cancer.


Genetic ancestry and risk of mortality among U.S. Latinas with breast cancer.
Multiple studies have reported that Latina women in the United States are diagnosed with breast cancer at more advanced stages and have poorer survival than non-Latina White women. However, Latinas are a heterogeneous group with individuals having different proportions of European, Indigenous American, and African genetic ancestry. In this study, we evaluated the association between genetic ancestry and survival after breast cancer diagnosis among 899 Latina women from the San Francisco Bay area. Genetic ancestry was estimated from single-nucleotide polymorphisms from an Affymetrix 6.0 array and we used Cox proportional hazards models to evaluate the association between genetic ancestry and breast cancer-specific mortality (tests were two-sided). Women were followed for an average of 9 years during which 75 died from breast cancer. Our results showed that Individuals with higher Indigenous American ancestry had increased risk of breast cancer-specific mortality [HR: 1.57 per 25% increase in Indigenous American ancestry; 95% confidence interval (CI): 1.08-2.29]. Adjustment for demographic factors, tumor characteristics, and some treatment information did not explain the observed association (HR: 1.75; 95%CI, 1.12-2.74). In an analysis in which ancestry was dichotomized, the hazard of mortality showed a two-fold increase when comparing women with less than 50% Indigenous American ancestry to women with 50% or more [HR, 1.89, 95%CI, 1.10-3.24]. This was also reflected by Kaplan-Meier survival estimates (P for log-rank test of 0.003). Overall, results suggest that genetic factors and/or unmeasured differences in treatment or access to care should be further explored to understand and reduce ethnic disparities in breast cancer outcomes.


Structural and functional analysis of the avian leukemia virus constitutive transport element.
The observation that cells restrict the nuclear export of incompletely spliced transcripts via the canonical nuclear mRNA export pathway implies that all retroviruses should have evolved a way to direct the unspliced form of their genomic RNA into an alternate export pathway. While the Crm1-dependent pathway used by complex retroviruses to export incompletely spliced viral transcripts is now fairly well understood, less is known about how simple retroviruses accomplish this task. However, the Mason-Pfizer monkey virus (MPMV) has been shown to encode a structured RNA sequence, termed the constitutive transport element (CTE), that recruits a cellular RNA export factor termed Tap. Here we demonstrate that a CTE previously proposed to be present in the avian sarcoma/leukemia (ASV/ALV) family of retroviruses indeed functions as a potent RNA export signal. We have mapped single- and double-stranded regions present in the ASV/ALV CTE in vitro and report that this CTE is predicted to fold into a structure bearing three distinct RNA stem-loops. However, only the central stem-loop is critical for CTE function and this 69-nt structure is, in fact, sufficient when present as a dimer. While the ASV/ALV CTE is shown to function independently of Crm1, as also previously reported for the MPMV CTE, it lacks any evident sequence homology to the highly conserved MPMV CTE sequence. Together, these data define the secondary structure and biological activity of an avian CTE sequence that may access a novel nuclear RNA export pathway.


Is sleep disruption a trigger for postpartum psychosis?
An episode of postpartum psychosis can be devastating for a woman and her family, and it is vital we understand the factors involved in the aetiology of this condition. Sleep and circadian rhythm disruption is a plausible candidate but further research is needed that builds on the latest advances in chronobiology and neuroscience.


Management of infants born to women infected with hepatitis B in the military healthcare system.
Hepatitis B virus (HBV) is endemic worldwide. Given significant rates of infectivity, all infants born to Hepatitis B surface antigen positive mothers need to receive treatment at birth, immunization and post-vaccination serologic testing. However, not all infants complete these requirements. We performed a retrospective review of the management of infants born to Hepatitis B infected mothers at two large military hospitals in the United States that use a global electronic medical record to track patient results. We then compared these results to those recently published by the National Perinatal Hepatitis B Prevention Program (PHBPP), which does not include hospitals in the United States Military Healthcare System. Our results show that although all infants were managed appropriately at birth and immunization rates were very high, post vaccination follow-up testing rates were much lower than those seen in centers participating in the PHBPP. The rates of post vaccination serological testing were significantly higher for infants born to Hepatitis B e antigen positive mothers and those referred to a pediatric infectious disease specialist. Despite use of a global electronic medical record in the United States Military Healthcare System, management of HBV-exposed infants does not always follow recommended guidelines. These infants could benefit from a more systematic method of follow-up, similar to the PHBPP, to ensure HBV serologic testing is obtained after the vaccination series is complete.


Eruptive Calcified Nodules as a Potential Mechanism of Acute Coronary Thrombosis and Sudden Death.
Calcified nodule (CN) has a unique plaque morphology, in which an area of nodular calcification causes disruption of the fibrous cap with overlying luminal thrombus. CN is reported to be the least frequent cause of acute coronary thrombosis, and the pathogenesis of CN has not been well studied. The purpose of this study is to provide a comprehensive morphologic assessment of the CN in addition to providing an evolutionary perspective as to how CN causes acute coronary thrombosis in patients with acute coronary syndromes. A total of 26 consecutive CN lesions from 25 subjects from our autopsy registry were evaluated. Detailed morphometric analysis was performed to understand the plaque characteristics of CN and nodular calcification. The mean age was 70 years, with a high prevalence of diabetes and chronic kidney disease. CNs were equally distributed between men and women, with 61.5% of CNs found in the right coronary artery (n = 16), mainly within its mid-portion (56%). All CNs demonstrated surface nonocclusive luminal thrombus, consisting of multiple nodular fragments of calcification, protruding and disrupting the overlying fibrous cap, with evidence of endothelial cell loss. The degree of circumferential sheet calcification was significantly less in the culprit section (89° [interquartile range: 54° to 177°]) than in the adjacent proximal (206° [interquartile range: 157° to 269°], p = 0.0034) and distal (240° [interquartile range: 178° to 333°], p = 0.0004) sections. Polarized picrosirius red staining showed the presence of necrotic core calcium at culprit sites of CNs, whereas collagen calcium was more prevalent at the proximal and distal regions of CNs. Our study suggests that fibrous cap disruption in CN with overlying thrombosis is initiated through the fragmentation of necrotic core calcifications, which is flanked-proximally and distally-by hard, collagen-rich calcification in coronary arteries, which are susceptible to mechanical stress.


International organisations and crisis management: Do crises enable or constrain IO autonomy?
This article seeks to bridge the gap between the literature on international organisations (IO) and the field of crisis management (CM) by focusing on two themes: how crisis conditions lead organisations to centralise decision-making and how this subsequently affects an international organisation's autonomy. We do this based on two dimensions inspired by the CM literature, that is, the degree of the perceived time pressure and the precrisis legal institutional framework. The plausibility of the analytical framework is assessed on the basis of three cases: the WHO's dealing with the SARS crisis; the European Commission's dealing with the Mad Cow Disease crisis; and the UN's handling of the humanitarian crisis in the Great Lakes region. The results show that the perceived time pressure affected IO autonomy in so far as higher time pressure that rendered IO autonomy stronger, whereas with regard to the institutional framework no stringent pattern could be seen. Moreover, based on our findings, we propose that IO autonomy in crisis situations also depends on the framing of an issue in terms on impartiality, on the extent to which the IO in question is subject to politicisation, as well as on the degree to which it possesses specific technical expertise.


Influence of inducers and inhibitors on the metabolism in vitro and neurochemical effects in vivo of MDMA.
(S)-(+)- and (R)-(-)-3,4-methylenedioxymethamphetamine (MDMA) were metabolized in vitro by rat liver microsomes via N-demethylation to 3,4-methylenedioxyamphetamine (MDA). Whereas no difference was found in the biotransformation of the two enantiomers in the male rat or in the phenobarbital (PB) treated animals of either sex, more than twice as much MDA was formed from (S)-(+)- than from (R)-(-)-MDMA in the untreated female rat. Although 3-methylcholanthrene (3MC) pretreated rat liver microsomes were less active than those from the untreated rats of the same sex, they formed more MDA from (+)- than from (-)-MDMA. The enantioselective metabolism thus appears to be associated with the relative abundance of individual cytochrome P-450 isozymes. (S)-(+)- and (R)-(-)-MDMA.HCl (20 mg/kg) were about equipotent in depleting serotonin (5-HT) levels in the frontal cortex at 3 hrs and 1 wk following oral administration to female rats. Pretreatment of rats with SKF-525A attenuated and that with PB enhanced the 5-HT depleting potential of either isomer at 3 hrs. The 5-HT depleting potency of (+)-MDMA was significantly greater than that of its (-)-antipode at 3 hr in PB pretreated, but not in SKF-525A pretreated animals. The results suggest that the neurochemical effects of MDMA are caused by the formation of an active metabolite in vivo, and since both enantiomers were N-demethylated in vitro to approximately the same extent by PB pretreated rat liver microsomes, the active metabolite may be other than MDA.


Generating a synthetic genome by whole genome assembly: phiX174 bacteriophage from synthetic oligonucleotides.
We have improved upon the methodology and dramatically shortened the time required for accurate assembly of 5- to 6-kb segments of DNA from synthetic oligonucleotides. As a test of this methodology, we have established conditions for the rapid (14-day) assembly of the complete infectious genome of bacteriophage X174 (5386 bp) from a single pool of chemically synthesized oligonucleotides. The procedure involves three key steps: (i). gel purification of pooled oligonucleotides to reduce contamination with molecules of incorrect chain length, (ii). ligation of the oligonucleotides under stringent annealing conditions (55 degrees C) to select against annealing of molecules with incorrect sequences, and (iii). assembly of ligation products into full-length genomes by polymerase cycling assembly, a nonexponential reaction in which each terminal oligonucleotide can be extended only once to produce a full-length molecule. We observed a discrete band of full-length assemblies upon gel analysis of the polymerase cycling assembly product, without any PCR amplification. PCR amplification was then used to obtain larger amounts of pure full-length genomes for circularization and infectivity measurements. The synthetic DNA had a lower infectivity than natural DNA, indicating approximately one lethal error per 500 bp. However, fully infectious X174 virions were recovered after electroporation into Escherichia coli. Sequence analysis of several infectious isolates verified the accuracy of these synthetic genomes. One such isolate had exactly the intended sequence. We propose to assemble larger genomes by joining separately assembled 5- to 6-kb segments; approximately 60 such segments would be required for a minimal cellular genome.


Generation and long-haul transmission of polarization-switched QPSK at 42.9 Gb/s.
We demonstrate, for the first time, the generation and transmission of polarization-switched QPSK (PS-QPSK) signals at 42.9 Gb/s. Long-haul transmission of PS-QPSK is experimentally investigated in a recirculating loop and compared with transmission of dual-polarization QPSK (DP-QPSK) at 42.9 Gb/s per channel. A reduction in the required OSNR of 0.7 dB was found at a BER of 3.8 x 10(-3), resulting in an increase in maximum reach of more than 30% for a WDM system operating on a 50 GHz frequency grid. The maximum reach of 13640 km for WDM PS-QPSK is, to the best of our knowledge, the longest distance reported for 40 Gb/s WDM transmission, over an uncompensated link, with standard fiber and amplification.


Effect of Modified Otago Exercises on Postural Balance, Fear of Falling, and Fall Risk in Older Fallers With Knee Osteoarthritis and Impaired Gait and Balance: A Secondary Analysis.
Osteoarthritis (OA) is considered an established risk factor for falls. Published studies evaluating secondary falls prevention strategies among individuals with OA are limited. To evaluate the effect of a personalized home-based exercise program to improve postural balance, fear of falling, and falls risk in older fallers with knee OA and gait and balance problems. Randomized controlled trial. University of Malaya Medical Centre. Fallers who had both radiological OA and a Timed Up and Go (TUG) score of over 13.5 seconds. Postural sway (composite sway) was quantified with the Modified Clinical Test of Sensory Interaction on Balance (mCTSIB) under 4 different sensory conditions: eyes open on firm surface, eyes closed on firm surface, eyes open on unstable foam surface, and eyes closed on unstable foam surface. Participants were asked to stand upright and to attempt to hold their position for 10 seconds for each test condition. The average reading for all conditions were calculated. Participants randomized to the intervention arm received a home-based modified Otago Exercise Program (OEP) as part of a multifactorial intervention, whereas control participants received general health advice and conventional treatment. This was a secondary subgroup analysis from an original randomized controlled trial, the Malaysian Falls Assessment and Intervention Trial (MyFAIT) (trial registration number: ISRCTN11674947). Posturography using a long force plate balance platform (Balancemaster, NeuroCom, USA), the Knee injury and Osteoarthritis Outcome Score (KOOS) and the short-form Falls Efficacy Scale-International (short FES-I) were assessed at baseline and 6 months. Results of 41 fallers with radiological evidence of OA and impaired TUG (intervention, 17; control, 24) were available for the final analysis. Between-group analysis revealed significant improvements in the Modified Clinical Test of Sensory Interaction on Balance (mCTSIB), Limits of Stability (LOS), and short FES-I scores by the intervention group compared to the control group at 6 months. No significant difference in time to first fall or in fall-free survival between the intervention and control groups was found. Home-based balance and strength exercises benefited older fallers with OA and gait and balance disorders by improving postural control, with no observable trend in reduction of fall recurrence. Our findings will now inform a future, adequately powered, randomized controlled study using fall events as definitive outcomes. I.


AHR regulates WT1 genetic programming during murine nephrogenesis.
Mounting evidence suggests that the blueprint of chronic renal disease is established during early development by environmental cues that dictate alterations in differentiation programming. Here we show that aryl hydrocarbon receptor (AHR), a lig-and-activated basic helix-loop-helix-PAS homology domain transcription factor, disrupts murine renal differentiation by interfering with Wilms tumor suppressor gene (WT1) signaling in the developing kidney. Embryonic kidneys of C57BL/6J Ahr⁻/⁻ mice at gestation d (GD) 14 showed reduced condensation in the nephrogenic zone and decreased numbers of differentiated structures compared with wild-type mice. These deficits correlated with increased expression of the (+) 17aa Wt1 splice variant, decreased mRNA levels of Igf-1 rec., Wnt-4 and E-cadherin, and reduced levels of 52 kDa WT1 protein. AHR knockdown in wild-type embryonic kidney cells mimicked these alterations with notable increases in (+) 17aa Wt1 mRNA, reduced levels of 52 kDa WT1 protein, and increased (+) 17aa 40-kDa protein. AHR downregulation also reduced Igf-1 rec., Wnt-4, secreted frizzled receptor binding protein-1 (sfrbp-1) and E-cadherin mRNAs. In the case of Igf-1 rec. and Wnt-4, genetic disruption was fully reversed upon restoration of cellular Wt1 protein levels, confirming that functional interactions between AHR and Wt1 represent a likely molecular target for renal developmental interference.


The biochemistry and fidelity of synthesis by the apicoplast genome replication DNA polymerase Pfprex from the malaria parasite Plasmodium falciparum.
Plasmodium falciparum, the major causative agent of human malaria, contains three separate genomes. The apicoplast (an intracellular organelle) contains an ∼35-kb circular DNA genome of unusually high A/T content (>86%) that is replicated by the nuclear-encoded replication complex Pfprex. Herein, we have expressed and purified the DNA polymerase domain of Pfprex [KPom1 (Klenow-like polymerase of malaria 1)] and measured its fidelity using a LacZ-based forward mutation assay. In addition, we analyzed the kinetic parameters for the incorporation of both complementary and noncomplementary nucleotides using Kpom1 lacking 3'→5' exonucleolytic activity. KPom1 exhibits a strongly biased mutational spectrum in which T→C is the most frequent single-base substitution and differs significantly from the closely related Escherichia coli DNA polymerase I. Using E. coli harboring a temperature-sensitive polymerase I allele, we established that KPom1 can complement the growth-defective phenotype at an elevated temperature. We propose that the error bias of KPom1 may be exploited in the complementation assay to identify nucleoside analogs that mimic this base-mispairing and preferentially inhibit apicoplast DNA replication.


Nuclear and Mitochondrial DNA Analyses of Golden Eagles (Aquila chrysaetos canadensis) from Three Areas in Western North America; Initial Results and Conservation Implications.
Understanding the genetics of a population is a critical component of developing conservation strategies. We used archived tissue samples from golden eagles (Aquila chrysaetos canadensis) in three geographic regions of western North America to conduct a preliminary study of the genetics of the North American subspecies, and to provide data for United States Fish and Wildlife Service (USFWS) decision-making for golden eagle management. We used a combination of mitochondrial DNA (mtDNA) D-loop sequences and 16 nuclear DNA (nDNA) microsatellite loci to investigate the extent of gene flow among our sampling areas in Idaho, California and Alaska and to determine if we could distinguish birds from the different geographic regions based on their genetic profiles. Our results indicate high genetic diversity, low genetic structure and high connectivity. Nuclear DNA Fst values between Idaho and California were low but significantly different from zero (0.026). Bayesian clustering methods indicated a single population, and we were unable to distinguish summer breeding residents from different regions. Results of the mtDNA AMOVA showed that most of the haplotype variation (97%) was within the geographic populations while 3% variation was partitioned among them. One haplotype was common to all three areas. One region-specific haplotype was detected in California and one in Idaho, but additional sampling is required to determine if these haplotypes are unique to those geographic areas or a sampling artifact. We discuss potential sources of the high gene flow for this species including natal and breeding dispersal, floaters, and changes in migratory behavior as a result of environmental factors such as climate change and habitat alteration. Our preliminary findings can help inform the USFWS in development of golden eagle management strategies and provide a basis for additional research into the complex dynamics of the North American subspecies.


Effect of type and severity of intimate partner violence on women's health and service use: findings from a primary care trial of women afraid of their partners.
Intimate partner violence (IPV) has major affects on women's wellbeing. There has been limited investigation of the association between type and severity of IPV and health outcomes. This article describes socio-demographic characteristics, experiences of abuse, health, safety, and use of services in women enrolled in the Women's Evaluation of Abuse and Violence Care (WEAVE) project. We explored associations between type and severity of abuse and women's health, quality of life, and help seeking. Women (aged 16-50 years) attending 52 Australian general practices, reporting fear of partners in last 12 months were mailed a survey between June 2008 and May 2010. Response rate was 70.5% (272/386). In the last 12 months, one third (33.0%) experienced Severe Combined Abuse, 26.2% Physical and Emotional Abuse, 26.6% Emotional Abuse and/or Harassment only, 2.7% Physical Abuse only and 12.4% scored negative on the Composite Abuse Scale. A total of 31.6% of participants reported poor or fair health and 67.9% poor social support. In the last year, one third had seen a psychologist (36.6%) or had 5 or more general practitioner visits (34.3%); 14.7% contacted IPV services; and 24.4% had made a safety plan. Compared to other abuse groups, women with Severe Combined Abuse had poor quality of life and mental health, despite using more medications, counseling, and IPV services and were more likely to have days out of role because of emotional issues. In summary, women who were fearful of partners in the last year, have poor mental health and quality of life, attend health care services frequently, and domestic violence services infrequently. Those women experiencing severe combined physical, emotional, and sexual abuse have poorer quality of life and mental health than women experiencing other abuse types. Health practitioners should take a history of type and severity of abuse for women with mental health issues to assist access to appropriate specialist support.