The association of autoimmune disorders with inflammatory bowel disease.
Medical records of patients with ulcerative colitis (n = 858), Crohn's disease (n = 378) and coeliac disease (n = 148) were examined to determine the prevalence of associated autoimmune disorders. Of outpatient controls (n = 300), 2 per cent had at least one autoimmune disorder, compared to 7 per cent with ulcerative colitis, 2 per cent with Crohn's disease and 6 per cent with coeliac disease. Inclusion of primary sclerosing cholangitis with the autoimmune disorders increased the overall prevalence in ulcerative colitis to over 9 per cent. The results provide further indirect evidence of involvement of autoimmune mechanisms in the pathogenesis of ulcerative colitis.


New insights into estrogenic regulation of O6-methylguanine DNA-methyltransferase (MGMT) in human breast cancer cells: Co-degradation of ER-α and MGMT proteins by fulvestrant or O6-benzylguanine indicates fresh avenues for therapy.
Endocrine therapy using estrogen receptor-α (ER-α) antagonists for attenuating horm2one-driven cell proliferation is a major treatment modality for breast cancers. To exploit any DNA repair deficiencies associated with endocrine therapy, we investigated the functional and physical interactions of ER-α with O6-methylguanine DNA methyltransferase (MGMT), a unique DNA repair protein that confers tumor resistance to various anticancer alkylating agents. The ER-α -positive breast cancer cell lines (MCF-7, T47D) and ER- negative cell lines (MDAMB-468, MDAMB-231), and established inhibitors of ER-α and MGMT, namely, ICI-182,780 (Faslodex) and O6-benzylguanine, respectively, were used to study MGMT- ER interactions. The MGMT gene promoter was found to harbor one full and two half estrogen-responsive elements (EREs) and two antioxidant-responsive elements (AREs). MGMT expression was upregulated by estrogen, downregulated by tamoxifen in Western blot and promoter-linked reporter assays. Similarly, both transient and stable transfections of Nrf-2 (nuclear factor-erythroid 2-related factor-2) increased the levels of MGMT protein and activity 3 to 4-fold reflecting novel regulatory nodes for this drug-resistance determinant. Of the different ER-α antagonists tested, the pure anti-estrogen fulvestrant was most potent in inhibiting the MGMT activity in a dose, time and ER-α dependent manner, similar to O6-benzylguanine. Interestingly, fulvestrant exposure led to a degradation of both ER-α and MGMT proteins and O6-benzylguanine also induced a specific loss of ER-α and MGMT proteins in MCF-7 and T47D breast cancer cells with similar kinetics. Immunoprecipitation revealed a specific association of ER-α and MGMT proteins in breast cancer cells. Furthermore, silencing of MGMT gene expression triggered a decrease in the levels of both MGMT and ER-α proteins. The involvement of proteasome in the drug-induced degradation of both proteins was also demonstrated. Fulvestrant enhanced the cytotoxicity of MGMT-targeted alkylating agents, namely, temozolomide and BCNU by 3 to 4-fold in ER-α positive cells, but not in ER-negative cells. We conclude that MGMT and ER-α proteins exist as a complex and are co-targeted for ubiquitin-conjugation and subsequent proteasomal degradation. The findings offer a clear rationale for combining alkylating agents with endocrine therapy.


Functional deficits of the attentional networks in autism.
Attentional dysfunction is among the most consistent observations of autism spectrum disorders (ASD). However, the neural nature of this deficit in ASD is still unclear. In this study, we aimed to identify the neurobehavioral correlates of attentional dysfunction in ASD. We used the Attention Network Test-Revised and functional magnetic resonance imaging to examine alerting, orienting, and executive control functions, as well as the neural substrates underlying these attentional functions in unmedicated, high-functioning adults with ASD (n = 12) and matched healthy controls (HC, n = 12). Compared with HC, individuals with ASD showed increased error rates in alerting and executive control, accompanied by lower activity in the mid-frontal gyrus and the caudate nucleus for alerting, and by the absence of significant functional activation in the anterior cingulate cortex (ACC) for executive control. In addition, greater behavioral deficiency in executive control in ASD was correlated with less functional activation of the ACC. These findings of behavioral and neural abnormalities in alerting and executive control of attention in ASD may suggest core attentional deficits, which require further investigation.


Wnt1 Boosts Fracture Healing by Enhancing Bone Formation in the Fracture Callus.
Despite considerable improvement in fracture care, 5%-10% of all fractures still heal poorly or result in nonunion formation. Therefore, there is an urgent need to identify new molecules that can be used to improve bone fracture healing. One activator of the Wnt-signaling cascade, Wnt1, has recently gained attention for its intense osteoanabolic effect on the intact skeleton. The aim of the present study was to investigate whether Wnt1 might be a promising molecule to accelerate fracture healing both in skeletally healthy and osteoporotic mice that display a diminished healing capacity. Transgenic mice for a temporary induction of Wnt1 specifically in osteoblasts (Wnt1-tg) were subjected to femur osteotomy. Non-ovariectomized and ovariectomized Wnt1-tg mice displayed significantly accelerated fracture healing based on a strong increase in bone formation in the fracture callus. Transcriptome profiling revealed that Hippo/yes1-associated transcriptional regulator (YAP)-signaling and bone morphogenetic protein (BMP) signaling pathways were highly enriched in the fracture callus of Wnt1-tg animals. Immunohistochemical staining confirmed increased activation of YAP1 and expression of BMP2 in osteoblasts in the fracture callus. Therefore, our data indicate that Wnt1 boosts bone formation during fracture healing via YAP/BMP signaling both under healthy and osteoporotic conditions. To further test a potential translational application of Wnt1, we applied recombinant Wnt1 embedded into a collagen gel during critical-size bone-defect repair. Mice treated with Wnt1 displayed increased bone regeneration compared to control mice accompanied by increased YAP1/BMP2 expression in the defect area. These findings are of high clinical relevance because they indicate that Wnt1 could be used as a new therapeutic agent to treat orthopedic complications in the clinic. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).


Is active sacroiliitis on MRI associated with radiographic damage in axial spondyloarthritis? Real-life data from the ASAS and DESIR cohorts.
To assess any association between bone marrow oedema on MRI of the sacroiliac joints (MRI-SIJ) according to local readings in daily practice and the development of structural damage on radiographs of the SIJ (X-SIJ) in axial spondyloarthritis (axSpA). Patients with axSpA from the Assessment of the SpondyloArthritis international Society (ASAS) and DEvenir des Spondylarthopathies Indifférenciées Récentes (DESIR) multicentre cohorts were included. MRI-SIJ and X-SIJ were obtained at baseline, and X-SIJ at follow-up after a mean 4.6 years (ASAS) and 5.1 years (DESIR). All images were scored by local readers. Structural damage in the X-SIJ was defined according to the modified New York criteria. The percentage of structural net progression (number of 'progressors' minus the number of 'regressors' divided by the total number of patients) was assessed and the effect of bone marrow oedema on MRI-SIJ on X-SIJ damage evaluated by multivariable logistic regression. In total, 125 (ASAS-cohort) and 415 (DESIR-cohort) patients had baseline MRI-SIJ and complete X-SIJ data available. According to local readings, progression and 'improvement' in X-SIJ was seen in both the ASAS- and DESIR-cohort, yielding a net progression that was higher in the former than in the latter (19.2% and 6.3%). In multivariable analysis, baseline bone marrow oedema on MRI-SIJ was strongly associated with X-SIJ structural progression in both ASAS (odds ratio = 3.2 [95% CI: 1.3; 7.9]), and DESIR (odds ratio = 7.6 [95% CI: 4.3; 13.2]). Inflammation on MRI-SIJ is associated with future radiographic progression according to local readings despite an expected increased imprecision invoked by local readings.


Affinity-based capture and identification of protein effectors of the growth regulator ppGpp.
The nucleotide ppGpp is a highly conserved regulatory molecule in bacteria that helps tune growth rate to nutrient availability. Despite decades of study, how ppGpp regulates growth remains poorly understood. Here, we developed and validated a capture-compound mass spectrometry approach that identified >50 putative ppGpp targets in Escherichia coli. These targets control many key cellular processes and include 13 enzymes required for nucleotide synthesis. We demonstrated that ppGpp inhibits the de novo synthesis of all purine nucleotides by directly targeting the enzyme PurF. By solving a structure of PurF bound to ppGpp, we designed a mutation that ablates ppGpp-based regulation, leading to dysregulation of purine-nucleotide synthesis following ppGpp accumulation. Collectively, our results provide new insights into ppGpp-based growth control and a nearly comprehensive set of targets for future exploration. The capture compounds developed should also enable the rapid identification of ppGpp targets in any species, including pathogens.


Event-level prediction of urban crime reveals a signature of enforcement bias in US cities.
Policing efforts to thwart crime typically rely on criminal infraction reports, which implicitly manifest a complex relationship between crime, policing and society. As a result, crime prediction and predictive policing have stirred controversy, with the latest artificial intelligence-based algorithms producing limited insight into the social system of crime. Here we show that, while predictive models may enhance state power through criminal surveillance, they also enable surveillance of the state by tracing systemic biases in crime enforcement. We introduce a stochastic inference algorithm that forecasts crime by learning spatio-temporal dependencies from event reports, with a mean area under the receiver operating characteristic curve of ~90% in Chicago for crimes predicted per week within ~1,000 ft. Such predictions enable us to study perturbations of crime patterns that suggest that the response to increased crime is biased by neighbourhood socio-economic status, draining policy resources from socio-economically disadvantaged areas, as demonstrated in eight major US cities.


Citizen science project reveals high diversity in Didymellaceae (Pleosporales, Dothideomycetes).
Fungal communities play a crucial role in maintaining the health of managed and natural soil environments, which directly or indirectly affect the properties of plants and other soil inhabitants. As part of a Citizen Science Project initiated by the Westerdijk Fungal Biodiversity Institute and the Utrecht University Museum, which aimed to describe novel fungal species from Dutch garden soil, the diversity of Didymellaceae, which is one of the largest families in the Dothideomycetes was investigated. A preliminary analysis of the ITS and LSU sequences from the obtained isolates allowed the identification of 148 strains belonging to the family. Based on a multi-locus phylogeny of a combined ITS, LSU, rpb2 and tub2 alignment, and morphological characteristics, 20 different species were identified in nine genera, namely Ascochyta, Calophoma, Didymella, Juxtiphoma, Nothophoma, Paraboeremia, Phomatodes, Stagonosporopsis, and Xenodidymella. Several isolates confirmed to be ubiquitous plant pathogens or endophytes were for the first time identified from soil, such as Ascochyta syringae, Calophoma clematidis-rectae, and Paraboeremia litseae. Furthermore, one new genus and 12 novel species were described from soil: Ascochyta benningiorum sp. nov., Didymella degraaffiae sp. nov., D. kooimaniorum sp. nov., Juxtiphoma kolkmaniorum sp. nov., Nothophoma brennandiae sp. nov., Paraboeremia rekkeri sp. nov., P. truiniorum sp. nov., Stagonosporopsis stuijvenbergii sp. nov., S. weymaniae sp. nov., Vandijckomycella joseae gen. nov. et sp. nov., V. snoekiae sp. nov., and Xenodidymella weymaniae sp. nov. From the results of this study, soil was revealed to be a rich substrate for members of Didymellaceae, several of which were previously known only from diseased or apparently healthy plant hosts.


Nanopore sequencing: Review of potential applications in functional genomics.
Molecular biology has been led by various measurement technologies, and increased throughput has developed omics analysis. The development of massively parallel sequencing technology has enabled access to fundamental molecular data and revealed genomic and transcriptomic signatures. Nanopore sequencers have driven such evolution to the next stage. Oxford Nanopore Technologies Inc. provides a new type of single molecule sequencer using protein nanopore that realizes direct sequencing without DNA synthesizing or amplification. This nanopore sequencer can sequence an ultra-long read limited by the input nucleotide length, or can determine DNA/RNA modifications. Recently, many fields such as medicine, epidemiology, ecology, and education have benefited from this technology. In this review, we explain the features and functions of the nanopore sequencer, introduce various situations where it has been used as a critical technology, and expected future applications.


Genetic variants in TNFα, TGFB1, PTGS1 and PTGS2 genes are associated with diisocyanate-induced asthma.
Diisocyanates are the most common cause of occupational asthma, but risk factors are not well defined. A case-control study was conducted to investigate whether genetic variants in inflammatory response genes (TNFα, IL1α, IL1β, IL1RN, IL10, TGFB1, ADAM33, ALOX-5, PTGS1, PTGS2 and NAG-1/GDF15) are associated with increased susceptibility to diisocyanate asthma (DA). These genes were selected based on their role in asthmatic inflammatory processes and previously reported associations with asthma phenotypes. The main study population consisted of 237 Caucasian French Canadians from among a larger sample of 280 diisocyanate-exposed workers in two groups: workers with specific inhalation challenge (SIC) confirmed DA (DA(+), n = 95) and asymptomatic exposed workers (AW, n = 142). Genotyping was performed on genomic DNA, using a 5' nuclease PCR assay. After adjusting for potentially confounding variables of age, smoking status and duration of exposure, the PTGS1 rs5788 and TGFB1 rs1800469 single nucleotide polymorphisms (SNP) showed a protective effect under a dominant model (OR = 0.38; 95% CI = 0.17, 0.89 and OR = 0.38; 95% CI = 0.18, 0.74, respectively) while the TNFα rs1800629 SNP was associated with an increased risk of DA (OR = 2.08; 95% CI = 1.03, 4.17). Additionally, the PTGS2 rs20417 variant showed an association with increased risk of DA in a recessive genetic model (OR = 6.40; 95% CI = 1.06, 38.75). These results suggest that genetic variations in TNFα, TGFB1, PTGS1 and PTGS2 genes contribute to DA susceptibility.


17β-Estradiol Regulates Microglia Activation and Polarization in the Hippocampus Following Global Cerebral Ischemia.
17β-Estradiol (E2) is a well-known neuroprotective hormone, but its role in regulation of neuroinflammation is less understood. Recently, our lab demonstrated that E2 could regulate the NLRP3 (NOD-like receptor protein 3) inflammasome pathway in the hippocampus following global cerebral ischemia (GCI). Here, we examined the ability of E2 to regulate activation and polarization of microglia phenotype in the hippocampus after global cerebral ischemia (GCI). Our in vivo study in young adult ovariectomized rats showed that exogenous low-dose E2 profoundly suppressed microglia activation and quantitatively shifted microglia from their "activated," amoeboid morphology to a "resting," ramified morphology after GCI. Further studies using M1 "proinflammatory" and M2 "anti-inflammatory" phenotype markers showed that E2 robustly suppressed the "proinflammatory" M1 phenotype, while enhancing the "anti-inflammatory" M2 microglia phenotype in the hippocampus after GCI. These effects of E2 may be mediated directly upon microglia, as E2 suppressed the M1 while enhancing the M2 microglia phenotype in LPS- (lipopolysaccharide-) activated BV2 microglia cells in vitro. E2 also correspondingly suppressed proinflammatory while enhancing anti-inflammatory cytokine gene expression in the LPS-treated BV2 microglia cells. Finally, E2 treatment abolished the LPS-induced neurotoxic effects of BV2 microglia cells upon hippocampal HT-22 neurons. Collectively, our study findings suggest a novel E2-mediated neuroprotective effect via regulation of microglia activation and promotion of the M2 "anti-inflammatory" phenotype in the brain.


Gender and laterality affect recurrences of acute anterior uveitis.
Acute anterior uveitis (AAU) associated with HLA-B27 or axial spondyloarthritis (axial SpA) is primarily unilateral and recurrent. We tested the hypotheses that disease laterality and gender affected recurrences of AAU. We studied 207 AAU subjects who were either HLA-B27 positive or had a verified history of axial SpA with documentation of the first uveitis episode. We recorded gender, laterality, duration, and time between episodes. Of 207 subjects, 126 (60.9%) had axial spondyloarthritis. Of the 179 with known HLA-B27 status, 174 (97.2%) were HLA-B27 positive. The initial episode of AAU occurred slightly more often in the right eye, 109 (52.6%), than in the left, 91 (44.0%) or bilaterally, 7 (3.4%), but the difference between right and left was not significant (p=0.23). Interestingly, 69.4% of subsequent episodes occurred in the same eye affected previously (95% CI 59.3%, 78.3%, p=0.0001). In subjects with recurrent AAU, the probability of being disease-free for one year was 38.9% (95% CI 29.1%, 52.0%) using Kaplan-Meier estimates. Univariate analyses showed that male gender (p=0.03) and AAU which recurred in the same eye (p=0.04) was associated with a shorter time interval between episodes. Multivariate analysis by the Cox proportional hazards model showed similar results. The initial episode of unilateral AAU associated with HLA-B27 or axial SpA randomly affects either eye. Subsequent episodes occur more often in the same eye previously affected. Male gender and history of unilateral AAU in the same eye are associated with a shortened time interval between relapses.


Potential of milk mid-IR spectra to predict metabolic status of cows through blood components and an innovative clustering approach.
Unbalanced metabolic status in the weeks after calving predisposes dairy cows to metabolic and infectious diseases. Blood glucose, IGF-I, non-esterified fatty acids (NEFA) and β-hydroxybutyrate (BHB) are used as indicators of the metabolic status of cows. This work aims to (1) evaluate the potential of milk mid-IR spectra to predict these blood components individually and (2) to evaluate the possibility of predicting the metabolic status of cows based on the clustering of these blood components. Blood samples were collected from 241 Holstein cows on six experimental farms, at days 14 and 35 after calving. Blood samples were analyzed by reference analysis and metabolic status was defined by k-means clustering (k=3) based on the four blood components. Milk mid-IR analyses were undertaken on different instruments and the spectra were harmonized into a common standardized format. Quantitative models predicting blood components were developed using partial least squares regression and discriminant models aiming to differentiate the metabolic status were developed with partial least squares discriminant analysis. Cross-validations were performed for both quantitative and discriminant models using four subsets randomly constituted. Blood glucose, IGF-I, NEFA and BHB were predicted with respective R 2 of calibration of 0.55, 0.69, 0.49 and 0.77, and R 2 of cross-validation of 0.44, 0.61, 0.39 and 0.70. Although these models were not able to provide precise quantitative values, they allow for screening of individual milk samples for high or low values. The clustering methodology led to the sharing out of the data set into three groups of cows representing healthy, moderately impacted and imbalanced metabolic status. The discriminant models allow to fairly classify the three groups, with a global percentage of correct classification up to 74%. When discriminating the cows with imbalanced metabolic status from cows with healthy and moderately impacted metabolic status, the models were able to distinguish imbalanced group with a global percentage of correct classification up to 92%. The performances were satisfactory considering the variables are not present in milk, and consequently predicted indirectly. This work showed the potential of milk mid-IR analysis to provide new metabolic status indicators based on individual blood components or a combination of these variables into a global status. Models have been developed within a standardized spectral format, and although robustness should preferably be improved with additional data integrating different geographic regions, diets and breeds, they constitute rapid, cost-effective and large-scale tools for management and breeding of dairy cows.


Molecular diagnosis of the myeloproliferative neoplasms: UK guidelines for the detection of JAK2 V617F and other relevant mutations.
Molecular genetic assays for the detection of the JAK2 V617F (c.1849G>T) and other pathogenetic mutations within JAK2 exon 12 and MPL exon 10 are part of the routine diagnostic workup for patients presenting with erythrocytosis, thrombocytosis or otherwise suspected to have a myeloproliferative neoplasm. A wide choice of techniques are available for the detection of these mutations, leading to potential difficulties for clinical laboratories in deciding upon the most appropriate assay, which can lead to problems with inter-laboratory standardization. Here, we discuss the most important issues for a clinical diagnostic laboratory in choosing a technique, particularly for detection of the JAK2 V617F mutation at diagnosis. The JAK2 V617F detection assay should be both specific and sensitive enough to detect a mutant allele burden as low as 1-3%. Indeed, the use of sensitive assays increases the detection rate of the JAK2 V617F mutation within myeloproliferative neoplasms. Given their diagnostic relevance, it is also beneficial and relatively straightforward to screen JAK2 V617F negative patients for JAK2 exon 12 mutations (in the case of erythrocytosis) or MPL exon 10 mutations (thrombocytosis or myelofibrosis) using appropriate assays. Molecular results should be considered in the context of clinical findings and other haematological or laboratory results.


Sucrose control of phytochrome A signaling in Arabidopsis.
The expression of the Arabidopsis plastocyanin (PC) gene is developmentally controlled and regulated by light. During seedling development, PC gene expression is transiently induced, and this induction can be repressed by sucrose. In transgenic seedlings carrying a PC promoter-luciferase fusion gene, the luciferase-induced in vivo luminescence was similarly repressed by sucrose. From a mutagenized population of such transgenic seedlings, we selected for mutant seedlings that displayed a high luminescence level when grown on a medium with 3% sucrose. This screening of mutants resulted in the isolation of several sucrose-uncoupled (sun) mutants showing reduced repression of luminescence by sucrose. Analysis of the sun mutants revealed that the accumulation of PC and chlorophyll a/b binding protein (CAB) mRNA was also sucrose uncoupled, although the extent of uncoupling varied. The effect of sucrose on far-red light high-irradiance responses was studied in wild-type, sun1, sun6, and sun7 seedlings. In wild-type seedlings, sucrose repressed the far-red light-induced cotyledon opening and inhibition of hypocotyl elongation. sun7 seedlings showed reduced repression of these responses. Sucrose also repressed the far-red light-induced block of greening in wild-type seedlings, and both sun6 and sun7 were affected in this response. The results provide evidence for a close interaction between sucrose and light signaling pathways. Moreover, the sun6 and sun7 mutants genetically identify separate branches of phytochrome A-dependent signal transduction pathways.


Lack of association between acellular pertussis vaccine and seizures in early childhood.
Receipt of diphtheria-tetanus-whole-cell pertussis vaccine (diphtheria-tetanus toxoids-pertussis [DTP]) is associated with seizures. Limited population-based studies have been conducted on the risk for seizures after receipt of diphtheria-tetanus-acellular pertussis vaccine (diphtheria-tetanus-acellular pertussis [DTaP]). We conducted a retrospective study from 1997-2006 by using risk-interval cohort and self-controlled case series (SCCS) analyses on automated data at 7 managed care organizations that participate in the Vaccine Safety Datalink (VSD). Eligible children included the 1997-2006 VSD cohort of patients who were aged 6 weeks to 23 months and had not received DTP during the study period. A seizure event (febrile or afebrile) was defined by International Classification of Diseases, Ninth Revision, Clinical Modification diagnoses assigned to an inpatient or emergency department setting. The exposed period was composed of a predefined 4 person-days after each DTaP dose. All of the remaining observation periods outside the exposed periods were categorized as unexposed. The risk-interval cohort method compared the incidence of seizures between the exposed and unexposed cohorts. In the SCCS method, the comparison was performed between the same patient's exposed and unexposed period. We identified 7191 seizure events among 433,654 children. The adjusted incidence rate ratio of seizures across all doses was 0.87 in cohort analysis and 0.91 in SCCS analysis. We did not observe an increased risk for seizures after DTaP vaccination among children who were aged 6 weeks to 23 months. These findings provide reassuring evidence on the safety of DTaP with respect to seizures.


TAPIR, a web server for the prediction of plant microRNA targets, including target mimics.
We present a new web server called TAPIR, designed for the prediction of plant microRNA targets. The server offers the possibility to search for plant miRNA targets using a fast and a precise algorithm. The precise option is much slower but guarantees to find less perfectly paired miRNA-target duplexes. Furthermore, the precise option allows the prediction of target mimics, which are characterized by a miRNA-target duplex having a large loop, making them undetectable by traditional tools. The TAPIR web server can be accessed at: http://bioinformatics.psb.ugent.be/webtools/tapir. Supplementary data are available at Bioinformatics online.


Hypaphorine from the ectomycorrhizal fungus Pisolithus tinctorius counteracts activities of indole-3-acetic acid and ethylene but not synthetic auxins in eucalypt seedlings.
Very little is known about the molecules regulating the interaction between plants and ectomycorrhizal fungi during root colonization. The role of fungal auxin in ectomycorrhiza has repeatedly been suggested and questioned, suggesting that, if fungal auxin controls some steps of colonized root development, its activity might be tightly controlled in time and in space by plant and/or fungal regulatory mechanisms. We demonstrate that fungal hypaphorine, the betaine of tryptophan, counteracts the activity of indole-3-acetic acid (IAA) on eucalypt tap root elongation but does not affect the activity of the IAA analogs 2,4-D ((2,4-dichlorophenoxy)acetic acid) or NAA (1-naphthaleneacetic acid). These data suggest that IAA and hypaphorine interact during the very early steps of the IAA perception or signal transduction pathway. Furthermore, while seedling treatment with 1-amincocyclopropane-1-carboxylic acid (ACC), the precursor of ethylene, results in formation of a hypocotyl apical hook, hypaphorine application as well as root colonization by Pisolithus tinctorius, a hypaphorine-accumulating ectomycorrhizal fungus, stimulated hook opening. Hypaphorine counteraction with ACC is likely a consequence of hypaphorine interaction with IAA. In most plant-microbe interactions studied, the interactions result in increased auxin synthesis or auxin accumulation in plant tissues. The P. tinctorius / eucalypt interaction is intriguing because in this interaction the microbe down-regulates the auxin activity in the host plant. Hypaphorine might be the first specific IAA antagonist identified.


Synopsis of Guidelines for the Clinical Management of Cerebral Cavernous Malformations: Consensus Recommendations Based on Systematic Literature Review by the Angioma Alliance Scientific Advisory Board Clinical Experts Panel.
Despite many publications about cerebral cavernous malformations (CCMs), controversy remains regarding diagnostic and management strategies. To develop guidelines for CCM management. The Angioma Alliance ( www.angioma.org ), the patient support group in the United States advocating on behalf of patients and research in CCM, convened a multidisciplinary writing group comprising expert CCM clinicians to help summarize the existing literature related to the clinical care of CCM, focusing on 5 topics: (1) epidemiology and natural history, (2) genetic testing and counseling, (3) diagnostic criteria and radiology standards, (4) neurosurgical considerations, and (5) neurological considerations. The group reviewed literature, rated evidence, developed recommendations, and established consensus, controversies, and knowledge gaps according to a prespecified protocol. Of 1270 publications published between January 1, 1983 and September 31, 2014, we selected 98 based on methodological criteria, and identified 38 additional recent or relevant publications. Topic authors used these publications to summarize current knowledge and arrive at 23 consensus management recommendations, which we rated by class (size of effect) and level (estimate of certainty) according to the American Heart Association/American Stroke Association criteria. No recommendation was level A (because of the absence of randomized controlled trials), 11 (48%) were level B, and 12 (52%) were level C. Recommendations were class I in 8 (35%), class II in 10 (43%), and class III in 5 (22%). Current evidence supports recommendations for the management of CCM, but their generally low levels and classes mandate further research to better inform clinical practice and update these recommendations. The complete recommendations document, including the criteria for selecting reference citations, a more detailed justification of the respective recommendations, and a summary of controversies and knowledge gaps, was similarly peer reviewed and is available on line www.angioma.org/CCMGuidelines .


Evaluation of Precision in Optoacoustic Tomography for Preclinical Imaging in Living Subjects.
Optoacoustic tomography (OT) is now widely used in preclinical imaging; however, the precision (repeatability and reproducibility) of OT has yet to be determined. Methods: We used a commercial small-animal OT system. Measurements in stable phantoms were used to independently assess the impact of system variables on precision (using coefficient of variation, COV), including acquisition wavelength, rotational position, and frame averaging. Variables due to animal handling and physiology, such as anatomic placement and anesthesia conditions, were then assessed in healthy nude mice using the left kidney and spleen as reference organs. Temporal variation was assessed by repeated measurements over hours and days both in phantoms and in vivo. Sensitivity to small-molecule dyes was determined in phantoms and in vivo; precision was assessed in vivo using IRDye800CW. Results: OT COV in a stable phantom was less than 2.8% across all wavelengths over 30 d. The factors with the greatest impact on signal repeatability in phantoms were rotational position and user experience, both of which still resulted in a COV of less than 4% at 700 nm. Anatomic region-of-interest size showed the highest variation, at 12% and 18% COV in the kidney and spleen, respectively; however, functional SO2 measurements based on a standard operating procedure showed an exceptional reproducibility of less than 4% COV. COV for repeated injections of IRDye800CW was 6.6%. Sources of variability for in vivo data included respiration rate, degree of user experience, and animal placement. Conclusion: Data acquired with our small-animal OT system were highly repeatable and reproducible across subjects and over time. Therefore, longitudinal OT studies may be performed with high confidence when our standard operating procedure is followed.


Oral health status and knowledge among 10-15years old type 1 diabetes mellitus children and adolescents in Bengaluru.
Type 1 diabetes mellitus (T1DM) is a chronic systemic metabolic disease. This disorder affects mainly children and adolescents. The main complications of diabetes mellitus affect the organs and tissues rich in capillary vessels such as kidney, retina, and nerves. These complications are secondary to the development of microangiopathy. Similar changes in small vessels can be found in the oral tissues. There is a significant increase in gingival inflammation and plaque seen in children with T1DM. The aim of this study is to assess the oral health status and knowledge among T1DM children and young adolescents aged 10-15 years in Bengaluru. One hundred and seventy-five 10-15 year-old children with T1DM and 175 age, sex, and socioeconomic status matched nondiabetic controls were included in the study. Oral health status was assessed using community periodontal Index and decayed/decayed-missing/missing-filled/filled teeth index (DMFT/dmft). Oral health knowledge was assessed using 11 item questionnaire. Chi-square test and Student's t-test were used in the statistical analysis. With regard to periodontal status, subjects with healthy periodontal tissue were less in diabetic than control group. Patients with bleeding and calculus were more in diabetic group than control group. The difference between diabetic group and control group was statistically significant (P = 0.001).The mean number of DMFT/dmft were less in diabetics (0.07 ± 0.006)/(0.26 ± 0.05) compared to control groups (0.1 ± 0.01)/(0.84 ± 0.2), respectively. Overall, oral health knowledge was more among diabetic patients (8.3 ± 1.7) compared to controls (7.5 ± 1.8). The results of the present study showed more gingival changes and higher oral health knowledge in diabetic group when compared to control group.


Dyspareunia in postmenopausal women: a critical review.
Dyspareunia, or pain during sexual intercourse, is among the problems most frequently reported by postmenopausal women. Past literature has almost unanimously attributed dyspareunic pain occurring during or after the menopausal transition to declining estrogen levels and vaginal atrophy. To critically review the literature on the prevalence, risk factors, etiology, clinical presentation and treatment of postmenopausal dyspareunia. The present review also examines the traditional and widely held conceptualization of postmenopausal dyspareunia as a direct symptom of hormonal decline. Searches of medical and psychological databases were performed for relevant articles and empirical studies. The methodological quality and outcomes of the studies were systematically reviewed. Available empirical evidence suggests that dyspareunia is common in postmenopausal women, and that it is not highly correlated with menopausal status, estrogen levels or vaginal atrophy. Decreasing levels of endogenous estrogen contribute to the development of dyspareunia in postmenopausal women suffering from vaginal atrophy. Hormonal supplementation is beneficial in alleviating their pain. However, a substantial proportion of treated women do not report relief. Postmenopausal dyspareunia occurring concurrently with vaginal atrophy is strongly associated with a lack of estrogen in the genital tract. However, a significant percentage of postmenopausal women experience dyspareunic pain that is not caused by hypoestrogenism. It is likely that other types of dyspareunia that occur premenopausally are also occurring in postmenopausal women. Research is needed to adequately address this issue. A change in perspective toward a multiaxial pain-focused approach is proposed for future research concerning dyspareunia in postmenopausal women.


Multiple myeloma: an immunoclinical study of disease and response to treatment.
Plasma cytokines and immune markers were assessed during the clinical management of 42 patients with multiple myeloma, MM. Of the patients 22/42 (all with progressive disease) were studied from the time of diagnosis, through various treatment regimes, to remission, progression or death. 5/42 patients had monoclonal gammopathy of undetermined significance (MGUS), 8/42 others had either indolent MM or stable MM, and a further 7/42 with progressive disease were also studied. IL-6, TNF-alpha, IL-1 alpha, IL-1 beta, beta 2 microglobulin (beta 2M), and neopterin were estimated in bloods taken under optimal conditions for cytokine detection. The levels were compared with a panel of samples from healthy volunteers. Both immunoreactive and biologically active plasma IL-6 levels were measured. Pretreatment IL-6 levels (both immunoreactive and biologically active) were found to correlate with severity of disease. In 13/22 patients with progressive disease who had been followed from the time of diagnosis over a 12-month period or until death, pretreatment IL-6 levels were predictive of response to therapy. Elevated plasma levels of TNF-alpha, beta 2M and neopterin were found in patients with progressive multiple myeloma, and this correlated with renal impairment. The analytes measured during the course of chemotherapy did not show correlation with disease progression or response to therapy.


Active-passive mode-locked Nd:YAG laser with passive negative feedback.
Stationary ultrashort light pulses of 10-psec duration and with an energy of 10 microJ per pulse were obtained from an active-passive mode-locked Nd:YAG laser by using a two-photon absorption limiter (GaAs) inserted into the resonator. The stability of energy in the steady-state part of the pulse train, containing approximately 90 pulses, is better than +/-1.5%. The dynamics of the pulse-shortening mechanism are described, and it is shown that maximum pulse compression is reached after only approximately 10 round trips.


Implementation of effective practices in health facilities: a systematic review of cluster randomised trials.
The capacity for health systems to support the translation of research in to clinical practice may be limited. The cluster randomised controlled trial (cluster RCT) design is often employed in evaluating the effectiveness of implementation of evidence-based practices. We aimed to systematically review available evidence to identify and evaluate the components in the implementation process at the facility level using cluster RCT designs. All cluster RCTs where the healthcare facility was the unit of randomisation, published or written from 1990 to 2014, were assessed. Included studies were analysed for the components of implementation interventions employed in each. Through iterative mapping and analysis, we synthesised a master list of components used and summarised the effects of different combinations of interventions on practices. Forty-six studies met the inclusion criteria and covered the specialty groups of obstetrics and gynaecology (n=9), paediatrics and neonatology (n=4), intensive care (n=4), internal medicine (n=20), and anaesthetics and surgery (n=3). Six studies included interventions that were delivered across specialties. Nine components of multifaceted implementation interventions were identified: leadership, barrier identification, tailoring to the context, patient involvement, communication, education, supportive supervision, provision of resources, and audit and feedback. The four main components that were most commonly used were education (n=42, 91%), audit and feedback (n=26, 57%), provision of resources (n=23, 50%) and leadership (n=21, 46%). Future implementation research should focus on better reporting of multifaceted approaches, incorporating sets of components that facilitate the translation of research into practice, and should employ rigorous monitoring and evaluation.


Hole-transporting small molecules based on thiophene cores for high efficiency perovskite solar cells.
Two new electron-rich molecules, 2,3,4,5-tetra[4,4'-bis(methoxyphenyl)aminophen-4"-yl]-thiophene (H111) and 4,4',5,5'-tetra[4,4'-bis(methoxyphenyl)aminophen-4"-yl]-2,2'-bithiophene (H112), which contain thiophene cores with arylamine side groups, are reported. When used as the hole-transporting material (HTM) in perovskite-based solar cell devices, power conversion efficiencies of up to 15.4% under AM 1.5G solar simulation were obtained. This is the highest efficiency achieved with HTMs not composed of 2,2',7,7'-tetrakis(N,N'-di-p-methoxyphenylamine)-9,9'-spirobifluorene (spiro-OMeTAD) and its isomers. Both HTMs, especially H111, have great potential to replace expensive spiro-OMeTAD given their much simpler and less expensive syntheses.


Urinary metabolites of [1,2,3-13C]acrylonitrile in rats and mice detected by 13C nuclear magnetic resonance spectroscopy.
Acrylonitrile, a carcinogen in rats, undergoes extensive metabolism via two routes: direct glutathione conjugation or epoxidation. Metabolism to cyanoethylene oxide may mediate the carcinogenic and toxic activity of acrylonitrile. To characterize comprehensively the metabolism in vivo of acrylonitrile, the detection and identification of metabolites in urine of rodents dosed with acrylonitrile have been carried out using NMR spectroscopy. Following administration of [1,2,3-13C]acrylonitrile to male Fisher 344 rats (10 or 30 mg/kg, po) or B6C3F1 mice (10 mg/kg, po), urine samples were collected for 24 h. Carbon-13 NMR spectra were acquired directly on the urine samples after centrifugation and addition of 10-25% D2O. Resonances were assigned to carbons of acrylonitrile metabolites on the basis of chemical shift, proton multiplicity, carbon-carbon coupling, and calculated values of shift, and by comparison with standards. The proton multiplicity of each carbon was determined by heteronuclear 2D J-resolved spectroscopy (HET2DJ), and the carbon-carbon connectivities of resonances were determined using incredible natural abundance double quantum transfer spectroscopy (INADEQUATE). The metabolites identified in rat urine were thiocyanate, N-acetyl-S-(2-cyanoethyl)cysteine, N-acetyl-S-(2-hydroxyethyl)cysteine, N-acetyl-S-(1-cyano-2-hydroxyethyl)cysteine, thiodiglycolic acid, thionyldiacetic acid, and S-(carboxymethyl)cysteine or its N-acetyl derivative. These metabolites were also identified in mouse urine. Metabolites were quantitated by integrating metabolite carbon resonances with respect to that of dioxane added at a known concentration. Thiodiglycolic acid and (carboxymethyl)cysteine (or its N-acetyl derivative) were the major metabolites in the mouse, while N-acetyl-S-(2-cyanoethyl)cysteine and N-acetyl-S-(2-hydroxyethyl)cysteine were the major metabolites in the rat. Metabolites derived from cyanoethylene oxide (CEO) accounted for approximately 60% of the products excreted in rat urine, compared with 80% in the urine from mice. Differences between rat and mouse in the further metabolism of CEO were also observed. The proportion of the dose metabolized via CEO may be an important determinant of the toxicity and carcinogenicity of acrylonitrile.


Bond strength of two resin cements to titanium after different surface conditioning methods.
This study evaluated the bond strength of two resin cements (Panavia F and Super Bond) to titanium after various surface conditioning techniques. The cements were applied using polyethylene tubes. After thermocycling, the specimens were tested in a universal testing machine for shear bond strength. Panavia F demonstrated significantly higher bond strength values than Super Bond. Of the conditioning techniques, Al2O3+Silane+Sinfony and Silano Pen+AP demonstrated significantly lower bond strength values than Al2O3+Cesead II Opaque Primer and 110 µm SiOx+Silane. The combination of Panavia and 110 µm SiOx+Silane, Al2O3+AP, or Al2O3+Cesead II, and the combination of Super Bond and 110 µm SiOx+Silane or Al2O3+Cesead II, can be recommended for improving the bond strength of resin cement to titanium.


Projected cancer risks from computed tomographic scans performed in the United States in 2007.
The use of computed tomographic (CT) scans in the United States (US) has increased more than 3-fold since 1993 to approximately 70 million scans annually. Despite the great medical benefits, there is concern about the potential radiation-related cancer risk. We conducted detailed estimates of the future cancer risks from current CT scan use in the US according to age, sex, and scan type. Risk models based on the National Research Council's "Biological Effects of Ionizing Radiation" report and organ-specific radiation doses derived from a national survey were used to estimate age-specific cancer risks for each scan type. These models were combined with age- and sex-specific scan frequencies for the US in 2007 obtained from survey and insurance claims data. We estimated the mean number of radiation-related incident cancers with 95% uncertainty limits (UL) using Monte Carlo simulations. Overall, we estimated that approximately 29 000 (95% UL, 15 000-45 000) future cancers could be related to CT scans performed in the US in 2007. The largest contributions were from scans of the abdomen and pelvis (n = 14 000) (95% UL, 6900-25 000), chest (n = 4100) (95% UL, 1900-8100), and head (n = 4000) (95% UL, 1100-8700), as well as from chest CT angiography (n = 2700) (95% UL, 1300-5000). One-third of the projected cancers were due to scans performed at the ages of 35 to 54 years compared with 15% due to scans performed at ages younger than 18 years, and 66% were in females. These detailed estimates highlight several areas of CT scan use that make large contributions to the total cancer risk, including several scan types and age groups with a high frequency of use or scans involving relatively high doses, in which risk-reduction efforts may be warranted.


A randomized trial of a program to reduce the use of psychoactive drugs in nursing homes.
Although psychoactive medications have substantial side effects in the elderly, these drugs are used frequently in nursing homes. Few interventions have succeeded in changing this situation, and little is known about the clinical effects of such interventions. We studied six matched pairs of nursing homes; at one randomly selected nursing home in each pair, physicians, nurses, and aides participated in an educational program in geriatric psychopharmacology. At base line we determined the type and quantity of drugs received by all residents (n = 823), and a blinded observer performed standardized clinical assessments of the residents who were taking psychoactive medications. After the five-month program, drug use and patient status were reassessed. Scores on an index of psychoactive-drug use, measuring both the magnitude and the probable inappropriateness of medication use, declined significantly more in the nursing homes in which the program was carried out (experimental nursing homes) than in the control nursing homes (decrease, 27 percent vs. 8 percent; P = 0.02). The use of antipsychotic drugs was discontinued in more residents in the experimental nursing homes than in the control nursing homes (32 percent vs. 14 percent); the comparable figures for the discontinuation of long-acting benzodiazepines were 20 percent vs. 9 percent, and for antihistamine hypnotics, 45 percent vs. 21 percent. In the experimental nursing homes residents who were initially taking antipsychotic drugs showed less deterioration on several measures of cognitive function than similar residents in the control facilities, but they were more likely to report depression. Those who were initially taking benzodiazepines or antihistamine hypnotic agents reported less anxiety than controls but had more loss of memory. Most other measures of clinical status remained unchanged in both groups. An educational program targeted to physicians, nurses, and aides can reduce the use of psychoactive drugs in nursing homes without adversely affecting the overall behavior and level of functioning of the residents.


Visual Acuity Outcomes after Anti-Vascular Endothelial Growth Factor Treatment for Neovascular Age-Related Macular Degeneration: Age-Related Eye Disease Study 2 Report Number 19.
To analyze best-corrected visual acuity (BCVA) outcomes after anti-vascular endothelial growth factor (VEGF) treatment for neovascular age-related macular degeneration (AMD). Prospective cohort study of participants enrolled in a clinical trial of oral supplements and receiving anti-VEGF therapy in routine clinical practice. Age-Related Eye Disease Study 2 (AREDS2) participants (50-85 years of age) whose eyes met AREDS2 inclusion criteria at baseline (no late AMD, BCVA ≥20/100, no previous anti-VEGF injections) but received at least 1 anti-VEGF injection for incident neovascular AMD during follow-up. Participants underwent refracted BCVA testing, ophthalmoscopic examination, and stereoscopic color fundus photography at baseline and annual study visits over 5 years. Self-reports of anti-VEGF injections (numbers, dates, and names of drug) were collected at baseline and annual study visits and during telephone calls every 6 months. Primary outcome measures were mean refracted BCVA and proportions of eyes with BCVA of 20/40 or better and 20/200 or worse. An exploratory outcome measure was the mean number of self-reported anti-VEGF injections. One thousand one hundred five eyes of 986 AREDS2 participants met the inclusion criteria; of these, 977 participants (99.1%) underwent at least 1 posttreatment visit. At the first and subsequent annual examinations after the first injection, mean refracted BCVAs were 68.0 letters (Snellen equivalent, 20/40), 66.1 letters, 64.7 letters, 63.2 letters, and 61.5 letters (Snellen equivalent, 20/60). Proportions of eyes with BCVA of 20/40 or better were 59.3%, 55.1%, 53.5%, 50.6%, and 49.7%, and those with BCVA of 20/200 or worse were 5.5%, 8.6%, 9.4%, 12.4%, and 14.4%. Mean annual numbers of self-reported anti-VEGF injections per eye were 2.9, 3.9, 3.3, 3.1, and 3.0. Refracted BCVA data were obtained in a clinical trial environment but were related to anti-VEGF treatment administered in normal clinical practice. Visual outcomes declined slowly with increased follow-up time: mean BCVA decreased by approximately 1.5 to 2 letters per year. At 5 years, half of eyes achieved BCVA of 20/40 or better, but approximately one sixth showed BCVA of 20/200 or worse. These data may be useful in assessing the long-term effects of anti-VEGF therapy.


Preference for concentric orientations in the mouse superior colliculus.
The superior colliculus is a layered structure important for body- and gaze-orienting responses. Its superficial layer is, next to the lateral geniculate nucleus, the second major target of retinal ganglion axons and is retinotopically organized. Here we show that in the mouse there is also a precise organization of orientation preference. In columns perpendicular to the tectal surface, neurons respond to the same visual location and prefer gratings of the same orientation. Calcium imaging and extracellular recording revealed that the preferred grating varies with retinotopic location, and is oriented parallel to the concentric circle around the centre of vision through the receptive field. This implies that not all orientations are equally represented across the visual field. This makes the superior colliculus different from visual cortex and unsuitable for translation-invariant object recognition and suggests that visual stimuli might have different behavioural consequences depending on their retinotopic location.


Body piercings and posttraumatic stress disorder symptoms in young adults.
Body piercing, which is prevalent in young adults, has been suggested to be associated with features usually related to posttraumatic stress disorder (PTSD) such as high-risk behaviours and psychopathological symptoms and might be motivated by a wish to deal with prior traumatic experiences. However, to date, no research has investigated the relationship between this practice and PTSD symptoms. The present research aims to investigate the possible relationship between body piercing and PTSD symptoms in French-speaking young adults. According to our results, having two or more body piercings was associated with a twofold increased risk for scoring above the cut-off score for PTSD on the PTSD checklist. Our findings suggest that two or more body piercings might serve as an identifiable marker for PTSD symptoms and may have important implications for clinical screening.


Chromatin insulator elements block transgene silencing in engineered human embryonic stem cell lines at a defined chromosome 13 locus.
Lineage reporters of human embryonic stem cell (hESC) lines are useful for differentiation studies and drug screening. Previously, we created reporter lines driven by an elongation factor 1 alpha (EF1α) promoter at a chromosome 13q32.3 locus in the hESC line WA09 and an abnormal hESC line BG01V in a site-specific manner. Expression of reporters in these lines was maintained in long-term culture at undifferentiated state. However, when these cells were differentiated into specific lineages, reduction in reporter expression was observed, indicating transgene silencing. To develop an efficient and reliable genetic engineering strategy in hESCs, we used chromatin insulator elements to flank single-copy transgenes and integrated the combined expression constructs via PhiC31/R4 integrase-mediated recombination technology to the chromosome 13 locus precisely. Two copies of cHS4 double-insulator sequences were placed adjacent to both 5' and 3' of the promoter reporter constructs. The green fluorescent protein (GFP) gene was driven by EF1α or CMV early enhancer/chicken β actin (CAG) promoter. In the engineered hESC lines, for both insulated CAG-GFP and EF1α-GFP, constitutive expression at the chromosome 13 locus was maintained during prolonged culture and in directed differentiation assays toward diverse types of neurons, pancreatic endoderm, and mesodermal progeny. In particular, described here is the first normal hESC fluorescent reporter line that robustly expresses GFP in both the undifferentiated state and throughout dopaminergic lineage differentiation. The dual strategy of utilizing insulator sequences and integration at the constitutive chromosome 13 locus ensures appropriate transgene expression. This is a valuable tool for lineage development study, gain- and loss-of-function experiments, and human disease modeling using hESCs.


Mechanotransduction of the endothelial glycocalyx mediates nitric oxide production through activation of TRP channels.
The endothelial surface glycocalyx (ESG) is a carbohydrate-rich layer found on the vascular endothelium, serving critical functions in the mechanotransduction of blood flow-induced forces. One of the most important protective functions of the ESG is to mediate the production of nitric oxide (NO) in response to blood flow. However, the detailed mechanism underlying ESG's mechanotransduction of the production of NO has not been completely identified. Herein, using the cultured rat brain microvascular endothelial cells (bEnd.3) as a model system, we have implemented a combined atomic force and fluorescence microscopy approach to show that the ESG senses and transduces vertical mechanical stretch to produce NO. This rapid NO production is dependent on the presence of both heparan sulfate (HS) and hyaluronic acid (HA) in ESG, as the removal of HS and/or HA leads to a significant decrease in NO production. Moreover, the production of NO is dependent on the intake of Ca2+ via endothelial transient receptor potential (TRP) channels. Together, our results demonstrate the molecular mechanism of rapid production of NO in response to vertical mechanical stretch.


Effectiveness of a clinically integrated e-learning course in evidence-based medicine for reproductive health training: a randomized trial.
For evidence-based practice to embed culturally in the workplace, teaching of evidence-based medicine (EBM) should be clinically integrated. In low-middle-income countries (LMICs) there is a scarcity of EBM-trained clinical tutors, lack of protected time for teaching EBM, and poor access to relevant databases in languages other than English. To evaluate the effects of a clinically integrated e-learning EBM course incorporating the World Health Organization (WHO) Reproductive Health Library (RHL) on knowledge, skills, and educational environment compared with traditional EBM teaching. International cluster randomized trial conducted between April 2009 and November 2010 among postgraduate trainees in obstetrics-gynecology in 7 LMICs (Argentina, Brazil, Democratic Republic of the Congo, India, Philippines, South Africa, Thailand). Each training unit was randomized to an experimental clinically integrated course consisting of e-modules using the RHL for learning activities and trainee assessments (31 clusters, 123 participants) or to a control self-directed EBM course incorporating the RHL (29 clusters, 81 participants). A facilitator with EBM teaching experience was available at all teaching units. Courses were administered for 8 weeks, with assessments at baseline and 4 weeks after course completion. The study was completed in 24 experimental clusters (98 participants) and 22 control clusters (68 participants). Primary outcomes were change in EBM knowledge (score range, 0-62) and skills (score range, 0-14). Secondary outcome was educational environment (5-point Likert scale anchored between 1 [strongly agree] and 5 [strongly disagree]). At baseline, the study groups were similar in age, year of training, and EBM-related attitudes and knowledge. After the trial, the experimental group had higher mean scores in knowledge (38.1 [95% CI, 36.7 to 39.4] in the control group vs 43.1 [95% CI, 42.0 to 44.1] in the experimental group; adjusted difference, 4.9 [95% CI, 2.9 to 6.8]; P < .001) and skills (8.3 [95% CI, 7.9 to 8.7] vs 9.1 [95% CI, 8.7 to 9.4]; adjusted difference, 0.7 [95% CI, 0.1 to 1.3]; P = .02). Although there was no difference in improvement for the overall score for educational environment (6.0 [95% CI, -0.1 to 12.0] vs 13.6 [95% CI, 8.0 to 19.2]; adjusted difference, 9.6 [95% CI, -6.8 to 26.1]; P = .25), there was an associated mean improvement in the domains of general relationships and support (-0.5 [95% CI, -1.5 to 0.4] vs 0.3 [95% CI, -0.6 to 1.1]; adjusted difference, 2.3 [95% CI, 0.2 to 4.3]; P = .03) and EBM application opportunities (0.5 [95% CI, -0.7 to 1.8] vs 2.9 [95%, CI, 1.8 to 4.1]; adjusted difference, 3.3 [95% CI, 0.1 to 6.5]; P = .04). In a group of LMICs, a clinically integrated e-learning EBM curriculum in reproductive health compared with a self-directed EBM course resulted in higher knowledge and skill scores and improved educational environment. anzctr.org.au Identifier: ACTRN12609000198224.


Non-Contact Assessment of Peripheral Artery Haemodynamics Using Infrared Video Thermography.
Skin temperature has long been used as a natural indicator of vascular diseases in the extremities. Considerable correlation between oscillations in skin surface temperature and oscillations of skin blood flow has previously been demonstrated. We hypothesised that the impairment of blood flow in stenotic (subcutaneous) peripheral arteries would influence cutaneous temperature such that, by measuring gradients in the temperature distribution over skin surfaces, one may be able to diagnose or quantify the progression of vascular conditions in whose pathogenesis a reduction in subcutaneous blood perfusion plays a critical role (e.g. peripheral artery disease). As proof of principle, this study investigates the local changes in the skin temperature of healthy humans (15 male, [Formula: see text] years old, BMI [Formula: see text] kg/m 2) undergoing two physical challenges designed to vary their haemodynamic status. Skin temperature was measured in four central regions (forehead, neck, chest, and left shoulder) and four peripheral regions (left upper arm, forearm, wrist, and hand) using an infrared thermal camera. We compare inter-region patterns. Median temperature over the peripheral regions decreased from baseline after both challenges (maximum decrease: [Formula: see text] °C at 60 s after exercise; [Formula: see text] and [Formula: see text] °C at 180 s of cold-water immersion; [Formula: see text]). Median temperature over the central regions showed no significant changes. Our results show that the non-contact measurement of perfusion-related changes in peripheral temperature from infrared video data is feasible. Further research will be directed towards the thermographic study of patients with symptomatic peripheral vascular disease.


Prevalence of muscle-strengthening activities in women: the WIN study.
Aerobic and muscle-strengthening activities are related to morbidities and mortality. Resistance exercise/strength training items are included in national surveys, but the manner in which muscle-strengthening activity is queried varies among these surveys. The purpose of this study was to use different self-report measures to examine the prevalence of meeting the 2008 Physical Activity Guidelines for Americans regarding muscle-strengthening activities among women. We surveyed 606 community-dwelling women at 4 points in time across a 1.5- to 3-year time period to determine whether the respondents met the national physical activity guidelines for performing muscle-strengthening activities ≥ 2 days per week. Results were consistent across time but depended on the manner in which the question was asked. If asked to reflect over the past month or a general question about the typical number of days engaged, approximately 40% of women reported engaging in ≥ 2 days per week of resistance exercise/strength training. However, when reports were obtained weekly for 13 weeks, only approximately 18% of respondents met the guidelines. Results indicate that the timing and nature of questioning can substantially influence the self-reported prevalence of muscle-strengthening physical activities for community-dwelling women.


Graded zirconia glass for resistance to veneer fracture.
Failures of zirconia-based all-ceramic restorations appear to be predominantly chips and fractures in the porcelain veneer, from occlusally induced sliding contact damage. We hypothesized that such failure may be substantially mitigated by controlled grading of the elastic modulus at the ceramic surface. In this study, we fabricated graded structures by infiltrating glass into zirconia plates, resulting in improved aesthetics and diminished modulus at the surfaces. Individual plates were then embedded in epoxy or cemented to dental composites and subjected to single- or multi-cycle sliding contact. Plates of porcelain-veneered zirconia and monolithic zirconia served as controls. Graded zirconia-glass structures exhibited over 3 times better resistance to single-cycle sliding damage than monolithic zirconia and 25 times better than veneered zirconia, and had a fatigue sliding damage resistance comparable with that of monolithic zirconia. These zirconia-glass materials can be engineered in shades from white to yellow, and have potentially better cementation properties than homogeneous zirconia.


Hypothalamic inferior lobe and lateral torus connections in a percomorph teleost, the red cichlid (Hemichromis lifalili).
The neuroanatomic connections of the inferior lobe and the lateral torus of the percomorph Hemichromis lifalili were investigated by 1,1', dioctadecyl-3,3,3',3'-tetramethylindo-carbocyanine perchlorate (DiI) tracing. The inferior lobe and the lateral torus both receive afferents from the secondary gustatory nucleus. Additional afferents reach the inferior lobe from the nucleus glomerulosus, nucleus suprachiasmaticus, dorsal and central posterior thalamic nucleus, nucleus lateralis valvulae, magnocellular part of the magnocellular nucleus of the preoptic region, caudal nucleus of the preglomerular region, posterior tuberal nucleus, area dorsalis of the telencephalon, and a tegmental nucleus (T2). Efferents from the inferior lobe and the lateral torus terminate in the dorsal hypothalamic neuropil and corpus mamillare. Furthermore, the inferior lobe projects to the medial nucleus of the lateral tuberal hypothalamus and perhaps makes axo-axonal synapses in the tractus tectobulbaris rectus. The inferior lobe and the torus lateralis have reciprocal connections with the preglomerular tertiary gustatory nucleus and posterior thalamic nucleus and are also mutually interconnected. The inferior lobe is also reciprocally connected with the medial nucleus of the preglomerular region, reticular formation and sparsely with the anterior dorsal thalamic and the ventromedial thalamic nuclei. Thus, whereas the lateral torus is exclusively connected with the gustatory system, the inferior lobe is of a multisensory nature. In comparison with the goldfish (Carassius auratus), the connectivity pattern of the inferior lobe of Hemichromis lifalili reflects its specialization with respect to the visual system, as it receives qualitative (i.e., dorsal posterior, anterior, and ventromedial thalamic nuclei) as well as quantitative (i.e., nucleus glomerulosus) additional visual input.


[Evaluation of good manufacturing practices in the elaboration of enteral formulas in public hospitals of Santiago (Chile)].
The development of enteral formulas (FE) is subject to various risks of contamination. The World Health Organization (WHO) and the Food and Agriculture Organization (FAO), have worried about alerting, recommendations and documents released to prevent contamination the FE, suggesting the standardization and protocols for all procedures involved. The study was aimed to evaluate compliance with the technical criteria contained in a Guideline for Good Practice of Manufacture in relation to the development, maintenance and administration of enteral nutrition in hospitals of Santiago, in the Metropolitan Area. The verification criteria considered Physical Plant, Equipment and Implementation, Hygienic and Sanitary Standards, Human Resources, Organization and Management, Safety and Warranty Quality Assurance. 639 criteria were defined, 309 risk Type 1, by mayor risk of producing pollution. The study was conducted by observing Central Units Enteral Formulas and interview with the caregiver. Medium of compliance for each group of criteria risk 1 and overall, was analyzed. A total of 14 public hospitals were studied. The degree of compliance with the 639 reached a median of 33.2% (p25-75 31.6%-40.4%), with the lowest value for physical plant with 27.9% (p25-75 23.9%-38.2%) and the highest for human resources with 52.4% (p25-75 44.1%-52.4%). Median compliance for risk criteria Type 1 was only 31.8% (p25-75 27.5%-41.2%). Most of the units tested, meets less than half of the internationals recommendations, or the Ministry of Health of Chile. It should develop protocols and train staff to ensure quality and safety in the development of enteral formulas and reduce risk of infection.


Death as an event: a commentary on Robert Morison.
1) We have no need to abandon either the concept of death as an event or the efforts to set forth reasonable criteria for determining that a man has indeed died. 2) We need to recover both an attitude that is more accepting of death and a greater concern for the human needs of the dying patient. But we should not contaminate these concerns with the interests of relatives, potential transplant recipients, or "society." To do so would be both wrong and dangerous. 3) We should pause to note some of the heavy costs of technological progress in medicine: the dehumanization of the end of life, both for those who die and for those who live on; and the befogging of the minds of intelligent and moral men with respect to the most important human matters.


Heat strain and gross efficiency during endurance exercise after lower, upper, or whole body precooling in the heat.
The maximal power that muscles can generate is reduced at low muscle temperatures. However, in prolonged heavy exercise in the heat, a high core temperature may be the factor limiting performance. Precooling has been shown to delay the attainment of hyperthermia. It is still unclear if the whole body should be cooled or if the active muscles should be excluded from cooling in order to maintain muscle power. An experiment was performed to compare thermal strain and gross efficiency following whole body or partial body cooling. Eight well-trained participants performed 40 min of 60% VO2max cycling exercise in a 30 degrees C, 70% relative humidity climatic chamber after four different precooling sessions in a water perfused suit: N (no precooling), CC (45 min whole body precooling), WC (45 min lower body precooling), and CW (45 min upper body precooling). The uncooled body part was warmed in such a way that the core temperature did not differ from that in session N. Gross efficiency was used to compare performance between the sessions since it indicates how much oxygen is needed for a certain external load. The gross efficiency did not differ significantly between the sessions. Differences in heat loss and heat storage were observed during the first 20 min of exercise. The evaporative heat loss in session WC (305 +/- 67 W) and CW (284 +/- 68 W) differed from session N (398 +/- 77 W) and CC (209 +/- 58 W). More heat was stored in session CC (442 +/- 125 W) than in sessions WC (316 +/- 39 W), CW (307 +/- 63 W), and N (221 +/- 65 W). It was confirmed that precooling reduces heat strain during exercise in the heat. No differences in heat strain and gross efficiency were observed between precooling of the body part with the exercising muscles and precooling of the tissues elsewhere in the body.


Postexposure prophylaxis for common infectious diseases.
Postexposure prophylaxis (PEP) is effective in preventing illness after potential or documented exposure to a variety of microbial pathogens and in reducing the risk of secondary spread of infection. Guidelines have been published by the Centers for Disease Control and Prevention and the Advisory Committee on Immunization Practices for proper use of PEP for bloodborne pathogens, for microorganisms transmitted by either airborne or droplet spread or through direct contact, and for infections acquired after traumatic injuries. Depending on the type of exposure, different forms of PEP are available, including vaccines, immune globulins, antibiotics, and antiviral medications. Physicians should assess a patient's potential need for PEP based on several factors, including the type of exposure, the timing and severity of illness in the source patient, the exposed person's susceptibility to infectious diseases of concern, and the relative risks and benefits of the PEP regimen in an individual situation. Immunity to certain infectious diseases can be ensured with prior infection or vaccination, and by serologic testing in patients with a negative or uncertain history. PEP should be given to persons exposed to index cases of pertussis and invasive meningococcal infection regardless of immunization history, and should be given following rabies and tetanus exposure regardless of the length of delay. In general, PEP should be given as soon as possible following a high-risk exposure. Persons exposed to bloodborne pathogens should have baseline testing for human immunodeficiency virus, hepatitis B virus, and hepatitis C virus antibodies, and follow-up testing at six weeks, three months, and six months postexposure.


Canadian home care policy and practice in rural and remote settings: challenges and solutions.
With the aging of the population, especially in Canadian rural areas, providing home care services will be particularly challenging as care is needed by increasingly vulnerable rural older adults in increasingly vulnerable rural settings with fewer services, supports, and caregivers. The purpose of this paper is to present examples of the federal (e.g., First Nations and Inuit Home and Community Care) and provincial (e.g., Ontario's Community Care Access Centres) home care policy context in which Canadian home care is provided, to identify the challenges faced by home care providers in meeting the needs of rural residents, and to offer solutions to these challenges. The most pressing challenges in aging rural settings are to ensure effective access to quality health care services and to address the shortage of home care providers, especially registered nurses. Provincial and federal home care models would be enhanced by an integrative model of continuing care and a national home care framework that would address the broader funding and human resource issues. Other uniquely rural recruitment and retention strategies are suggested such as maximizing the "fit" between the home care provider's attributes and the needs and expectations of the rural community. Sufficient public funding and resources for rural and remote home care programs are needed to develop and implement (1) the expanded role of case managers; (2) health care teams that include both professionals and paraprofessionals; (3) standardized assessment tools and reporting systems; (4) innovative use and training in the use of technology; and (5) partnerships that optimize resources and build support networks for rural home care providers, clients, and family and friend caregivers.


The epidemiology of neonatal tumours. Report of an international working group.
Neonatal tumours occur every 12,500-27,500 live births and comprise 2% of childhood malignancies, but there is little clarity as to their real prevalence, sites of origin and pathological nature as reported series vary. As an entity, neonatal tumours provide a unique window of opportunity to study tumours in which minimal environmental interference has occurred. The majority of tumours present with a mass at birth (e.g., teratomas, neuroblastomas, mesoblastic nephroma, fibromatosis), which are not infrequently identified on antenatal ultrasound. Histologically, teratoma and neuroblastoma remain the two main tumour types encountered with soft tissue sarcoma, renal tumours, CNS tumours and leukaemia being the next most common tumour types identified. Malignant tumours are uncommon in the neonatal period per se and benign tumours may have malignant potential. A particular problem exists in clinical classification, as histological features of malignancy do not always correlate with clinical behaviour. Benign tumours may also be life threatening because of their size and location. Other tumours may demonstrate local invasiveness, but no metastatic potential, and tumours that are clearly malignant may demonstrate unpredictable or uncertain behaviour. Screening programmes have brought more tumours to light, but do not appear to affect the overall prognosis. They may provide clues to the stage at which tumours develop in foetu. The aetiology of cancer in children is multifactorial and includes both genetic and environmental factors. The association between congenital abnormalities and tumours is well established (15% of neonatal tumours). Genetic defects are highly likely in neonatal tumours and include those with a high risk of malignancy (e.g., retinoblastoma), but also genetically determined syndromes with an increased risk of malignancy and complex genetic rearrangements. Tumours are mostly genetically related at a cellular level and factors influencing cellular maturation or apoptosis within the developing foetus may continue to operate in the neonatal period. Cytogenetics of neonatal neoplasms appear to differ from neoplasms in older children, thus possibly explaining some of the observed differences in clinical behaviour. Certain constitutional chromosome anomalies, however, specifically favour tumours occurring in the foetal and neonatal period. In support of this hypothesis, certain cytogenetic anomalies appear to be specific to neonates, and a number of examples are explored. Other environmental associations include ionizing radiation, drugs taken during pregnancy, infections, tumours in the mother and environmental exposure.


Mechanistic insights into the inhibition and size effects of graphene oxide nanosheets on the aggregation of an amyloid-β peptide fragment.
The aggregation of amyloid-β (Aβ), which involves the formation of small oligomers and mature fibrils, has received considerable attention in the past few decades due to its close link with Alzheimer's disease (AD). The inhibition of β-sheet formation has been considered as the primary therapeutic strategy for AD. In this respect, graphene oxide (GO) has gained significant attention because of its high solubility, good biocompatibility and inhibitory effect on the aggregation of Aβ and the 33-42 fragment (Aβ33-42). However, the inhibitory mechanism at the atomic level remains elusive. Herein, we investigated the oligomerization of Aβ33-42 by performing replica exchange molecular dynamics simulations on four Aβ33-42 peptide chains in the absence and presence of two different sizes of GO. Our simulations show that isolated Aβ33-42 can form fibril-prone extended β-sheets and barrel-like structures, whereas they are suppressed in the presence of GO nanosheets. Our data reveal that GO inhibits Aβ33-42 oligomerization by making Aβ33-42 peptides separate from each other through strong interactions with M35. With the same total number of atoms, GO120 displays better inhibitory effect than GO60 by providing a larger effective contact surface area. This study provides the molecular mechanism of GO in inhibiting the aggregation of Aβ33-42, which might offer a theoretical insight into the design of drugs against AD at the atomic level.


Clinical validation and assessment of a modular fluorescent imaging system and algorithm for rapid detection and quantification of dental plaque.
Significant numbers of adults and children have untreated plaque due to poor oral hygiene and consequently suffer from associate dental and systemic diseases. A handheld device equipped with 405 nm light-emitting diodes was constructed to examine the prevalence of red fluorescence signatures associated with dental plaque. This device was used for in vivo imaging of all four incisors and all four canines of twenty-eight consenting human subjects. The same areas were further imaged under white light illumination with a commercial image-processing based plaque-imaging device, and evaluated by a hygienist and dentist. A custom computer vision algorithm using pixel information was developed to calculate plaque coverage ratios ranging from 0 (no plaque) to 1 (complete plaque coverage) for images captured by both devices. The algorithm calculated red fluorescence-based plaque coverage ratios ranging from 0.011 to 0.211 for the subjects imaged. Clinical assessment and statistical analyses of associated plaque ratios of the 405 nm device images indicated high sensitivity and specificity in detecting dental plaque by the experimental device compared to the commercial reference device. The low-cost and open source 405 nm device and the associated computer vision algorithm successfully captured red fluorescence signatures associated with dental plaque and demonstrated comparable performance to a commercially available device. Therefore, a proof of concept validation was provided for the construction and application of a sensitive cost-effective plaque-detecting device. A miniaturized mobile adaptable version of the device was also provided, together with and a step-by-step guide for device assembly and webhost the associated software, to facilitate open-source access to a cost-effective at-home, in-clinic oral care technology. ClinicalTrials.gov NCT03379337, December 19 2017. Retrospectively registered.


Hsp90 rescues PTK6 from proteasomal degradation in breast cancer cells.
PTK6 [protein tyrosine kinase 6; also known as Brk (breast tumour kinase)] is a non-receptor tyrosine kinase, closely related to Src, but evolutionarily distinct, that is up-regulated in various cancers, including breast cancer. Hsp90 (heat-shock protein 90) was identified as a PTK6-interacting protein in HEK (human embryonic kidney)-293 cells overexpressing PTK6. Hsp90 interacted with the PTK6 tyrosine kinase catalytic domain, but catalytic activity was not required for the interaction. Geldanamycin, an Hsp90 inhibitor, significantly decreased the PTK6 protein level through proteasome-dependent degradation, but did not affect the level of Src. Geldanamycin treatment also decreased phosphorylation of PTK6 substrates due to reduced amounts of PTK6. Moreover, overexpression of CHIP [C-terminus of Hsc70 (heat-shock cognate 70)-interacting protein], a chaperone-dependent E3 ligase, enhanced proteosomal degradation of PTK6. Geldanamycin increased the interaction of PTK6 with CHIP, but decreased the interaction of PTK6 with Hsp90. We also found that endogenous PTK6 associated with Hsp90 and geldanamycin decreased expression of endogenous PTK6 in breast carcinoma cells. Finally, we report that silencing endogenous CHIP expression in breast carcinoma cells inhibited geldanamycin-induced PTK6 reduction. These results demonstrate that Hsp90 plays an essential role in regulating PTK6 stability and suggest that Hsp90 inhibitors may be useful as therapeutic drugs for PTK6-positive cancers, including breast cancer.


Immunochemical evidence of trifluoroacetylated cytochrome P-450 in the liver of halothane-treated rats.
Four hours after the administration of halothane to phenobarbital-pretreated rats, subcellular fractions of liver were isolated and the proteins in the fractions were separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis, transferred to nitrocellulose sheets, and immunochemically stained with anti-trifluoroacetylated antibodies. The microsomal fraction contained the highest level of trifluoroacetylated adducts. Its major trifluoroacetylated component was immunochemically identified as a phenobarbital-inducible form of cytochrome P-450 (54 kDa), whereas the other observed trifluoroacetylated protein fraction (59 kDa) was not identified. The plasma membrane fraction also contained a 54-kDa trifluoroacetylated adduct, which was immunochemically related to the 54-kDa cytochrome P-450. Microsomes from untreated rats that were administered halothane contained only the 59-kDa trifluoroacetylated protein fraction. The specificity of the immunochemical staining for the bound oxidative metabolite of halothane was confirmed by the finding that rats treated with deuterated halothane had considerably less stained liver proteins than did those treated with halothane. These results suggest that the CF3COX oxidative metabolite of halothane is so reactive that it binds predominantly to the cytochrome P-450 that produced it.


Amyloid imaging of Lewy body-associated disorders.
Clinicopathologic studies of Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB) commonly reveal abnormal β-amyloid deposition in addition to diffuse Lewy bodies (α-synuclein aggregates), but the relationship among these neuropathologic features and the development of dementia in these disorders remains uncertain. The purpose of this study was to determine whether amyloid-β deposition detected by PET imaging with Pittsburgh Compound B (PIB) distinguishes clinical subtypes of Lewy body-associated disorders. Nine healthy controls, 8 PD with no cognitive impairment, 9 PD with mild cognitive impairment, 6 DLB, and 15 PDD patients underwent [(11)C]-PIB positron emission tomography imaging, clinical examination, and cognitive testing. The binding potential (BP) of PIB for predefined regions and the mean cortical BP (MCBP) were calculated for each participant. Annual longitudinal follow-up and postmortem examinations were performed on a subset of participants. Regional PIB BPs and the proportion of individuals with abnormally elevated MCBP were not significantly different across participant groups. Elevated PIB binding was associated with worse global cognitive impairment in participants with Lewy body disorders but was not associated with any other clinical or neuropsychological features, including earlier onset or faster rate of progression of cognitive impairment. These results suggest that the presence of fibrillar amyloid-β does not distinguish between clinical subtypes of Lewy body-associated disorders, although larger numbers are needed to more definitively rule out this association. Amyloid-β may modify the severity of global cognitive impairment in individuals with Lewy body-associated dementia.


Logic-operated mathematical morphology and its optical implementation.
A more powerful tool for binary image processing, i.e., logic-operated mathematical morphology (LOMM), is proposed. With LOMM the image and the structuring element (SE) are treated as binary logical variables, and the MULTIPLY between the image and the SE in correlation is replaced with 16 logical operations. A total of 12 LOMM operations are obtained. The optical implementation of LOMM is described. The application of LOMM and its experimental results are also presented.


Vascular and metabolic effects of methacholine in relation to insulin action in muscle.
Methacholine (MC) is a nitric oxide vasodilator, but unlike other vasodilators, it potentiates insulin-mediated glucose uptake by muscle. The present study aimed to resolve whether this action was the result of a vascular effect of MC leading to increased muscle perfusion or a direct effect of MC on the myocytes. We hypothesise that vascular-mediated insulin-stimulated glucose uptake responses to MC occur at lower doses than direct myocyte MC-mediated increases in glucose uptake. The vascular and metabolic effects of this vasodilator were examined in rats in vivo using a novel local infusion technique, and in the pump-perfused rat hindlimb under conditions of constant flow. Local infusion of low-dose MC (0.3 micromol/l) into the epigastric artery of one leg (test) in vivo markedly increased femoral blood flow and decreased vascular resistance, without effects in the contra-lateral leg. Capillary recruitment, but not glucose uptake, was increased in the test leg. All increases caused by MC were confined to the test leg and blocked by local infusion into the test leg of N-nitro-L-arginine methyl ester (L-NAME), but not by infusion of N-nitro-D-arginine methyl ester (D-NAME). In the constant-flow pump-perfused rat hindlimb, infusion of 0.6 micromol/l MC vasodilated the pre-constriction effected by 70 nmol/l noradrenaline or 300 nmol/l serotonin, and this was blocked by 10 micromol/l L-NAME. 2-Deoxyglucose in muscle was increased by 30 micromol/l MC (p<0.05), but was unaffected by 3 micromol/l MC. All increases in 2-deoxyglucose uptake by 30 micromol/l MC were blocked by 10 micromol/l L-NAME. MC has dose-dependent effects both on the vasculature and on muscle metabolism. At low dose (0.3-3 micromol/l), MC is a potent vasodilator in muscle, both in vivo and in vitro, without metabolic effects; at higher doses (> or =30 micromol/l) MC has a direct metabolic effect leading to increased glucose uptake. Both the vascular and metabolic effects are sensitive to L-NAME. The low-dose enhancement of insulin action in vivo by MC, which has been reported previously, thus seems to be attributable to vascular effects.


[Computerized tomography utilization for stroke inpatients in the Brazilian Health System].
Stroke is a leading reason for hospitalization in the Brazilian Health System. Computerized tomography has been indicated as the main diagnostic method to define stroke treatment. The aim of this paper was to evaluate the utilization of computerized tomography in hospitalizations due to stroke. The source of data was the Brazilian hospital information system. The study population comprised adult stroke inpatients in Brazil in the Brazilian Health System, between April 2006 and December 2007. Data analysis was descriptive for stroke and for each separate subgroup. Of the 328,087 stroke inpatients, 73.5% had not done a computerized tomography scan. Among hospitalizations that underwent a computed tomography scan, 22.3% had access to one test, and only 4.2% had two tests. Besides underuse, the computed tomography scans performed did not improve the encoding of the disease subgroup.


Development of a core outcome set for the evaluation of interventions to prevent COVID-19 in care homes (COS-COVID-PCARE Study).
People living in care homes have experienced devastating impact from COVID-19. As interventions to prevent the transmission of COVID-19 are developed and evaluated, there is an urgent need for researchers to agree on the outcomes used when evaluating their effectiveness. Having an agreed set of outcomes that are used in all relevant trials can ensure that study results can be compared. The aim of the study was to develop a core outcome set (COS) for trials assessing the effectiveness of pharmacological and non-pharmacological interventions for preventing COVID-19 infection and transmission in care homes. The study used established COS methodology. A list of candidate outcomes was identified by reviewing registered trials to evaluate interventions to prevent COVID-19 in care homes. Seventy key stakeholders participated in a Delphi survey, rating the candidate outcomes on a nine-point scale over two rounds, with the opportunity to propose additional outcomes. Stakeholders included care home representatives (n = 19), healthcare professionals (n = 20), people with personal experience of care homes (n = 7), researchers (n = 15) and others (n = 9). Outcomes were eligible for inclusion if they met an a priori threshold. A consensus meeting with stakeholders resulted in agreement of the final outcome set. Following the Delphi and consensus meeting, twenty-four outcomes were recommended for inclusion. These are grouped across four domains of infection, severity of illness, mortality, and 'other' (intervention specific or life impact). Due to the considerable heterogeneity between care homes, residents, and interventions, the relevance and importance of outcomes may differ between trial contexts. Intervention-specific outcomes would be included only where relevant to a given trial, thus reducing the measurement burden. Using a rapid response approach, a COS for COVID-19 prevention interventions in care homes has been developed. Future work should focus on identifying instruments for measuring these outcomes, and the interpretation and application of the COS across different trial contexts. Beyond COVID-19, the outcomes identified in this COS may have relevance to other infectious diseases in care homes, and the rapid response approach may be useful as preparation for future pandemics.


Avoidance response of juvenile Pacific treefrogs to chemical cues of introduced predatory bullfrogs.
Bullfrogs (Rana catesbeiana), native to eastern North America, were introduced into Oregon in the 1930's. Bullfrogs are highly efficient predators that are known to eat a variety of prey including other amphibians. In laboratory experiments, we investigated whether juvenile Pacific treefrogs (Hyla regilla) recognize adult bullfrogs as a predatory threat. The ability of prey animals to acquire recognition of an introduced predator has important implications for survival of the prey. We found that treefrogs from a population that co-occurred with bullfrogs showed a strong avoidance of chemical cues of bullfrogs. In contrast, treefrogs from a population that did not co-occur with bullfrogs, did not respond to the bullfrog cues. Additional experiments showed that both populations of treefrogs use chemical cues to mediate predation risk. Treefrogs from both populations avoided chemical alarm cues from injured conspecifics.


High density lipoprotein cholesterol as a predictor of cardiovascular disease mortality in men and women: the follow-up study of the Lipid Research Clinics Prevalence Study.
With data from the Lipid Research Clinics Prevalence Study used as a baseline, an average of 8.4 years of mortality follow-up has been completed for 8,825 male and female participants who were at least 30 years of age at the time of the study. The participants were examined at 10 North American sites during 1972-1976. Univariate findings for high density lipoprotein (HDL) cholesterol in the 7,569 persons initially free of coronary heart disease indicate an inverse relation with cardiovascular disease mortality for men and women. Controlling for age, low density lipoprotein (LDL) cholesterol, triglycerides, body mass index, systolic blood pressure, and smoking, multivariate analysis results indicate inverse relations between HDL cholesterol and cardiovascular disease mortality. In men, the cardiovascular disease mortality rate ratio for HDL cholesterol increments of 10 mg/dl was similar to the cardiovascular disease mortality rate ratio for LDL cholesterol increments of 30 mg/dl. In women, HDL cholesterol is more closely related to cardiovascular disease than is LDL cholesterol. HDL cholesterol is inversely related to both coronary heart disease and other cardiovascular disease mortality in both sexes, though the relation of HDL cholesterol with coronary heart disease mortality in women approached statistical significance only for the combined end point of suspect and definite cases. No relation was observed in either sex group between HDL cholesterol and noncardiovascular disease mortality. This study, only the second large prospective study evaluating the role of HDL cholesterol in women, confirms both the importance and the independence in both men and women of HDL cholesterol in the epidemiology of coronary heart disease and other cardiovascular disease mortality.


Carbamazepine versus valproate monotherapy for epilepsy: a meta-analysis.
To provide an overview of the evidence comparing carbamazepine (CBZ) and valproate (VPA) monotherapy for epilepsy, investigating whether existing data support the current practice of preferring CBZ for partial-onset and VPA for generalized-onset seizures. We performed meta-analysis of randomized controlled trials by using individual patient data. Our strategy included searches of (a) Medline, 1966-2000; (b) The Cochrane Library 2000, issue 4; and (c) the pharmaceutical industry. Outcome measures were time to discontinuation of allocated treatment, time to 12-month remission, and time to first seizure after randomization. Results are expressed as hazard ratios (HRs; 95% CI), where HR>1 indicates that an event is more likely with VPA. A test for an interaction between treatment and seizure type (partial vs. generalized onset) also was undertaken. Data were available for 1,265 patients from five trials. Overall results (HR, 95% CI) were Time to treatment discontinuation, 0.97 (0.79-1.18); 12-Month remission, 0.87 (0.74-1.02); and First seizure, 1.09 (0.96-1.25), suggesting no overall difference for these outcomes. The test for an interaction between Treatment and Seizure type was significant for time to first seizure, but for no other outcome. The age distribution of adults classified as having generalized seizures indicated that significant numbers of patients may have had their seizures misclassified. We found some evidence to support the preference of CBZ for partial-onset seizures, but no evidence to support the preference of VPA for generalized-onset seizures. Confidence intervals are too wide to infer equivalence. Misclassification of patients may have confounded our results and has important implications for future trials.


Knowledge Attitude and Perception of Sex Education among School Going Adolescents in Ambala District, Haryana, India: A Cross-Sectional Study.
Adolescence is a highly dynamic period characterised by rapid growth and development. Adolescents have limited knowledge about sexual and reproduction health, and know little about the natural processes of puberty, sexual health, pregnancy or reproduction. Sex education should be an integral part of the learning process beginning in childhood and continuing into adult life, because it is lifelong process. This study was carried out to identify the knowledge and attitude of imparting sex education in school going adolescents in rural and urban area of Ambala district. A cross sectional study design was used to study the knowledge of reproductive and sexual health among school going children. A total of 743 adolescents from age group of 13-19 year were studied, using self designed semi-structured questionnaire to assess the knowledge regarding reproductive and sexual health among adolescents. The mean age of study subjects was 15.958±1.61 years, majority of adolescents i.e., 93.5% favour sex education. An 86.3% said sex education can prevent the occurrence of AIDS and 91.5% of adolescents prefer doctors should give them sex education followed by 83.0% school/teacher and least preference was parents 37.3%. There were substantial lacunae in the knowledge about reproductive and sexual health. Students felt that sex education is necessary and should be introduced in the school curriculum.