Algorithm for rapid determination of optical scattering parameters.
Preliminary experiments at the NIST Spectral Tri-function Automated Reference Reflectometer (STARR) facility have been conducted with the goal of providing the diffuse optical properties of a solid reference standard with optical properties similar to human skin. Here, we describe an algorithm for determining the best-fit parameters and the statistical uncertainty associated with the measurement. The objective function is determined from the profile log likelihood, including both experimental and Monte Carlo uncertainties. Initially, the log likelihood is determined over a large parameter search box using a relatively small number of Monte Carlo samples such as 2·104. The search area is iteratively reduced to include the 99.9999% confidence region, while doubling the number of samples at each iteration until the experimental uncertainty dominates over the Monte Carlo uncertainty. Typically this occurs by 1.28·106 samples. The log likelihood is then fit to determine a 95% confidence ellipse. The inverse problem requires the values of the log likelihood on many points. Our implementation uses importance sampling to calculate these points on a grid in an efficient manner. Ultimately, the time-to-solution is approximately six times the cost of a Monte Carlo simulation of the radiation transport problem for a single set of parameters with the largest number of photons required. The results are found to be 64 times faster than our implementation of Particle Swarm Optimization.


The influence of miniscrew insertion torque.
The aim of this in vitro study was to evaluate the progressive development of surface microdamage produced following the insertion of orthodontic miniscrews (OMs) into 1.5 mm thick porcine tibia bone using maximum insertion torque values of 12 Ncm, 18 Ncm, and 24 Ncm. Aarhus OMs (diameter 1.5 mm; length 6 mm) were inserted into 1.5 mm porcine bone using a torque limiting hand screwdriver set at 12 Ncm, 18 Ncm, and 24 Ncm. A custom rig equipped with a compression load cell was used to record the compression force exerted during manual insertion. A sequential staining technique was used to identify microdamage viewed under laser confocal microscopy. Virtual slices were created and stitched together to form a compressed two-dimensional composition of the microdamage. Histomorphometric parameters, including total damage area, diffuse damage area, maximum crack length, maximum damage radius, and maximum diffuse damage radius, were measured. Kruskal-Wallis Tests and Wilcoxon Rank-Sum Tests were used to analyse the generated data. All OMs inserted using 12 Ncm failed to insert completely, while partial insertion was observed for two OMs inserted at 18 Ncm. Complete insertion was achieved for all OMs inserted at 24 Ncm. Histomorphometrically, OMs inserted using 24 Ncm produced a significantly larger diffuse damage area (P < 0.05; P < 0.05) and maximum diffuse damage radius (P < 0.05; P < 0.05), for both the entry and exit surfaces, respectively, compared with the 12 Ncm and 18 Ncm groups. Insertion torque can influence the degree of OM insertion and, subsequently, the amount of microdamage formed following insertion into 1.5 mm thick porcine tibia bone. An increase in insertion torque corresponds with greater insertion depth and larger amounts of microdamage.


The KRAS-variant is associated with risk of developing double primary breast and ovarian cancer.
A germline microRNA binding site-disrupting variant, the KRAS-variant (rs61764370), is associated with an increased risk of developing several cancers. Because this variant is most strongly associated with ovarian cancer risk in patients from hereditary breast and ovarian families (HBOC), and with the risk of premenopausal triple negative breast cancer, we evaluated the association of the KRAS-variant with women with personal histories of both breast and ovarian cancer, referred to as double primary patients. Germline DNA from double primary patients was tested for the KRAS-variant (n = 232). Confirmation of pathologic diagnoses, age of diagnoses, interval between ovarian cancer diagnosis and sample collection, additional cancer diagnoses, and family history were obtained when available. All patients were tested for deleterious BRCA mutations. The KRAS-variant was significantly enriched in uninformative (BRCA negative) double primary patients, being found in 39% of patients accrued within two years of their ovarian cancer diagnosis. Furthermore, the KRAS-variant was found in 35% of uninformative double primary patients diagnosed with ovarian cancer post-menopausally, and was significantly associated with uninformative double primary patients with a positive family history. The KRAS-variant was also significantly enriched in uninformative patients who developed more then two primary cancers, being found in 48% of women with two breast primaries plus ovarian cancer or with triple primary cancers. These findings further validate the importance of the KRAS-variant in breast and ovarian cancer risk, and support the association of this variant as a genetic marker for HBOC families previously considered uninformative.


Minimally invasive removal of a recurrent lumbar herniated nucleus pulposus by the small incised microendoscopic discectomy interlaminar approach.
In this report, we introduce two cases of recurrent herniated nucleus pulposus (HNP) at L5-S1 that were successfully removed using the small incised microendoscopic discectomy (sMED) technique, proposed by Dezawa and Sairyo in 2011. sMED was performed via the interlaminar approach with a percutaneous endoscope. The patients had previously underdone microendoscopic discectomy for HNP. For the recurrent HNP, the sMED interlaminar approach was selected because the HNP occurred at the level of L5-S1; the percutaneous endoscopic transforaminal approach was not possible for anatomical reasons. To perform sMED via the interlaminar approach, we employed new, specially made devices to enable us to use this technique. In conclusion, sMED is the most minimally invasive approach available for HNP, and its limitations have been gradually eliminated with the introduction specially made devices. In the near future, percutaneous endoscopic surgery could be the gold standard for minimally invasive disc surgery.


[Clinical characteristics and ALB gene mutation analysis of Korean patients with bisalbuminemia].
Bisalbuminemia is a hereditary or an acquired condition characterized by the presence of 2 albumin variants with different mobilities on serum protein electrophoresis (SPE). The clinical significance of bisalbuminemia has not been clearly established. However, some regions of the albumin variant may affect the biochemical analysis of biomolecules such as steroid or thyroid hormones by altering their albumin-binding affinities. In this study, we analyzed the clinical manifestations, genetic variations, and the albumin-binding characteristics in Korean patients with bisalbuminemia. We performed SPE for samples from 580 Korean subjects and identified bisalbuminemia on the basis of the results of SPE. The clinical and biochemical characteristics, ALB gene mutations, and the structures of the albumin variants of patients with bisalbuminemia were analyzed. SPE showed bisalbuminemia in 2 patients. One patient showed a genetic variation known as Nagasaki-1 (Asp293Gly) and the other showed a hitherto unreported missense mutation (c.593A>T; Lys198Ile). In both cases, the serum concentrations of the substances with binding affinity for albumin were not affected, and the mutation sites of the albumin were not located with the protein-binding loci. The 2 Korean patients with bisalbuminemia showed genetic variations, including a novel missense mutation. The ALB gene analysis with 3D modeling is useful for determining the nature of bisalbuminemia and for predicting the effects on the albumin-binding affinity of other biochemical compounds.


Morphogenesis of early 1, 2-dimethylhydrazine-induced lesions and latent period reduction of colon carcinogenesis in mice by a variant of Citrobacter freundii.
The morphogenesis of 1, 2-dimethylhydrazine (DMH)-induced lesions in the colon of outbred NIH Swiss mice was determined for up to 5 months of treatment. The effect of hyperplasia on DMH carcinogenesis was also evaluated by introducing a transient hyperplastic stimulus to the colon during the chronic weekly treatment regimen of DMH. The hyperplastic stimulus was a naturally occurring disease of mice, transmissible murine colonic hyperplasia, which is caused by a variant of Citrobacter freundii. In control mice, those not receiving the bacterium, weekly injections of the carcinogen induced neoplastic changes first detectable at two months of treatment in all segments of the colon and in both sexes. The changes increased in frequency and severity with time. Diffuse mucosal hyperpladia and chronic inflammatory and degenerative changes were also associated with DMH after prolonged treatment. The hyperplastic stimulus of C. freundii reduced the latent period for appearance of early DMH tumors, but it had no influence on already established DMH tumors.


Bisphenol A and its derivatives tetrabromobisphenol A and tetrachlorobisphenol A induce apelin expression and secretion in ovarian cancer cells through a peroxisome proliferator-activated receptor gamma-dependent mechanism.
Epidemiological studies have reported that humans have detectable levels of not only bisphenol A (BPA), but also its halogenated derivatives tetrabromobisphenol A (TBBPA) and tetrachlorobisphenol A (TCBPA), in the serum. Our previous study showed that BPA promotes ovarian cancer progression by directly inducing cell proliferation and migration or by indirectly increasing leptin receptor expression, which creates more binding sites for leptin. In this study, we examined the expression of apelin and its receptor in non-cancer and cancer cell lines derived from the human ovary, and further explored whether the expression of apelin and its receptor is modulated by BPA and its derivatives. We found that the apelin receptor expression level was higher in epithelial cancer cells than in granulosa tumour cells, whereas the reverse was true for apelin expression and secretion. BPA, TBBPA and TCBPA at low nanomolar concentrations increased apelin expression and secretion in the epithelial ovarian cancer cell line OVCAR-3, which involved the peroxisome proliferator-activated receptor γ but not oestrogen receptors. We also found evidence that secreted apelin acts as a mitogenic factor in OVCAR-3 cells, and that BPA intensifies its activity. Taken together, our results suggest that BPA and its derivatives induce ovarian cancer cell progression by up-regulating apelin, which acts as a mitogenic factor in these cells.


Analysis of certain variables in the agar dilution susceptibility test.
This study examined (i) the activity of gentamicin added to agar in ratios of 1:100 and 1:1,000 to produce a final concentration of 1 mug/ml, (ii) the uniformity of distribution of gentamicin in agar in relation to the amount of mixing, and (iii) the effect of agar depth on the activity of gentamicin against Pseudomonas aeruginosa. Although the ratio of antibiotic solution to agar had no significant effects on activity of the antibiotic, the amount of mixing did. Agar depth had no significant effect on the activity of gentamicin.


Research traceability using provenance services for biomedical analysis.
We outline the approach being developed in the neuGRID project to use provenance management techniques for the purposes of capturing and preserving the provenance data that emerges in the specification and execution of workflows in biomedical analyses. In the neuGRID project a provenance service has been designed and implemented that is intended to capture, store, retrieve and reconstruct the workflow information needed to facilitate users in conducting user analyses. We describe the architecture of the neuGRID provenance service and discuss how the CRISTAL system from CERN is being adapted to address the requirements of the project and then consider how a generalised approach for provenance management could emerge for more generic application to the (Health)Grid community.


Fetal hypoxemia causes abnormal myocardial development in a preterm ex utero fetal ovine model.
In utero hypoxia is a major cause of neonatal morbidity and mortality and predisposes to adult cardiovascular disease. No therapies exist to correct fetal hypoxia. In a new ex utero fetal support system, we tested the hypothesis that hypoxemic support of the fetus impairs myocardial development, whereas normoxic support allows normal myocardial development. Preterm fetal lambs were connected via umbilical vessels to a low-resistance oxygenator and placed in a sterile-fluid environment. Control normoxic fetuses received normal fetal oxygenation, and hypoxemic fetuses received subphysiologic oxygenation. Fetuses with normal in utero development served as normal controls. Hypoxemic fetuses exhibited decreased maximum cardiac output in both ventricles, diastolic function, myocyte and myocyte nuclear size, and increased myocardial capillary density versus control normoxic fetuses. There were no differences between control normoxic fetuses in the fetal support system and normal in utero controls. Chronic fetal hypoxemia resulted in significant abnormalities in myocyte architecture and myocardial capillary density as well as systolic and diastolic cardiac function, whereas control fetuses showed no differences. This ex utero fetal support system has potential to become a significant research tool and novel therapy to correct fetal hypoxia.


The effect of Baduanjin exercise on health-related physical fitness of college students: A randomized controlled trial.
The continuous decline in the physical fitness of college students has become a serious social problem worldwide. Therefore, it is necessary to explore the effective method improving college students' physique. Previous studies have shown that Baduanjin exercise is beneficial in improving sleeping quality, mental health, body flexibility, and body physique. However, the evidence is unclear whether Baduanjin exercise can be recommended as an effective exercise to promote health-related physical fitness of college students. A total of 130 college students were recruited and randomly allocated to either the Baduanjin training or the control group at a ratio of 1:1. The students in the Baduanjin training group received a 12-week supervised Baduanjin exercise training intervention with a frequency of 1 h each day and 4 days per week, while those in the control group did not receive any specific exercise intervention and were informed to maintain their original lifestyle for 12 weeks. The outcomes of health-related physical fitness involving measurements of body flexibility, muscular strength, cardiopulmonary fitness, and body endurance were measured at baseline and after the 12-week intervention period. Mixed linear model was used to analyze the effect of the Baduanjin exercise intervention. Mixed linear model analyses showed that the Baduanjin training group had a significant increase in the composite scores of health-related physical fitness compared to the control group from baseline to 12-week post-intervention with a medium effect size (d = 0.68, P = 0.006). Moreover, there were significant improvements in vital capacity, physical flexibility, 800/1,000 m endurance running, and body composition (measured by body mass index (BMI), fat mass and body fat ratio) at end of 12-week intervention in the Baduanjin training group. No adverse events were observed in this trial. Regular Baduanjin training may be an effective, safe exercise form to promote the health-related physical fitness of young adults. Chinese Clinical Trial Registry, ChiCTR-IOR-17013011. http://www.chictr.ogr.cn.


Antioxidant vitamin supplementation in asthma.
The influence of nutrition on chronic bronchial asthma has an important place in the management of this disease. Evidence suggests that specific inflammatory abnormalities exist in the airways of subjects suffering from mild-to-moderate persistent asthma, in whom an inflammatory state is often associated with increased generation of reactive oxygen species and the damaging effects of free radicals. For this reason oxidant stress may be an important pathogenic factor in the progress of the disease. The role of nutrition in bronchial asthma is related to antioxidant vitamins A, C, and E. By counteracting oxidants and reducing external attacks (bacteria, virus, toxins, xenobiotics) in the lung, antioxidant vitamins modulate the development of asthma and the impairment of pulmonary function. Dietary studies suggest relations between oxidative stress, bronchial inflammation, development of asthmatic symptoms, and reduction of cellular functions. Dietary interventions may reduce oxidant stress and prevent or minimize asthmatic symptoms. Such interventions may provide a cost-effective approach to asthma management that may supplement current pharmacological strategies, although this conclusion is not supported by many randomized, placebo-controlled studies. The aim of this short review is to summarize current knowledge regarding the relations between antioxidant vitamins and the treatment of bronchial asthma.


The role of vascular echography in the management of complications associated with central venous access for hemodialysis in cancer patients: two case reports and literature review.
Central venous catheter implantation for hemodialysis is commonly performed in large centers and its complications are sometimes associated with insufficient training of those who perform it, but may also be related to the patient's clinical condition. The present study reports two cases of complications related to use of a short-stay catheter for hemodialysis. In the first case, the cannula was inadvertently inserted into the left subclavian artery, causing arterial thrombosis, which was conservatively managed and good collateral perfusion was documented with vascular echography. The second case illustrates an incidental finding of Central Venous Septic Thrombosis in a patient who had used a catheter for a week, which was treated with antibiotic therapy, anticoagulation, and ultrasound control. In both cases, surgical intervention would have been high risk because of the patients' poor prognosis. Vascular ultrasonography enabled monitoring of these clinical situations and use of less aggressive treatments.


Volume dependency for culture of fungi from respiratory secretions and increased sensitivity of Aspergillus quantitative PCR.
Diagnosis of aspergillosis is often difficult. We compared fungal yields from respiratory specimens using the Health Protection Agency standard culture method (BSOP57), a higher volume undiluted culture method Mycology Reference Centre Manchester (MRCM) and Aspergillus quantitative real time polymerase chain reaction (qPCR). Sputum, bronchial aspirate and bronchoalveolar lavage (BAL) samples (total 23) were collected from aspergillosis patients. One fraction of all samples was cultured using the MRCM method, one BSOP57 and one was used for qPCR. The recovery rate for fungi was significantly higher by MRCM (87%) than by BSOP57 (8.7%) from all 23 specimens. Sputum samples were 44% positive by MRCM compared to no fungi isolated (0%) by BSOP57. Bronchial aspirates were 75% positive by MRCM and 0% by BSOP57. BAL samples were positive in 20% by MRCM and 10% by BSOP57. qPCR was always more sensitive than culture (95.6%) from all samples. In general, over 100 mould colonies (81 Aspergillus fumigatus) were grown using the MRCM method compared with only one colony from BSOP57. This study provides a reference point for standardisation of respiratory sample processing in diagnostic laboratories. Culture from higher volume undiluted respiratory specimens has a much higher yield for Aspergillus than BSOP57. qPCR is much more sensitive than culture and the current UK method requires revision.


The role of Pitx2 and Pitx3 in muscle stem cells gives new insights into P38α MAP kinase and redox regulation of muscle regeneration.
Skeletal muscle regeneration depends on satellite cells. After injury these muscle stem cells exit quiescence, proliferate and differentiate to regenerate damaged fibres. We show that this progression is accompanied by metabolic changes leading to increased production of reactive oxygen species (ROS). Using Pitx2/3 single and double mutant mice that provide genetic models of deregulated redox states, we demonstrate that moderate overproduction of ROS results in premature differentiation of satellite cells while high levels lead to their senescence and regenerative failure. Using the ROS scavenger, N-Acetyl-Cysteine (NAC), in primary cultures we show that a physiological increase in ROS is required for satellite cells to exit the cell cycle and initiate differentiation through the redox activation of p38α MAP kinase. Subjecting cultured satellite cells to transient inhibition of P38α MAP kinase in conjunction with NAC treatment leads to their rapid expansion, with striking improvement of their regenerative potential in grafting experiments.


Causes of and prevention strategies for hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is a challenging malignancy of global importance. It is associated with a high rate of mortality and its prevalence in the United States and in Western Europe is increasing. Cirrhosis is the strongest and the most common known risk factor for HCC, usually due to hepatitis C virus (HCV) and hepatitis B virus (HBV) infections. However, different lines of evidence identify in non-alcoholic fatty liver disease (NAFLD) a possible relevant risk factor for occurrence of HCC. Given the continuing increase in the prevalence of obesity and diabetes, the incidence of non-alcoholic steatohepatitis-related HCC may also be expected to increase, and a potential role of behavior treatment and/or insulin-sensitizing drugs can be envisaged. Vaccination against HBV is the most efficient primary prevention measure currently available to reduce the HCC incidence and mortality in high-incidence areas, while data on the role of interferon (IFN) and nucleos(t)ide analogues (NUC) are still controversial. The pooling of data from the literature suggests a slight preventive effect of antiviral therapy on HCC development in patients with HCV-related cirrhosis, but the preventive effect is limited to sustained virological responders.


L-arginine decreases inflammation and modulates the nuclear factor-kappaB/matrix metalloproteinase cascade in mdx muscle fibers.
Duchenne muscular dystrophy (DMD) is a lethal, X-linked disorder associated with dystrophin deficiency that results in chronic inflammation, sarcolemma damage, and severe skeletal muscle degeneration. Recently, the use of L-arginine, the substrate of nitric oxide synthase (nNOS), has been proposed as a pharmacological treatment to attenuate the dystrophic pattern of DMD. However, little is known about signaling events that occur in dystrophic muscle with l-arginine treatment. Considering the implication of inflammation in dystrophic processes, we asked whether L-arginine inhibits inflammatory signaling cascades. We demonstrate that L-arginine decreases inflammation and enhances muscle regeneration in the mdx mouse model. Classic stimulatory signals, such as proinflammatory cytokines interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha, are significantly decreased in mdx mouse muscle, resulting in lower nuclear factor (NF)-kappaB levels and activity. NF-kappaB serves as a pivotal transcription factor with multiple levels of regulation; previous studies have shown perturbation of NF-kappaB signaling in both mdx and DMD muscle. Moreover, L-arginine decreases the activity of metalloproteinase (MMP)-2 and MMP-9, which are transcriptionally activated by NF-kappaB. We show that the inhibitory effect of L-arginine on the NF-kappaB/MMP cascade reduces beta-dystroglycan cleavage and translocates utrophin and nNOS throughout the sarcolemma. Collectively, our results clarify the molecular events by which L-arginine promotes muscle membrane integrity in dystrophic muscle and suggest that NF-kappaB-related signaling cascades could be potential therapeutic targets for DMD management.


Proximate costs of fighting in male cichlid fish: the role of injuries and energy metabolism.
While much is known about the functional significance of strategic decisions in animal fighting, relatively little is understood about the mechanisms that underlie the making of those decisions. In mechanistic terms, strategic decisions, such as either escalating a fight or giving up, are made in relation to the proximate costs that opponents inflict (or can potentially inflict) upon one another. These costs include physical injury and also the physiological consequences of engaging in an energetically demanding activity. We studied the role of injury and energy metabolism during fights between male cichlid fish, Tilapia zillii. In relation to injuries incurred during fights, scale loss differed depending on whether the winner was smaller or larger than its opponent; smaller winners inflicted significantly more damage on their opponents than they received, whereas this difference was not apparent in those fights won by the larger fish. In relation to energy metabolism, escalated fighting resulted in a significant depletion of total sugar reserves in the muscle and the liver. It appears that the muscle energy reserves are respired anaerobically, as was evident from the accumulation of lactate in the muscle. Losers had significantly higher levels of muscle lactate than winners. Together, the injury data and the metabolic data suggest that escalated fighting is costly for both winners and losers, but especially so for losers. These data are discussed in relation to models of animal decision making and we conclude that the difference between opponents in the proximate costs incurred during fighting is likely to underlie the making of decisions such as continuing, giving up or escalating the fight. Copyright 1998 The Association for the Study of Animal Behaviour. Copyright 1998 The Association for the Study of Animal Behaviour.


Polyneuropathy associated with duodenal infusion of levodopa in Parkinson's disease: features, pathogenesis and management.
Patients with Parkinson's disease (PD) treated with oral levodopa have a higher prevalence of chronic, prevalently sensory, usually mild axonal polyneuropathy (PNP). Several studies showed a positive association among PNP, cumulative levodopa dosage, low serum B12 and high-homocysteine and methylmalonic acid level. Anecdotal severe acute or subacute PNPs thought to be Guillain-Barré syndrome have been reported in patients receiving continuous intraduodenal infusion of levodopa/carbidopa intestinal gel (LCIG). We report an additional acute case and by a systematic literature search we also reviewed the clinical and laboratory features of 13 other acute and 21 subacute PNP cases occurring during LCIG treatment. In series with at least nine patients, the mean frequency of acute and subacute PNP is 13.6% and the mortality rate at 6 months in acute cases is 14%. The great majority of PNP cases displayed axonal sensory-motor and reduced vitamin B12 levels, and alterations of metabolites of 1-carbon pathway were found in most patients. We discuss the possible role of high-levodopa dosage, vitamin B12, B6 and folate deficiency and accumulation of homocysteine and methylmalonic acid in the pathogenesis to conclude that there is enough, although circumstantial, evidence that alterations of 1-carbon pathway are implicated also in acute and subacute PNP during LCIG usage. There is no solid proof for a dysimmune pathogenesis and in our opinion acute, subacute and chronic PNP, either after oral levodopa or LCIG, represent a continuum. Finally, we propose recommendations for prevention and management of PNP occurring during LCIG treatment.


Is there a delay in the antidepressant effect? A meta-analysis.
It has long been thought that there is a delay of several weeks before a true antidepressant effect occurs, although this theory has increasingly come into question. The goals of this meta-analysis were to determine whether significant drug-placebo separation occurs during the first 2 weeks of treatment and to ascertain whether the timing of response to antidepressant medication and placebo is distinct. Seventy-six double-blind, placebo-controlled trials conducted between 1981 and 2000, included in a recently published meta-analysis that evaluated placebo response rates in depressed outpatients, were reviewed. In addition, each issue of 6 psychiatric journals from January 1992 through December 2001 was reviewed. Forty-seven studies that evaluated antidepressant medications with established efficacy, performed weekly or biweekly (every other week) evaluations, and presented the time course of improvement as measured by the Hamilton Rating Scale for Depression were included in our meta-analysis. The time course of improvement on active medication and placebo was nearly identical, as 60.2% and 61.6% of the improvement that occurred on active medication and placebo, respectively, took place during the first 2 weeks of treatment. Drug-placebo differences were not only present but were most pronounced during the first 2 weeks of treatment and diminished in a stepwise fashion thereafter. A series of subanalyses confirmed that this early drug-placebo separation was clinically observable and represented a true drug effect. These results challenge the notion that a delay exists before a true antidepressant effect occurs.


The sensory arrays of the ant, Temnothorax rugatulus.
Individual differences in response thresholds to task-related stimuli may be one mechanism driving task allocation among social insect workers. These differences may arise at various stages in the nervous system. We investigate variability in the peripheral nervous system as a simple mechanism that can introduce inter-individual differences in sensory information. In this study we describe size-dependent variation of the compound eyes and the antennae in the ant Temnothorax rugatulus. Head width in T. rugatulus varies between 0.4 and 0.7 mm (2.6-3.8 mm body length). But despite this limited range of worker sizes we find sensory array variability. We find that the number of ommatidia and of some, but not all, antennal sensilla types vary with head width. The antennal array of T. rugatulus displays the full complement of sensillum types observed in other species of ants, although at much lower quantities than other, larger, studied species. In addition, we describe what we believe to be a new type of sensillum in hymenoptera that occurs on the antennae and on all body segments. T. rugatulus has apposition compound eyes with 45-76 facets per eye, depending on head width, with average lens diameters of 16.5 μm, rhabdom diameters of 5.7 μm and inter-ommatidial angles of 16.8°. The optical system of T. rugatulus ommatidia is severely under focussed, but the absolute sensitivity of the eyes is unusually high. We discuss the functional significance of these findings and the extent to which the variability of sensory arrays may correlate with task allocation.


Population-based estimates of engagement in HIV care and mortality using double-sampling methods following home-based counseling and testing in western Kenya.
Data on engagement in HIV care from population-based samples in sub-Saharan Africa are limited. The objective of this study was to use double-sampling methods to estimate linkage to HIV care, ART initiation, and mortality among all adults diagnosed with HIV by a comprehensive home-based counseling and testing (HBCT) program in western Kenya. HBCT was conducted door-to-door from December 2009 to April 2011 in three sub-counties of western Kenya by AMPATH (Academic Model Providing Access to Healthcare). For those identified as HIV-positive, data were merged with electronic medical records to determine engagement with HIV care. A randomly-drawn follow-up sample of 120 adults identified via HBCT who had not linked to care as of June 2015 in Bunyala sub-county were visited by trained fieldworkers to ascertain HIV care engagement and vital status. Double-sampled data were used to generate, via multinomial regression, predicted probabilities of engagement in care and mortality among those whose status could not be ascertained by matching with the electronic medical records in the three catchments. Incorporating information from the double-sampling yielded estimates of prospective linkage to HIV care that ranged from 40-45%. Mortality estimates of those who did not engage in care following HBCT ranged from 12-16%. Among those who linked to care following HBCT, between 72-81% initiated ART. In settings without universal national identifiers, rates of linkage to care from community-based programs may be subject to substantial underestimation. Follow-up samples of those with missing information can be used to partially correct this bias, as has been demonstrated previously for mortality among those who were lost-to-care programs. There is a need for harmonized data systems across health systems and programs.


A polygenic predictor of treatment-resistant depression using whole exome sequencing and genome-wide genotyping.
Treatment-resistant depression (TRD) occurs in ~30% of patients with major depressive disorder (MDD) but the genetics of TRD was previously poorly investigated. Whole exome sequencing and genome-wide genotyping were available in 1209 MDD patients after quality control. Antidepressant response was compared to non-response to one treatment and non-response to two or more treatments (TRD). Differences in the risk of carrying damaging variants were tested. A score expressing the burden of variants in genes and pathways was calculated weighting each variant for its functional (Eigen) score and frequency. Gene-based and pathway-based scores were used to develop predictive models of TRD and non-response using gradient boosting in 70% of the sample (training) which were tested in the remaining 30% (testing), evaluating also the addition of clinical predictors. Independent replication was tested in STAR*D and GENDEP using exome array-based data. TRD and non-responders did not show higher risk to carry damaging variants compared to responders. Genes/pathways associated with TRD included those modulating cell survival and proliferation, neurodegeneration, and immune response. Genetic models showed significant prediction of TRD vs. response and they were improved by the addition of clinical predictors, but they were not significantly better than clinical predictors alone. Replication results were driven by clinical factors, except for a model developed in subjects treated with serotonergic antidepressants, which showed a clear improvement in prediction at the extremes of the genetic score distribution in STAR*D. These results suggested relevant biological mechanisms implicated in TRD and a new methodological approach to the prediction of TRD.


Transcranial ultrasound in acute stroke: from diagnosis to therapy.
In the last few years, several studies have improved our knowledge and understanding of the dynamic nature of the recanalization process during stroke thrombolysis. Transcranial Doppler ultrasound provides a unique opportunity to assess several aspects of clot dissolution by means of continuous monitoring of recanalization during and after administration of tissue plasminogen activator. This approach allows us to evaluate at the patient's bedside and in real time the beginning, timing, speed and degree of artery reopening, as well as to document reocclusion after successful recanalization. Moreover, the simultaneous clinical assessment during transcranial Doppler monitoring allows correlation of the hemodynamic changes with the clinical course and outcome. Experimental studies have shown that ultrasound (US)-accelerated thrombolysis may be further enhanced by administration of microbubbles (MBs). Low-frequency US with high power has been demonstrated to produce cavitation and fluid motion in the thrombus. The MBs, by acting as cavitation nuclei, lower the amount of energy needed for cavitation. Application of high-acoustic-pressure US has been shown to induce nonlinear oscillations of MBs, leading to a continuous absorption of energy until the bubbles explode, releasing the absorbed energy. A multicenter randomized phase II trial of MB-enhanced thrombolysis in acute stroke is under way.


Ciclosporin treatment of suspected granulomatous meningoencephalomyelitis in three dogs.
Granulomatous meningoencephalomyelitis is an idiopathic disease of the central nervous system of presumed dysimmune origin. This disorder is characterised histologically by an angiocentric inflammatory reaction involving the brain, the spinal cord, and/or the leptomeninges. To date, the standard treatment for granulomatous meningoencephalomyelitis consists of immunosuppressive dosages of glucocorticoids. Ciclosporin A, a potent immunosuppressive agent that blocks the transcription of cytokine genes in activated T cells, has been proposed as a therapeutic alternative. In the present study of three dogs with suspected granulomatous meningoencephalomyelitis, microemulsified ciclosporin, at a dose of 10 mg/kg once daily for at least six weeks, then reducing to 5 mg/kg daily, was administered after a variable period of glucocorticoid treatment, and resulted in a complete resolution of clinical signs. Satisfactory improvement of clinical signs after ciclosporin administration took more time than after glucocorticoid administration. Six weeks after the beginning of ciclosporin treatment, clinical results were similar to those obtained with prednisolone. Adverse effects were minimal with ciclosporin, with only intermittent vomiting.


Kinetics of the inhibition of human pancreatic elastase by recombinant eglin c. Influence of elastin.
Recombinant eglin c is a potent reversible inhibitor of human pancreatic elastase. At pH 7.4 and 25 degrees C, kass. = 7.3 x 10(5) M-1.s-1, kdiss. = 2.7 x 10(-4) s-1 and Ki = 3.7 x 10(-10) M. Stopped-flow kinetic indicate that the formation of the stable enzyme-inhibitor complex is not preceded by a fast pre-equilibrium complex or that the latter has a dissociation constant greater than 0.3 microM. The elastase-eglin c complex is much less stable at pH 5.0 and 25 degrees C, where kdiss. = 1.1 x 10(-2) s-1 and Ki = 7.3 x 10(-8) M. At pH 7.4 the activation energy for kass. is 43.9 kJ.mol-1 (10.5 kcal.mol-1). The kass. increases between pH 5.0 and 8.0 and remains essentially constant up to pH 9.0. This pH-dependence could not be described by a simple ionization curve. Both alpha 2-macroglobulin and alpha 1-proteinase inhibitor are able to dissociate the elastase-eglin c complex, as evidenced by measurement of the enzymic activity of alpha 2-macroglobulin-bound elastase or by polyacrylamide-gel electrophoresis of mixtures of alpha 1-proteinase inhibitor and elastase-eglin c complex. The rough estimate of kdiss. obtained with the alpha 2-macroglobulin dissociation experiment (1.6 x 10(-4) s-1) was of the same order of magnitude as the constant measured with the progress curve method. Eglin c strongly inhibits the solubilization of human aorta elastin by human pancreatic elastase. The extent of inhibition is the same whether elastase is added to a suspension of elastin and eglin c or whether elastase is preincubated with elastin for 3 min before addition of eglin c. However, the efficiency of the inhibitor sharply decreases if elastase is reacted with elastin for more prolonged periods.


Early endoscopy of oesophagus, stomach, and duodenal bulb in patients with haematemesis and melaena.
Oesophago-gastro-duodenoscopy was successfully performed in 196 of 208 patients admitted with haematemesis or melaena, or both. A precise visual diagnosis was made in 80% of all patients and in 96% of those where the final diagnosis lay within the oesophagus, stomach, and first two parts of the duodenum. Bleeding oesophagitis was more common and bleeding duodenal ulcer less common than in other series using mainly radiology. Altogether, 26% of all patients with endoscopically-proved duodenal ulcers were bleeding from another site, and 15.4% of all patients had more than one lesion. This fact, and inability to detect surface lesions limits the value of acute barium radiology, which was performed in only 81 patients. Accurate diagnosis should lead to better understanding of individual lesions and more rational management of individual patients. Where a good service is available oesophago-gastro-duodenoscopy should be performed on all bleeding patients within 24 hours of admission.


Dynamic risk assessment to improve quality of care in patients with atrial fibrillation: the 7th AFNET/EHRA Consensus Conference.
The risk of developing atrial fibrillation (AF) and its complications continues to increase, despite good progress in preventing AF-related strokes. This article summarizes the outcomes of the 7th Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA) held in Lisbon in March 2019. Sixty-five international AF specialists met to present new data and find consensus on pressing issues in AF prevention, management and future research to improve care for patients with AF and prevent AF-related complications. This article is the main outcome of an interactive, iterative discussion between breakout specialist groups and the meeting plenary. AF patients have dynamic risk profiles requiring repeated assessment and risk-based therapy stratification to optimize quality of care. Interrogation of deeply phenotyped datasets with outcomes will lead to a better understanding of the cardiac and systemic effects of AF, interacting with comorbidities and predisposing factors, enabling stratified therapy. New proposals include an algorithm for the acute management of patients with AF and heart failure, a call for a refined, data-driven assessment of stroke risk, suggestions for anticoagulation use in special populations, and a call for rhythm control therapy selection based on risk of AF recurrence. The remaining morbidity and mortality in patients with AF needs better characterization. Likely drivers of the remaining AF-related problems are AF burden, potentially treatable by rhythm control therapy, and concomitant conditions, potentially treatable by treating these conditions. Identifying the drivers of AF-related complications holds promise for stratified therapy.


Change in Brain Plasmalogen Composition by Exposure to Prenatal Undernutrition Leads to Behavioral Impairment of Rats.
Epidemiological studies suggest that poor nutrition during pregnancy influences offspring predisposition to experience developmental and psychiatric disorders. Animal studies have shown that maternal undernutrition leads to behavioral impairment, which is linked to alterations in monoaminergic systems and inflammation in the brain. In this study, we focused on the ethanolamine plasmalogen of the brain as a possible contributor to behavioral disturbances observed in offspring exposed to maternal undernutrition. Maternal food or protein restriction between gestational day (GD) 5.5 and GD 10.5 resulted in hyperactivity of rat male adult offspring. Genes related to the phospholipid biosynthesis were found to be activated in the PFC, but not in the NAcc or striatum, in the offspring exposed to prenatal undernutrition. Corresponding to these gene activations, increased ethanolamine plasmalogen (18:0p-22:6) was observed in the PFC using mass spectrometry imaging. A high number of crossings and the long time spent in the center area were observed in the offspring exposed to prenatal undernutrition and were mimicked in adult rats via the intravenous injection of ethanolamine plasmalogen (18:0p-22:6) incorporated into the liposome. Additionally, plasmalogen (18:0p-22:6) increased only in the PFC, and not in the NAcc or striatum. These results suggest that brain plasmalogen is one of the key molecules to control behavior, and its injection using liposome is a potential therapeutic approach for cognitive impairment.SIGNIFICANCE STATEMENT Maternal undernutrition correlates to developmental and psychiatric disorders. Here, we found that maternal undernutrition in early pregnancy led to hyperactivity in rat male offspring and induced gene activation of phospholipid-synthesizing enzyme and elevation of ethanolamine plasmalogen (18:0p-22:6) level in the PFC. Intravenous injection of ethanolamine plasmalogen (18:0p-22:6) incorporated into the liposome maintained crossing activity and the activity was circumscribed to the center area for a long time period, as in prenatally undernourished offspring with aberrant behavior. Furthermore, the amount of ethanolamine plasmalogen (18:0p-22:6) increased in the PFC of the rat after injection. Our result suggests that brain plasmalogen is one of the key molecules to control behavior and that its injection using liposome is a potential therapeutic approach for cognitive impairment.


Outcomes of Direct Facial-to-Hypoglossal Neurorrhaphy with Parotid Release.
Lesions of the temporal bone and cerebellopontine angle and their management can result in facial nerve paralysis. When the nerve deficit is not amenable to primary end-to-end repair or interpositional grafting, nerve transposition can be used to accomplish the goals of restoring facial tone, symmetry, and voluntary movement. The most widely used nerve transposition is the hypoglossal-facial nerve anastamosis, of which there are several technical variations. Previously we described a technique of single end-to-side anastamosis using intratemporal facial nerve mobilization and parotid release. This study further characterizes the results of this technique with a larger patient cohort and longer-term follow-up. The design of this study is a retrospective chart review and the setting is an academic tertiary care referral center. Twenty-one patients with facial nerve paralysis from proximal nerve injury at the cerebellopontine angle underwent facial-hypoglossal neurorraphy with parotid release. Outcomes were assessed using the Repaired Facial Nerve Recovery Scale, questionnaires, and patient photographs. Of the 21 patients, 18 were successfully reinnervated to a score of a B or C on the recovery scale, which equates to good oral and ocular sphincter closure with minimal mass movement. The mean duration of paralysis between injury and repair was 12.1 months (range 0 to 36 months) with a mean follow-up of 55 months. There were no cases of hemiglossal atrophy, paralysis, or subjective dysfunction. Direct facial-hypoglossal neurorrhaphy with parotid release achieved a functional reinnervation and good clinical outcome in the majority of patients, with minimal lingual morbidity. This technique is a viable option for facial reanimation and should be strongly considered as a surgical option for the paralyzed face.


The peritoneum as a natural scaffold for vascular regeneration.
The peritoneum has the same developmental origin as blood vessels, is highly reactive and poorly thrombogenic. We hypothesize that parietal peritoneum can sustain development and regeneration of new vessels. The study comprised two experimental approaches. First, to test surgical feasibility and efficacy of the peritoneal vascular autograft, we set up an autologous transplantation procedure in pigs, where a tubularized parietal peritoneal graft was covered with a metal mesh and anastomosed end-to-end in the infrarenal aorta. Second, to dissect the contribution of graft vs host cells to the newly developed vessel wall, we performed human-to-rat peritoneal patch grafting in the abdominal aorta and examined the origin of endothelial and smooth muscle cells. In pig experiments, the graft remodeled to an apparently normal blood vessel, without thrombosis. Histology confirmed arterialization of the graft with complete endothelial coverage and neointimal hyperplasia in the absence of erosion, inflammation or thrombosis. In rats, immunostaining for human mitochondri revealed that endothelial cells and smooth muscle cells rarely were of human origin. Remodeling of the graft was mainly attributable to local cells with no clear evidence of c-kit+ endothelial progenitor cells or c-kit+ resident perivascular progenitor cells. The parietal peritoneum can be feasibly used as a scaffold to sustain the regeneration of blood vessels, which appears to occur through the contribution of host-derived resident mature cells.


Fine specificity of equine infectious anaemia virus gp90-specific antibodies associated with protective and enhancing immune responses in experimentally infected and immunized ponies.
Equine infectious anaemia virus (EIAV) provides a model for examining the natural immunological control of a persistent lentivirus infection and for evaluating the efficacy of various vaccine strategies. As an initial characterization of antibody responses associated with protective or enhancing immune responses elicited by experimental infections or vaccinations, we have utilized synthetic peptide ELISA to characterize the fine specificity of antibodies to linear determinants of the EIAV surface glycoprotein, gp90. The data indicated that serum antibodies associated with protective or enhancing immune responses differed quantitatively and qualitatively in their pattern of reactivity to gp90 peptides. Protective and enhancing EIAV vaccines could also be distinguished by their ability to evoke anamnestic antibody responses to gp90 peptides. These studies demonstrate for the first time definitive differences in the specificity of protective and enhancing antibody responses to EIAV and emphasize the importance of using native viral glycoprotein immunogens in lentivirus vaccines.


Liver regeneration after liver resection: clinical aspects and correlation with infective complications.
To investigate whether early liver regeneration after resection in patients with hepatic tumors might be influenced by post-operative infective complications. A retrospective analysis of 27 liver resections for tumors performed in a single referral center from November 2004 to January 2010. Regeneration was evaluated by multidetector computed tomography at a mean follow-up of 43.85 d. The Clavien-Dindo classification was used to evaluate postoperative events in the first 6 mo after transplantation, and Centers for Disease Control and Prevention definitions were used for healthcare associated infections data. Generalized linear regression models with Gaussian family distribution and log link function were used to reveal the principal promoters of early liver regeneration. Ten of the 27 patients (37%) underwent chemotherapy prior to surgery, with a statistically significant prevalence of patients with metastasis (P = 0.007). Eight patients (30%) underwent embolization, 3 with primary tumors, and 5 with secondary tumors. Twenty patients (74%) experienced complications, with 12 (60%) experiencing Clavien-Dindo Grade 3a to 5 complications. Regeneration ≥ 100% occurred in 10 (37%) patients. The predictors were smaller future remnant liver volume (-0.002; P < 0.001), and a greater spleen volume/future remnant liver volume ratio (0.499; P = 0.01). Patients with a resection of ≥ 5 Couinaud segments experienced greater early regeneration (P = 0.04). Nine patients experienced surgical site infections, and in 7 cases Clavien-Dindo Grade 3a to 4 complications were detected (P = 0.016). There were no significant differences between patients with primary or secondary tumors, and either onset or infections or severity of surgical complications. Regardless of the onset of infective complications, future remnant liver and spleen volumes may be reliable predictors of early liver regeneration after hepatic resection on an otherwise healthy liver.


Anticonvulsant effects of gamma surgery in a model of chronic spontaneous limbic epilepsy in rats.
The management of intractable epilepsy remains a challenge, despite advances in its surgical and nonsurgical treatment. The identification of low-risk, low-cost therapeutic strategies that lead to improved outcome is therefore an important ongoing goal of basic and clinical research. Single-dose focal ionizing beam radiation delivered at necrosis-inducing and subnecrotic levels was investigated for its effects on seizure activity by using an established model of chronic recurrent spontaneous limbic seizures in rats. A single 90-minute period of repetitive electrical stimulation (inducing stimulus) of the hippocampus in rats elicited a single episode of status epilepticus, followed by a 2- to 4-week seizure-free period. Spontaneous recurrent seizures developed subsequently and persisted for the duration of monitoring (2-10 months). Simultaneous computerized electroencephalography and video recording were used to monitor the animals. After the establishment of spontaneous recurrent seizures, bilateral radiation centered in the ventral hippocampal formation was administered with the Leksell gamma knife, aided by a stereotactic device custom made for small animals. A center dose of 10, 20, or 40 Gy was administered using a 4-mm collimator. Control animals were subjected to the same seizure-inducing stimulus but underwent a sham treatment instead of gamma irradiation. In a second experiment, the authors examined the effects of gamma irradiation on the proclivity of hippocampal neurons to display epileptiform discharges. Naive animals were irradiated with a single 40-Gy dose, as already described. Slices of the hippocampus were prepared from animals killed between 1 and 178 days postirradiation. Sensitivity to penicillin-induced epileptiform spiking was examined in vitro in slices prepared from control and irradiated rat brains. In the first experiment, single doses of 20 or 40 Gy (but not 10 Gy) reduced substantially, and in some cases eliminated, behaviorally and electrographically recognized seizures. Significant reductions in both the frequency and duration of spontaneous seizures were observed during a follow-up period of up to 10 months postradiation. Histological examination of the targeted region did not reveal signs of necrosis. These findings indicate that single-dose focal ionizing beam irradiation at subnecrotic dosages reduces or eliminates repetitive spontaneous seizures in a rat model of temporal lobe epilepsy. In the second experiment, synaptically driven neuronal firing was shown to be intact in hippocampal neurons subjected to 40-Gy doses. However, the susceptibility to penicillin-induced epileptiform activity was reduced in the brain slices of animals receiving 40-Gy doses, compared with those from control rats that were not irradiated. The results provide rational support for the utility of subnecrotic gamma irradiation as a therapeutic strategy for treating epilepsy. These findings also provide evidence that a functional increase in the seizure threshold of hippocampal neurons contributes to the anticonvulsant influence of subnecrotic gamma irradiation.


WHAMM is essential for spindle formation and spindle actin polymerization in maturing mouse oocytes.
WHAMM (WAS Protein Homolog Associated with Actin, Golgi Membranes, and Microtubules) is involved in Golgi membrane association, microtubule binding, and actin nucleation as a nucleation-promoting factor, which activates the actin-related protein 2/3 complex (the Arp2/3 complex). However, the role of WHAMM in mammalian oocyte maturation is poorly understood. The presence of WHAMM mRNA and protein during all stages of mouse oocyte maturation has been verified. It is mainly co-localized with the actin cage permeating the spindle during mouse oocyte maturation. Through the knockdown of WHAMM, we confirmed that it regulates spindle formation and affects the localization of the microtubule-organizing center (MTOC) during the early stages of spindle formation. Moreover, depletion of WHAMM impaired the formation of the spindle actin and chromosome alignment, which might be the cause of chromosomal aneuploidy and abnormal, asymmetric division. Treatment with brefeldin A (BFA), an inhibitor of vesicle transport from the endoplasmic reticulum (ER) to the Golgi apparatus, induced abnormal and dispersed localization of WHAMM. Taken together, these findings show that WHAMM is an essential component of the actin cytoskeleton machinery and plays a crucial role in oocyte maturation, presumably by controlling the formation of spindles with normal length by activating the formation of the spindle actin via the Arp2/3 complex.


β-Cell Function and Clinical Outcome in Nondiabetic Patients With Acute Ischemic Stroke.
Little is known about how β-cell dysfunction affects clinical outcome after ischemic stroke. We examined whether β-cell function is associated with clinical outcome after acute ischemic stroke and if so, whether insulin resistance influences this association in a prospective study of patients with acute stroke. A total of 3590 nondiabetic patients with acute ischemic stroke (mean age, 71 years) were followed up for 3 months. β-Cell function was assessed using the homeostasis model assessment for β-cell function (HOMA-β). Study outcomes were poor functional outcome (modified Rankin Scale score, 3–6) and stroke recurrence at 3 months after stroke onset and neurological deterioration (≥2-point increase in the National Institutes of Health Stroke Scale score) at discharge. Logistic regression analysis was used to evaluate the association between quintile levels of serum HOMA-β and clinical outcomes. The age- and sex-adjusted odds ratios for poor functional outcome and neurological deterioration increased significantly with decreasing HOMA-β levels (P for trend, <0.001 and 0.001, respectively). These associations became more prominent after adjustment for HOMA-insulin resistance and were substantially unchanged even after further adjustment for other confounders, namely, body mass index, dyslipidemia, hypertension, estimated glomerular filtration rate, stroke subtype, National Institutes of Health Stroke Scale score on admission, and reperfusion therapy (odds ratio [95% CI] for the first versus fifth quintile of HOMA-β, 3.30 [2.15–5.08] for poor functional outcome and 10.69 [4.99–22.90] for neurological deterioration). Such associations were not observed for stroke recurrence. In stratified analysis for the combination of HOMA-β and HOMA-insulin resistance levels, lower HOMA-β and higher HOMA-insulin resistance levels were independently associated with increased risks of poor functional outcome and neurological deterioration. Our findings suggest that β-cell dysfunction is significantly associated with poor short-term clinical outcome independently of insulin resistance in nondiabetic patients with acute ischemic stroke.


ATP-dependent reduction of cysteine-sulphinic acid by S. cerevisiae sulphiredoxin.
Proteins contain thiol-bearing cysteine residues that are sensitive to oxidation, and this may interfere with biological function either as 'damage' or in the context of oxidant-dependent signal transduction. Cysteine thiols oxidized to sulphenic acid are generally unstable, either forming a disulphide with a nearby thiol or being further oxidized to a stable sulphinic acid. Cysteine-sulphenic acids and disulphides are known to be reduced by glutathione or thioredoxin in biological systems, but cysteine-sulphinic acid derivatives have been viewed as irreversible protein modifications. Here we identify a yeast protein of relative molecular mass M(r) = 13,000, which we have named sulphiredoxin (identified by the US spelling 'sulfiredoxin', in the Saccharomyces Genome Database), that is conserved in higher eukaryotes and reduces cysteine-sulphinic acid in the yeast peroxiredoxin Tsa1. Peroxiredoxins are ubiquitous thiol-containing antioxidants that reduce hydroperoxides and control hydroperoxide-mediated signalling in mammals. The reduction reaction catalysed by sulphiredoxin requires ATP hydrolysis and magnesium, involving a conserved active-site cysteine residue which forms a transient disulphide linkage with Tsa1. We propose that reduction of cysteine-sulphinic acids by sulphiredoxin involves activation by phosphorylation followed by a thiol-mediated reduction step. Sulphiredoxin is important for the antioxidant function of peroxiredoxins, and is likely to be involved in the repair of proteins containing cysteine-sulphinic acid modifications, and in signalling pathways involving protein oxidation.


Comparing performance of multinomial logistic regression and discriminant analysis for monitoring access to care for acute myocardial infarction.
One way to monitor patient access to emergent health care services is to use patient characteristics to predict arrival time at the hospital after onset of symptoms. This predicted arrival time can then be compared with actual arrival time to allow monitoring of access to services. Predicted arrival time could also be used to estimate potential effects of changes in health care service availability, such as closure of an emergency department or an acute care hospital. Our goal was to determine the best statistical method for prediction of arrival intervals for patients with acute myocardial infarction (AMI) symptoms. We compared the performance of multinomial logistic regression (MLR) and discriminant analysis (DA) models. Models for MLR and DA were developed using a dataset of 3,566 male veterans hospitalized with AMI in 81 VA Medical Centers in 1994-1995 throughout the United States. The dataset was randomly divided into a training set (n = 1,846) and a test set (n = 1,720). Arrival times were grouped into three intervals on the basis of treatment considerations: <6 hours, 6-12 hours, and >12 hours. One model for MLR and two models for DA were developed using the training dataset. One DA model had equal prior probabilities, and one DA model had proportional prior probabilities. Predictive performance of the models was compared using the test (n = 1,720) dataset. Using the test dataset, the proportions of patients in the three arrival time groups were 60.9% for <6 hours, 10.3% for 6-12 hours, and 28.8% for >12 hours after symptom onset. Whereas the overall predictive performance by MLR and DA with proportional priors was higher, the DA models with equal priors performed much better in the smaller groups. Correct classifications were 62.6% by MLR, 62.4% by DA using proportional prior probabilities, and 48.1% using equal prior probabilities of the groups. The misclassifications by MLR for the three groups were 9.5%, 100.0%, 74.2% for each time interval, respectively. Misclassifications by DA models were 9.8%, 100.0%, and 74.4% for the model with proportional priors and 47.6%, 79.5%, and 51.0% for the model with equal priors. The choice of MLR or DA with proportional priors, or DA with equal priors for monitoring time intervals of predicted hospital arrival time for a population should depend on the consequences of misclassification errors.


High-resolution protein interaction map of the Drosophila melanogaster p38 mitogen-activated protein kinases reveals limited functional redundancy.
Functional redundancy is a pivotal mechanism that supports the robustness of biological systems at a molecular, cellular, and organismal level. The extensive prevalence of redundancy in molecular networks has been highlighted by recent systems biology studies; however, a detailed mechanistic understanding of redundant functions in specific signaling modules is often missing. We used affinity purification of protein complexes coupled to tandem mass spectrometry to generate a high-resolution protein interaction map of the three homologous p38 mitogen-activated protein kinases (MAPKs) in Drosophila and assessed the utility of such a map in defining the extent of common and unique functions. We found a correlation between the depth of integration of individual p38 kinases into the protein interaction network and their functional significance in cultured cells and in vivo. Based on these data, we propose a central role of p38b in the Drosophila p38 signaling module, with p38a and p38c playing more peripheral, auxiliary roles. We also present the first in vivo evidence demonstrating that an evolutionarily conserved complex of p38b with glycogen synthase links stress sensing to metabolic adaptation.


Trace analysis of corticosteroids (CSs) in environmental waters by liquid chromatography-tandem mass spectrometry.
Natural and synthetic corticosteroids (CSs) are a class of steroid hormones which could potentially disturb the corticosteroid signaling pathways in wildlife and humans. In this study, a sensitive and robust analytical method using solid phase extraction (SPE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed for simultaneous analysis of sub-ng/L concentrations of 26 CSs in highly complex natural water matrices. The method performance was validated for WWTP influent, effluent, surface water and finished drinking water. Low practical quantification levels (PQLs) were achieved as 0.008-0.16 ng/L in finished drinking water, 0.019-0.50 ng/L in surface water, 0.047-1.5 ng/L in WWTP effluent, and 0.10-3.1 ng/L in WWTP influent, respectively, with the recoveries ranging from 70% to 130%. The cleanup performance and matrix interferences were also evaluated. This method was then applied to the analysis of target CSs in WWTP influent and effluent samples collected from a local WWTP, as well as surface water downstream of the WWTP outfall, detecting an average summed CS concentration of 744 ng/L in influent, 23.4 ng/L in effluent and 10.9 ng/L in surface water. Four synthetic CSs (triamcinolone acetonide, fluocinolone acetonide, clobetasol propionate, and fluticasone propionate) were found poorly removed in the WWTP. The developed method provides a tool to obtain occurrence data of corticosteroids in environmental waters, which will permit assessing their risk to environmental organisms.


Alternative splicing of CD200 is regulated by an exonic splicing enhancer and SF2/ASF.
CD200, a type I membrane glycoprotein, plays an important role in prevention of inflammatory disorders, graft rejection, autoimmune diseases and spontaneous fetal loss. It also regulates tumor immunity. A truncated CD200 (CD200(tr)) resulting from alternative splicing has been identified and characterized as a functional antagonist to full-length CD200. Thus, it is important to explore the mechanism(s) controlling alternative splicing of CD200. In this study, we identified an exonic splicing enhancer (ESE) located in exon 2, which is a putative binding site for a splicing regulatory protein SF2/ASF. Deletion or mutation of the ESE site decreased expression of the full-length CD200. Direct binding of SF2/ASF to the ESE site was confirmed by RNA electrophoretic mobility shift assay (EMSA). Knockdown of expression of SF2/ASF resulted in the same splicing pattern as seen after deletion or mutation of the ESE, whereas overexpression of SF2/ASF increased expression of the full-length CD200. In vivo studies showed that viral infection reversed the alternative splicing pattern of CD200 with increased expression of SF2/ASF and the full-length CD200. Taken together, our data suggest for the first time that SF2/ASF regulates the function of CD200 by controlling CD200 alternative splicing, through direct binding to an ESE located in exon 2 of CD200.


Factors influencing the stillbirth rates in single and multiple births in Sweden, 1869 to 1967.
Temporal variations in the stillbirth rate among singletons, twins and triplets in Sweden between 1869 and 1967 were studied. Both among single and multiple births there were marked secular decreasing trends in the stillbirth rates. Based on our long time series since 1869, this study confirms that among twins and triplets the stillbirth rate was higher among same-sexed than among opposite-sexed sets. Comparisons between the stillbirth rates among twin births in urban and rural regions indicate higher stillbirth rates in rural areas. In addition, the stillbirth rates among twins of unmarried mothers were higher than those of twins of married mothers. These findings also hold for both same-sexed and opposite-sexed twin pairs. Analyses of the stillbirth rates for singletons and for different types of twins indicate that up to 1950 the risk of stillbirth among males was almost constantly between 15% to 20% higher than among females. After that the difference in the risk decreased. Comparisons with other populations were performed.


Oxidative stress impairs energy metabolism in primary cells and synovial tissue of patients with rheumatoid arthritis.
In this study, we examined the effect of oxidative stress on cellular energy metabolism and pro-angiogenic/pro-inflammatory mechanisms of primary rheumatoid arthritis synovial fibroblast cells (RASFC) and human umbilical vein endothelial cells (HUVEC). Primary RASFC and HUVEC were cultured with the oxidative stress inducer 4-hydroxy-2-nonenal (4-HNE), and extracellular acidification rate, oxygen consumption rate, mitochondrial function and pro-angiogenic/pro-inflammatory mechanisms were assessed using the Seahorse analyser, complex I-V activity assays, random mutation mitochondrial capture assays, enzyme-linked immunosorbent assays and functional assays, including angiogenic tube formation, migration and invasion. Expression of angiogenic growth factors in synovial tissue (ST) was assessed by IHC in patients with rheumatoid arthritis (RA) undergoing arthroscopy before and after administration of tumour necrosis factor inhibitors (TNFi). In RASFC and HUVEC, 4-HNE-induced oxidative stress reprogrammed energy metabolism by inhibiting mitochondrial basal, maximal and adenosine triphosphate-linked respiration and reserve capacity, coupled with the reduced enzymatic activity of oxidative phosphorylation complexes III and IV. In contrast, 4-HNE elevated basal glycolysis, glycolytic capacity and glycolytic reserve, paralleled by an increase in mitochondrial DNA mutations and reactive oxygen species. 4-HNE activated pro-angiogenic responses of RASFC, which subsequently altered HUVEC invasion and migration, angiogenic tube formation and the release of pro-angiogenic mediators. In vivo markers of angiogenesis (vascular endothelial growth factor, angiopoietin 2 [Ang2], tyrosine kinase receptor [Tie2]) were significantly associated with oxidative damage and oxygen metabolism in the inflamed synovium. Significant reduction in ST vascularity and Ang2/Tie2 expression was demonstrated in patients with RA before and after administration of TNFi. Oxidative stress promotes metabolism in favour of glycolysis, an effect that may contribute to acceleration of inflammatory mechanisms and subsequent dysfunctional angiogenesis in RA.


Surgical excision for anterior-process fractures of the calcaneus.
Most fractures of the anterior process of the calcaneus are successfully treated with cast immobilization. Eighteen of the twenty-five patients in this study were so treated successfully, although their symptoms persisted for variable periods after removal of the cast. Seven of the twenty-five patients had excision of the fracture fragment, two of whom were not relieved of their symptoms after excision. Both of these patients had had a missed diagnosis and no prior treatment of a fracture that had gone on to non-union. This suggests that the correct initial diagnosis and treatment are important, particularly if the fracture fragment is large, and that early excision of the fragment is usually not necessary or advisable.


Evaluation of the bleeding patient.
The recent development and widespread use of flexible fiberoptic endoscopy and visceral arteriography have revolutionized the evaluation of patients presenting with gastrointestinal hemorrhage. The bleeding lesion can now be precisely identified within a few minutes to hours of a patient's arrival, allowing specific treatment to begin much earlier than was previously possible. The logical sequence of diagnostic studies is different for three different groups of patients with gastrointestinal bleeding. Those whose bleeding is active or recent require rapid evaluation, while those with chronic bleeding may be evaluated first by the more traditional and less hazardous barium radiologic studies. This revolutionary improvement in diagnostic accuracy should improve the survival of patients with gastrointestinal hemorrhage.


Digital PCR to detect and quantify heteroresistance in drug resistant Mycobacterium tuberculosis.
Drug resistance in Mycobacterium tuberculosis presents an enormous public health threat. It is typically defined as >1% of drug resistant colonies using the agar proportion method. Detecting small numbers of drug resistant Tb in a population, also known as heteroresistance, is challenging with current methodologies. Here we have utilized digital PCR to detect heteroresistance within M. tuberculosis populations with excellent accuracy versus the agar proportion method. We designed dual TaqMan-MGB probes to detect wild-type and mutant sequences of katG (315), rpoB (531), gyrA (94,95) and rrs (1401), genes that associate with resistance to isoniazid, rifampin, fluoroquinolone, and aminoglycoside respectively. We generated heteroresistant mixtures of susceptible and extensively drug resistant Tb, followed by DNA extraction and digital PCR. Digital PCR yielded a close approximation to agar proportion's percentages of resistant colonies, and yielded 100% concordance with agar proportion's susceptible/resistant results. Indeed, the digital PCR method was able to identify mutant sequence in mixtures containing as little as 1000∶1 susceptible:resistant Tb. By contrast, real-time PCR or PCR followed by Sanger sequencing were less sensitive and had little resolution to detect heteroresistance, requiring fully 1∶1 or 10∶1 susceptible:resistant ratios in order to detect resistance. Our assay can also work in sputum so long as sufficient quantities of Tb are present (>1000 cfu/ml). This work demonstrates the utility of digital PCR to detect and quantify heteroresistance in drug resistant Tb, which may be useful to inform treatment decisions faster than agar proportion.


Increased risk of graft failure in kidney transplant recipients after a diagnosis of dyspepsia or gastroesophageal reflux disease.
Gastrointestinal complications are common in patients who undergo kidney transplantation and may affect posttransplant outcomes. We examined the incidence and predictors of gastroesophageal reflux disease (GERD) and dyspepsia and their associations with graft survival and mortality after transplant. We examined United States Renal Data System data and Medicare billing claims to identify diagnoses of dyspepsia and GERD among Medicare beneficiaries transplanted in 1995-2002 (n=42,257). Among GERD cases, we identified patients with reflux esophagitis (RE). We determined independent predictors of upper gastrointestinal complications and modeled these conditions as time-dependent outcomes predictors with Cox regression. The 3-year cumulative incidences of GERD, RE, and dyspepsia were 20%, 5%, and 6%, respectively. Overall, 23% of transplant recipients received a diagnosis of at least one of these complications by 3 years after transplant. Female gender and a pretransplant upper gastrointestinal disease diagnosis predicted posttransplant gastrointestinal complications. Older age, obesity, Caucasian, and African-American race were associated to increased risk of developing GERD. Patients diagnosed with any of the examined upper gastrointestinal complications experienced an increased risk of graft-failure (hazard ratio 1.58; 95% confidence interval 1.48-1.69) and death (hazard ratio 1.61; 95% confidence interval 1.46-1.77). Upper gastrointestinal complications are relatively common after kidney transplantation and are associated with a significantly increased risk of graft loss and death. Further research is needed to elucidate mechanisms underlying the observed adverse prognoses conferred by diagnosis of upper gastrointestinal complications after kidney transplant.


Initial clinical studies with copovithane.
Copovithane is a new copolymer of low molecular weight and with a significant in vivo antitumor activity in preclinical trials. The mechanism of action is unknown. Ninety-one patients with various metastatic neoplasms beyond the curable stage were treated with copovithane by weekly intravenous administration. Dose levels ranged from 1 to 33 g/m2/week. No dose-limiting toxicity was reached. Tolerance was excellent, with minor fatigue, occasional nausea, and intermittent proteinuria as the only significant side effects in less than 25% of patients. Two patients achieved a partial remission, and five patients reached minor responses during therapy. Antitumor effects were noted only in cutaneous and subcutaneous metastases. Extensive immunologic evaluation revealed some improvement in helper:suppressor T cell ratio, in vitro cytotoxicity tests, and lymphocyte blastogenic responses in patients treated at intermediate levels. The immunologic testing also suggested that the higher dose levels (22-33 g/m2 weekly) might adversely affect the immune response. The clinical relevance of these changes is uncertain. Phase II clinical trials are recommended utilizing weekly doses between 10 and 15 g/m2.


In vitro study of the influence of virginiamycin and spiramycin on the composition and biochemical activities of the gastrointestinal flora of piglets. II. Influence on the biochemical activities of the microflora.
Chemical analysis was carried out on 54 in vitro fermentations to study the influence of nutritional doses of Virginiamycin and Spiramycin on the metabolic activity of the gastro-intestinal flora of 18 in vivo treated piglets. Changes in the decomposition of glucose and the production of NH3, volatile acids and lactic acid are recorded in function of time. These results are in good accordance with changes noted in the composition of the bacterial flora, such as a marked decrease in the production of lactic acid, caused by Virginiamycin, combined with a decrease in the number of Lactobacilli and Enterococci. Virginiamycin caused marked changes in the metabolic activity of certain groups of bacteria, while there was only a slight effect noted for Spiramycin, although in vivo treatments with this antibiotic still show up in the results of the in vitro incubations. The overall results indicate that both antibiotics have marked influences on the intestinal flora of the pig, either by selective inhibiting of the flora resulting in a change of the metabolities formed, either by a change in the metabolic activity of some bacterial groups.


Venetoclax in Previously Treated Waldenström Macroglobulinemia.
BCL2 is overexpressed and confers prosurvival signaling in malignant lymphoplasmacytic cells in Waldenström macroglobulinemia (WM). Venetoclax is a potent BCL2 antagonist and triggers in vitro apoptosis of WM cells. The activity of venetoclax in WM remains to be clarified. We performed a multicenter, prospective phase II study of venetoclax in patients with previously treated WM (NCT02677324). Venetoclax was dose-escalated from 200 mg to a maximum dose of 800 mg daily for up to 2 years. Thirty-two patients were evaluable, including 16 previously exposed to Bruton tyrosine kinase inhibitors (BTKis). All patients were MYD88 L265P-mutated, and 17 carried CXCR4 mutations. The median time to minor and major responses was 1.9 and 5.1 months, respectively. Previous exposure to BTKis was associated with a longer time to response (4.5 v 1.4 months; P < .001). The overall, major, and very good partial response rates were 84%, 81%, and 19%, respectively. The major response rate was lower in those with refractory versus relapsed disease (50% v 95%; P = .007). The median follow-up time was 33 months, and the median progression-free survival was 30 months. CXCR4 mutations did not affect treatment response or progression-free survival. The only recurring grade ≥ 3 treatment-related adverse event was neutropenia (n = 14; 45%), including one episode of febrile neutropenia. Laboratory tumor lysis without clinical sequelae occurred in one patient. No deaths have occurred. Venetoclax is safe and highly active in patients with previously treated WM, including those who previously received BTKis. CXCR4 mutation status did not affect treatment response.


HIV prevention in the era of HAART: implications for providers.
This article reviews the medical literature regarding the association between reduced HIV viremia caused by use of HAART and the risk of HIV transmission, finding that there is a correlation but that it is not absolute. It then examines the behavioral literature, which indicates that there is evidence, though far from conclusive, that, for some, increased sexual risk taking may be related to attitudes and beliefs about combination therapy. The article also considers the message about HIV prevention being presented by public health programs and ways in which health care providers can outline changing circumstances and enable the patient to make informed choices in "gray areas."


[Vaccination in old age: an overview].
Vaccinations against infectious diseases are a highly effective preventive measure, especially in old age due to the higher susceptibility to infections. As the effectiveness of vaccinations decreases in old age due to immune senescence but also due to comorbidities, specific, more immunogenic vaccines have been developed for this target group. In Germany, the Standing Commission on Vaccination (STIKO) publishes annually updated vaccination recommendations also specifically for the 60+ years age group. Since 2018, standard vaccinations for this group have included herpes zoster vaccination with adjuvanted inactivated vaccine. Since 2021, the use of the quadrivalent influenza high-dose vaccine is recommended for this age group. Currently, the annual COVID-19 vaccination and the single pneumococcal vaccination with the new 20-valent conjugate vaccine have been added as standard vaccinations. The free STIKO app provides an always up to date overview of standard and indicated vaccinations for all age groups.


Provision of intravenous therapy in a skilled nursing facility.
Intravenous therapy is one of the admission criteria for the geriatric patient to enter a skilled nursing facility. Because of shortened hospital stays, more and more geriatric patients are placed in this type of nursing home. These facilities are also potential alternatives to hospitalization of the nursing home resident who requires I.V. therapy. Multiple factors, such as the aging population, federal programs for the elderly, and the economic health care climate, have contributed to the emergence of the skilled nursing facility as a practice setting for I.V. therapy. As the acuity of nursing home residents continues to rise, I.V. therapy will become a more frequent treatment modality. Therefore, I.V. nurses must be aware of the impact of provision of this service in the skilled nursing facility setting.


Central Nervous System Involvement in Common Variable Immunodeficiency: A Case of Acute Unilateral Optic Neuritis in a 26-Year-Old Italian Patient.
Common Variable Immunodeficiency (CVID) is a group of heterogeneous primary immunodeficiencies sharing defective B lymphocytes maturation and dysregulated immune response and resulting in impaired immunoglobulin production. Clinical picture encompasses increased susceptibility to infections, hematologic malignancies, inflammatory, and autoimmune diseases. Neurological manifestations are uncommon and optic neuritis has been previously reported only in one case with bilateral involvement. We hereby report a case of a 26-year-old man affected by CVID undergoing regular immunoglobulin supplementation, who presented with acute unilateral demyelinating optic neuritis and lymphocytic pleocytosis in the cerebrospinal fluid. A variety of infectious, inflammatory, and neoplastic conditions were excluded and a diagnosis of clinically isolated optic neuritis was made. The patient was treated with a short course of intravenous steroids with complete recovery. Overall, this case expands our current knowledge about clinical spectrum of complications in CVID and highlights the need for further research about this complex disease.


Human neuropathological and animal model evidence supporting a role for Fas-mediated apoptosis and inflammation in cervical spondylotic myelopathy.
Although cervical spondylotic myelopathy is a common cause of chronic spinal cord dysfunction in humans, little is known about the molecular mechanisms underlying the progressive neural degeneration characterized by this condition. Based on animal models of cervical spondylotic myelopathy and traumatic spinal cord injury, we hypothesized that Fas-mediated apoptosis and inflammation may play an important role in the pathobiology of human cervical spondylotic myelopathy. We further hypothesized that neutralization of the Fas ligand using a function-blocking antibody would reduce cell death, attenuate inflammation, promote axonal repair and enhance functional neurological outcomes in animal models of cervical spondylotic myelopathy. We examined molecular changes in post-mortem human spinal cord tissue from eight patients with cervical spondylotic myelopathy and four control cases. Complementary studies were conducted using a mouse model of cervical spondylotic myelopathy (twy/twy mice that develop spontaneous cord compression at C2-C3). We observed Fas-mediated apoptosis of neurons and oligodendrocytes and an increase in inflammatory cells in the compressed spinal cords of patients with cervical spondylotic myelopathy. Furthermore, neutralization of Fas ligand with a function-blocking antibody in twy/twy mice reduced neural inflammation at the lesion mediated by macrophages and activated microglia, glial scar formation and caspase-9 activation. It was also associated with increased expression of Bcl-2 and promoted dramatic functional neurological recovery. Our data demonstrate, for the first time in humans, the potential contribution of Fas-mediated cell death and inflammation to the pathobiology of cervical spondylotic myelopathy. Complementary data in a murine model of cervical spondylotic myelopathy further suggest that targeting the Fas death receptor pathway is a viable neuroprotective strategy to attenuate neural degeneration and optimize neurological recovery in cervical spondylotic myelopathy. Our findings highlight the possibility of medical treatments for cervical spondylotic myelopathy that are complementary to surgical decompression.


Serodiagnostic assays for celiac disease based on the open or closed conformation of the autoantigen, transglutaminase 2.
The autoantigen of celiac disease, transglutaminase 2 (TG2), adopts an open conformation during enzymatic activation. We studied diagnostic accuracy of serodiagnostic assays using TG2 in its open and closed conformation as antigens in patients with diagnostic difficulties. The open TG2 antibody (TG2ab) test identified 93% of untreated celiac patients in contrast to 44%, 27%, and 68% detected by closed and conventional TG2ab and endomysial antibody (EmA) tests, respectively. The assay was able to detect 60% of non-responding celiac patients seronegative for conventional TG2ab and EmA. The titers of the open TG2abs were higher than those of the closed TG2abs. The serological test utilizing TG2 in an open conformation was more accurate than the other assays in finding active celiac disease even in patients having negative or borderline conventional celiac autoantibodies and in revealing poor dietary response non-invasively. It thus offers a promising tool in the diagnostics and follow-up of celiac disease.


[Medico-genetic study of the population of Uzbekistan. VIII. Territorial distribution of hereditary diseases in the population of four regions of the Khorezm province and its genetic load].
The load of hereditary diseases was estimated on the basis of data obtained during medical-genetic study of the population of four districts of Khorezm province. The load of autosomal recessive disorders comprised 2-3 X 10(-3) affected, that of autosomal dominant disorders - 0.4-0.5 X 10(-3) and that of X-linked disorders - 0.2-0.4 X 10(-3) males. The main part of patients with autosomal recessive disorders belonged to separate families randomly spread over the populations. A trend for local accumulation of families with the same disorder was observed in small populations. It was shown that overall frequency of autosomal recessive genes per individual increased with the increase in the population size.


Heritability and repeatability of sexual performance scores of rams.
Sexual performance has been subjectively measured with a libido test during screening of rams before public sale and breeding at the U.S. Sheep Experiment Station from 1990 to 2000. The objective of this study was to determine whether sexual performance was genetically influenced. Sexual performance scores ranged from 1 to 6 with scores increasing from sexually inactive to highly sexually active in the presence of estrous ewes. The overall average score was 3.5+/-0.02. Records from four breeds (Columbia, n = 807; Polypay, n = 1,668; Rambouillet, n = 1,208; and Targhee, n = 1,002) were combined into one analysis because breeds had similar phenotypic variances. Total number of records was 4,685, which included a second sexual performance test on 1,212 rams in the following year. Variance components were estimated using a REML algorithm. Fixed effects were breed of ram, selection line within breed, and year by breed. A permanent environmental effect for ram was included to account for repeated observations on individual animals. Age and weight of the rams at time of the libido test were linear covariates and were breed-specific. Adjusted means for sexual performance scores did not differ among breeds (P > 0.05). Age was a significant effect (P < 0.01), with sexual performance score increasing 0.05 units for each month of age. The additive genetic variance was estimated as 0.54. The estimate of variance due to ram permanent environmental effects was 1.19. The residual variance was estimated to be 0.67. The heritability estimate was moderate (0.22+/-0.04) and repeatability was high (0.72). These results imply that one screening for sexual performance provides a reliable measure of sexual performance and that favorable response to selection for ram serving capacity may be expected.


Betahistine hydrochloride in Méniére's disease.
A double-blind, placebo-controlled, cross-over clinical trial was performed to assess the effect of betahistine hydrochloride (Serc) in Ménière's disease. The diagnosis was based on paroxysmal attacks of rotational vertigo, with tinnitus, and a fluctuating sensori-neural deafness, together with the results of auditory and vestigular tests. Twenty-eight patients were admitted to the trial over 3 years. Twenty-two patients completed the trial. In total, they received betahistine 32 mg daily, for a period of 16 weeks, and placebo also for the same length of time, preceded in every case by a 4-week pre-treatment period. Daily symptom score cards were kept. There was a statistically significant improvement in favour of the drug with regard to vertigo, tinnitus and deafness. Vertigo was the most responsive symptom. No adverse reactions were observed.


Contour of the GnRH pulse independently modulates gonadotropin secretion in the human male.
GnRH pulse frequency, amplitude, and interpulse interval have all been demonstrated to regulate gonadotropin secretion individually. We tested the hypothesis that the contour of the GnRH pulse also modulates gonadotropin output in 10 men with isolated GnRH deficiency in whom a fixed GnRH dose was administered at a constant physiologic frequency by either instantaneous bolus or by 1-, 5-, or 30-min infusions. LH, FSH and free alpha subunit (FAS) responses were also compared to spontaneous gonadotropin secretion in normal adult men. While the LH and FAS pulses following the instantaneous bolus and 1-min infusion of GnRH were indistinguishable, further increases in the duration of gonadotrope stimulation by GnRH were associated with progressive decreases in all parameters of gonadotropin secretion (mean levels, amplitude, peak levels, AUC). FSH secretion was also decreased following variations in the contour of the GnRH pulse, although overall changes were less dramatic than for LH and FAS. The LH pulses following the bolus GnRH stimulation were indistinguishable from spontaneous LH pulses occurring in normal men whereas those stimulated by the 1-, 5-, and 30-min infusions of GnRH became progressively blunted with the lowest levels of secretion occurring after the longest infusion. In sharp contrast, FAS pulse parameters in the GnRH-deficient subjects greatly exceeded those of normal men regardless of the contour of the GnRH stimulus, whereas mean FSH levels were all modestly (although significantly) higher than those of normal adult men. These results demonstrate that the pituitary is sensitive to subtle changes in the contour of the GnRH stimulus, with a more prolonged duration of GnRH stimulation resulting in a diminished pituitary response. Alterations of the contour of endogenous GnRH secretion may represent an additional mechanism for altering gonadotrope function and provide additional evidence for the differential regulation of LH, FAS, and FSH by GnRH. However, the previously reported elevated levels of FAS secretion in GnRH-deficient men undergoing long-term GnRH replacement are not explained by abnormalities of GnRH contour.


Influence of grating parameters on the performance of a high-power blue external-cavity semiconductor laser.
The influence of grating parameters, including the diffraction efficiency and ruling density, on the performance of high-power blue external-cavity (EC) semiconductor lasers has been studied. We find that for the Littrow-type EC laser with a zeroth-order diffracted beam as a coupling output, the high zeroth-order diffraction efficiency benefits the high external light extraction efficiency, and the high first-order diffraction efficiency contributes to the low threshold current and the wide wavelength tuning bandwidth. By using a grating with a zeroth-order diffraction efficiency of 76% and a first-order diffraction efficiency of 11.5%, the external light extraction efficiency can reach up to 80% with an output power of more than 1200 mW and a tuning bandwidth of 3.6 nm. When a grating with a first-order diffraction efficiency of 58.5% and a zeroth-order diffraction efficiency of 28.6% is used, the threshold current is reduced by 46% at the central Fabry-Perot resonance wavelength. Moreover, a tuning bandwidth of 8.3 nm ranging from 442.2 nm to 450.5 nm with an output power of more than 500 mW is achieved. Besides, we also find that the high ruling density is helpful in obtaining narrow lasing linewidth, especially for the EC laser system injected with low current. By using a grating with a ruling density of 2400 grooves/mm, the spectral linewidth of the EC laser can be narrowed to be 0.02 nm with an operating current of 300 mA. As the injection current is increased, the lasing linewidth is little affected by the ruling density of the grating due to the broadened feedback spectrum by the flattening of gain spectrum. The results above shed light on the improvement of the performance of EC lasers by selecting appropriate parameters for the grating.


Automated VR therapy for improving positive self-beliefs and psychological well-being in young patients with psychosis: a proof of concept evaluation of Phoenix VR self-confidence therapy.
Low self-confidence in patients with psychosis is common. This can lead to higher symptom severity, withdrawal from activities, and low psychological well-being. There are effective psychological techniques to improve positive self-beliefs but these are seldom provided in psychosis services. With young people with lived experience of psychosis we developed a scalable automated VR therapy to enhance positive-self beliefs. The aim was to conduct a proof of concept clinical test of whether the new VR self-confidence therapy (Phoenix) may increase positive self-beliefs and psychological well-being. Twelve young patients with non-affective psychosis and with low levels of positive self-beliefs participated. Over 6 weeks, patients were provided with a stand-alone VR headset so that they could use Phoenix at home and were offered weekly psychologist meetings. The outcome measures were the Oxford Positive Self Scale (OxPos), Brief Core Schema Scale, and Warwick-Edinburgh Well-being Scale (WEMWBS). Satisfaction, adverse events and side-effects were assessed. Eleven patients provided outcome data. There were very large end-of-treatment improvements in positive self-beliefs (OxPos mean difference = 32.3; 95% CI: 17.3, 47.3; Cohen's d=3.0) and psychological well-being (WEMWBS mean difference = 11.2; 95% CI: 8.0, 14.3; Cohen's d=1.5). Patients rated the quality of the VR therapy as: excellent (n=9), good (n=2), fair (n=0), poor (n=0). An average of 5.3 (SD=1.4) appointments were attended. Uptake of the VR intervention was high, satisfaction was high, and side-effects extremely few. There were promising indications of large improvements in positive self-beliefs and psychological well-being. A randomized controlled clinical evaluation is warranted.