A double dissociation between accuracy and time of execution on attentional tasks in Alzheimer's disease and multi-infarct dementia.
Two cancellation/attentional tasks: (i) Lines Cancellation (LC) and Multiple Features Targets Cancellation (MFTC) and (ii) a standard battery of neuropsychological tests, the Mental Deterioration Battery (MDB), were administered to 68 patients with dementia of the Alzheimer's type (DAT) and 40 patients with multi-infarct dementia (MID), who were accurately matched for the overall severity of dementia, and to 40 normal controls. Both accuracy and time of execution were considered in evaluating performance on the two cancellation tasks, which involved visuospatial exploration and psychomotor speed, but were differently demanding in terms of selective attention. On the first cancellation task (LC), requiring a lower attentional load, the two demented patient groups performed at the same level of accuracy. On the second cancellation task (MFTC), which was more demanding in terms of selective and divided attention, DAT patients were significantly less accurate than MID patients, making a higher number of 'false-alarm' errors. Conversely, the time employed in the execution of both LC and MFTC took longer for MID than for DAT patients, suggesting a greater impairment of psychomotor speed in MID. In the MDB, DAT patients scored significantly worse than MID patients on several measures of episodic memory (the immediate recall, delayed recall and delayed recognition of Rey's Auditory Verbal Learning Test) and on a test of visual-spatial memory. These data suggest that, while psychomotor speed and the lower (sensorimotor) levels of attention are preferentially impaired in subcortical forms of dementia such as MID, the higher levels of selective and divided attention are more markedly disrupted in the Alzheimer type of dementia.


Does unstable mood increase risk of suicide? Theory, research and practice.
Suicide represents a substantial problem, with significant societal and personal impact. The identification of factors influencing suicide risk is an important step in preventing self-harming behaviour. In this article the authors explore whether emotional instability increases risk of suicide, beyond that of mood intensity. This article provides a summary of existing theory and indirect evidence in support of an association between emotional instability and suicidality. A systematic literature search (Embase, Medline, PsychInfo) was carried out on literature conducted up to October, 2011. Meta-analysis was used to assess the strength of the proposed association. The systematic search identified 20 journal articles meeting the inclusion criteria, including retrospective questionnaire design studies and research conducted across several time-points. Meta-analysis revealed a moderate association, which remained statistically significant even when only including studies conducted over multiple time-points. This effect was attenuated, but remained significant, when controlling for study selection bias. Retrospective questionnaire studies failed to adequately control for mood level. Little is still currently understood about the types of emotional instability (e.g., dysoria, anxiety) most associated with suicidality. Future avenues of investigation include micro- to macro-longitudinal research and the differentiation of emotion subtypes and instability metrics. Momentary assessment techniques may help to detect subtle fluctuations in mood leading to more effective and immediate intervention. Psychosocial intervention strategies for treating unstable emotions are discussed.


On Kinetic Constraints That Catalysis Imposes on Elementary Processes.
Catalysis, the acceleration of product formation by a substance that is left unchanged, typically results from multiple elementary processes, including diffusion of the reactants toward the catalyst, chemical steps, and release of the products. While efforts to design catalysts are often focused on accelerating the chemical reaction on the catalyst, catalysis is a global property of the catalytic cycle that involves all processes. These are controlled by both intrinsic parameters such as the composition and shape of the catalyst and extrinsic parameters such as the concentration of the chemical species at play. We examine here the conditions that catalysis imposes on the different steps of a reaction cycle and the respective role of intrinsic and extrinsic parameters of the system on the emergence of catalysis by using an approach based on first-passage times. We illustrate this approach for various decompositions of a catalytic cycle into elementary steps, including non-Markovian decompositions, which are useful when the presence and nature of intermediate states are a priori unknown. Our examples cover different types of reactions and clarify the constraints on elementary steps and the impact of species concentrations on catalysis.


Lekking without a paradox in the buff-breasted sandpiper.
Females in lek-breeding species appear to copulate with a small subset of the available males. Such strong directional selection is predicted to decrease additive genetic variance in the preferred male traits, yet females continue to mate selectively, thus generating the lek paradox. In a study of buff-breasted sandpipers (Tryngites subruficollis), we combine detailed behavioral observations with paternity analyses using single-locus minisatellite DNA probes to provide the first evidence from a lek-breeding species that the variance in male reproductive success is much lower than expected. In 17 and 30 broods sampled in two consecutive years, a minimum of 20 and 39 males, respectively, sired offspring. This low variance in male reproductive success resulted from effective use of alternative reproductive tactics by males, females mating with solitary males off leks, and multiple mating by females. Thus, the results of this study suggests that sexual selection through female choice is weak in buff-breasted sandpipers. The behavior of other lek-breeding birds is sufficiently similar to that of buff-breasted sandpipers that paternity studies of those species should be conducted to determine whether leks generally are less paradoxical than they appear.


Proportional hazards under Conway-Maxwell-Poisson cure rate model and associated inference.
Cure rate models or long-term survival models play an important role in survival analysis and some other applied fields. In this article, by assuming a Conway-Maxwell-Poisson distribution under a competing cause scenario, we study a flexible cure rate model in which the lifetimes of non-cured individuals are described by a Cox's proportional hazard model with a Weibull hazard as the baseline function. Inference is then developed for a right censored data by the maximum likelihood method with the use of expectation-maximization algorithm and a profile likelihood approach for the estimation of the dispersion parameter of the Conway-Maxwell-Poisson distribution. An extensive simulation study is performed, under different scenarios including various censoring proportions, sample sizes, and lifetime parameters, in order to evaluate the performance of the proposed inferential method. Discrimination among some common cure rate models is then done by using likelihood-based and information-based criteria. Finally, for illustrative purpose, the proposed model and associated inferential procedure are applied to analyze a cutaneous melanoma data.


Performance of non-laboratory staff for diagnostic testing and specimen collection in HIV programs: A systematic review and meta-analysis.
In most high HIV burden countries, many HIV patients do not have reliable access to required diagnostic laboratory tests. Task shifting of clinical tasks to lower cadres of health care workers and lay counselors has been successful in scaling up treatment for HIV and may also be an effective strategy in expanding access to essential diagnostic testing. We screened major electronic databases between 1 January 2005 to 26 August 2018 to identify studies assessing ease of use and accuracy of task shifting of HIV-related diagnostic testing and/or specimen collection to non-laboratory health staff. Two independent reviewers screened all titles and abstracts for studies that analyzed diagnostic accuracy, patient impact, ease-of-use, or cost-effectiveness. Studies were assessed for quality, bias, and applicability following the QUADAS-2 framework. We generated summary estimates using random-effects meta-analyses. We identified 42 relevant studies. Overall, point-of-care CD4 testing performed by non-laboratory staff had a mean bias of -54.44 (95% CI: -72.40 --36.48) compared to conventional laboratory-based. Though studies were limited, the diagnostic accuracy of point-of-care alanine transaminase enzyme (ALT) and hemoglobin testing performed by non-laboratory staff was comparable to conventional laboratory-based testing by laboratory professionals. Point-of-care testing and/or specimen collection were generally found to be acceptable and easy to use for non-laboratory staff. Task shifting of testing using point-of-care technologies to non-laboratory staff was comparable to laboratory professionals operating the same technology in the laboratory. Some variability was observed comparing the performance of point-of-care CD4 testing by non-laboratory staff to conventional laboratory-based technologies by laboratory professionals indicating potential lower performance was likely technological rather than operator caused. The benefits of task shifting of testing may outweigh any possible harms as task shifting allows for increased decentralization, access of specific diagnostics, and faster result delivery.


Tako-tsubo cardiomyopathy complicated by recurrent torsade de pointes in a patient with anorexia nervosa.
We report the case of a 57-year-old woman with anorexia nervosa showing evidence of "tako-tsubo" cardiomyopathy complicated by several syncopes due to recurrent episodes of torsades de pointes. Prolongation of QT interval and QT dispersion have been reported both in the "tako-tsubo" cardiomyopathy and in anorexia nervosa. The QT prolongation and the QT dispersion has been linked as risk indicators for sudden cardiac death. The combination of "tako-tsubo" cardiomyopathy with a condition associated with the prolongation of QT and/or with an increase of QT dispersion, such as anorexia nervosa, makes the acute and subacute prognosis of this disease much more severe than usual.


The association of coffee consumption with the risk of osteoporosis and fractures: a systematic review and meta-analysis.
To elucidate the association of coffee and bone health would help fracture risk reduction via dietary intervention. Although those who had higher coffee consumption were less likely to have osteoporosis, the associations between coffee consumption and fracture risk need further investigations with better study designs. The associations between coffee consumption and the risk of osteoporosis and fracture remain inconclusive. We aimed to better quantify these associations by conducting meta-analyses of observational studies. Relevant studies were systematically searched on PubMed, Web of Science, Cochrane library, and Embase Database up to November 25, 2021. The odds ratio (OR) or relative risk (RR) with 95% confidence intervals (CI) was pooled and a dose-response analysis was performed. Four studies with 7114 participants for osteoporosis and thirteen studies with 391,956 participants for fracture incidence were included in the meta-analyses. High versus low coffee consumption was associated with a lower risk of osteoporosis [pooled OR (95% CI): 0.79 (0.65-0.92)], while it was non-significantly associated with fracture incidence [pooled OR (95% CI): 0.86 (0.67-1.05) at hip and 0.89 (0.42-1.36) at non-hip]. A non-linear association between the level of coffee consumption and hip fracture incidence was shown (P = 0.004). The pooled RR (95% CI) of hip fracture risk in those who consumed 1, 2-3, 4, and ≥ 9 cups of coffee per day was 0.92 (0.87-0.97), 0.89 (0.83-0.95), 0.91 (0.85-0.98), and 1.10 (0.76-1.59), respectively. The significance in the association between coffee consumption and the hip fracture incidence decreased in those studies that had larger sample size, higher quality, and more adjustments. A dose-dependent relationship may exist between coffee consumption and hip fracture incidence. The effect of high versus low coffee consumption was influenced by study designs. Further studies with dedicated designs are needed to confirm the independent effects of coffee consumption on bone health.


Extra-abdominal metastases from epithelial ovarian carcinoma: an analysis of 20 cases.
To investigate the clinicopathologic risk factors associated with extra-abdominal metastases in epithelial ovarian carcinoma patients and to determine prognostic factors associated with survival. A retrospective chart review was conducted on 20 cases of epithelial ovarian carcinoma patients with extra-abdominal metastases and 645 cases of epithelial ovarian carcinoma patients without extra-abdominal metastases treated at our unit between 1993 and 2007. A total of 25 extra-abdominal metastatic sites were diagnosed in 20 patients. Sites of metastases were lung, n = 7; skin, n = 6; pleura, n = 5; brain, n = 3; mediastinal lymph node, n = 3; and bone, n = 1. Median interval time between diagnosis of epithelial ovarian carcinoma and documentation of metastatic disease of these 18 patients was 16 months. Median survival time after extra-abdominal metastases was 11 months. In a univariate analysis, Karnofsky performance status (KPS), clinical stage, and sensitivity of primary chemotherapy were the risk factors significantly associated with extra-abdominal metastases. These risk factors remained significant in multivariate analysis. In univariate analysis KPS, sensitivity of primary chemotherapy, metastatic site, and systemic therapy after diagnosis of extra-abdominal metastases were the factors significantly associated with survival. Some clinicopathologic risk factors may associate with extra-abdominal metastases. Prognosis after documentation of extra-abdominal metastases from epithelial ovarian carcinoma is poor. The important prognostic factors associated with survival are KPS, sensitivity of primary chemotherapy, metastatic site, and systemic therapy after diagnosis of extra-abdominal metastases.


3D facial phenotyping by biometric sibling matching used in contemporary genomic methodologies.
The analysis of contemporary genomic data typically operates on one-dimensional phenotypic measurements (e.g. standing height). Here we report on a data-driven, family-informed strategy to facial phenotyping that searches for biologically relevant traits and reduces multivariate 3D facial shape variability into amendable univariate measurements, while preserving its structurally complex nature. We performed a biometric identification of siblings in a sample of 424 children, defining 1,048 sib-shared facial traits. Subsequent quantification and analyses in an independent European cohort (n = 8,246) demonstrated significant heritability for a subset of traits (0.17-0.53) and highlighted 218 genome-wide significant loci (38 also study-wide) associated with facial variation shared by siblings. These loci showed preferential enrichment for active chromatin marks in cranial neural crest cells and embryonic craniofacial tissues and several regions harbor putative craniofacial genes, thereby enhancing our knowledge on the genetic architecture of normal-range facial variation.


Dominance Between Plasmids Determines the Extent of Biofilm Formation.
Bacterial biofilms have an impact in medical and industrial environments because they often confer protection to bacteria against harmful agents, and constitute a source from which microorganisms can disperse. Conjugative plasmids can enhance bacterial ability to form biofilms because conjugative pili act as adhesion factors. However, plasmids may interact with each other, either facilitating or inhibiting plasmid transfer. Accordingly, we asked whether effects on plasmid transfer also impacts biofilm formation. We measured biofilm formation of Escherichia coli cells harboring two plasmid types, or when the two plasmids were present in the same population but carried in different cells. Using eleven natural isolated conjugative plasmids, we confirmed that some indeed promote biofilm formation and, importantly, that this ability is correlated with conjugative efficiency. Further we studied the effect of plasmid pairs on biofilm formation. We observed increased biofilm formation in approximately half of the combinations when both plasmids inhabited the same cell or when the plasmids were carried in different cells. Moreover, in approximately half of the combinations, independent of the co-inhabitation conditions, one of the plasmids alone determined the extent of biofilm formation - thus having a dominant effect over the other plasmid. The molecular mechanisms responsible for these interactions were not evaluated here and future research is required to elucidate them.


Introduction of OXA-48-producing Enterobacteriaceae to Israeli hospitals by medical tourism.
The carbapenemase OXA-48 has been reported from different Mediterranean countries. It is mostly encoded on a single plasmid in various Enterobacteriaceae species. We characterized the epidemiological and molecular features of OXA-48-producing Enterobacteriaceae (OPE) in Israel. Epidemiological investigation was conducted by the National Center for Infection Control. Genotyping was performed using multilocus sequence typing. The bla(OXA-48)-carrying plasmids were investigated using S1 endonuclease and restriction fragment length polymorphism (RFLP). Conjugation efficiency of the bla(OXA-48)-carrying plasmids was studied in a filter mating experiment. Since 2007, four OPE-infected patients were identified, all non-Israeli (two Palestinian, one Jordanian and one Georgian). Three had prior hospitalization; two in Jordan and one in Georgia. The bla(OXA-48) gene was detected in three Escherichia coli strains belonging to different clonal complexes, one Klebsiella oxytoca and one Klebsiella pneumoniae sequence type 101, as previously reported from Tunisia and Spain. In all isolates, the bla(OXA-48) gene was located inside Tn1999.2 and was carried on a 60 kb plasmid with an identical RFLP pattern. The plasmid was able to conjugate from Klebsiella spp. to E. coli, and had a conjugation efficiency up to ~10000 times higher than that of pKpQIL. OPE, introduced mainly by medical tourism, are an emerging threat to patients from affected Mediterranean countries. The bla(OXA-48)-carrying plasmid demonstrated remarkable conjugation efficiency, which is probably important in the success of its dissemination.


The effect of mutations in the MHC class I peptide binding groove on the cytotoxic T lymphocyte recognition of the Kb-restricted ovalbumin determinant.
The H-2Kb-restricted cytotoxic T lymphocyte (CTL) response directed against ovalbumin (OVA) is specific for a region contained within the sequence OVA253-276. In this study we have characterized this response by examining the class I-restricted presentation of OVA peptides by the naturally occurring Kb mutant (Kbm) glycoproteins Kbm1, Kbm3, Kbm5, Kbm8, Kbm10, Kbm11 and Kbm23. To facilitate this study we derived a series of somatic cell hybrid targets expressing the various Kbm class I molecules. Experiments using bulk OVA-specific CTL from C57BL/6 mice demonstrated that all the Kbm molecules except for Kbm1 and Kbm8 could present OVA peptides for effective T cell recognition. Clonal analysis revealed a more complex and relatively diverse pattern of CTL recognition of the Kbm/peptide combinations. This diversity is unlikely to result from the existence of multiple, independent Kb-restricted T cell determinants within OVA, since all CTL tested were specific for a single region between residues 259 and 273. Examination of the fine specificity of Kbm presentation identified individual changes at residues 77, 80 and 116 which affected T cell recognition. The results imply that these changes do not inhibit peptide binding since some clones could recognize peptide presented by a particular Kbm molecule, while other clones could not. All three residues reside within the peptide-binding cleft of the class I protein and are not expected to directly contact the T cell receptor. Although we did not formally demonstrate that OVA binding by Kbm vs. Kb is quantitatively identical, our results are best explained by postulating that the changes at residues 77, 80 and 116 indirectly affect T cell recognition by altering peptide conformation. Taken together our results suggest that changes within the class I binding site can profoundly modify peptide presentation without significantly inhibiting peptide-class I association.


Effects of two surface finishes on the color of cemented and colored anatomic-contour zirconia crowns.
The esthetic appearance of anatomic-contour zirconia restorations is influenced by the shade of the coloring liquid and the optical properties of the luting cements. However, few studies are available on the effects of surface-finishing methods and luting cements on colored anatomic-contour zirconia restorations. The purpose of this in vitro study was to investigate the effects of surface finishing methods on the color distribution of colored anatomic-contour zirconia crowns before and after being cemented onto abutments. Implant-supported anatomic-contour zirconia premolar crowns were fabricated and immersed in A3-coloring liquid for 30 seconds. The colored zirconia crowns were separated into 3 groups according to the method of surface treatment: no treatment (N), polishing (P), and glazing (G). The zirconia crowns without coloring liquid application served as the control group. CIELab color coordinates were obtained, and color differences (ΔE) between shaded crowns were calculated with a spectrophotometer. The color stability of the crown before and after cement application was also investigated. Before cement application, the mean color difference between groups N and P was 2.85 ΔE units, whereas the mean ΔE value between groups N and G was 3.27. Mean ΔE values with and without cement application among groups ranged from 2.75 to 3.45 ΔE units. The color appearance of the colored zirconia crowns was strongly influenced by the surface-finishing methods and luting cement application.


400000 nematode ESTs on the Net.
The parasitic nematode expressed sequence tag (EST) project, a collaboration between University of Edinburgh and the Wellcome Trust Sanger Institute in the UK and the Genome Sequencing Center, St Louis, MO, USA, is currently generating sequence information from >30 different species of nematode. Over 400000 nematode ESTs are now available and at least another 130000 are planned. Here, an update is provided on the status of the project and describes the database tools being developed to disseminate these data.


Improvement of Basal Cell Carcinomas in Patients with Nevoid Basal Cell Carcinoma Syndrome Following by 5-Aminolevulinic Acid Photodynamic Therapy: A Case Report.
Nevoid basal cell carcinoma syndrome (NBCCS) is a rare autosomal dominant-inherited disease characterized by multiple basal cell carcinomas, multiple keratocystic odontogenic tumors, palmar and/or plantar pits. A 50-year-old male patient presented to our hospital with multiple plaques and maculopapular lesions on his face and trunk for more than 20 years. A skin biopsy revealed a number of discrete nests of basaloid cells in the dermis where the peripheral cells are arrayed like a palisade. Multiple odontogenic keratocysts and falx cerebri calcification were found. The diagnosis of NBCCS was made. We treated this patient with 5-aminolevulinic acid photodynamic therapy (ALA-PDT) with red light activation, 5% imiquimod cream and surgical excision for the basal cell carcinomas. All the skin lesions on his face improved substantially after eight sessions of red-light ALA-PDT from clinical observation. Red-light ALA-PDT proved to be a good therapeutic method for NBCCS in this case.


Comparison of the 6-minute walk distance test performed on a non-motorised treadmill and in a corridor in healthy elderly subjects.
To compare the 6-minute walk distance (6MWD) test performed on a non-motorised treadmill (6MWD-T) with the 6MWD test performed in a corridor (6MWD-C) in healthy elderly subjects. Sixteen healthy elderly individuals. Participants performed three 6MWD-T tests and three 6MWD-C tests on two different days. Distance walked was recorded in metres. Perceived exertion and leg fatigue were rated on the modified Borg scale before and after each test. Using the Bland and Altman limits of agreement analysis method, the mean difference between the two methods was 153.3m (limits of agreement: 28 to 278). The mean difference between days 1 and 2 for the 6MWD-C test was -7.2m (limits of agreement: -45.4 to 30.8), and the mean difference between days 1 and 2 for the 6MWD-T test was -1.6m (limits of agreement: -64.0 to 60.7). The mean difference between the first and second repetitions of the 6MWD-C test was -5m (limits of agreement: -41 to 31), and the mean difference between the first and second repetitions of the 6MWD-T test was -17m (limits of agreement: -85 to 51). The 6MWD-C and 6MWD-T tests are not interchangeable. However, the results showed good test-retest reliability between days and between test repetitions for both tests. Therefore, the 6MWD-T test may offer an alternative option to the 6MWD-C test when a 30-m corridor is not available. These findings may have implications for execution of the 6MWT-T test within cardiac and pulmonary rehabilitation.


Genealogy of an ancient protein family: the Sirtuins, a family of disordered members.
Sirtuins genes are widely distributed by evolution and have been found in eubacteria, archaea and eukaryotes. While prokaryotic and archeal species usually have one or two sirtuin homologs, in humans as well as in eukaryotes we found multiple versions and in mammals this family is comprised of seven different homologous proteins being all NAD-dependent de-acylases. 3D structures of human SIRT2, SIRT3, and SIRT5 revealed the overall conformation of the conserved core domain but they were unable to give a structural information about the presence of very flexible and dynamically disordered regions, the role of which is still structurally and functionally unclear. Recently, we modeled the 3D-structure of human SIRT1, the most studied member of this family, that unexpectedly emerged as a member of the intrinsically disordered proteins with its long disordered terminal arms. Despite clear similarities in catalytic cores between the human sirtuins little is known of the general structural characteristics of these proteins. The presence of disorder in human SIRT1 and the propensity of these proteins in promoting molecular interactions make it important to understand the underlying mechanisms of molecular recognition that reasonably should involve terminal segments. The mechanism of recognition, in turn, is a prerequisite for the understanding of any functional activity. Aim of this work is to understand what structural properties are shared among members of this family in humans as well as in other organisms. We have studied the distribution of the structural features of N- and C-terminal segments of sirtuins in all known organisms to draw their evolutionary histories by taking into account average length of terminal segments, amino acid composition, intrinsic disorder, presence of charged stretches, presence of putative phosphorylation sites, flexibility, and GC content of genes. Finally, we have carried out a comprehensive analysis of the putative phosphorylation sites in human sirtuins confirming those sites already known experimentally for human SIRT1 and 2 as well as extending their topology to all the family to get feedback of their physiological functions and cellular localization. Our results highlight that the terminal segments of the majority of sirtuins possess a number of structural features and chemical and physical properties that strongly support their involvement in activities of recognition and interaction with other protein molecules. We also suggest how a multisite phosphorylation provides a possible mechanism by which flexible and intrinsically disordered segments of a sirtuin supported by the presence of positively or negatively charged stretches might enhance the strength and specificity of interaction with a particular molecular partner.


Exposure to untrustworthy websites in the 2016 US election.
Although commentators frequently warn about echo chambers, little is known about the volume or slant of political misinformation that people consume online, the effects of social media and fact checking on exposure, or the effects of political misinformation on behaviour. Here, we evaluate these questions for websites that publish factually dubious content, which is often described as fake news. Survey and web-traffic data from the 2016 US presidential campaign show that supporters of Donald Trump were most likely to visit these websites, which often spread through Facebook. However, these websites made up a small share of people's information diets on average and were largely consumed by a subset of Americans with strong preferences for pro-attitudinal information. These results suggest that the widespread speculation about the prevalence of exposure to untrustworthy websites has been overstated.


Sequencing Ultrarare Targets with Compound Nucleic Acid Cytometry.
Targeted sequencing enables sensitive and cost-effective analysis by focusing resources on molecules of interest. Existing methods, however, are limited in enrichment power and target capture length. Here, we present a novel method that uses compound nucleic acid cytometry to achieve million-fold enrichments of molecules >10 kbp in length using minimal prior target information. We demonstrate the approach by sequencing HIV proviruses in infected individuals. Our method is useful for rare target sequencing in research and clinical applications, including for identifying cancer-associated mutations or sequencing viruses infecting cells.


Regional atrophy associated with cognitive and motor function in prodromal Huntington disease.
Neuroimaging studies suggest that volumetric MRI measures of specific brain structures may serve as excellent biomarkers in future clinical trials of Huntington disease (HD). Demonstration of the clinical significance of these measures is an important step in determining their appropriateness as potential outcome measures. Measures of gray- and white-matter lobular volumes and subcortical volumes (caudate, putamen, globus pallidus, thalamus, nucleus accumbens, hippocampus) were obtained from MRI scans of 516 individuals who tested positive for the HD gene expansion, but were not yet exhibiting signs or symptoms severe enough to warrant diagnosis ("pre-HD"). MRI volumes (corrected for intracranial volume) were correlated with cognitive, motor, psychiatric, and functional measures known to be sensitive to subtle changes in pre-HD. Caudate, putamen, and globus pallidus volumes consistently correlated with cognitive and motor, but not psychiatric or functional measures in pre-HD. Volumes of white matter, nucleus accumbens, and thalamus, but not cortical gray matter, also correlated with some of the motor and cognitive measures. Results of regression analyses suggest that volumes of basal ganglia structures contributed more highly to the prediction of most motor and cognitive variables than volumes of other brain regions. These results support the use of volumetric measures, especially of the basal ganglia, as outcome measures in future clinical trials in pre-HD. Results may also assist investigators in selecting the most appropriate measures for treatment trials that target specific clinical features or regions of neuropathology.


Identification of ErbB3-stimulated genes using modified representational difference analysis.
The epidermal growth factor receptor (EGFR) family of tyrosine kinases is involved in the growth of normal and tumour cells. The specific contribution of each of the four family members to these processes remains unclear. In the present study we have used a PCR-based subtractive approach to identify differences in messages induced in response to activation of ErbB3 and EGFR. The approach described is a modification of the representational difference analysis technique adapted for analysis of cDNA, which we have modified to permit identification of differential gene expression using as little as 20 microg of total RNA as the starting material. The mRNA obtained from EGF-stimulated NIH-3T3 cells expressing chimaeric EGFR-ErbB3 receptors provided the tester amplicons (small PCR-amplified fragments) which were subtracted against driver amplicons derived from unstimulated NIH-3T3 cells expressing the EGFR-ErbB3 chimaera or EGF-stimulated NIH-3T3 cells overexpressing the EGFR. A total of 22 different clones were isolated, 90% of which showed increased expression in the tester amplicons. Six of these, corresponding to known DNA sequences, were selected for further Northern blot analysis against total RNA prepared from the starting cell lines. Of these, the gene encoding the protein dlk (or a closely related protein, Pref-1) was identified as being regulated by ErbB3 but not by the EGFR. Other genes appeared to be elevated by both ErbB3 and EGFR, including those encoding c-jun, Ret finger protein (RFP), neuroleukin and amyloid protein precursor. One gene product, TIS11, was identified as being regulated by EGFR but not by ErbB3.


Hybrid surgery for early gastric cancer.
Endoscopic submucosal dissection (ESD) is the most suitable treatment option in terms of minimally invasive treatment for potential node-negative early gastric cancers (EGCs). Furthermore, making the resection area of the primary lesion as small as possible is ideal for the patient's quality of life, even for potential node-positive EGC. An endoluminal approach is a reasonable option with which to minimize stomach resection area, because this procedure can be accurately demarcated from the inside. From this point of view, endoscopic full-thickness resection (EFTR) may be optimal, while laparoscopic assistance would be more desirable to create a more secure procedure. However, hybrid EFTR for EGCs has two limitations, which must be solved. First, concerns regarding iatrogenic tumor seeding via transluminal communication between the inside and outside of the tract exist. The second limitation relates to the determination of lymphadenectomy. Conventional lymphadenectomy, which involves the removal of the majority of feeding arteries, can lead to necrosis of the remaining gastric wall. Therefore, the resection area of lymphadenectomy should also be carefully determined. To address these two problems, a non-exposed hybrid EFTR combined with sentinel node navigation surgery (SNNS) would be the most ideal method of minimally invasive surgery for EGCs.


Parapartum mental illness: an interview follow-up study.
A total of 54 parapartum mentally ill mothers and 89 controls were followed up approximately 6 years after childbirth. In total, 80% of the patients avoided further pregnancies during the follow-up period, compared to 58% of the controls (non-significant difference). One-third of the patients did not live together with their child, compared to only 3% of the controls. Index mothers tended to report more problematic relationships with their children. Poor childhood relationships during the mother's own childhood seem to be of special significance for the development of these problems. This study suggests a rather gloomy prognosis for parapartum mental illness. The suicide rate was 4.5%. In total, 22% of the patients, compared to none of the controls, had been on sick leave during the last 3 years, or had received a disability pension owing to mental illness at the time of the follow-up. The readmission rate for psychiatric in-patient care was 46% in the patient group.


Melanin's Journey from Melanocytes to Keratinocytes: Uncovering the Molecular Mechanisms of Melanin Transfer and Processing.
Skin pigmentation ensures efficient photoprotection and relies on the pigment melanin, which is produced by epidermal melanocytes and transferred to surrounding keratinocytes. While the molecular mechanisms of melanin synthesis and transport in melanocytes are now well characterized, much less is known about melanin transfer and processing within keratinocytes. Over the past few decades, distinct models have been proposed to explain how melanin transfer occurs at the cellular and molecular levels. However, this remains a debated topic, as up to four different models have been proposed, with evidence presented supporting each. Here, we review the current knowledge on the regulation of melanin exocytosis, internalization, processing, and polarization. Regarding the different transfer models, we discuss how these might co-exist to regulate skin pigmentation under different conditions, i.e., constitutive and facultative skin pigmentation or physiological and pathological conditions. Moreover, we discuss recent evidence that sheds light on the regulation of melanin exocytosis by melanocytes and internalization by keratinocytes, as well as how melanin is stored within these cells in a compartment that we propose be named the melanokerasome. Finally, we review the state of the art on the molecular mechanisms that lead to melanokerasome positioning above the nuclei of keratinocytes, forming supranuclear caps that shield the nuclear DNA from UV radiation. Thus, we provide a comprehensive overview of the current knowledge on the molecular mechanisms regulating skin pigmentation, from melanin exocytosis by melanocytes and internalization by keratinocytes to processing and polarization within keratinocytes. A better knowledge of these molecular mechanisms will clarify long-lasting questions in the field that are crucial for the understanding of skin pigmentation and can shed light on fundamental aspects of organelle biology. Ultimately, this knowledge can lead to novel therapeutic strategies to treat hypo- or hyper-pigmentation disorders, which have a high socio-economic burden on patients and healthcare systems worldwide, as well as cosmetic applications.


Trends and Predictors of Repeat Mental Health Visits to a Pediatric Emergency Department in Hamilton, Ontario.
From 2007-2017, pediatric emergency department (ED) visits for mental health concerns increased by 66% in Canada, with repeat visits accounting for a significant proportion of all visits. Our objective was to examine patient and visit characteristics associated with repeat visits to a tertiary care pediatric ED for mental health concerns. Data were obtained from the administrative records of McMaster Children's Hospital ED for mental health-related visits from February 2013-December 2017. Data on 9,018 ED visits made by 4,976 unique patients were included in this study. Logistic regression analysis was used to examine characteristics associated with repeat visit within six months of index presentation. 22% (n=1,088) of individuals returned to the ED for a mental health concern within six months following their index visit. A repeat visit within six months was associated with female sex (OR=1.19, p=0.019), age of 14-17 years (OR=1.42, p=0.016), receiving a risk assessment by the emergency psychiatry team (OR=1.63, p<0.001) and having an inpatient psychiatric admission (OR=1.67, p<0.001) at the index visit. Receiving anxiety-related discharge diagnoses at an index visit reduced the odds of a repeat visit within 6 months (OR=0.76, p=0.035), while receiving depression-related discharge diagnoses increased the odds of a repeat visit, but only for females (OR=1.3, p=0.011 vs. OR=0.93, p=0.589 for males). We found that approximately one in five patients presenting to the ED for a mental health concern have a repeat visit within six months, consistent with previous studies. This study provides support for previously identified risk factors for repeat visits and offers information on interactions between patient sex and diagnosis.


Hippocampal damage in mouse and human forms of systemic autoimmune disease.
Systemic lupus erythematosus (SLE) is frequently accompanied by neuropsychiatric (NP) and cognitive deficits of unknown etiology. By using autoimmune MRL-lpr mice as an animal model of NP-SLE, we examine the relationship between autoimmunity, hippocampal damage, and behavioral dysfunction. Fluoro Jade B (FJB) staining and anti-ubiquitin (anti-Ub) immunocytochemistry were used to assess neuronal damage in young (asymptomatic) and aged (diseased) mice, while spontaneous alternation behavior (SAB) was used to estimate the severity of hippocampal dysfunction. The causal relationship between autoimmunity and neuropathology was tested by prolonged administration of the immunosuppressive drug cyclophosphamide (CY). In comparison to congenic MRL +/+ controls, SAB acquisition rates and performance in the "reversal" trial were impaired in diseased MRL-lpr mice, suggesting limited use of the spatial learning strategy. FJB-positive neurons and anti-Ub particles were frequent in the CA3 region. Conversely, CY treatment attenuated the SAB deficit and overall FJB staining. Similarly to mouse brain, the hippocampus from a patient who died from NP-SLE showed reduced neuronal density in the CA3 region and dentate gyrus, as well as increased FJB positivity in these regions. Gliosis and neuronal loss were observed in the gray matter, and T lymphocytes and stromal calcifications were common in the choroid plexus. Taken together, these results suggest that systemic autoimmunity induces significant hippocampal damage, which may underlie affective and cognitive deficits in NP-SLE.


BTX concentrations near a stage II implemented petrol station.
A combined monitoring and dispersion modelling methodology was applied for assessing air quality at three different levels of proximity to the selected service station: (I) next to the fuel pumps, (II) in the surrounding environment, and (III) in the background. Continuous monitoring and passive sampling were used for achieving high temporal and spatial resolution, respectively. A Gaussian dispersion model (CALINE4) was used for assessing the road traffic contribution to the local concentrations under different meteorological conditions. It was established that Stage 2 vapour recovery reduces BTX concentrations not only near the pumps, but also in their surrounding environment. However, there is evidence that the efficiency of the system is wind speed dependent. The modelling simulation of the worst case wind scenario revealed the significance of local traffic emissions. It was shown that the traffic contribution even from a single road in the vicinity of the station can, under certain conditions, be higher than the contribution of the station itself to the local BTX levels. Finally, after comparison with previous studies, the concentrations measured near the service station (which was situated in a rural environment) appear to be lower than those observed in busy street canyons in city centres. It can be concluded, although Stage 2 recovery system effectively reduces working VOC losses in service stations, that it will only have a limited positive impact on local air quality if the service station is located in a heavily polluted area.


Harnessing the synthetic capabilities of glycopeptide antibiotic tailoring enzymes: characterization of the UK-68,597 biosynthetic cluster.
In this study, a draft genome sequence of Actinoplanes sp. ATCC 53533 was assembled, and an 81-kb biosynthetic cluster for the unusual sulfated glycopeptide UK-68,597 was identified. Glycopeptide antibiotics are important in the treatment of infections caused by Gram-positive bacteria. Glycopeptides contain heptapeptide backbones that are modified by many tailoring enzymes, including glycosyltransferases, sulfotransferases, methyltransferases, and halogenases, generating extensive chemical and functional diversity. Several tailoring enzymes in the cluster were examined in vitro for their ability to modify glycopeptides, resulting in the synthesis of novel molecules. Tailoring enzymes were also expressed in the producer of the glycopeptide aglycone A47934, generating additional chemical diversity. This work characterizes the biosynthetic program of UK-68,597 and demonstrates the capacity to expand glycopeptide chemical diversity by harnessing the unique chemistry of tailoring enzymes.


The biology of talc.
Data are presented on the effects on health of talc dusts from exposure in industry and use of talc-containing health products. The mineralogy of talc and the composition of cosmetic and industrial grade talc dusts are described. Studies in animals are reviewed, and epidemiological data are considered in relation to exposures that occur during industrial and consumer uses of talc dusts. Hamsters exposed to 8 mg/m3 of respirable cosmetic grade talc dust for up to 150 minutes a day for 300 consecutive days showed no difference in incidence or nature of pathological lesions from those observed in a group of untreated animals. A retrospective study of the causes of death of 227 talc mine millers exposed to cosmetic grade talc at the threshold limit value for talc (20 million parts per cubic foot) for an average of 15-8 years showed that the causes of death were no different from those in a control cohort not exposed to talc dust. The available data indicate that talc dust exposure in the modern mining of cosmetic grade talc does not appear to be injurious to health. The significantly lower dust exposure in the normal use of cosmetic grade talc dusts in talc-containing health and cosmetic products confirms that their use is not a hazard to health.


The influence of the learning climate on learning outcomes from Marte Meo counselling in dementia care.
To identify factors that affected the learning outcomes from Marte Meo counselling (MMC). Although MMC has shown promising results regarding learning outcomes for staff working in dementia-specific care units, the outcomes differ. Twelve individual interviews and four focus group interviews with staff who had participated in MMC were analysed through a qualitative content analysis. The learning climate has considerable significance for the experienced benefit of MMC and indicate that this learning climate depends on three conditions: establishing a common understanding of the content and form of MMC, ensuring staff's willingness to participate and the opportunity to do so, and securing an arena in the unit for discussion and interactions. Learning outcomes from MMC in dementia-specific care units appear to depend on the learning climate in the unit. Implication for nursing management The learning climate needs attention from the nursing management when establishing Marte Meo intervention in nursing homes. The learning climate can be facilitated through building common understandings in the units regarding why and how this intervention should take place, and by ensuring clarity in the relationship between the intervention and the organization's objectives.


Enzyme levels in individual rat muscle fibers.
Individual muscle fibers from the rat anterior tibialis and soleus muscles were each analyzed in duplicate for lactate dehydrogenase (LDH, EC 22.214.171.124), malate dehydrogenase (MDH, EC 220.127.116.11), 3-hydroxyacyl-CoA dehydrogenase (EC 126.96.36.199), fumarate hydrotase (EC 126.96.36.199), glycogen phosphorylase (EC 188.8.131.52), 6-phosphofructokinase (EC 18.104.22.168), pyruvate kinase (EC 22.214.171.124), fructose-bisphosphatase (EC 126.96.36.199), and creatine kinase (EC 184.108.40.206). A few fibers were also analyzed for adenylate kinase (EC 126.96.36.199). In general, there was a wide and almost continuous spectrum of coordinated enzyme activities. In the tibialis muscle, two fiber groups could be clearly distinguished on the basis of MDH activity. The high MDH group had on the average lower LDH activity, but there was a great deal of overlap in LDH between the two groups. Less overlap was observed for phosphorylase and fructose-bisphosphatase, both inversely related to MDH. Only one main group of fibers (presumably slow twitch) was found in the soleus muscle, although enzyme activities also covered a wide range. These soleus fibers were clearly distinguished from the high MDH tibialis group by much lower activities of LDH, pyruvate kinase, and fructose-bisphosphatase.


The effects of parallel versus perpendicular electrode orientations on EMG amplitude and mean power frequency from the biceps brachii.
The purposes of this study were threefold: (1) to compare the isometric torque-related patterns of absolute and normalized electromyographic (EMG) amplitude and mean power frequency (MPF) responses for electrode orientations that were parallel and perpendicular to the muscle fibers; (2) to examine the influence of electrode orientation on mean absolute EMG amplitude and MPF values; and (3) to determine the effects of normalization on mean EMG amplitude and MPF values from parallel and perpendicular electrode orientations. Ten adults (5 men and 5 women mean +/- SD age = 23.8 +/- 2.3 years) volunteered to participate in the investigation. Two sets of bipolar surface EMG electrodes (20 mm center to center) were placed parallel and perpendicular to the muscle fibers over the biceps brachii. The subjects performed a maximal voluntary isometric contraction (MVIC) test followed by randomly ordered submaximal muscle actions in 10% increments from 10 to 90% MVIC. Paired t-tests indicated that absolute EMG amplitude values for the parallel electrode orientation were greater (p < 0.05) than those for the perpendicular orientation at all isometric torque levels except 10% MVIC For normalized EMG amplitude values, however, there were no significant mean differences between electrode orientations. There were also no differences between electrode orientations for absolute or normalized EMG MPF values. In 30% of the cases, different torque-related patterns of responses were observed between the parallel and perpendicular electrode orientations for the absolute and normalized EMG amplitude and MPF values. Therefore, the results of the present study support the need for standardizing electrode orientation to compare the pattern of responses for EMG amplitude and MPF values and normalizing EMG amplitude data to compare the mean values.


Sustained Downregulation of Cortical Adrenergic Receptor Density with Maintenance Electroconvulsive Stimulation.
Central beta-adrenergic receptor downregulation is a robust and reversible neurochemical finding in animals after a course of electroconvulsive stimulation (ECS) or antidepressant drug administration. In addition, beta-receptors are essential components of monoamine-based models of affective disorder pathogenesis and treatment. We tested whether the downregulation in rat cortical beta-receptor density observed after an initial series of ECS is maintained over 2 months of maintenance ECS. Our findings confirm prior reports, in the absence of maintenance ECS, that receptor density is decreased after a course of 10 daily ECS, with recovery to baseline 16 days after the last ECS. In contrast, when maintenance ECS was given for 2 months after an initial series of 10 ECS, a schedule of maintenance ECS at two per week was sufficient to sustain the receptor downregulation. The results are discussed in terms of the neurochemical study of ECS in animals and implications for maintenance ECS.


Secondary metabolite biosynthetic diversity in the fungal family Hypoxylaceae and Xylaria hypoxylon.
To date little is known about the genetic background that drives the production and diversification of secondary metabolites in the Hypoxylaceae. With the recent availability of high-quality genome sequences for 13 representative species and one relative (Xylaria hypoxylon) we attempted to survey the diversity of biosynthetic pathways in these organisms to investigate their true potential as secondary metabolite producers. Manual search strategies based on the accumulated knowledge on biosynthesis in fungi enabled us to identify 783 biosynthetic pathways across 14 studied species, the majority of which were arranged in biosynthetic gene clusters (BGC). The similarity of BGCs was analysed with the BiG-SCAPE engine which organised the BGCs into 375 gene cluster families (GCF). Only ten GCFs were conserved across all of these fungi indicating that speciation is accompanied by changes in secondary metabolism. From the known compounds produced by the family members some can be directly correlated with identified BGCs which is highlighted herein by the azaphilone, dihydroxynaphthalene, tropolone, cytochalasan, terrequinone, terphenyl and brasilane pathways giving insights into the evolution and diversification of those compound classes. Vice versa, products of various BGCs can be predicted through homology analysis with known pathways from other fungi as shown for the identified ergot alkaloid, trigazaphilone, curvupallide, viridicatumtoxin and swainsonine BGCs. However, the majority of BGCs had no obvious links to known products from the Hypoxylaceae or other well-studied biosynthetic pathways from fungi. These findings highlight that the number of known compounds strongly underrepresents the biosynthetic potential in these fungi and that a tremendous number of unidentified secondary metabolites is still hidden. Moreover, with increasing numbers of genomes for further Hypoxylaceae species becoming available, the likelihood of revealing new biosynthetic pathways that encode new, potentially useful compounds will significantly improve. Reaching a better understanding of the biology of these producers, and further development of genetic methods for their manipulation, will be crucial to access their treasures.


Zebrafish as a model system for the study of hemostasis and thrombosis.
Although the zebrafish has been established as a research tool over the past two to three decades, in hematology it has primarily been used to investigate areas distinct from coagulation. The advantages of this vertebrate model include high fecundity, rapid and external development, and conservation of virtually all clotting factors in the zebrafish genomic sequence. Here, we summarize the growing application of this technology to the study of hemostasis and thrombosis. Loss of function studies have demonstrated conservation of function for a number of zebrafish coagulation factors. These include positive and negative regulators of coagulation, as well as key components of the thrombus itself, such as von Willebrand factor, fibrinogen, and thrombocytes. Such analyses have also been leveraged to aid in the understanding of human variation and disease, as well as to perform in-vivo structure/function experiments. The zebrafish is an organism that lends itself to a number of unique and powerful approaches not possible in mammals. This review demonstrates that there is a high degree of genetic and functional conservation of coagulation, portending future insights into hemostasis and thrombosis through the use of this model.


Delayed deformation of self-expanding stents after carotid artery stenting for postendarterectomy restenoses.
Carotid artery stenting has become an acceptable alternative for treating patients with severe atherosclerotic lesions, particularly those with significant surgical risks, such as recurrent stenosis after endarterectomy. Stent deformation, a phenomenon primarily associated with balloon-expandable stents, is largely avoided by exclusively using self-expanding stents in treating carotid artery stenosis. Nonetheless, we herein report two patients who presented with delayed Wallstent deformation after carotid artery stenting for postendarterectomy restenosis. Our cases highlight the need for caution because delayed deformation of self-expanding stents can occur, particularly during treatment of patients with postendarterectomy stenosis. Furthermore, poststent surveillance is imperative in identifying patients with severe restenosis after carotid artery stenting who need reintervention.


The Mitochondrial Genome of Eleusine indica and Characterization of Gene Content within Poaceae.
Plant mitochondrial (mt) genome assembly provides baseline data on size, structure, and gene content, but resolving the sequence of these large and complex organelle genomes remains challenging due to fragmentation, frequent recombination, and transfers of DNA from neighboring plastids. The mt genome for Eleusine indica (Poaceae: goosegrass) is comprehensibly analyzed here, providing key reference data for an economically significant invasive species that is also the maternal parent of the allotetraploid crop Finger millet (Eleusine coracana). The assembled E. indica genome contains 33 protein coding genes, 6 rRNA subunits, 24 tRNA, 8 large repetitive regions 15 kb of transposable elements across a total of 520,691 bp. Evidence of RNA editing and loss of rpl2, rpl5, rps14, rps11, sdh4, and sdh3 genes is evaluated in the context of an updated survey of mt genomic gene content across the grasses through an analysis of publicly available data. Hypothesized patterns of Poaceae mt gene loss are examined in a phylogenetic context to clarify timing, showing that rpl2 was transferred to the nucleus from the mitochondrion prior to the origin of the PACMAD clade.


Renal tubular acidosis in horses (1980-1999).
Renal tubular acidosis (RTA) is characterized by altered renal tubular function resulting in hyperchloremic metabolic acidosis. The purpose of the study was to describe RTA in 16 horses. No breed or sex predilection was found. The mean age at onset of the disease was 7 years of age. The type of diet had no apparent effect on development of RTA. The most common clinical signs were depression, poor performance, weight loss, and anorexia. Initial blood work revealed a marked hyperchloremic metabolic acidosis in all horses and a compensatory respiratory response in most horses. Sixty-three percent (10/16) of the horses had some evidence of renal damage or disease. Initial treatment consisted of large amounts of sodium bicarbonate given intravenously and orally for the prompt correction of the acidosis. Response to treatment was largely dependent on the rate of sodium bicarbonate administration. Long-term oral supplementation with NaHCO3 was required for the maintenance of normal acid-base status in individual horses. Recurrence of RTA was noted in 56% (9/16) of the horses. Horses with evidence of renal disease had multiple relapses. RTA should be considered as a differential diagnosis in horses with vague signs of depression, weight loss, and anorexia. The pathogenesis of RTA in horses remains uncertain, but prompt recognition and early aggressive intravenous sodium bicarbonate therapy followed by long-term oral supplementation seem to be important to successful management.


Sarilumab Plus Methotrexate in Patients With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate: Results of a Phase III Study.
To evaluate the efficacy and safety of sarilumab in combination with methotrexate (MTX) for the treatment of rheumatoid arthritis (RA). Adults with moderate-to-severe RA and an inadequate response to MTX were randomized (1:1:1) to receive sarilumab (doses of 150 mg or 200 mg) or placebo every 2 weeks in conjunction with weekly MTX for 52 weeks. Co-primary end points were the proportion of patients achieving American College of Rheumatology 20% (ACR20) improvement responses at week 24, change from baseline in the Health Assessment Questionnaire (HAQ) disability index (DI) at week 16, and change from baseline in the modified Sharp/van der Heijde score (SHS) of radiographic damage at week 52. Baseline characteristics were similar among the groups. For all 3 co-primary end points, the sarilumab 150 mg and 200 mg groups demonstrated statistically significant improvements as compared with the placebo group (ACR20 response rate at week 24, 58.0%, 66.4%, and 33.4%, respectively [P < 0.0001]; least squares mean change in HAQ DI at week 16, -0.53, -0.55, and -0.29, respectively [P < 0.0001]; and mean change in SHS at week 52, 0.90, 0.25, and 2.78, respectively [P < 0.0001]). The most common treatment-emergent adverse event was infection. In the sarilumab 150 mg, sarilumab 200 mg, and placebo groups, the incidence of serious infections was 2.6%, 4.0%, and 2.3%, respectively. Elevations in alanine aminotransferase levels >3-fold the upper limit of normal occurred in 9.5%, 8.0%, and 2.1% of patients, respectively; in 24 patients, this led to discontinuation of treatment. Elevated total cholesterol levels were observed in 36.8%, 43.0%, and 18.3% of patients, respectively. In patients receiving 150 mg and 200 mg sarilumab, neutrophil counts of 0.5 to <1.0 × 10(9) /liter were observed in 5.1% and 7.8% of patients, respectively, while neutrophil counts of <0.5 × 10(9) /liter were observed in 0.9% and 0.7% of patients, respectively; none of the patients receiving placebo experienced changes in neutrophil counts. In RA patients treated with sarilumab (150 mg or 200 mg every 2 weeks) in combination with MTX, both doses provided sustained clinical efficacy, as shown by significant improvements in symptomatic, functional, and radiographic outcomes. Sarilumab was generally well tolerated. The adverse events observed in this study were consistent with the effects of interleukin-6 signaling blockade.


Influence of genetic background on daily running-wheel activity differs with aging.
In humans, physical activity declines with age. We tested the hypothesis that genetic background and age interact to determine daily wheel-running physical activity patterns in mice. Five female mice from ten inbred strains (A/J, AKR/J, Balb/cJ, CBA/J, C3H/HeJ, C3Heb/FeJ, C57Bl/6J, C57L/J, DBA/2J, and SWR/J) were studied for 26 wk starting at 10 wk of age. All mice were housed in separate cages, each with a running wheel and magnetic sensor. Throughout the 26-wk period, age-related change in daily duration (P < 0.0001), daily distance (P < 0.0001), and average velocity (P = 0.0003) differed between the inbred strains. Unlike the other strains, SWR/J mice increased their running-wheel activity throughout the 6-mo time period. Broad-sense heritability estimations for the strains across the 26-wk period ranged between 0.410 and 0.855 for the three physical activity phenotypes. Furthermore, the broad-sense heritability estimates for daily running-wheel distance differed across time and suggested an interaction between genetic background and age on physical activity in these inbred mice.


Risk estimation of the SARS-CoV-2 acute respiratory disease outbreak outside China.
On December 31, 2019, the World Health Organization was alerted to the occurrence of cases of pneumonia in Wuhan, Hubei Province, China, that were caused by an unknown virus, which was later identified as a coronavirus and named the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We aimed to estimate the reproductive number of SARS-CoV-2 in the Hubei Province and evaluate the risk of an acute respiratory coronavirus disease (COVID-19) outbreak outside China by using a mathematical model and stochastic simulations. We constructed a mathematical model of SARS-CoV-2 transmission dynamics, estimated the rate of transmission, and calculated the reproductive number in Hubei Province by using case-report data from January 11 to February 6, 2020. The possible number of secondary cases outside China was estimated by stochastic simulations in various scenarios of reductions in the duration to quarantine and rate of transmission. The rate of transmission was estimated as 0.8238 (95% confidence interval [CI] 0.8095-0.8382), and the basic reproductive number as 4.1192 (95% CI 4.0473-4.1912). Assuming the same rate of transmission as in Hubei Province, the possibility of no local transmission is 54.9% with a 24-h quarantine strategy, and the possibility of more than 20 local transmission cases is 7% outside of China. The reproductive number for SARS-CoV-2 transmission dynamics is significantly higher compared to that of the previous SARS epidemic in China. This implies that human-to-human transmission is a significant factor for contagion in Hubei Province. Results of the stochastic simulation emphasize the role of quarantine implementation, which is critical to prevent and control the SARS-CoV-2 outbreak outside China.


A new method to purify hepatic CYP1A of Prochilodus scrofa, a Brazilian freshwater fish.
Cytochromes P450 constitute a superfamily of the phase I enzymes whose primary task is the detoxification of both endogenous and xenobiotic compounds. Fish, among non-mammalian species, have received great interest because they are a direct food source for humans as well as conveyors of toxic chemicals to human beings. The aim of the present study was the purification of the hepatic isoform of CYP1A in Prochilodus scrofa (Prochilodontidae), a Brazilian fish, using only one chromatographic step. The purification of CYP1A was done by Reverse Phase HPLC on a C18 column. Purified CYP1A was characterized with respect to electrophoretic, immunochemical and biocatalyst properties. CYP1A fractions produced a single uniform band on SDS-PAGE with an apparent molecular mass of 58 kDa. Purified CYP1A of P. scrofa showed strong cross-reactivity with antibodies directed against CYP1A from trout. The fraction was also encapsulated in two different reconstituted systems; one composed of neutral lipids and another of negatively charged lipids. In both of them, we could detect EROD activity but not PROD activity, which confirms that the CYP1A was purified with all its enzyme activity. There was an increase of activity when CYP1A and NADPH cytochrome P450 (CYP) reductase were encapsulated in negatively charged lipids, which confirms that the charge of lipid is essential to CYP1A activity. All these characteristics strongly suggest that this new procedure is efficient for purifying hepatic CYP1A from P. scrofa, showing that the CYP1A isoform of this fish has a highly conserved protein region.


Genome-wide association of drought-related and biomass traits with HapMap SNPs in Medicago truncatula.
Improving drought tolerance of crop plants is a major goal of plant breeders. In this study, we characterized biomass and drought-related traits of 220 Medicago truncatula HapMap accessions. Characterized traits included shoot biomass, maximum leaf size, specific leaf weight, stomatal density, trichome density and shoot carbon-13 isotope discrimination (δ(13) C) of well-watered M. truncatula plants, and leaf performance in vitro under dehydration stress. Genome-wide association analyses were carried out using the general linear model (GLM), the standard mixed linear model (MLM) and compressed MLM (CMLM) in TASSEL, which revealed significant overestimation of P-values by CMLM. For each trait, candidate genes and chromosome regions containing SNP markers were found that are in significant association with the trait. For plant biomass, a 0.5 Mbp region on chromosome 2 harbouring a plasma membrane intrinsic protein, PIP2, was discovered that could potentially be targeted to increase dry matter yield. A protein disulfide isomerase-like protein was found to be tightly associated with both shoot biomass and leaf size. A glutamate-cysteine ligase and an aldehyde dehydrogenase family protein with Arabidopsis homologs strongly expressed in the guard cells were two of the top genes identified by stomata density genome-wide association studies analysis.


Advancing Symptom Science Through Symptom Cluster Research: Expert Panel Proceedings and Recommendations.
An overview of proceedings, findings, and recommendations from the workshop on "Advancing Symptom Science Through Symptom Cluster Research" sponsored by the National Institute of Nursing Research (NINR) and the Office of Rare Diseases Research, National Center for Advancing Translational Sciences, is presented. This workshop engaged an expert panel in an evidenced-based discussion regarding the state of the science of symptom clusters in chronic conditions including cancer and other rare diseases. An interdisciplinary working group from the extramural research community representing nursing, medicine, oncology, psychology, and bioinformatics was convened at the National Institutes of Health. Based on expertise, members were divided into teams to address key areas: defining characteristics of symptom clusters, priority symptom clusters and underlying mechanisms, measurement issues, targeted interventions, and new analytic strategies. For each area, the evidence was synthesized, limitations and gaps identified, and recommendations for future research delineated. The majority of findings in each area were from studies of oncology patients. However, increasing evidence suggests that symptom clusters occur in patients with other chronic conditions (eg, pulmonary, cardiac, and end-stage renal disease). Nonetheless, symptom cluster research is extremely limited and scientists are just beginning to understand how to investigate symptom clusters by developing frameworks and new methods and approaches. With a focus on personalized care, an understanding of individual susceptibility to symptoms and whether a "driving" symptom exists that triggers other symptoms in the cluster is needed. Also, research aimed at identifying the mechanisms that underlie symptom clusters is essential to developing targeted interventions.


Twenty-four-hour preoperative endocrine profiles in women with benign and malignant breast disease.
Mean 24-hr growth hormone, luteinizing hormone, follicle-stimulating hormone, estradiol, and progesterone concentrations determined preoperatively in 16 women with benign breast masses and 17 patients with breast cancer were similar to those levels found in 25 age- and weight-matched control subjects. Mean 24-hr testosterone levels, however, were significantly elevated in women with breast cancer evaluated in the luteal phase of their cycles and were normal in postmenopausal breast cancer women. In addition, serum thyroid-stimulating hormone, thyroxine, cholesterol, and triglyceride levels were normal in these subjects. Plasma cortisols and urinary 17-hydroxysteroid excretion tended to be higher in both the benign and malignant breast disease group and probably reflected preoperative anxiety. Hence, we have found normal concentrations of a variety of endocrine and other biochemical agents that can stimulate breast tissue growth and/or have been previously reported to be disordered in women with breast cancer.


[Stoichiometry of microsomal oxidation reactions. Distribution of redox-equivalents in monooxygenase and oxidase reactions catalyzed by cytochrome P-450].
The stoichiometry of NADPH oxidation in rabbit liver microsomes was studied. It was shown that in uncoupled reactions cytochrome P-450, besides O2- generation catalyzes direct two- and four-electron reduction of O2 to produce H2O2 and water, respectively. With an increase in pH and ionic strength, the amount of O2 reduced via an one-electron route increases at the expense of the two-electron reaction. In parallel, with a rise in pH the steady-state concentration of the oxy-complex of cytochrome P-450 increases, while the synergism of NADPH and NADH action in the H2O2 formation reaction is replaced by competition. The four-electron reduction is markedly accelerated and becomes the main pathway of O2 reduction in the presence of a pseudo-substrate--perfluorohexane. Treatment of rabbit with phenobarbital, which induces the cytochrome P-450 isozyme specific to benzphetamine results in a 2-fold increase in the degree of coupling of NADPH and benzphetamine oxidation. The experimental results suggest that the ratio of reactions of one- and two-electron reduction of O2 is controlled by the ratio of rates of one- and two-electron reduction of cytochrome P-450. In the presence of pseudo-substrates cytochrome P-450 acts predominantly as a four-electron oxidase; one of possible reasons for the uncoupling of microsomal monooxygenase reactions is the multiplicity of cytochrome P-450 isozymes.


Potential applications of imaging and image-guided radiotherapy for brain metastases and glioblastoma to improve patient quality of life.
Treatment of glioblastoma multiforme (GBM) and brain metastasis remains a challenge because of the poor survival and the potential for brain damage following radiation. Despite concurrent chemotherapy and radiation dose escalation, local recurrence remains the predominant pattern of failure in GBM most likely secondary to repopulation of cancer stem cells. Even though radiotherapy is highly effective for local control of radio-resistant tumors such as melanoma and renal cell cancer, systemic disease progression is the cause of death in most patients with brain metastasis. Preservation of quality of life (QOL) of cancer survivors is the main issue for patients with brain metastasis. Image-guided radiotherapy (IGRT) by virtue of precise radiation dose delivery may reduce treatment time of patients with GBM without excessive toxicity and potentially improve neurocognitive function with preservation of local control in patients with brain metastasis. Future prospective trials for primary brain tumors or brain metastasis should include IGRT to assess its efficacy to improve patient QOL.


CSHM/SCHM Presidential Address, Discours Presidentiel, 26 May 2001: The Quota: "An Equally Serious Problem" for Us All.
The author explores the question-was a quota applied to the admission of women to the medical school of the University of Toronto? She uses a variety of sources, including class photographs, archives, statistics, personal recollections, and oral history. The existence of a quota from 1944 to 1968 is inferred from statistical patterns and confirmed by a surprising source. In closing, the historiographie implications of this project for research on other politically charged topics are considered.


Omental pseudocyst formation associated with perforated gastric duplication: a case report.
We present a case of omental pseudocyst associated with a perforated gastric duplication. A boy (2.5 years old) with an abdominal mass was admitted because thick-walled and thin-walled double cysts were identified on computed tomography and magnetic resonance imaging. At laparotomy, the double cysts were interconnected and located in the omentum with no communication to the stomach. Microscopic examination showed a thick-walled cyst composed solely of gastric tissue with muscle layers divided at the stricture between the 2 cysts and a thin-walled cyst without a true endothelial lining. Gastric duplications can be complicated with perforation and malignancy, and primary surgery is the first choice of treatment.


Molecular evaluation of Toxocara species in stray cats using loop-mediated isothermal amplification (lamp) technique as a rapid, sensitive and simple screening assay.
Toxocara species are parasitic nematodes of dogs and cats with a worldwide distribution. The adult worm lives in the intestine, and horizontal transmission of the infection occurs through eating paratenic host or embryonated eggs. This study aimed to estimate the molecular prevalence of Toxocara species in stray cats using the loop-mediated isothermal amplification (LAMP) technique. A total of 95 stool samples were randomly collected from stray cats in Khorramabad city in western Iran. Microscopic examination was performed after the separation and extraction of supernatants. The LAMP reaction was performed using the internal transcribed spacer 2 (ITS2) gene primers of Toxocara species and the appropriate master mix. The overall prevalence of Toxocara spp. in stray cats was 20% (19/95, CI 95%: 0.2 ± 0.08) by parasitological and molecular assessments. The microscopic examination of stool samples revealed that 19 samples were positive for Toxocara. The same 19 positive samples were also positive by the LAMP technique. Interestingly, based on the results of the LAMP assay, out of 95 studied samples, 18 (18.94%; CI 95%: 0.19 ± 0.08) specimens were Toxocara canis, while only 1 (1.05%; CI 95%: 0.005 ± 0.01) sample was diagnosed as Toxocara cati. The relatively high prevalence of Toxocara species in the studied cats shows the role of this species in spreading the parasite and the role of the cats in transmitting this zoonotic parasite. Preventive measures including the control of stray cat's population by castration and protection of public gardens where children play are recommended. The easy, highly sensitive and specific LAMP method is proposed for the differential detection of Toxocara species in animals and humans.


Analysis of protein phosphorylation in nerve terminal reveals extensive changes in active zone proteins upon exocytosis.
Neurotransmitter release is mediated by the fast, calcium-triggered fusion of synaptic vesicles with the presynaptic plasma membrane, followed by endocytosis and recycling of the membrane of synaptic vesicles. While many of the proteins governing these processes are known, their regulation is only beginning to be understood. Here we have applied quantitative phosphoproteomics to identify changes in phosphorylation status of presynaptic proteins in resting and stimulated nerve terminals isolated from the brains of Wistar rats. Using rigorous quantification, we identified 252 phosphosites that are either up- or downregulated upon triggering calcium-dependent exocytosis. Particularly pronounced were regulated changes of phosphosites within protein constituents of the presynaptic active zone, including bassoon, piccolo, and RIM1. Additionally, we have mapped kinases and phosphatases that are activated upon stimulation. Overall, our study provides a snapshot of phosphorylation changes associated with presynaptic activity and provides a foundation for further functional analysis of key phosphosites involved in presynaptic plasticity.


ProNGF promotes brain metastasis through TrkA/EphA2 induced Src activation in triple negative breast cancer cells.
Triple-Negative Breast Cancer is particularly aggressive, and its metastasis to the brain has a significant psychological impact on patients' quality of life, in addition to reducing survival. The development of brain metastases is particularly harmful in triple-negative breast cancer (TNBC). To date, the mechanisms that induce brain metastasis in TNBC are poorly understood. Using a human blood-brain barrier (BBB) in vitro model, an in vitro 3D organotypic extracellular matrix, an ex vivo mouse brain slices co-culture and in an in vivo xenograft experiment, key step of brain metastasis were recapitulated to study TNBC behaviors. In this study, we demonstrated for the first time the involvement of the precursor of Nerve Growth Factor (proNGF) in the development of brain metastasis. More importantly, our results showed that proNGF acts through TrkA independent of its phosphorylation to induce brain metastasis in TNBC. In addition, we found that proNGF induces BBB transmigration through the TrkA/EphA2 signaling complex. More importantly, our results showed that combinatorial inhibition of TrkA and EphA2 decreased TBNC brain metastasis in a preclinical model. These disruptive findings provide new insights into the mechanisms underlying brain metastasis with proNGF as a driver of brain metastasis of TNBC and identify TrkA/EphA2 complex as a potential therapeutic target.


Induced sputum 8-isoprostane concentrations in inflammatory airway diseases.
Induced sputum 8-iso-prostaglandin F(2alpha) (PGF(2alpha)) concentrations may be a useful marker of oxidative stress in airways disease. This study examines oxidative stress (measured by 8-iso-PGF(2alpha)) in airway disease according to disease type (asthma and bronchiectasis), disease activity (stable and acute asthma), and disease pattern (intermittent, mild, moderate, and severe persistent asthma). We compared subjects with stable asthma (n = 71) and bronchiectasis (n = 23) with healthy control subjects (n = 29). Another group of patients with asthma (n = 39) were assessed during and after acute exacerbation. Induced sputum 8-iso-PGF(2alpha) concentrations were validated and found to be elevated in subjects with stable asthma and bronchiectasis versus control subjects (median [interquartile range] 216 [103-389] and 698 [264-1,613] ng/L vs. 123 [41-290] ng/L, p < 0.001) and increased as clinical asthma pattern worsened (intermittent 115 [42-153], mild persistent 116 [89-229] ng/L, moderate persistent 183 [110-317] ng/L, severe persistent 387 [102-587] ng/L; p = 0.010). Sputum 8-iso-PGF(2alpha) concentrations were elevated during acute asthma and decreased with recovery (458 [227-950] ng/L vs. 214 [148-304] ng/L, p = 0.0002). We conclude that 8-iso-PGF(2alpha) is involved in the pathophysiology of inflammatory airway diseases, being related to disease type, pattern, and activity. Analysis of 8-iso-PGF(2alpha) concentrations in induced sputum provides a useful tool for monitoring oxidative stress and investigating strategies aimed at reducing oxidative stress in airways disease.


Soil carbon sequestration and biochar as negative emission technologies.
Despite 20 years of effort to curb emissions, greenhouse gas (GHG) emissions grew faster during the 2000s than in the 1990s, which presents a major challenge for meeting the international goal of limiting warming to <2 °C relative to the preindustrial era. Most recent scenarios from integrated assessment models require large-scale deployment of negative emissions technologies (NETs) to reach the 2 °C target. A recent analysis of NETs, including direct air capture, enhanced weathering, bioenergy with carbon capture and storage and afforestation/deforestation, showed that all NETs have significant limits to implementation, including economic cost, energy requirements, land use, and water use. In this paper, I assess the potential for negative emissions from soil carbon sequestration and biochar addition to land, and also the potential global impacts on land use, water, nutrients, albedo, energy and cost. Results indicate that soil carbon sequestration and biochar have useful negative emission potential (each 0.7 GtCeq. yr(-1) ) and that they potentially have lower impact on land, water use, nutrients, albedo, energy requirement and cost, so have fewer disadvantages than many NETs. Limitations of soil carbon sequestration as a NET centre around issues of sink saturation and reversibility. Biochar could be implemented in combination with bioenergy with carbon capture and storage. Current integrated assessment models do not represent soil carbon sequestration or biochar. Given the negative emission potential of SCS and biochar and their potential advantages compared to other NETs, efforts should be made to include these options within IAMs, so that their potential can be explored further in comparison with other NETs for climate stabilization.


Worrying and rumination are both associated with reduced cognitive control.
Persistent negative thought is a hallmark feature of both major depressive disorder and generalized anxiety disorder. Despite its clinical significance, little is known about the underlying mechanisms of persistent negative thought. Recent studies suggest that reduced cognitive control might be an explanatory factor. We investigated the association between persistent negative thought and switching between internal representations in working memory, using the internal shift task (IST). The IST was administered to a group of undergraduates, classified as high-ruminators versus low-ruminators, or high-worriers versus low-worriers. Results showed that high-ruminators and high-worriers have more difficulties to switch between internal representations in working memory as opposed to low-ruminators and low-worriers. Importantly, results were only significant when the negative stimuli used in the IST reflected personally relevant worry themes for the participants. The results of this study indicate that rumination and worrying are both associated with reduced cognitive control for verbal information that is personally relevant.


Titration calorimetric analysis of AcylCoA recognition by myristoylCoA:protein N-myristoyltransferase.
Saccharomyces cerevisiae myristoylCoA:protein N-myristoyltransferase (Nmt1p) is an essential enzyme that catalyzes the transfer of myristic acid (C14:0) from myristoylCoA to the N-terminus of cellular proteins with a variety of functions. Nmts from an assortment of species display remarkable in vivo specificity for this rare acyl chain. To better understand the mechanisms underlying this specificity, we have used isothermal titration calorimetry as well as kinetic measurements to study the interactions of Nmt1p with acylCoA analogs having variations in chain length and/or conformation, analogs with alterations in the thioester bond, and analogs with or without a 3'-phosphate in their CoA moiety. MyristoylCoA binds to Nmt1p with a Kd of 15 nM and a large exothermic deltaH (-25 kcal/mol). CoA derivatives of C12:0-C16:0 fatty acids bind to Nmt1p with similar affinity, but with much smaller deltaH and a correspondingly less negative TdeltaS than myristoylCoA. Replacing the thioester carbonyl group with a methylene or removing the 3'-phosphate of CoA is each sufficient to prevent the low enthalpy binding observed with myristoylCoA. The carbonyl and the 3'-phosphate have distinct and important roles in chain length recognition over the range C12-C16. Acyltransferase activity parallels binding enthalpy. The naturally occurring cis-5-tetradecenoylCoA and cis-5,8-tetradecadienoylCoA are used as alternative Nmt substrates in retinal photoreceptor cells, even though they do not exhibit in vitro kinetic or thermodynamic properties that are superior to those of myristoylCoA. The binding of an acylCoA is the first step in the enzyme's ordered reaction mechanism. Our findings suggest that within cells, limitation of Nmt substrate usage occurs through control of acylCoA availability. This indicates that full understanding of how protein acylation is controlled not only requires consideration of the acyltransferase and its peptide substrates but also consideration of the synthesis and/or presentation of its lipid substrates.


Identification and structural determination of the M(3) muscarinic acetylcholine receptor basolateral sorting signal.
Muscarinic acetylcholine receptors comprise a family of G-protein-coupled receptors that display differential localization in polarized epithelial cells. We identify a seven-residue sequence, Ala(275)-Val(281), in the third intracellular loop of the M(3) muscarinic receptor that mediates dominant, position-independent basolateral targeting in Madin-Darby canine kidney cells. Mutational analyses identify Glu(276), Phe(280), and Val(281) as critical residues within this sorting motif. Phe(280) and Val(281) comprise a novel dihydrophobic sorting signal as mutations of either residue singly or together with leucine do not disrupt basolateral targeting. Conversely, Glu(276) is required and cannot be substituted with alanine or aspartic acid. A 19-amino acid peptide representing the M(3) sorting signal and surrounding sequence was analyzed via two-dimensional nuclear magnetic resonance spectroscopy. Solution structures show that Glu(276) resides in a type IV beta-turn and the dihydrophobic sequence Phe(280)Val(281) adopts either a type I or IV beta-turn.


5-Year Outcomes After Left Atrial Appendage Closure: From the PREVAIL and PROTECT AF Trials.
The PROTECT AF (WATCHMAN Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation) trial demonstrated that left atrial appendage closure (LAAC) with the Watchman device (Boston Scientific, St. Paul, Minnesota) was equivalent to warfarin for preventing stroke in atrial fibrillation, but had a high rate of complications. In a second randomized trial, PREVAIL (Evaluation of the WATCHMAN LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy), the complication rate was low. The warfarin cohort experienced an unexpectedly low ischemic stroke rate, rendering the efficacy endpoints inconclusive. However, these outcomes were based on relatively few patients followed for a relatively short time. The final results of the PREVAIL trial, both alone and as part of a patient-level meta-analysis with the PROTECT AF trial, are reported with patients in both trials followed for 5 years. PREVAIL and PROTECT AF are prospective randomized clinical trials with patients randomized 2:1 to LAAC or warfarin; together, they enrolled 1,114 patients for 4,343 patient-years. Analyses are by intention-to-treat, and rates are events per 100 patient-years. For the PREVAIL trial, the first composite coprimary endpoint of stroke, systemic embolism (SE), or cardiovascular/unexplained death did not achieve noninferiority (posterior probability for noninferiority = 88.4%), whereas the second coprimary endpoint of post-procedure ischemic stroke/SE did achieve noninferiority (posterior probability for noninferiority = 97.5%); the warfarin arm maintained an unusually low ischemic stroke rate (0.73%). In the meta-analysis, the composite endpoint was similar between groups (hazard ratio [HR]: 0.820; p = 0.27), as were all-stroke/SE (HR: 0.961; p = 0.87). The ischemic stroke/SE rate was numerically higher with LAAC, but this difference did not reach statistical significance (HR: 1.71; p = 0.080). However, differences in hemorrhagic stroke, disabling/fatal stroke, cardiovascular/unexplained death, all-cause death, and post-procedure bleeding favored LAAC (HR: 0.20; p = 0.0022; HR: 0.45; p = 0.03; HR: 0.59; p = 0.027; HR: 0.73; p = 0.035; HR: 0.48; p = 0.0003, respectively). These 5-year outcomes of the PREVAIL trial, combined with the 5-year outcomes of the PROTECT AF trial, demonstrate that LAAC with Watchman provides stroke prevention in nonvalvular atrial fibrillation comparable to warfarin, with additional reductions in major bleeding, particularly hemorrhagic stroke, and mortality. (WATCHMAN Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation; NCT00129545; and Evaluation of the WATCHMAN LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy; NCT01182441).


Depth-dependent cerebral hemodynamic responses following direct cortical electrical stimulation (DCES) revealed by in vivo dual-optical imaging techniques.
We studied depth-dependent cerebral hemodynamic responses of rat brain following direct cortical electrical stimulation (DCES) in vivo with optical recording of intrinsic signal (ORIS) and near-infrared spectroscopy (NIRS). ORIS is used to visualize the immediate hemodynamic changes in cortical areas following the stimulation, whereas NIRS measures the hemodynamic changes originating from subcortical areas. We found strong hemodynamic changes in relation to DCES both in ORIS and NIRS data. In particular, the signals originating from cortical areas exhibited a tri-phasic response, whereas those originating from subcortical regions exhibited multi-phasic responses. In addition, NIRS signals from two different sets of source-detector separation were compared and analyzed to investigate the causality of perfusion, which demonstrated downstream propagation, indicating that the upper brain region reacted faster than the deep region.


Irritable bowel syndrome: focus on otilonium bromide.
Irritable bowel syndrome is a prevalent and chronic disorder, characterized by recurrent abdominal pain/discomfort, bloating and altered bowel habits. This condition affects an estimated 10-15% of the population worldwide and impacts heavily on a patient's daily life and ability to work, as well as healthcare resource utilization. Drug therapy aimed at correcting the primary symptoms of diarrhea/constipation/bloating may have little effect on abdominal pain, which results from visceral hypersensitivity. Smooth muscle relaxants or antispasmodics decrease the tone and contractility of intestinal smooth muscle, effectively managing abdominal pain. Otilonium bromide has been widely used worldwide and has been found to be safe and well tolerated, and superior to placebo for the reduction of symptoms and the prevention of symptom relapse in patients with irritable bowel syndrome.


HIPEC in T4a colon cancer: a defendable treatment to improve oncologic outcome?
Adequate estimation of the potential benefits of 'adjuvant' hyperthermia and intraperitoneal chemotherapy (HIPEC) in T4 patients through assessment of the burden of peritoneal carcinomatosis (PC) in T4 tumors and the risk of PC as the only metastatic site. Analysis of prospectively collected data on patients who underwent surgery for colon cancer (Jan 2004-Jan 2007). About 379 patients (M/F = 204/175) were included, with a median age of 71.8 years (range 35.4-95.0): 39 stage I, 126 stage II, 89 stage III, 116 stage IV disease (+9 with unknown stage). The median follow-up was 34.8months [range 0.0-79.4]. The 3- and 5-year overall survival rates (OS) were 68.4% (95% confidence interval (CI) 63.9%-72.4%) and 60.3% (95%CI 55.6%-64.7%). Relapse analysis was restricted to stages II-III T3 (N = 154) and T4 tumors (N = 19) with complete relapse data, of which 13.2% developed PC. PC has a detrimental effect on OS [HR 6.3 (95%CI: 3.1-13.0, P < 0.0001)]. 50% of T4a and 20% of T4b developed PC. The 1- and 3-year PC percentage was significantly lower for T3 (4.5% and 9.3%) than T4 tumors (15.6% and 36.7%) (P = 0.008). PC was the only metastatic site in 3/15 T3 [proportion 0.20, 95%CI (0.043-0.481)] and 5/8 T4 tumors with PC [proportion 0.625, 95%CI (0.245-0.915)] (P = 0.071). T4a colon tumors have a significantly higher risk of developing PC. Twenty-five percent (5/19) of stages II-III T4 tumors develop PC as the only metastatic site. This could define the possible window of opportunity for adjuvant HIPEC to prevent PC.


Distribution of language-related Cntnap2 protein in neural circuits critical for vocal learning.
Variants of the contactin associated protein-like 2 (Cntnap2) gene are risk factors for language-related disorders including autism spectrum disorder, specific language impairment, and stuttering. Songbirds are useful models for study of human speech disorders due to their shared capacity for vocal learning, which relies on similar cortico-basal ganglia circuitry and genetic factors. Here we investigate Cntnap2 protein expression in the brain of the zebra finch, a songbird species in which males, but not females, learn their courtship songs. We hypothesize that Cntnap2 has overlapping functions in vocal learning species, and expect to find protein expression in song-related areas of the zebra finch brain. We further expect that the distribution of this membrane-bound protein may not completely mirror its mRNA distribution due to the distinct subcellular localization of the two molecular species. We find that Cntnap2 protein is enriched in several song control regions relative to surrounding tissues, particularly within the adult male, but not female, robust nucleus of the arcopallium (RA), a cortical song control region analogous to human layer 5 primary motor cortex. The onset of this sexually dimorphic expression coincides with the onset of sensorimotor learning in developing males. Enrichment in male RA appears due to expression in projection neurons within the nucleus, as well as to additional expression in nerve terminals of cortical projections to RA from the lateral magnocellular nucleus of the nidopallium. Cntnap2 protein expression in zebra finch brain supports the hypothesis that this molecule affects neural connectivity critical for vocal learning across taxonomic classes.


A new nos gene downstream from nosDFY is essential for dissimilatory reduction of nitrous oxide by Rhizobium (Sinorhizobium) meliloti.
Rhizobium (Sinorhizobium) meliloti strains capable of dissimilatory nitrous oxide reduction (Nos+) carry a nosRZDFY gene cluster on a 10.1 kb EcoRI fragment of the nod megaplasmid near the fixGHIS genes. These nos genes are arranged in three complementation groups and the 10.1 kb EcoRI fragment is sufficient to confer Nos activity to R. meliloti strains lacking such activity. An overlapping HindIII fragment containing the nosRZDFY genes but missing a 0-6 kb HindIII-EcoRI downstream segment was found incapable of imparting Nos activity to strains unable to reduce nitrous oxide, suggesting the presence of other nos gene(s) in this region. Tn5 introduced near the HindIII site resulted in mutants with a Nos- phenotype. Complete sequence analysis of nosY showed that it was well-conserved with respect to that of Pseudomonas stutzeri. Two previously unreported genes downstream of nosY in R. meliloti were also revealed. Contiguous with nosY was a sequence showing 63% identity with the ORFL protein of P. stutzeri. It appeared to be in the same operon as nosDFY and was predicted to encode a membrane lipoprotein similar to the putative NosL of P. stutzeri. Unlike the latter protein, however, amino acid sequences typical of metal-binding sites and cysteine residues indicative of the active site of protein disulphide isomerase were absent in the predicted NosL of R. mellioti. The Tn5 mutations resulting in a Nos- phenotype were localized within a 966 nucleotide gene 31 nucleotides downstream of nosDFYL with the same orientation. The new gene, nosX, was determined to be in a separate complementation group. It encoded a periplasmic protein with homology in the C-terminal domain with Rnff of Rhodobacter capsulatus and with a hypothetical Escherichia coli protein, YOJK. It was concluded that there are seven genes constituting the nos cluster in R. meliloti. They are organized in four complementation groups and in the same orientation, spanning a distance of about 9 kb on the nod megaplasmid.


[Influence of food restriction on the biomechanical properties of the tibia in male rats of different age].
The changes of tibial bones biomechanical properties after 28 daily 40% declines of calorie content of feed and subsequent period of proceeding in a food ration were study in young and adult rats.28 day diminishing of calorie content of day's ration decline of bone mass, load capacity, stiffness, energy of elastic deformation of tibial bones. The indexes of biomechanics properties of bones were normalized after 28 daily period of proceeding in the ordinary ration of feed.