Psychological interventions for coronary heart disease.
Psychological interventions can form part of comprehensive cardiac rehabilitation programmes (CCR). These interventions may include stress management interventions, which aim to reduce stress, either as an end in itself or to reduce risk for further cardiac events in patients with heart disease. To determine the effectiveness of psychological interventions, in particular stress management interventions, on mortality and morbidity, psychological measures, quality of life, and modifiable cardiac risk factors, in patients with coronary heart disease (CHD). We searched CCTR to December 2001 (Issue 4, 2001), MEDLINE 1999 to December 2001 and EMBASE 1998 to the end of 2001, PsychINFO and CINAHL to December 2001. In addition, searches of reference lists of papers were made and expert advice was sought. RCTs of non-pharmacological psychological interventions, administered by trained staff, either single modality interventions or a part of CCR with minimum follow up of 6 months. Adults of all ages with CHD (prior myocardial infarction, coronary artery bypass graft or percutaneous transluminal coronary angioplasty, angina pectoris or coronary artery disease defined by angiography). Stress management (SM) trials were identified and reported in combination with other psychological interventions and separately. Studies were selected, and data were abstracted, independently by two reviewers. Authors were contacted where possible to obtain missing information. Thirty six trials with 12,841 patients were included. Of these, 18 (5242 patients) were SM trials. Quality of many trials was poor with the majority not reporting adequate concealment of allocation, and only 6 blinded outcome assessors. Combining the results of all trials showed no strong evidence of effect on total or cardiac mortality, or revascularisation. There was a reduction in the number of non-fatal reinfarctions in the intervention group (OR 0.78 (0.67, 0.90), but the two largest trials (with 4809 patients randomized) were null for this outcome, and there was statistical evidence of publication bias. Similar results were seen for the SM subgroup of trials. Provision of any psychological intervention or SM intervention caused small reductions in anxiety and depression. Few trials reported modifiable cardiac risk factors or quality of life. Overall psychological interventions showed no evidence of effect on total or cardiac mortality, but did show small reductions in anxiety and depression in patients with CHD. Similar results were seen for SM interventions when considered separately. However, the poor quality of trials, considerable heterogeneity observed between trials and evidence of significant publication bias make the pooled finding of a reduction in non-fatal myocardial infarction insecure.


A Cost Reimbursement Model for Hepatitis C Treatment Care Coordination.
To estimate the cost of delivering a hepatitis C virus care coordination program at 2 New York City health care provider organizations and describe a potential payment model for these currently nonreimbursed services. An economic evaluation of a hepatitis C care coordination program was conducted using micro-costing methods compared with macro-costing methods. A potential payment model was calculated for 3 phases: enrollment to treatment initiation, treatment initiation to treatment completion, and a bonus payment for laboratory evidence of successful treatment outcome (sustained viral response). Two New York City health care provider organizations. Care coordinators and peer educators delivering care coordination services were interviewed about time spent on service provision. De-identified individual-level data on study participant utilization of services were also used. Project INSPIRE is an innovative hepatitis C care coordination program developed by the New York City Department of Health and Mental Hygiene. Average cost per participant per episode of care for 2 provider organizations and a proposed payment model. The average cost per participant at 1 provider organization was $787 ($522 nonoverhead cost, $264 overhead) per episode of care (5.6 months) and $656 ($429 nonoverhead cost, $227 overhead, 5.7 months) at the other one. The first organization had a lower macro-costing estimate ($561 vs $787) whereas the other one had a higher macro-costing estimate ($775 vs $656). In the 3-phased payment model, phase 1 reimbursement would vary between the provider organizations from approximately $280 to $400, but reimbursement for both organizations would be approximately $220 for phase 2 and approximately $185 for phase 3. The cost of this 5.6-month care coordination intervention was less than $800 including overhead or less than $95 per month. A 3-phase payment model is proposed and requires further evaluation for implementation feasibility. Project INSPIRE's HCV care coordination program provides good value for a cost of less than $95 per participant per month. The payment model provides an incentive for successful cure of hepatitis C with a bonus payment; using the bonus payment to support HCV tele-mentoring expands HCV treatment capacity and empowers more primary care providers to treat their own patients with HCV.


Analysis of N-nitrosamines and other nitro(so) compounds in water by high-performance liquid chromatography with post-column UV photolysis/Griess reaction.
Despite their potential carcinogenicity and probable formation during water disinfection processes, little is known about the occurrence of other nitro(so) compounds than a few specific N-nitroso compounds such as N-nitrosodimethylamine (NDMA). An analytical method was developed to monitor various nitro(so) compounds including N-nitrosamines based on the Griess colorimetric determination of nitrite generated by UV-254 nm photolysis of nitro(so) compounds after separation by HPLC (HPLC-Post Column UV photolysis/Griess reaction (HPLC-PCUV)). To differentiate N-nitro(so) compounds (i.e. UV-labile) from other nitro(so) and N-containing compounds (i.e. UV-resistant), a pre-treatment was established by photolyzing solid-phase extracted samples at 254 nm (1000 mJ/cm(2)) and thus removing N-nitro(so) compounds selectively. Considering a 1000-fold concentration factor and extraction efficiencies (57-83%) during solid phase extraction, the method detection limits ranged from 4 to 28 ng/L for dimethylnitramine and eight N-nitrosamines (EPA 8270 nine nitrosamines mixture except for N-nitrosodiphenylamine). For four pool waters, the UV-resistant groups accounted for more than 78% of the estimated total concentration of nitro(so) and other N-containing compounds (6.1-48.6 nM). Only one unknown UV-labile compound was detected in one pool water (2.0-7.9 nM). NDMA was most frequently detected and N-nitrosodipropylamine (NDPA) and N-nitrosodibutylamine (NDBA) were additionally detected in one pool water. Chloramination of a secondary wastewater effluent with NDMA (0.2 nM) and UV-resistant compounds (7.9 nM) from a pilot-scale municipal wastewater treatment plant led to a significant formation of not only unidentified UV-resistant compounds (67.8 nM) and UV-labile compounds (14.6 nM), but also identified nitrosamines such as NDMA (4.3 nM), N-nitrosopiperidine (1.8 nM), NDPA (0.5 nM), and NDBA (0.5 nM). Overall, the novel HPLC-PCUV system is a powerful screening tool for the detection of (un)known N-nitro(so) as well as other nitro(so) and UV-induced nitrite-producing compounds.


Holoenzyme DNA polymerase III fixes mutations.
DNA polymerase III is required for mutagenesis after damage to the chromosome. This effect is not modulated by the presence or absence of DNA polymerase II activity in the cell. In cells containing a temperature-sensitive dnaE mutation, the alpha-subunit of DNA polymerase III is inactivated at the restrictive temperature, resulting in lethality. Cells containing the pcbA1 mutation can continue replication if DNA polymerase I activity is present. When such cells are shifted from the permissive to the restrictive temperature, mutagenesis decreases rapidly after 10 min. These results are compatible with conversion of the replicative apparatus from one containing a functional DNA polymerase III synthetic subunit to one containing DNA polymerase I. We also find that DNA polymerase I dependent replication is markedly sensitive to coumermycin A1. We conclude that DNA polymerase III holoenzyme with the alpha-subunit is required for fixing mutations in the genome.


Resilience among children and adolescents at risk for depression: Mediation and moderation across social and neurobiological contexts.
This article offers a multilevel perspective on resilience to depression, with a focus on interactions among social and neurobehavioral systems involved in emotional reactivity and regulation. We discuss models of cross-contextual mediation and moderation by which the social context influences or modifies the effects of resilience processes at the biological level, or the biological context influences or modifies the effects of resilience processes at the social level. We highlight the socialization of emotion regulation as a candidate process contributing to resilience against depression at the social context level. We discuss several factors and their interactions across levels-including genetic factors, stress reactivity, positive affect, neural systems of reward, and sleep-as candidate processes contributing to resilience against depression at the neurobehavioral level. We then present some preliminary supportive findings from two studies of children and adolescents at high risk for depression. Study 1 shows that elevated neighborhood level adversity has the potential to constrain or limit the benefits of protective factors at other levels. Study 2 indicates that ease and quickness in falling asleep and a greater amount of time in deep Stage 4 sleep may be protective against the development of depressive disorders for children. The paper concludes with a discussion of clinical implications of this approach.


Use of big data for drug development and for public and personal health and care.
The use of data analytics across the entire healthcare value chain, from drug discovery and development through epidemiology to informed clinical decision for patients or policy making for public health, has seen an explosion in the recent years. The increase in quantity and variety of data available together with the improvement of storing capabilities and analytical tools offer numerous possibilities to all stakeholders (manufacturers, regulators, payers, healthcare providers, decision makers, researchers) but most importantly, it has the potential to improve general health outcomes if we learn how to exploit it in the right way. This article looks at the different sources of data and the importance of unstructured data. It goes on to summarize current and potential future uses in drug discovery, development, and monitoring as well as in public and personal healthcare; including examples of good practice and recent developments. Finally, we discuss the main practical and ethical challenges to unravel the full potential of big data in healthcare and conclude that all stakeholders need to work together towards the common goal of making sense of the available data for the common good.


In Epigenomic Studies, Including Cell-Type Adjustments in Regression Models Can Introduce Multicollinearity, Resulting in Apparent Reversal of Direction of Association.
Background: Association studies of epigenome-wide DNA methylation and disease can inform biological mechanisms. DNA methylation is often measured in peripheral blood, with heterogeneous cell types with different methylation profiles. Influences such as adiposity-associated inflammation can change cell-type proportions, altering measured blood methylation levels. To determine whether associations between loci-specific methylation and outcomes result from cellular heterogeneity, many studies adjust for estimated blood cell proportions, but high correlations between methylation and cell-type proportions could violate the statistical assumption of no multicollinearity. We examined these assumptions in a population-based study. Methods: CDKN2A promoter CpG methylation was measured in peripheral blood from 812 adolescents aged 17 years (Western Australian Pregnancy Cohort Study). Loge adolescent BMI was used as the outcome in a regression analysis with DNA methylation as predictor, adjusting for age/sex. Further regression analyses additionally adjusted for estimated cell-type proportions using the reference-based Houseman method, and simulations modeled the effects of varying levels of correlation between cell proportions and methylation. Correlations between estimated cell proportions and CpG methylation from Illumina 450K were measured. Results: Lower DNA methylation was associated with higher BMI when cell-type adjustment was not included; for CpG4, β = -0.004 logeBMI/%methylation (95% CI -0.0065, -0.001; p = 0.003). The direction of association reversed when adjustment for six cell types was made; for CpG4, β = 0.004 logeBMI/%methylation (-0.0002, 0.0089; p = 0.06). Correlations between CpG methylation and cell-type proportions were high, and variance inflation factors (VIFs) were extremely high (25 to 113.7). Granulocyte count was correlated with BMI, and removing granulocytes from the regression model reduced all VIFs to <3.1, with persistence of a positive association between methylation and BMI [CpG4 β = 0.004 logeBMI/%methylation (-0.0002, 0.0088; p = 0.06)]. Simulations supported major effects of multicollinearity on regression results. Conclusions: Where cell types are highly correlated with other covariates in regression models, the statistical assumption of no multicollinearity may be violated. This can result in reversal of direction of association, particularly when examining associations with phenotypes related to inflammation, as CpG methylation may associate with changes in cell-type proportions. Removing predictors with high correlations from regression models may remove the multicollinearity. However, this might hinder biological interpretability.


Nrf2-mediated anti-oxidant effects contribute to suppression of non-alcoholic steatohepatitis-associated hepatocellular carcinoma in murine model.
The exact mechanisms of hepatocellular carcinoma development in non-alcoholic steatohepatitis remain unclear. In this study, we used a new class of high-fat diet, which could induce hepatocellular carcinoma development without the use of general chemical carcinogens or knockout mice. We investigated the correlation between hepatocellular carcinoma and oxidative stress/anti-oxidant effects after depletion of the gut microbiota by treatment with antibiotics. Mice fed with the steatohepatitis-inducing high-fat diet (STHD-01) for 41 weeks developed hepatocellular carcinoma. Antibiotic-treatment in mice fed with STHD-01 significantly depleted the gut microbiota and significantly ameliorated liver injury/histology. The tumor numbers of hepatocellular carcinoma were dramatically decreased by the antibiotics-treatment. We analyzed the factors involved in oxidative stress and anti-oxidant effects. Oxidative stress was elevated in mice fed with STHD-01, whereas some anti-oxidant factors were significantly elevated after antibiotics treatment. These results suggest that the gut microbiota is a key factor in improving oxidative stress induced by STHD-01 feeding.


Does respiratory syncytial virus lower respiratory illness in early life cause recurrent wheeze of early childhood and asthma? Critical review of the evidence and guidance for future studies from a World Health Organization-sponsored meeting.
Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection (LRTI) and hospitalization in infants and children globally. Many observational studies have found an association between RSV LRTI in early life and subsequent respiratory morbidity, including recurrent wheeze of early childhood (RWEC) and asthma. Conversely, two randomized placebo-controlled trials of efficacious anti-RSV monoclonal antibodies (mAbs) in heterogenous infant populations found no difference in physician-diagnosed RWEC or asthma by treatment group. If a causal association exists and RSV vaccines and mAbs can prevent a substantial fraction of RWEC/asthma, the full public health value of these interventions would markedly increase. The primary alternative interpretation of the observational data is that RSV LRTI in early life is a marker of an underlying predisposition for the development of RWEC and asthma. If this is the case, RSV vaccines and mAbs would not necessarily be expected to impact these outcomes. To evaluate whether the available evidence supports a causal association between RSV LRTI and RWEC/asthma and to provide guidance for future studies, the World Health Organization convened a meeting of subject matter experts on February 12-13, 2019 in Geneva, Switzerland. After discussing relevant background information and reviewing the current epidemiologic evidence, the group determined that: (i) the evidence is inconclusive in establishing a causal association between RSV LRTI and RWEC/asthma, (ii) the evidence does not establish that RSV mAbs (and, by extension, future vaccines) will have a substantial effect on these outcomes and (iii) regardless of the association with long-term childhood respiratory morbidity, severe acute RSV disease in young children poses a substantial public health burden and should continue to be the primary consideration for policy-setting bodies deliberating on RSV vaccine and mAb recommendations. Nonetheless, the group recognized the public health importance of resolving this question and suggested good practice guidelines for future studies.


Addressing secondary prevention of osteoporosis in fracture care: follow-up to "own the bone".
The majority of the 1.8 million individuals who sustain a fracture annually in the United States have osteopenia or osteoporosis, yet <15% of these patients subsequently receive treatment for osteoporosis. A prospective cohort study was conducted to assess the effect of two different interventions on the rate of osteoporosis treatment in patients with a fragility fracture. Patients who were fifty years of age or older and were hospitalized for the treatment of a fragility fracture at either of two academic institutions were eligible for inclusion in the study. The intervention at one hospital involved immediate care for osteoporosis, including initiation of pharmacologic therapy during hospitalization. The intervention at the other hospital involved delayed care, including recommendations for osteoporosis counseling, bone-mineral density testing, and potential treatment for osteoporosis that were communicated to the primary care physician after the patient was discharged from the hospital. Patients were surveyed by telephone six months after the fracture, and their medical and pharmacy records were reviewed to verify the osteoporosis treatment that they had received. The mean age was 73 ± 10 years in the immediate-care group and 74 ± 12 years in the delayed-care group. Eighty percent of the patients were women. Sixty-five percent of the patients in each group completed the telephone interview six months after the fracture, and most had seen their primary care physician and undergone bone-mineral density testing. The rate of bone-mineral density testing was 92% in the immediate-care group compared with 76% in the delayed-care group. Both immediate and delayed care for osteoporosis resulted in a significant increase in the treatment rate compared with the baseline rate of 0% (p < 0.001). However, the primary care physician had initiated osteoporosis therapy by six months after the fracture in only 30% of the patients in the delayed-care group compared with a treatment rate of 67% in the immediate-care group (p < 0.001). Limitations of the study include the possibility that the findings resulted from a difference between the two study centers rather than between the two strategies. In addition, because of the academic and integrated nature of the medical systems at which the study was conducted, the findings cannot necessarily be extrapolated to other types of institutions. In summary, a recommendation for osteoporosis treatment made by an orthopaedic surgeon to the patient's primary care physician resulted in an increase in the rate of bone-mineral density testing and in the rate of therapy compared with baseline. However, immediate initiation of osteoporosis care during hospitalization for the fragility fracture resulted in a higher rate of treatment--with two-thirds of the patients receiving therapy six months after the fracture--compared with delayed initiation.


OprD Repression upon Metal Treatment Requires the RNA Chaperone Hfq in Pseudomonas aeruginosa.
The metal-specific CzcRS two-component system in Pseudomonas aeruginosa is involved in the repression of the OprD porin, causing in turn carbapenem antibiotic resistance in the presence of high zinc concentration. It has also been shown that CzcR is able to directly regulate the expression of multiple genes including virulence factors. CzcR is therefore an important regulator connecting (i) metal response, (ii) pathogenicity and (iii) antibiotic resistance in P. aeruginosa. Recent data have suggested that other regulators could negatively control oprD expression in the presence of zinc. Here we show that the RNA chaperone Hfq is a key factor acting independently of CzcR for the repression of oprD upon Zn treatment. Additionally, we found that an Hfq-dependent mechanism is necessary for the localization of CzcR to the oprD promoter, mediating oprD transcriptional repression. Furthermore, in the presence of Cu, CopR, the transcriptional regulator of the CopRS two-component system also requires Hfq for oprD repression. Altogether, these results suggest important roles for this RNA chaperone in the context of environment-sensing and antibiotic resistance in P. aeruginosa.


Space-time interdependence: evidence against asymmetric mapping between time and space.
Time and space are intimately related, but what is the real nature of this relationship? Is time mapped metaphorically onto space such that effects are always asymmetric (i.e., space affects time more than time affects space)? Or do the two domains share a common representational format and have the ability to influence each other in a flexible manner (i.e., time can sometimes affect space more than vice versa)? In three experiments, we examined whether spatial representations from haptic perception, a modality of relatively low spatial acuity, would lead the effect of time on space to be substantially stronger than the effect of space on time. Participants touched (but could not see) physical sticks while listening to an auditory note, and then reproduced either the length of the stick or the duration of the note. Judgements of length were affected by concurrent stimulus duration, but not vice versa. When participants were allowed to see as well as touch the sticks, however, the higher acuity of visuohaptic perception caused the effects to converge so length and duration influenced each other to a similar extent. These findings run counter to the spatial metaphor account of time, and rather support the spatial representation account in which time and space share a common representational format and the directionality of space-time interaction depends on the perceptual acuity of the modality used to perceive space.


A BAYESIAN HIERARCHICAL SPATIAL POINT PROCESS MODEL FOR MULTI-TYPE NEUROIMAGING META-ANALYSIS.
Neuroimaging meta-analysis is an important tool for finding consistent effects over studies that each usually have 20 or fewer subjects. Interest in meta-analysis in brain mapping is also driven by a recent focus on so-called "reverse inference": where as traditional "forward inference" identifies the regions of the brain involved in a task, a reverse inference identifies the cognitive processes that a task engages. Such reverse inferences, however, requires a set of meta-analysis, one for each possible cognitive domain. However, existing methods for neuroimaging meta-analysis have significant limitations. Commonly used methods for neuroimaging meta-analysis are not model based, do not provide interpretable parameter estimates, and only produce null hypothesis inferences; further, they are generally designed for a single group of studies and cannot produce reverse inferences. In this work we address these limitations by adopting a non-parametric Bayesian approach for meta analysis data from multiple classes or types of studies. In particular, foci from each type of study are modeled as a cluster process driven by a random intensity function that is modeled as a kernel convolution of a gamma random field. The type-specific gamma random fields are linked and modeled as a realization of a common gamma random field, shared by all types, that induces correlation between study types and mimics the behavior of a univariate mixed effects model. We illustrate our model on simulation studies and a meta analysis of five emotions from 219 studies and check model fit by a posterior predictive assessment. In addition, we implement reverse inference by using the model to predict study type from a newly presented study. We evaluate this predictive performance via leave-one-out cross validation that is efficiently implemented using importance sampling techniques.


Folate and risk of breast cancer: a meta-analysis.
Epidemiologic findings are inconsistent concerning risk for breast cancer associated with low folate intake or blood folate levels. We performed a meta-analysis of prospective and case-control studies to examine folate intake and levels in relation to risk of breast cancer. We searched MEDLINE for studies of this association that were published in any language from January 1, 1966, through November 1, 2006. Study-specific risk estimates were pooled by use of a random-effects model. All statistical tests were two-sided. Folate intake in increments of 200 microg/day was not associated with the risk of breast cancer in prospective studies (estimated summary relative risk [RR] = 0.97, 95% confidence interval [CI] = 0.88 to 1.07, for dietary folate [eight studies; 302,959 participants and 8367 patients with breast cancer], and RR = 1.01, 95% CI = 0.97 to 1.05, for total folate [six studies; 306,209 participants and 8165 patients with breast cancer]) but was statistically significantly inversely associated with risk in case-control studies (estimated summary odds ratio [OR] = 0.80, 95% CI = 0.72 to 0.89, for dietary folate [13 studies; 8558 case patients and 10,812 control subjects], and OR = 0.93, 95% CI = 0.81 to 1.07, for total folate [three studies; 2184 case patients and 3233 control subjects]). High blood folate levels versus low levels were not statistically significantly associated with the risk of breast cancer in prospective studies (OR = 0.81, 95% CI = 0.59 to 1.10 [three studies]) or in case-control studies (OR = 0.41, 95% CI = 0.15 to 1.10 [two studies]). Among the two prospective studies and two case-control studies that stratified by alcohol consumption, high folate intake (comparing the highest with the lowest category) was associated with a statistically significant decreased risk of breast cancer among women with moderate or high alcohol consumption (summary estimate = 0.51, 95% CI = 0.41 to 0.63) but not among women with low or no alcohol consumption (summary estimate = 0.95, 95% CI = 0.78 to 1.15). Few studies examined whether the relation between folate intake and breast cancer was modified by intakes of methionine or vitamins B6 and B12, and the findings were inconsistent. No clear support for an overall relationship between folate intake or blood folate levels and breast cancer risk was found. Adequate folate intake may reduce the increased risk of breast cancer that has been associated with moderate or high alcohol consumption.


Understanding metric-related pitfalls in image analysis validation.
Validation metrics are key for the reliable tracking of scientific progress and for bridging the current chasm between artificial intelligence (AI) research and its translation into practice. However, increasing evidence shows that particularly in image analysis, metrics are often chosen inadequately in relation to the underlying research problem. This could be attributed to a lack of accessibility of metric-related knowledge: While taking into account the individual strengths, weaknesses, and limitations of validation metrics is a critical prerequisite to making educated choices, the relevant knowledge is currently scattered and poorly accessible to individual researchers. Based on a multi-stage Delphi process conducted by a multidisciplinary expert consortium as well as extensive community feedback, the present work provides the first reliable and comprehensive common point of access to information on pitfalls related to validation metrics in image analysis. Focusing on biomedical image analysis but with the potential of transfer to other fields, the addressed pitfalls generalize across application domains and are categorized according to a newly created, domain-agnostic taxonomy. To facilitate comprehension, illustrations and specific examples accompany each pitfall. As a structured body of information accessible to researchers of all levels of expertise, this work enhances global comprehension of a key topic in image analysis validation.


Clinical trial design in acute lung injury--issues and controversies.
The evolution of scientific investigation in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is replete with examples of effective bench-to-bedside transitions, pioneering research methodology, and international collaboration. This article highlights for clinicians a selection of challenges and controversies of clinical trial design in ALI and ARDS. A section on Patient Selection highlights controversial trade-offs between homogeneous and heterogeneous study populations. A section on Clinical Protocols covers blinding, process-of-care interventions, usual-care control groups, and standardized protocols for adjunctive care. The third section discusses the quest for ideal Study Outcomes. The final section presents Interpretation Controversies, such as early stopping of clinical trials.


Postponement of satiety by blockade of brain cholecystokinin (CCK-B) receptors.
Exogenous cholecystokinin (CCK) decreases food intake and causes satiety in animals and man. However, it has not been established that endogenous CCK causes satiety or whether the response is mediated by peripheral-type (CCK-A) or brain-type (CCK-B) receptors. The development of potent and selective antagonists for CCK-A (MK-329) and CCK-B (L-365,260) receptors now allows these issues to be addressed. The CCK-A antagonist MK-329 and the CCK-B antagonist L-365,260 increased food intake in partially satiated rats and postponed the onset of satiety; however, L-365,260 was 100 times more potent than MK-329 in increasing feeding and preventing satiety. These results suggest that endogenous CCK causes satiety by an agonist action on CCK-B receptors in the brain.


SALINE ARTHROGRAPHY OF THE DISTAL INTERPHALANGEAL JOINT FOR LOW-FIELD MAGNETIC RESONANCE IMAGING OF THE EQUINE PODOTROCHLEAR BURSA: FEASIBILITY STUDY.
Abnormalities of the deep digital flexor tendon, navicular bone, and collateral sesamoidean ligament can be difficult to visualize using magnetic resonance imaging (MRI) if bursal fluid is absent. The use of saline podotrochlear bursography improves podotrochlear apparatus evaluation, however, the technique has disadvantages. The objective of this prospective feasibility study was to describe saline arthrography of the distal interphalangeal joint as an alternative technique for improving MRI visualization of the deep digital flexor tendon, navicular bone, collateral sesamoidean ligament, and podotrochlear bursa, and to compare this technique with saline podotrochlear bursography. Eight paired cadaver forelimbs were sampled. Saline podotrochlear bursography or saline arthrography techniques were randomly assigned to one limb, with the alternate technique performed on the contralateral limb. For precontrast and postcontrast studies using each technique, independent observers scored visualization of the dorsal aspect of the deep digital flexor tendon, palmar aspect of the navicular bone, collateral sesamoidean ligament, and podotrochlear bursa. Both contrast techniques improved visualization of structures over precontrast MR images and visualization scores for both techniques were similar. Findings from this study demonstrated that saline arthrography is feasible and comparable to saline podotrochlear bursography for producing podotrochlear bursa distension and separation of the structures of the podotrochlear apparatus on nonweight bearing limbs evaluated with low-field MRI. Clinical evaluation of saline arthrography on live animals is needed to determine if this technique is safe and effective as an alternative to saline podotrochlear bursography in horses with suspected pathology of the podotrochlear apparatus.


Mammalian SAD kinases are required for neuronal polarization.
Electrical activity in neurons is generally initiated in dendritic processes then propagated along axons to synapses, where it is passed to other neurons. Major structural features of neurons-their dendrites and axons-are thus related to their fundamental functions: the receipt and transmission of information. The acquisition of these distinct properties by dendrites and axons, called polarization, is a critical step in neuronal differentiation. We show here that SAD-A and SAD-B, mammalian orthologs of a kinase needed for presynaptic differentiation in Caenorhabditis elegans, are required for neuronal polarization. These kinases will provide entry points for unraveling signaling mechanisms that polarize neurons.


A novel multimodal fusion framework for early diagnosis and accurate classification of COVID-19 patients using X-ray images and speech signal processing techniques.
COVID-19 outbreak has become one of the most challenging problems for human being. It is a communicable disease caused by a new coronavirus strain, which infected over 375 million people already and caused almost 6 million deaths. This paper aims to develop and design a framework for early diagnosis and fast classification of COVID-19 symptoms using multimodal Deep Learning techniques. we collected chest X-ray and cough sample data from open source datasets, Cohen and datasets and local hospitals. The features are extracted from the chest X-ray images are extracted from chest X-ray datasets. We also used cough audio datasets from Coswara project and local hospitals. The publicly available Coughvid DetectNow and Virufy datasets are used to evaluate COVID-19 detection based on speech sounds, respiratory, and cough. The collected audio data comprises slow and fast breathing, shallow and deep coughing, spoken digits, and phonation of sustained vowels. Gender, geographical location, age, preexisting medical conditions, and current health status (COVID-19 and Non-COVID-19) are recorded. The proposed framework uses the selection algorithm of the pre-trained network to determine the best fusion model characterized by the pre-trained chest X-ray and cough models. Third, deep chest X-ray fusion by discriminant correlation analysis is used to fuse discriminatory features from the two models. The proposed framework achieved recognition accuracy, specificity, and sensitivity of 98.91%, 96.25%, and 97.69%, respectively. With the fusion method we obtained 94.99% accuracy. This paper examines the effectiveness of well-known ML architectures on a joint collection of chest-X-rays and cough samples for early classification of COVID-19. It shows that existing methods can effectively used for diagnosis and suggesting that the fusion learning paradigm could be a crucial asset in diagnosing future unknown illnesses. The proposed framework supports health informatics basis on early diagnosis, clinical decision support, and accurate prediction.


Synthetic cannabinoids nano-micelles for the management of triple negative breast cancer.
Triple-negative breast cancer (TNBC) is a highly heterogeneous disease with poor prognosis and inadequate therapeutic outcome. This contribution reports the use of a cannabinoid derivative, WIN55,212-2 (WIN) on the growth of TNBC in a 4T1 syngeneic mouse model. To reduce the well-known psychoactive side effects of cannabinoids, we prepared a nanomicellar formulation of WIN (SMA-WIN). In vivo biodistribution, in silico ADME predictions, anticancer activity, and psychoactive effect of WIN and SMA-WIN studies suggest that SMA-WIN formulation can reduce to greater extent tumor growth with milder psychoactive side effects when compared to free drug. Finally, the effects of WIN and SMA-WIN in combination with doxorubicin (Doxo), an established chemotherapeutic agent for the treatment of TNBC, were investigated in vitro and in vivo. SMA-WIN in combination with Doxo showed therapeutic efficacy and was able to reduce the tumor volume of TNBC murine model drastically. Moreover, SMA-WIN, while favoring drug tumor accumulation, minimized the adverse psychoactive effects that have impeded the use of this agent in the clinic. To our knowledge, this is the first report for the assessment of cannabinoid nanoparticles in vivo for the treatment of TNBC and its enhanced anticancer effect at low doses with Doxo. These findings suggest a new therapeutic strategy in the management of TNBC.


Alcohol alters whole body composition, inhibits bone formation, and increases bone marrow adiposity in rats.
Chronic alcohol abuse is a risk factor for osteoporosis and sarcopenia, but the long-term effects of alcohol on the immature musculoskeletal system are less clear. The present investigation in growing rats was designed to determine the effects of alcohol consumption on body composition, muscle mass, and bone mass, architecture, and turnover. Few studies have focused on the long-term effects of drinking on bone and muscle during skeletal maturation. Alcohol was included in the diet of 4-week-old male Sprague-Dawley rats (35% caloric intake) for 3 months. The controls were fed an isocaloric alcohol-free liquid diet ad libitum. A second study was performed in which the controls were pair-fed to the alcohol-fed animals. Compared to ad libitum-fed age-matched controls, alcohol-fed rats weighed less and had lower lean mass, fat mass, and percent body fat. In addition, they had lower slow- and fast-twitch muscle mass, lower total body bone mineral content and bone mineral density, and lower cancellous bone volume in the lumbar vertebra and proximal tibia. The effects of alcohol consumption on body composition were reduced when compared to the pair-fed control diet, indicating that caloric restriction was a comorbidity factor. In contrast, the effects of alcohol to decrease bone formation and serum leptin and IGF-I levels and to increase bone marrow adiposity appeared independent of caloric restriction. The skeletal abnormalities in growing alcohol-fed rats were due to a combination of effects specific to alcohol consumption and alcohol-induced caloric restriction.


Hyper-Rayleigh light scattering from an aqueous suspension of purple membrane.
Here we report the first observation of hyper-Rayleigh light scattering from bacteriorhodopsin in the form of an aqueous suspension of unoriented purple membranes. A typical purple membrane suspension used in our experiments contains approximately 10(8) randomly oriented purple membranes. Each purple membrane contains approximately 10(5) bacteriorhodopsin molecules in a two-dimensional crystallinearray. Hyper-Rayleigh light scattering is observed when the purple membrane suspension is illuminated with light that has a wavelength of 1064 nm. We propose that the 532-nm scattered light from each of the bacteriorhodopsin molecules in a single purple membrane is coherent, and that the scattered light from different purple membranes is incoherent. This proposal is supported by the following experimental observations: (a) the 532-nm light intensity is proportional to the square of the incident power, (b) the intensity of the 532-nm signal is linearly proportional to the concentration of purple membrane in solution, (c) the scattered 532-nm light is incoherent, (d) the scattered 532-nm light intensity decreases if the size of the purple membranes is reduced while the bacteriorhodopsin concentration is kept constant, and (e) the 532-nm light is due to the retinal chromophore of the bacteriorhodopsin molecule. The ratio of horizontal polarized hyper-Rayleigh scattered light to vertically polarized hyper-Rayleigh scattered light gives the angle (23 ± 4°) of the retinal axis with respect to the plane of the purple membrane. The hyperpolarizability of the bacteriorhodopsin molecule is found to be 5 ± 0.4 × 10(-27) esu.


Current status of pig lung xenotransplantation.
Human organ transplantation has improved duration and quality of life for many people, but its full potential is critically limited by short supply of available organs. One solution is xenotransplantation, although this comes with its own set of challenges. Lungs in particular are highly sensitive to injury, during the transplantation process generally, and to multiple immune rejection mechanisms. Using pig lung donors, our lab has been working on lung transplants into baboons as a surrogate for a human recipient. Several ex vivo human blood perfusion models have also proven useful. The combination of these experiments allows us to test large animal models as well as whole organ or isolated endothelial reactions to perfusion with human blood. We have found that a multi-modality therapeutic approach to prevent various pathogenic cascades - such as antibody-driven complement activation, other immune pathway activation, thrombosis, and tissue ischemia-reperfusion injury - has met with progressively greater success to protect the xeno lung from injury. Pig gene knockout and human gene transfer has been perhaps the greatest contributor. This review will discuss mechanisms of xeno lung injury, relevant experimental models, as well as recent results and future targets for research.


Nurses' knowledge and skills in colonoscopy patients' pain management.
This study aimed to describe the knowledge and skills of nurses in managing pain during colonoscopy procedures. Colonoscopy is a procedure to diagnose diseases of the intestine, and patients consider it even painful. However, few studies have described patients' pain management during the colonoscopy procedure. A quantitative survey design was used. The data were collected from colonoscopy nurses with a self-completed semi-structured questionnaire developed for the study. The hospitals performing colonoscopies in Finland, with the exception of the ones where the questionnaire was pilot-tested, were included in the study (n = 12). The optional sample was drawn by mailing questionnaires (n = 147) to endoscopy units to be filled in by three colonoscopy nurses during 2002. The response rate was 79% (n = 116). The majority of nurses used versatile non-pharmacological methods of managing pain and had practice-based knowledge of pain management during the colonoscopy procedure, but pain education and the acquisition of new professional knowledge were rarely reported. Pain scales were not in use and ethical conversation was lacking among the endoscopy staff in most (95%) hospitals. The study showed that colonoscopy nurses used numerous non-pharmacological methods, but only rarely acquired professional knowledge. There was a lack of pain scales and ethical conversation in the participating endoscopy units. The results can be used to improve the treatment of pain during colonoscopy procedures and endoscopy nurses' education. Nurses should be motivated by education and ethical conversation. Future studies should aim to analyse patients' own evaluation of pain during the colonoscopy procedure. The applicability of the existing pain scales and non-pharmacological methods should be tested in practice.


Radiation hormesis, or, could all that radiation be good for us?
Nuclear medicine technologists work under significant radiation protection constraints. These constraints are based on the linear no-threshold (LNT) radiation paradigm, which was developed in the 1960s and was based largely on the deleterious effects of radiation as they were understood at the time. More recently, the theory of radiation hormesis, or a beneficial effect of low-level exposure to radiation, has gained recognition. This article reviews the history of attitudes toward radiation, describes the radiation hormesis hypothesis, examines some of the evidence that supports it, and suggests ways that radiation protection regulations might change if the hypothesis were to become accepted.


Clinical validity of increased cortical uptake of amyloid ligands on PET as a biomarker for Alzheimer's disease in the context of a structured 5-phase development framework.
The use of biomarkers has been proposed for diagnosing Alzheimer's disease in recent criteria, but some biomarkers have not been sufficiently investigated to justify their routine clinical use. Here, we evaluate in a literature review the clinical validity of amyloid positron emission tomography (PET) imaging using a structured framework developed for the assessment of oncological biomarkers. Homogenous criteria have been addressed in reviews of other Alzheimer's disease biomarkers. There is adequate evidence that the main aims of phases 1 (rationale for use) and 2 (discriminative ability) have been achieved. The aims of phase 3 (early detection ability) have been partly achieved, while phase 4 studies (performance in representative mild cognitive impairment patients) are currently ongoing. Phase 5 studies (quantification of impact and costs) are still to come. This review highlights the priorities to be pursued to enable the proper use of amyloid PET imaging in a clinical setting. Future investigations will primarily be large, phase 4 studies that will assess the utility of amyloid PET imaging in routine clinical practice.


Psychometric evaluation of the Korean version of the Hepatitis B Quality of Life Questionnaire.
The purpose of this study was to conduct a psychometric evaluation of the Korean version of the Hepatitis B Quality of Life Questionnaire (K-HBQOL), which is designed to assess the quality of life of patients with the hepatitis B virus (HBV). The K-HBQOL was developed by converting the original English version to Korean using a back-and-forth translation method. The translated questionnaire was distributed to 168 adults with HBV. Descriptive statistics were used to summarize the demographic characteristics of these participants. Confirmatory factor analysis and exploratory principal components analysis (CFA and PCA) were performed, applying varimax rotation and using Kaiser's eigenvalue-greater-than-one rule to examine the factor structure. The minimum average partial rule was also used to identify the number of components. The original factor model was not confirmed by CFA in this sample. Six components (Psychological Well-being, Stigmatization, Anticipation Anxiety, Weakness, Vitality, and Vulnerability) were extracted by PCA, with 69.11% of the total variance explained. In this process, one component present in the original factor model (Transmission) was not found, while another component (Weakness) was extracted. This study revealed the psychometric characteristics of the Korean version of the HBQOL for patients with hepatitis B. We suggest a study with a larger sample is needed to evaluate validity and reliability of the K-HBQOL for other Korean populations.


A second species of the North American mayfly genus Amercaenis Provonsha and McCafferty (Ephemeroptera: Caenidae).
A new species of the psammophilous and brushlegged North American genus Amercaenis Provonsha and McCafferty, Amercaenis cusabo Provonsha and McCafferty, new species, is described from larvae taken from the Black River (North Carolina), the Pee Dee River (North Carolina), and the Savannah River (Georgia and South Carolina). The new species differs from the only other known species of the genus, A. ridens (McDunnough), for example, in having segments 2 and 3 of the labial palps subequal in length, and having the transverse row of setae on the forefemora consisting of long spatulate setae. Adults provisionally assigned to the new species are associated with the larvae morphologically and in locale do not fit any other adults of North American Caenidae, and differ from the congener A. ridens by dark dorsal coloration. The two species of Americaenis are biogeoraphically disjunct.


Neuronal-specific impairment of heparan sulfate degradation in Drosophila reveals pathogenic mechanisms for Mucopolysaccharidosis type IIIA.
Mucopolysaccharidosis type IIIA (MPS IIIA) is a lysosomal storage disorder resulting from the deficit of the N-sulfoglucosamine sulfohydrolase (SGSH) enzyme that leads to accumulation of partially-degraded heparan sulfate. MPS IIIA is characterized by severe neurological symptoms, clinically presenting as Sanfilippo syndrome, for which no effective therapy is available. The lysosomal SGSH enzyme is conserved in Drosophila and we have identified increased levels of heparan sulfate in flies with ubiquitous knockdown of SGSH/CG14291. Using neuronal specific knockdown of SGSH/CG14291 we have also observed a higher abundance of Lysotracker-positive puncta as well as increased expression of GFP tagged Ref(2)P supporting disruption to lysosomal function. We have also observed a progressive defect in climbing ability, a hallmark of neurological dysfunction. Genetic screens indicate proteins and pathways that can functionally modify the climbing phenotype, including autophagy-related proteins (Atg1 and Atg18), superoxide dismutase enzymes (Sod1 and Sod2) and heat shock protein (HSPA1). In addition, reducing heparan sulfate biosynthesis by knocking down sulfateless or slalom expression significantly worsens the phenotype; an important observation given that substrate inhibition is being evaluated clinically as a treatment for MPS IIIA. Identifying the cellular pathways that can modify MPS IIIA neuropathology is an essential step in the development of novel therapeutic approaches to prevent and/or ameliorate symptoms in children with Sanfilippo syndrome.


Synthesis, Optical Properties, and Photocatalytic Activity of One-Dimensional CdS@ZnS Core-Shell Nanocomposites.
One-dimensional (1D) CdS@ZnS core-shell nanocomposites were successfully synthesized via a two-step solvothermal method. Preformed CdS nanowires with a diameter of ca. 45 nm and a length up to several tens of micrometers were coated with a layer of ZnS shell by the reaction of zinc acetate and thiourea at 180 °C for 10 h. It was found that uniform ZnS shell was composed of ZnS nanoparticles with a diameter of ca. 4 nm, which anchored on the nanowires without any surface pretreatment. The 1D CdS@ZnS core-shell nanocomposites were confirmed by XRD, SEM, TEM, HR-TEM, ED, and EDS techniques. The optical properties and photocatalytic activities of the 1D CdS@ZnS core-shell nanocomposites towards methylene blue (MB) and 4-chlorophenol (4CP) under visible light (λ > 420 nm) were separately investigated. The results show that the ZnS shell can effectively passivate the surface electronic states of the CdS cores, which accounts for the enhanced photocatalytic activities of the 1D CdS@ZnS core-shell nanocomposites compared to that of the uncoated CdS nanowires.


Yeast cell-wall synthesis.
1. A study of wall synthesis has been made by following the incorporation of radioactive glucose and threonine into the cytoplasm and wall of yeast. 2. Both glucose and threonine are incorporated into a mannan glycopeptide. The glucose is also synthesized into a structural glucan of the wall. 3. The mannan glycopeptide contains high-molecular-weight mannan and low-molecular-weight mannose and oligosaccharide units composed of mannose. Both types of carbohydrate are attached to the peptide. The extent of radioactive incorporation into these different carbohydrate constituents of the glycopeptide remained constant during a pulse-chase experiment. No evidence of a sequential synthesis of oligosaccharides and high-molecular-weight mannan was obtained. 4. Cycloheximide inhibits the incorporation of threonine into the wall but only partially inhibits the incorporation of glucose. Thus not all the polysaccharide deposited into the wall is dependent on a simultaneous peptide synthesis and incorporation. 5. Protoplasts grown in an iso-osmotic medium secreted a mannan polymer that was probably a glycopeptide.


Outcomes of total arterial revascularization vs conventional revascularization in patients undergoing coronary artery bypass graft surgery: A narrative review of major studies.
Coronary artery bypass grafting (CABG) is a widely used surgical procedure which improves clinical outcomes in appropriately selected patients. Conventionally, the greater saphenous vein is often used in CABG. However, due to their higher long-term patency rates, arterial conduits are routinely used, with the left internal thoracic artery (LITA) on left anterior descending (LAD) being the gold standard in CABG. Our aim in the present work was to investigate the outcomes of a total arterial grafting (TAG) on the whole heart, with no use of venous grafts, compared to mixed conduits in real-world data. A literature search was conducted in the bibliographic databases PubMed and Web of Science. Only studies comparing TAG with conventional CABG (at least one venous graft plus one or more arterial grafts), with at least one hundred patients in each group were included in this review. After study selection, a total of 15 relevant studies were evaluated and discussed in the present review. Results indicated that TAG is a highly efficient technique, and multiple arterial grafts can be used to reliably revascularize all coronary artery territories. TAG was more beneficial in terms of both short and long-term outcomes and its use should be encouraged. Large randomized clinical trials are needed to confirm the superiority of total arterial grafting with regard to long-term outcomes.


Development of a tool to measure clinical competence in occupational therapy: a pilot study?
Clinical competence is generally defined as a combination of knowledge, skill and professional behaviour. It is typically assessed using written tests, direct observation, chart audit, client satisfaction surveys and supervisor ratings. This paper describes the development and evaluation of a chart-stimulated recall (CSR) measure that combines the methods of chart audit and clinician interview to assess the clinical competence of practicing occupational therapists. The CSR tool was developed using the Canadian Guidelines for Client-Centred Practice and taps global domains of competence: use of theory, assessment, program planning, intervention, discharge planning, follow-up, program evaluation, clinical reasoning and professional behaviours. This pilot study involved two independent raters/interviewers who assessed twelve occupational therapy clinicians on two occasions using a random sample of client cases/records on each occasion Results indicate that the CSR tool is not only reliable and valid, but also sufficiently generic to be used in a variety of practice settings as a global measure of on-the-job performance.


Review of current blood transfusions strategies in a mature level I trauma center: were we wrong for the last 60 years?
Recent military experience reported casualties who receive > 10 units of packed red blood cells (PRBC) in 24 hours have 20% versus 65% mortality when the fresh-frozen plasma (FFP) to PRBC ratio was 1:1 versus 1:4, respectively. We hypothesize a similar improvement in mortality in civilian trauma patients that require massive transfusion and are treated with a FFP to PRBC ratio closer to 1:1. Four-year retrospective study of all trauma patients who underwent emergency surgery in an urban Level I Trauma Center. Patients were divided into two groups; those that received < or = 10 units or > 10 units of PRBC during and after initial surgical intervention. Only patients who received transfusion of both FFP and PRBC were included in the analysis. The primary research question was the impact of initial FFP:PRBC ratio on mortality. Other variables for analysis included patient age, gender, mechanism, and Injury Severity Scale score. Both univariate and multivariate analysis were used to assess the relationship between outcome and predictors. A total of 2,746 patients underwent surgical intervention of which 1,985 (72.2%) received no transfusion. Of those that received transfusion, 626 (22.8%) received < or = 10 units of PRBC and 135 (4.9%) > 10 units of PRBC. Out of the 626 patients that received < or = 10 units of PRBC, 250 (39.9%) received FFP and 376 (60.1%) received no FFP. All the patients that received > 10 units PRBC received FFP. In univariate analysis, a significant difference in mortality was found in patients who received > 10 units of PRBC (26% vs. 87.5%) when FFP:PRBC ratio was 1:1 versus 1:4 (p = 0.0001). Multivariate analysis in the group of patients that received > 10 units of PRBC showed a FFP:PRBC ratio of 1:4 was consistent with increased risk of mortality (relative risk, 18.88; 95% CI, 6.32-56.36; p = 0.001), when compared with a ratio of 1:1. Patients who received < or = 10 units of PRBC had a trend toward increased mortality (21.2% vs.11.8%) when the FFP:PRBC ratio was 1:4 versus 1:1 (p: 0.06). An FFP to PRBC ratio close to 1:1 confers a survival advantage in patients requiring massive transfusion.


Organic and inorganic nitrogen nutrition of western red cedar, western hemlock and salal in mineral N-limited cedar-hemlock forests.
Western red cedar (Thuja plicata Donn.), western hemlock (Tsuga heterophylla Raf. Sarge) and salal (Gaultheria shallon Pursh) are the main species growing in cedar-hemlock forests on Vancouver Island, Canada. Based on the dominance of organic N in these systems, we tested the hypotheses that: (1) organic N can be utilized by the three plant species; and (2) salal, which is ericoid mycorrhizal and has high tannin concentration in its tissues, would absorb more N from the complex organic N compounds than the other two species. The abilities of cedar, hemlock and salal to take up 15N,13C-labelled glutamic acid were measured and the capacities of the three species to use nitrate (NO3-), ammonium (NH4+), glutamic acid, protein and protein-tannin N were compared over a 20-day period. Based on 13C enrichment, all three species absorbed at least a portion of glutamic acid intact. Cedar, hemlock and salal also showed similar patterns of N uptake from the NO3-, NH4+, glutamic acid, protein and protein-tannin treatments. The largest proportions of applied N were taken up from the NO3- and NH4+ treatments while smaller amounts of N were absorbed from the organic N compounds. Thus organic N was accessed to a modest degree by all three species, and salal did not have a greater capacity to utilize protein and protein-tannin-N.


Axonal growth therapeutics: regeneration or sprouting or plasticity?
Loss of function after neurological injury frequently occurs through the interruption of axonal connectivity, rather than through cell loss. Functional deficits persist because a multitude of inhibitory factors in degenerating myelin and astroglial scar prevent axonal growth in the adult brain and spinal cord. Given the high clinical significance of achieving functional recovery through axonal growth, substantial research effort has been, and will be, devoted toward this desirable goal. Unfortunately, the labels commonly used in the literature to categorize post-injury axonal anatomy might hinder advancement. In this article, we present an argument for the importance of developing precise terms that describe axonal growth in terms of the inciting event, the distance of axonal extension and the timing of axonal growth. The phenotypes produced by molecular interventions that overcome astroglial scar or myelin-associated inhibitors are reframed and discussed in this context.


Begonia wuzhishanensis (sect. Diploclinium, Begoniaceae), a new species from Hainan Island, China.
Hainan is the largest island of the Indo-Burma Biodiversity Hotspot and has the best preserved and most extensive tropical forests in China. A recent study on distribution of endangered species in China identifies southern Hainan as one of eight hotspots for plant conservation in the country. In continuation of our studies of Asian Begonia, we report the discovery of an attractive undescribed species, B. wuzhishanensis C.-I Peng, X.H. Jin & S.M. Ku, from Hainan Island. Living plant of the new species, Begonia wuzhishanensis, was collected in 2009 and cultivated in the experimental greenhouse for morphological and cytological studies. It flowered consecutively in 2012 and 2013 in the experimental greenhouse, Academia Sinica. It was assigned to the large, heterogeneous sect. Diploclinium. The chromosome number of this new species was determined to be 2n = 26. A careful study of literature, herbarium specimens and living plants, both in the wild and in cultivation, support the recognition of the new species Begonia wuzhishanensis, which is described in this paper. Begonia wuzhishanensis is currently known only from Fanyang, Wuzhishan Mountain in the center of the island. A line drawing, color plate, and a distribution map are provided to aid in identification.


Achieved blood pressure and cardiovascular outcomes in high-risk patients: results from ONTARGET and TRANSCEND trials.
Studies have challenged the appropriateness of accepted blood pressure targets. We hypothesised that different levels of low blood pressure are associated with benefit for some, but harm for other outcomes. In this analysis, we assessed the previously reported outcome data from high-risk patients aged 55 years or older with a history of cardiovascular disease, 70% of whom had hypertension, from the ONTARGET and TRANSCEND trials investigating ramipril, telmisartan, and their combination, with a median follow-up of 56 months. Detailed descriptions of randomisation and intervention have already been reported. We analysed the associations between mean blood pressure achieved on treatment; prerandomisation baseline blood pressure; or time-updated blood pressure (last on treatment value before an event) on the composite outcome of cardiovascular death, myocardial infarction, stroke, and hospital admission for heart failure; the components of the composite outcome; and all-cause death. Analysis was done by Cox regression analysis, ANOVA, and χ2. These trials were registered with ClinicalTrials.gov, number NCT00153101. Recruitment for ONTARGET took place between Dec 1, 2001, and July 31, 2008. TRANSCEND took place between Nov 1, 2001, and May 30, 2004. 30 937 patients were recruited from 733 centres in 40 countries and followed up for a median of 56 months. In ONTARGET, 25 127 patients known to be tolerant to angiotensin-converting-enzyme (ACE)-inhibitors were randomly assigned after a run-in period to oral ramipril 10 mg/day (n=8407), telmisartan 80 mg/day (n=8386), or the combination of both (n=8334). In TRANSCEND, 5810 patients who were intolerant to ACE-inhibitors were randomly assigned to oral telmisartan 80 mg/day (n=2903) or placebo (n=2907). Baseline systolic blood pressure (SBP) 140 mm Hg or higher was associated with greater incidence of all outcomes compared with 120 mm Hg to less than 140 mm Hg. By contrast, a baseline diastolic blood pressure (DBP) less than 70 mm Hg was associated with the highest risk for most outcomes compared with all DBP categories 70 mm Hg or more. In 4052 patients with SBP less than 120 mm Hg on treatment, the risk of the composite cardiovascular outcome (adjusted hazard ratio [HR] 1·14, 95% CI 1·03-1·26), cardiovascular death (1·29, 1·12-1·49), and all deaths (1·28, 1·15-1·42) were increased compared with those in whom SBP was 120-140 mm Hg during treatment (HR 1 for all outcomes, n=16099). No harm or benefit was observed for myocardial infarction, stroke, or hospital admission for heart failure. Mean achieved SBP more accurately predicted outcomes than baseline or time-updated SBP, and was associated with the lowest risk at approximately 130 mm Hg, and at 110-120 mm Hg risk increased for the combined outcome, cardiovascular death, and all-cause death except stroke. A mean DBP less than 70 mm Hg (n=5352) during treatment was associated with greater risk of the composite primary outcome (HR 1·31, 95% CI 1·20-1·42), myocardial infarction (1·55, 1·33-1·80), hospital admission for heart failure (1·59, 1·36-1·86) and all-cause death (1·16, 1·06-1·28) than a DBP 70-80 mm Hg (14 305). A pretreatment and mean on-treatment DBP of about 75 mm Hg was associated with the lowest risk. Mean achieved SBP less than 120 mm Hg during treatment was associated with increased risk of cardiovascular outcomes except for myocardial infarction and stroke. Similar patterns were observed for DBP less than 70 mm Hg, plus increased risk for myocardial infarction and hospital admission for heart failure. Very low blood pressure achieved on treatment was associated with increased risks of several cardiovascular disease events. These data suggest that the lowest blood pressure possible is not necessarily the optimal target for high-risk patients, although it is not possible to rule out some effect of reverse causality. Boehringer Ingelheim.


Monitoring of brain and systemic oxygenation in neurocritical care patients.
Maintenance of adequate oxygenation is a mainstay of intensive care, however, recommendations on the safety, accuracy, and the potential clinical utility of invasive and non-invasive tools to monitor brain and systemic oxygenation in neurocritical care are lacking. A literature search was conducted for English language articles describing bedside brain and systemic oxygen monitoring in neurocritical care patients from 1980 to August 2013. Imaging techniques e.g., PET are not considered. A total of 281 studies were included, the majority described patients with traumatic brain injury (TBI). All tools for oxygen monitoring are safe. Parenchymal brain oxygen (PbtO2) monitoring is accurate to detect brain hypoxia, and it is recommended to titrate individual targets of cerebral perfusion pressure (CPP), ventilator parameters (PaCO2, PaO2), and transfusion, and to manage intracranial hypertension, in combination with ICP monitoring. SjvO2 is less accurate than PbtO2. Given limited data, NIRS is not recommended at present for adult patients who require neurocritical care. Systemic monitoring of oxygen (PaO2, SaO2, SpO2) and CO2 (PaCO2, end-tidal CO2) is recommended in patients who require neurocritical care.


Increased susceptibility to infection due to infusion of exogenous chemotaxin.
Previous studies indicate that endogenous chemotaxins, such as the chemotactic factor C5a, may modulate the function of neutrophils (PMNs) and account for increased susceptibility to infection after injury. These effects were investigated by continuously infusing rats with saline or the chemotaxin formyl-methionyl-leucyl-phenylalanine (FMLP). Rats that sustained a full-thickness burn covering 30% of total body surface area and whose wounds were inoculated with Pseudomonas aeruginosa had a significantly shorter survival when FMLP was infused (6.5 +/- 0.91 days) than did saline-infused rats (9.9 +/- 0.83 days). Rats infused with FMLP had significantly more leukocytes in their burn wounds, significantly fewer PMNs in the circulating pool, and the same number of PMNs at the site of FMLP infusion compared with the saline-treated group. These findings support the hypothesis that chemotaxins generated by tissue injury or sepsis contribute to increased susceptibility to infection.


Hypoxia increases muscle hypertrophy induced by resistance training.
Recent studies have shown that low-intensity resistance training with vascular occlusion (kaatsu training) induces muscle hypertrophy. A local hypoxic environment facilitates muscle hypertrophy during kaatsu training. We postulated that muscle hypertrophy can be more efficiently induced by placing the entire body in a hypoxic environment to induce muscle hypoxia followed by resistance training. Fourteen male university students were randomly assigned to hypoxia (Hyp) and normoxia (Norm) groups (n = 7 per group). Each training session proceeded at an exercise intensity of 70% of 1 repetition maximum (RM), and comprised four sets of 10 repetitions of elbow extension and flexion. Students exercised twice weekly for 6 wk and then muscle hypertrophy was assessed by magnetic resonance imaging and muscle strength was evaluated based on 1RM. Muscle hypertrophy was significantly greater for the Hyp-Ex (exercised flexor of the hypoxia group) than for the Hyp-N (nonexercised flexor of the hypoxia group) or Norm-Ex flexor (P < .05, Bonferroni correction). Muscle hypertrophy was significantly greater for the Hyp-Ex than the Hyp-N extensor. Muscle strength was significantly increased early (by week 3) in the Hyp-Ex, but not in the Norm-Ex group. This study suggests that resistance training under hypoxic conditions improves muscle strength and induces muscle hypertrophy faster than under normoxic conditions, thus representing a promising new training technique.


Anion exchange membranes containing no β-hydrogen atoms on ammonium groups: synthesis, properties, and alkaline stability.
Novel anion conductive polymer membranes have been designed and synthesized to investigate whether the absence of β-hydrogen atoms of ammonium groups affects the membranes' properties and chemical stability. The hydrophilic monomer, 2,2-bis(4-chlorobenzyl)-2-phenyl-ethylamine (3), was obtained via a two-step reaction with an overall yield of 98% under mild reaction conditions. Ni(0)-promoted copolymerization of 3 with 2,2-bis(4-chlorophenyl)hexafluoropropane (1) afforded high molecular weight copolymers (M n = 12.8-19.6 kDa, M w = 82.1-224.6 kDa). After quaternization with iodomethane, QBAF-BS polymers formed bendable, robust membranes from solution casting. The ion exchange capacity (IEC) of the membranes ranged from 1.50 to 2.44 mequiv. g-1. The membranes exhibited high hydroxide ion conductivity in water (up to 191 mS cm-1 at 80 °C for IEC = 2.25 mequiv. g-1), suggesting that the newly designed hydrophilic structure was effective in improving the ion conductivity. Based on small-angle X-ray scattering (SAXS) analyses and transmission electron microscopy (TEM) images, all membranes featured nano-phase separated morphology with a large dependence on the copolymer composition. The strain properties were improved on increasing the content of the hydrophilic component up to IEC = 2.25 mequiv. g-1, above which the strain became smaller due to the larger water absorption. The membranes were not stable under harsh alkaline conditions (in 8 M KOH at 80 °C) gradually losing the hydroxide ion conductivity. Compared to our previous AEMs which contained typical aliphatic ammonium groups, the lack of β-hydrogen atoms did not practically improve the alkaline stability of AEMs possibly due to the main chain degradation but contributed to higher ion conductivity.


Miniaturized high-intensity focused ultrasound device in patients with glaucoma: a clinical pilot study.
To evaluate the relative safety and potential efficacy of high-intensity focused ultrasound cyclocoagulation by a miniaturized annular device containing six piezoceramic transducers in patients with refractory glaucoma. This was a three-center prospective interventional pilot study. Twelve eyes of 12 patients with refractory glaucoma were insonified using a ring-shaped probe containing six miniaturized high-frequency transducers operating at 21 MHz. Ultrasound biomicroscopy (UBM) and a complete ophthalmic examination were performed before the procedure and at 1 day, 1 week, 1 month, and 3 months after the procedure. Additional visits were performed 6 and 12 months after the procedure. Intraocular pressure was significantly reduced (P < 0.01) from a mean preoperative value of 37.9 ± 10.7 mm Hg to a mean postoperative value of 27.3 ± 12.4, 25.2 ± 11.3, 25.2 ± 7.7, 24.8 ± 9.8, and 26.3 ± 5.1 mm Hg at 1 day, 1 week, 1 month, 3 months, and 6 months, respectively, and to a mean value of 24.7 ± 8.5 at the last follow-up visit. No major intraoperative or postoperative complications occurred. Minor postoperative corneal complications developed in four patients with previous corneal abnormalities: superficial punctate keratitis (n = 3) and central superficial corneal ulceration (n = 1). UBM showed cystic involution of the ciliary body in 9 of the 12 eyes and a suprachoroidal fluid space in 8 of the 12 eyes. Ultrasonic circular cyclocoagulation using high-intensity focused ultrasound delivered by a circular miniaturized device containing six piezoceramic transducers seems to be an effective and well-tolerated method to reduce intraocular pressure in patients with refractory glaucoma.


Managing the multigenerational nursing team.
Today's workforce is more diverse in age than ever before. This study examined the generational profiles of two groups (the Silent Generation, and Baby Boomers vs. Generation X and Generation Y) in terms of the following variables: characteristics, communication styles, and significance of tasks. The purpose was to assist nurse managers to maximize departmental effectiveness by capitalizing on the unique characteristics of the multigenerational nursing team. A descriptive design was used to examine nursing staff perceptions of their generational profiles, communication styles, and significance of tasks. The convenience sample included registered nurses, nurse technicians and nursing secretaries from two departments, a medical-surgical and a critical care department (N = 62). The study provided participants with the opportunity to give their interpretations of their generational types. Similarities and differences of generational profiles were found between the two groups. There were no significant differences in communication style and significance of tasks between the two groups (P > .05). However, there were differences in expectations regarding commitment to the manager versus the organization and the type and timing of rewards for performance. All four generational groups had vastly different employment demands and different needs for orientation, training, advancement, benefits, perks, and retirement options.


Is the 7th TNM edition suitable for biological predictor in early gastric cancer?
The clinical and prognostic value of the previous node classification of TNM staging in early gastric cancer (EGC) has been less definitive. The aim was to assess the suitability of the revised node staging for prediction of clinical behavior of EGC. Between 2005 and 2008, 1,845 patients were diagnosed with EGC and underwent surgery at Severance Hospitals. Clinicopathological characteristics were analyzed with comparisons between sixth and seventh TNM staging. When comparing IB with IIA upstaged based on seventh staging, poor differentiation, signet ring cell, diffuse, undifferentiated types, perineural invasion (PNI), larger size and younger age, were more significantly associated with IIA. Clinicopathological factors were compared between N0/N1 and N2/N3 based on both staging. In mucosal cancer, younger age, diffuse and undifferentiated types were more significantly associated with N2/N3 based on seventh staging. In submucosal cancer, larger size, poor differentiation, signet ring cell, diffuse, undifferentiated types, PNI and deeper submucosal invasion, were more significantly associated with N2/N3 based on seventh staging. Upstaging in EGC based on the revised TNM staging reflects more aggressive biological behavior of cancer. The new TNM staging system may be informative in prediction of biological behavior of EGC as well as prognosis and survival.


[Cannabis, hemp and hashish: always returning].
Cannabis has a long story, the story of an endless return through ages and countries, all over the world. There is no mention of an "hedonist" use of cannabis in Ancient Greek or Roman sources but cannabism is largely attested in Orient as early as in the Middle Ages, even if many tales about Haschishins and Crusaders remain highly controversial. The "come back" of cannabism can be traced back in Europe at the end of XVIIIth century after the Egyptian campaigns of Bonaparte. Thus was launched an increasing vogue of orientalism, soonly after followed by the emergence of cannabism in Paris or London and, half a century later, the United States. After a brief armistice, cannabis rises up again with force at the end of XXth century, all over the world. In our times cannabis remains in the centre of all discussions about hallucinogen substances and many ethical, moral or medical questions are still unanswered. Our final comments will go to the everlasting "come back" of cannabism: search of exotism, attempt to escape from reality or as suggested by recent physiologic studies, close inter-relations between sensorial paths and the upper brainstem centers.


Association Between Vaso-Occlusive Crises and Opioid Prescriptions Among Patients with Sickle Cell Disease: A Retrospective Claims-Based Study.
Background/Objectives: Among sickle cell disease (SCD) patients, vaso-occlusive crises (VOCs) are recurrent and unpredictable attacks of acute pain. These pain crises are often treated with analgesics, including opioids, which have been associated with misuse and overdose. The aim of this study was to examine the association between VOC events and opioid use and assess the association between opioid prescriptions and health care resource utilization among SCD patients. Methods: This was a retrospective cohort study using Texas Medicaid medical and prescription claims between September 2011 and August 2016. The index date was the first SCD diagnosis. Patients (2-63 years) with at least one inpatient or two outpatient SCD diagnoses, who were continuously enrolled during 12 months postindex, were included in the study. The primary outcome was number of opioid prescriptions, while the independent variable was number of VOC events. Covariates included age, gender, nonopioid medication use, nonstudy SCD-related medication (penicillin and folic acid) use, evidence of blood transfusions, number of SCD-related complications, number of SCD-related comorbid conditions, and Charlson Comorbidity Index score. Negative binomial regression analysis was used to address study objectives. Results: Of 3368 included patients, 1978 (58.7%) had at least one opioid prescription with a mean of 4.2 (SD=7.2). Overall, 2071 (61.5%) had at least one VOC event with an average of 2.9 (SD=4.4). The results from the negative binomial regression showed that for every increase in VOC events, the number of opioid prescriptions increased by 9.5% (Incidence rate ratio=1.095, 95% CI: 1.078-1.111; P ≤ 0.0001). Other significant covariates associated with higher opioid use included age (13 and older compared to 2-12) and increase in the number of nonopioid pain medications, nonstudy SCD-related medications, and SCD-related complications. Conclusions: The majority of SCD patients had at least one VOC event and were prescribed opioids during the 12-month study period. We found that each VOC event was associated with a 9.5% increase in the use of opioids. SCD guidelines recommend opioids for the treatment of VOC-related pain. Payers and providers should be aware of opioid use in this population, consider appropriate VOC prevention measures, and provide SCD patients with access to appropriate pain management.


Evaluation of a task-specific checklist and global rating scale for ultrasound-guided regional anesthesia.
Checklists and global rating scales (GRSs) are used for assessment of anesthesia procedural skills. The purpose of this study was to evaluate the reliability and validity of a recently proposed assessment tool comprising a checklist and GRS specific for ultrasound-guided regional anesthesia. In this prospective, fully crossed study, we videotaped 30 single-target nerve block procedures performed by anesthesia trainees. Following pilot assessment and observer training, videos were assessed in random order by 6 blinded, expert observers. Interrater reliability was evaluated with intraclass correlation coefficients (ICCs) based on a 2-way random-effects model that took into account both agreement and correlation between observer results. Construct validity and feasibility were also evaluated. The ICC between assessors' total scores was 0.44 (95% confidence interval, 0.27-0.62). All 6 observers scored "experienced trainees" higher than "inexperienced trainees" (median total score 76.7 vs 54.2, P = 0.01), supporting the test's construct validity. The median time to assess the videos was 4 minutes 29 seconds. This is the first study to evaluate the reliability and validity of a combined checklist and GRS for ultrasound-guided regional anesthesia using multiple observers and taking into account both absolute agreement and correlation in determining the ICC of 0.44 for interrater reliability. There was evidence to support construct validity.


Interprofessional Team Collaboration as a Mediator Between Workplace Social Capital and Patient Safety Climate: A Cross-Sectional Study.
Patient-safety climate is one of the most important organizational factors contributing to health care quality. We hypothesized that a patient safety climate is fostered by the willingness to collaborate and trust among members as well as by daily collaborative practices. This study aimed to clarify the effect of workplace social capital on patient safety climate. We also sought to investigate the mediating effect of interprofessional team collaboration on the relationship between workplace social capital and patient safety climate. This cross-sectional survey was conducted from November 2021 to January 2022 using anonymous web-based questionnaires. The survey was distributed to 1495 employees working in a hospital in Tokyo, Japan. The questionnaire included the patient safety climate scale, workplace social capital scale, Japanese version of the Assessment of Interprofessional Team Collaboration Scale-II (AITCS-II-J), and demographic items. Structural equation modeling was performed to verify the associations among the 3 variables. In addition, a significance test for indirect effects was conducted using the bootstrap method to confirm the mediating effect of AITCS-II-J. A total of 725 employees participated in this survey, and 632 data items were analyzed. Nurses were the highest number of respondents (68.2%), followed by physicians (13.3%). Workplace social capital and patient safety were directly and significantly associated (β = .309, P < .01). Furthermore, the partially indirect effect of the AITCS-II-J on the association between workplace social capital and patient safety climate was also significant (β = .430, P < .01). Workplace social capital was significantly and directly related to patient safety climate and was also significantly related to patient safety climate partially mediated by interprofessional team collaboration. Our findings suggest the importance of workplace social capital and routine multidisciplinary collaboration for a patient safety climate to manage health care quality.


A platelet membrane glycoprotein (GP) deficiency in healthy blood donors: Naka- platelets lack detectable GPIV (CD36).
It has recently been shown that the Naka antigen, which is absent in 3% to 11% of Japanese blood donors, is expressed on platelet glycoprotein IV (GPIV; CD36) (Tomiyama et al, BLOOD, 75:684, 1990). In the present studies, flow cytometry was used to distinguish differences in the reactivity of Naka+ and Naka- platelets with both OKM5, a monoclonal antibody that recognizes an epitope on GPIV, and with polyclonal anti-GPIV antibody. OKM5 was also used to screen 871 platelet concentrates prepared from healthy US blood donors. Three of these showed markedly deficient binding of 125I-OKM5 or an incidence of 0.34%. Two of these donors were re-accessed and showed less than 1% binding of 125I-OKM5 as compared with 10,300 +/- 1,500 binding sites per platelet in controls (n = 4). Platelets from these two US donors were radiolabeled (125I, 3H) and compared with control platelets and with platelets from Japanese Naka+ and Naka- donors by crossed immunoelectrophoresis, protein blots, immunoprecipitation, and two-dimensional gel electrophoresis. GPIV could not be detected by any of these techniques in the Naka- platelets nor in the donors whose platelets showed deficient binding of OKM5. These results suggest that GPIV functions as an isoantigen rather than an alloantigen in immunizing Naka- platelet recipients. This is the first report of the absence of a major platelet membrane GP in healthy blood donors.


Graphical presentation of results from scientific computer models.
The graphical presentation of the results of complex computer model calculations is frequently as important as the computation, since it is generally through such presentations that the modeler and the modeler's audience derive the maximum amount of information. In this article graphical techniques for presenting multidimensional model results are reviewed and examples are given of the most useful forms of presentation. Color graphics is used increasingly for the presentation of model results, and three types of color displays are discussed here: the chromatic plot, the binary chromatic plot, and the ternary chromatic plot. Their use is illustrated with examples from computer modeling of air quality in the urban atmosphere.


Divergent SATB1 expression across human life span and tissue compartments.
Special AT-rich binding protein-1 (SATB1) is a global chromatin organizer capable of activating or repressing gene transcription in mice and humans. The role of SATB1 is pivotal for T-cell development, with SATB1-knockout mice being neonatally lethal, although the exact mechanism is unknown. Moreover, SATB1 is dysregulated in T-cell lymphoma and proposed to suppress transcription of the Pdcd1 gene, encoding the immune checkpoint programmed cell death protein 1 (PD-1). Thus, SATB1 expression in T-cell subsets across different tissue compartments in humans is of potential importance for targeting PD-1. Here, we comprehensively analyzed SATB1 expression across different human tissues and immune compartments by flow cytometry and correlated this with PD-1 expression. We investigated SATB1 protein levels in pediatric and adult donors and assessed expression dynamics of this chromatin organizer across different immune cell subsets in human organs, as well as in antigen-specific T cells directed against acute and chronic viral infections. Our data demonstrate that SATB1 expression in humans is the highest in T-cell progenitors in the thymus, and then becomes downregulated in mature T cells in the periphery. Importantly, SATB1 expression in peripheral mature T cells is not static and follows fine-tuned expression dynamics, which appear to be tissue- and antigen-dependent. Furthermore, SATB1 expression negatively correlates with PD-1 expression in virus-specific CD8+ T cells. Our study has implications for understanding the role of SATB1 in human health and disease and suggests an approach for modulating PD-1 in T cells, highly relevant to human malignancies or chronic viral infections.


Anchored phylogenomics unravels the evolution of spider flies (Diptera, Acroceridae) and reveals discordance between nucleotides and amino acids.
The onset of phylogenomics has contributed to the resolution of numerous challenging evolutionary questions while offering new perspectives regarding biodiversity. However, in some instances, analyses of large genomic datasets can also result in conflicting estimates of phylogeny. Here, we present the first phylogenomic scale study of a dipteran parasitoid family, built upon anchored hybrid enrichment and transcriptomic data of 240 loci of 43 ingroup acrocerid taxa. A new hypothesis for the timing of spider fly evolution is proposed, wielding recent advances in divergence time dating, including the fossilized birth-death process to show that the origin of Acroceridae is younger than previously proposed. To test the robustness of our phylogenetic inferences, we analyzed our datasets using different phylogenetic estimation criteria, including supermatrix and coalescent-based approaches, maximum-likelihood and Bayesian methods, combined with other approaches such as permutations of the data, homogeneous versus heterogeneous models, and alternative data and taxon sets. Resulting topologies based on amino acids and nucleotides are both strongly supported but critically discordant, primarily in terms of the monophyly of Panopinae. Conflict was not resolved by controlling for compositional heterogeneity and saturation in third codon positions, which highlights the need for a better understanding of how different biases affect different data sources. In our study, results based on nucleotides were both more robust to alterations of the data and different analytical methods and more compatible with our current understanding of acrocerid morphology and patterns of host usage.


Identification of genetic modifiers of murine hepatic β-glucocerebrosidase activity.
The acid β-glucocerebrosidase (GCase) enzyme cleaves glucosylceramide into glucose and ceramide. Loss of function variants in the gene encoding for GCase can lead to Gaucher disease and Parkinson's disease. Therapeutic strategies aimed at increasing GCase activity by targeting a modulating factor are attractive and poorly explored. To identify genetic modifiers, we measured hepatic GCase activity in 27 inbred mouse strains. A genome-wide association study (GWAS) using GCase activity as a trait identified several candidate modifier genes, including Dmrtc2 and Arhgef1 (p=2.1x10-7), and Grik5 (p=2.1x10-7). Bayesian integration of the gene mapping with transcriptomics was used to build integrative networks. The analysis uncovered additional candidate GCase regulators, highlighting modules of the acute phase response (p=1.01x10-8), acute inflammatory response (p=1.01x10-8), fatty acid beta-oxidation (p=7.43x10-5), among others. Our study revealed previously unknown candidate modulators of GCase activity, which may facilitate the design of therapies for diseases with GCase dysfunction.


Survey: interpolation methods in medical image processing.
Image interpolation techniques often are required in medical imaging for image generation (e.g., discrete back projection for inverse Radon transform) and processing such as compression or resampling. Since the ideal interpolation function spatially is unlimited, several interpolation kernels of finite size have been introduced. This paper compares 1) truncated and windowed sinc; 2) nearest neighbor; 3) linear; 4) quadratic; 5) cubic B-spline; 6) cubic; g) Lagrange; and 7) Gaussian interpolation and approximation techniques with kernel sizes from 1 x 1 up to 8 x 8. The comparison is done by: 1) spatial and Fourier analyses; 2) computational complexity as well as runtime evaluations; and 3) qualitative and quantitative interpolation error determinations for particular interpolation tasks which were taken from common situations in medical image processing. For local and Fourier analyses, a standardized notation is introduced and fundamental properties of interpolators are derived. Successful methods should be direct current (DC)-constant and interpolators rather than DC-inconstant or approximators. Each method's parameters are tuned with respect to those properties. This results in three novel kernels, which are introduced in this paper and proven to be within the best choices for medical image interpolation: the 6 x 6 Blackman-Harris windowed sinc interpolator, and the C2-continuous cubic kernels with N = 6 and N = 8 supporting points. For quantitative error evaluations, a set of 50 direct digital X rays was used. They have been selected arbitrarily from clinical routine. In general, large kernel sizes were found to be superior to small interpolation masks. Except for truncated sinc interpolators, all kernels with N = 6 or larger sizes perform significantly better than N = 2 or N = 3 point methods (p << 0.005). However, the differences within the group of large-sized kernels were not significant. Summarizing the results, the cubic 6 x 6 interpolator with continuous second derivatives, as defined in (24), can be recommended for most common interpolation tasks. It appears to be the fastest six-point kernel to implement computationally. It provides eminent local and Fourier properties, is easy to implement, and has only small errors. The same characteristics apply to B-spline interpolation, but the 6 x 6 cubic avoids the intrinsic border effects produced by the B-spline technique. However, the goal of this study was not to determine an overall best method, but to present a comprehensive catalogue of methods in a uniform terminology, to define general properties and requirements of local techniques, and to enable the reader to select that method which is optimal for his specific application in medical imaging.


Two-component signal transduction system CBO0787/CBO0786 represses transcription from botulinum neurotoxin promoters in Clostridium botulinum ATCC 3502.
Blocking neurotransmission, botulinum neurotoxin is the most poisonous biological substance known to mankind. Despite its infamy as the scourge of the food industry, the neurotoxin is increasingly used as a pharmaceutical to treat an expanding range of muscle disorders. Whilst neurotoxin expression by the spore-forming bacterium Clostridium botulinum appears tightly regulated, to date only positive regulatory elements, such as the alternative sigma factor BotR, have been implicated in this control. The identification of negative regulators has proven to be elusive. Here, we show that the two-component signal transduction system CBO0787/CBO0786 negatively regulates botulinum neurotoxin expression. Single insertional inactivation of cbo0787 encoding a sensor histidine kinase, or of cbo0786 encoding a response regulator, resulted in significantly elevated neurotoxin gene expression levels and increased neurotoxin production. Recombinant CBO0786 regulator was shown to bind to the conserved -10 site of the core promoters of the ha and ntnh-botA operons, which encode the toxin structural and accessory proteins. Increasing concentration of CBO0786 inhibited BotR-directed transcription from the ha and ntnh-botA promoters, demonstrating direct transcriptional repression of the ha and ntnh-botA operons by CBO0786. Thus, we propose that CBO0786 represses neurotoxin gene expression by blocking BotR-directed transcription from the neurotoxin promoters. This is the first evidence of a negative regulator controlling botulinum neurotoxin production. Understanding the neurotoxin regulatory mechanisms is a major target of the food and pharmaceutical industries alike.


Children are more susceptible to central fatigue than adults.
Performance in high-intensity exercise is dependent on the ability to activate motor units. The main aim of this study was to test the hypothesis that adult men and women (age 19-27 years) are able to maintain higher levels of voluntary activation (VA) in knee extensor muscles than boys and girls (age 12-14 years). The volunteers (n = 7 in each group) performed three 5-s maximal voluntary contractions (MVCs) and a continuous 2-min MVC. The VA and fatigue of the muscles was assessed by applying 250-ms 100-HZ test tetani (TT100HZ). During brief MVCs girls showed lower VA than women, but the difference between boys and men was not significant. During the 2-min MVC, VA in boys and girls was more depressed than in adults. The end-exercise values of the relative TT100HZ torque correlated with the average VA during the exercise. Thus, the results of the study support the hypothesis that children are more susceptible to central fatigue than adults. This should be taken into account when evaluating results of fitness tests that require high levels of motor unit activation.


Emerging paradigms and questions on pro-angiogenic bone marrow-derived myelomonocytic cells.
Cancer-related inflammation has emerged in recent years as a major event contributing to tumor angiogenesis, tumor progression and metastasis formation. Bone marrow-derived and inflammatory cells promote tumor angiogenesis by providing endothelial progenitor cells that differentiate into mature endothelial cells, and by secreting pro-angiogenic factors and remodeling the extracellular matrix to stimulate angiogenesis though paracrine mechanisms. Several bone marrow-derived myelonomocytic cells, including monocytes and macrophages, have been identified and characterized by several laboratories in recent years. While the central role of these cells in promoting tumor angiogenesis, tumor progression and metastasis is nowadays well established, many questions remain open and new ones are emerging. These include the relationship between their phenotype and function, the mechanisms of pro-angiogenic programming, their contribution to resistance to anti-angiogenic treatments and to metastasis and their potential clinical use as biomarkers of angiogenesis and anti-angiogenic therapies. Here, we will review phenotypical and functional aspects of bone marrow-derived myelonomocytic cells and discuss some of the current outstanding questions.