Signal transduction underlying the control of urinary bladder smooth muscle tone by muscarinic receptors and β-adrenoceptors

The normal physiological contraction of the urinary bladder, which is required for voiding, is predominantly mediated by muscarinic receptors, primarily the M3 subtype, with the M2 subtype providing a secondary backup role. Bladder relaxation, which is required for urine storage, is mediated by β-adrenoceptors, in most species involving a strong β3-component. An excessive stimulation of contraction or a reduced relaxation of the detrusor smooth muscle during the storage phase of the micturition cycle may contribute to bladder dysfunction known as the overactive bladder. Therefore, interference with the signal transduction of these receptors may be a viable approach to develop drugs for the treatment of overactive bladder. The prototypical signaling pathway of M3 receptors is activation of phospholipase C (PLC), and this pathway is also activated in the bladder. Nevertheless, PLC apparently contributes only in a very minor way to bladder contraction. Rather, muscarinic-receptor-mediated bladder contraction involves voltage-operated Ca2+ channels and Rho kinase. The prototypical signaling pathway of β-adrenoceptors is an activation of adenylyl cyclase with the subsequent formation of cAMP. Nevertheless, cAMP apparently contributes in a minor way only to β-adrenoceptor-mediated bladder relaxation. BKCa channels may play a greater role in β-adrenoceptor-mediated bladder relaxation. We conclude that apart from muscarinic receptor antagonists and β-adrenoceptor agonists, inhibitors of Rho kinase and activators of BKCa channels may have potential to treat an overactive bladder

Vaccine Protection Against Zika Virus from Brazil

Zika virus (ZIKV) is a flavivirus that is responsible for an unprecedented current epidemic in Brazil and the Americas1,2. ZIKV has been causally associated with fetal microcephaly, intrauterine growth restriction, and other birth defects in both humans3–8 and mice9–11. The rapid development of a safe and effective ZIKV vaccine is a global health priority1,2, but very little is currently known about ZIKV immunology and mechanisms of immune protection. Here we show that a single immunization of a plasmid DNA vaccine or a purified inactivated virus vaccine provides complete protection in susceptible mice against challenge with a ZIKV outbreak strain from northeast Brazil. This ZIKV strain has recently been shown to cross the placenta and to induce fetal microcephaly and other congenital malformations in mice11. We produced DNA vaccines expressing full-length ZIKV pre-membrane and envelope (prM-Env) as well as a series of deletion mutants. The full-length prM-Env DNA vaccine, but not the deletion mutants, afforded complete protection against ZIKV as measured by absence of detectable viremia following challenge, and protective efficacy correlated with Env-specific antibody titers. Adoptive transfer of purified IgG from vaccinated mice conferred passive protection, and CD4 and CD8 T lymphocyte depletion in vaccinated mice did not abrogate protective efficacy. These data demonstrate that protection against ZIKV challenge can be achieved by single-shot subunit and inactivated virus vaccines in mice and that Env-specific antibody titers represent key immunologic correlates of protection. Our findings suggest that the development of a ZIKV vaccine for humans will likely be readily achievable

Efeito da sequência de mistura nas propriedades de blendas PA6/ABS compatibilizadas com o copolímero SMA Effect from the blending sequence on the properties of PA6/ABS blends compatibilized with SMA copolymer

Blendas de poliamida 6 (PA6) com acrilonitrila-butadieno-estireno (ABS) foram preparadas em uma extrusora de rosca dupla, utilizando-se o copolímero estireno-anidrido maleico (SMA), com 7% de anidrido maleico, como compatibilizante. O efeito de três sequências de mistura na microestrutura e propriedades das blendas foi estudado. A morfologia e as propriedades mecânicas dos materiais foram caracterizadas por microscopia eletrônica de transmissão (MET) e testes de resistência ao impacto e módulo de elasticidade, respectivamente. Os resultados mostraram que a morfologia e propriedades mecânicas das blendas ternárias foram bastante diferentes e dependem da sequência de mistura. A blenda preparada pela mistura simultânea de todos os componentes, em uma única extrusão, apresentou melhor tenacidade. Por outro lado, quando o ABS e o SMA foram misturados juntos em uma primeira extrusão, antes da incorporação da PA6 em uma segunda extrusão, o valor da resistência ao impacto encontrado foi menor que o da matriz PA6 e da blenda sem compatibilizante PA6/ABS. Evidências de reações químicas entre o compatibilizante SMA e a matriz PA6 também foram investigadas através de reometria de torque.Blends of polyamide 6 (PA6) with acrylonitrile-butadiene-estyrene (ABS) were prepared in a twin-screw extruder, using the styrene-maleic anhydride (SMA) copolymer containing 7% of maleic anhydride as compatibilizer. The effects from three blending sequences on the microstructure and properties of the blends were investigated. The morphology and mechanical properties of the materials were characterized by transmission electron microscopy and tensile and impact tests. The results showed that the morphology and mechanical properties of ternary blends depend on the sequence of blend preparation. The blend prepared using the mixture of all components in a single-pass extrusion showed the more significant improvement in the material toughness. However, when the ABS and SMA were melt mixed together in a first extrusion step prior to incorporating PA6 in a second extrusion, the impact strength is lower than that of the blend without compatibilizer PA6/ABS and PA6 matrix. Evidence of chemical reactions between the compatibilizer SMA and PA6 was also obtained using a torque rheometer

Influência das condições de processamento na obtenção de blendas PBT/ABS Influence of the processing parameters during preparation of PBT/ABS blends

Foram desenvolvidos dispositivos para obtenção de fitas extrudadas de blendas poli(tereftalato de butileno)/terpolímero acrilonitrila-butadieno-estireno (PBT/ABS), que serviram para correlacionar diretamente as condições de preparação destas blendas em extrusoras com rosca dupla corotacional e interpenetrante (ERDCI) com as suas propriedades. Quando compatibilizada com terpolímero reativo metacrilato de metila-co-metacrilato de glicidila-co-acrilato de etila (MGE), a blenda ternária PBT/ABS/MGE apresentou maior viscosidade, menor entalpia de fusão e menor temperatura de transição frágil dúctil (TTFD) que a blenda binária PBT/ABS, devido possivelmente à reação do grupo epóxi do MGE com os terminais de cadeias do PBT. A blenda compatibilizada e processada com velocidade de rotação das roscas de 120 rpm apresentou maior viscosidade, menor entalpia de fusão e melhores propriedades de resistência ao impacto que aquela processada a 240 rpm. A maior velocidade de rotação das roscas pode ter degradado os componentes da blenda. A taxa de alimentação foi a variável de processo que mais influenciou nas propriedades da blenda, pois a taxa de 3,5 kg/h deteriorou completamente as propriedades de impacto, reduziu a viscosidade e aumentou a entalpia de fusão, quando comparada com a taxa de 7,0 kg/h. A deterioração das propriedades de impacto foi atribuída ao maior tempo de residência da blenda na ERDCI, que submeteu a blenda ao cisalhamento e à temperatura por mais tempo, causando degradação dos componentes da blenda.In order to correlate processing conditions in intermeshing co-rotational twin-screw extrusion (ICTSE) and properties of PBT/ABS blends, devices have been developed to obtain extruded strips from PBT/ABS blends. The PBT/ABS blend compatibilized with reactive copolymer methyl methacrylate- glycidyl methacrylate (MGE) has shown higher viscosity, lower heat of fusion and lower ductile-brittle transition temperature (DBTT) when compared to the non compatibilized PBT/ABS blend, possibly due to chemical reactions between MGE epoxy groups and the molecule end groups from PBT. Concerning the screw rotation, the compatibilized blend processed with 120 rpm has shown higher viscosity, lower heat of fusion and better impact strength properties than the one processed with 240 rpm. This could be a consequence of degradation of the blend components, caused by higher screw rotation. The feeding rate has presented itself as the processing parameter with the greater influence on blend properties. A feeding rate of 3.5 kg/h has severely compromised impact strength properties, reduced the viscosity and increased the heat of fusion, in contrast to a feeding rate of 7.0 kg/h. These observations can be attributed to a higher residence time, with the blend being submitted to higher temperature and shear for a long time, leading to the degradation of blend constituents

Feasibility of Using a Nationally Representative Telephone Survey to Monitor Multiple Sclerosis Prevalence in the United States

Background: Multiple sclerosis (MS) is the most common chronic neurologic disease of young adults, placing a heavy burden on patients, families, and the healthcare system. Ongoing surveillance of the incidence and prevalence of MS is critical for health policy and research, but feasible options are limited in the United States and many other countries. We investigated the feasibility of monitoring the prevalence of MS using a large national telephone survey of the adult US population. Methods: We developed questions to estimate the lifetime prevalence and age of onset of MS using the US-based Behavioral Risk Factor Surveillance System (BRFSS) and piloted these questions in 4 states (MN, RI, MD, and TX). There was a total of 45,198 respondents aged 18 years and above. Analyses investigated individual state and combined prevalence estimates along with health-related comorbidities and limitations. MS prevalence estimates from the BRFSS were compared to estimates from multi-source administrative claims and traditional population-based methods. Results: The estimated lifetime prevalence of self-reported MS (per 100,000 adults) was 682 (95% CI 528-836); 384 (95% CI 239-529) among males and 957 (95% CI 694-1,220) among females. Estimates were consistent across the 4 states but much higher than recently published estimates using population-based administrative claims data. This was observed for both national results and for MS prevalence estimates from other studies within specific states (MN, RI, and TX). Prevalence estimates for Caucasian, African American, and Hispanic respondents were 824, 741, and 349 per 100,000 respectively. Age and sex distributions were consistent with prior epidemiologic reports. Comorbidity and functional limitations were more pronounced among female than male respondents. Conclusions: While yielding higher overall MS prevalence estimates compared to recent studies, this large-scale self-report telephone method yielded relative prevalence estimates (e.g., prevalence patterns of MS by sex, age, and race-ethnicity) that were generally comparable to other surveillance approaches. With certain caveats, population-based telephone surveys may eventually offer the ability to investigate novel disease correlates and are relatively feasible, and affordable. Further work is needed to create a valid question set and methodology for case ascertainment before this approach could be adopted to accurately estimate MS prevalence

Data from: A new way to estimate neurologic disease prevalence in the United States

Objective: Considerable gaps exist in knowledge regarding the prevalence of neurologic diseases, such as multiple sclerosis (MS), in the United States. Therefore, the MS Prevalence Working Group sought to review and evaluate alternative methods for obtaining a scientifically valid estimate of national MS prevalence in the current health care era. Methods: We carried out a strengths, weaknesses, opportunities, and threats (SWOT) analysis for 3 approaches to estimate MS prevalence: population-based MS registries, national probability health surveys, and analysis of administrative health claims databases. We reviewed MS prevalence studies conducted in the United States and critically examined possible methods for estimating national MS prevalence. Results: We developed a new 4-step approach for estimating MS prevalence in the United States. First, identify administrative health claim databases covering publicly and privately insured populations in the United States. Second, develop and validate a highly accurate MS case-finding algorithm that can be standardly applied in all databases. Third, apply a case definition algorithm to estimate MS prevalence in each population. Fourth, combine MS prevalence estimates into a single estimate of US prevalence, weighted according to the number of insured persons in each health insurance segment. Conclusions: By addressing methodologic challenges and proposing a new approach for measuring the prevalence of MS in the United States, we hope that our work will benefit scientists who study neurologic and other chronic conditions for which national prevalence estimates do not exist

A new way to estimate neurologic disease prevalence in the United States: Illustrated with MS

Considerable gaps exist in knowledge regarding the prevalence of neurologic diseases, such as multiple sclerosis (MS), in the United States. Therefore, the MS Prevalence Working Group sought to review and evaluate alternative methods for obtaining a scientifically valid estimate of national MS prevalence in the current health care era.MethodsWe carried out a strengths, weaknesses, opportunities, and threats (SWOT) analysis for 3 approaches to estimate MS prevalence: population-based MS registries, national probability health surveys, and analysis of administrative health claims databases. We reviewed MS prevalence studies conducted in the United States and critically examined possible methods for estimating national MS prevalence.ResultsWe developed a new 4-step approach for estimating MS prevalence in the United States. First, identify administrative health claim databases covering publicly and privately insured populations in the United States. Second, develop and validate a highly accurate MS case-finding algorithm that can be standardly applied in all databases. Third, apply a case definition algorithm to estimate MS prevalence in each population. Fourth, combine MS prevalence estimates into a single estimate of US prevalence, weighted according to the number of insured persons in each health insurance segment.ConclusionsBy addressing methodologic challenges and proposing a new approach for measuring the prevalence of MS in the United States, we hope that our work will benefit scientists who study neurologic and other chronic conditions for which national prevalence estimates do not exist

Noninvasive detection of colonic biomarkers using fecal messenger RNA

A noninvasive method utilizing feces, containing sloughed colonocytes, as a sensitive technique for detecting diagnostic colonic biomarkers as well as a method for isolating poly A +RNA from feces. The method allows the isolation and quantitation of specific eukarotic mRNAs as candidate biomarkers for colon cancer isolated from feces.U

Data from: Validation of an algorithm for identifying MS cases in administrative health claims datasets

Objective: To develop a valid algorithm for identifying multiple sclerosis (MS) cases in administrative health claims (AHC) datasets. Methods: We used 4 AHC datasets from the Veterans Administration (VA), Kaiser Permanente Southern California (KPSC), Manitoba (Canada), and Saskatchewan (Canada). In the VA, KPSC, and Manitoba, we tested the performance of candidate algorithms based on inpatient, outpatient, and disease-modifying therapy (DMT) claims compared to medical records review using sensitivity, specificity, positive and negative predictive values, and interrater reliability (Youden J statistic) both overall and stratified by sex and age. In Saskatchewan, we tested the algorithms in a cohort randomly selected from the general population. Results: The preferred algorithm required ≥3 MS-related claims from any combination of inpatient, outpatient, or DMT claims within a 1-year time period; a 2-year time period provided little gain in performance. Algorithms including DMT claims performed better than those that did not. Sensitivity (86.6%–96.0%), specificity (66.7%–99.0%), positive predictive value (95.4%–99.0%), and interrater reliability (Youden J = 0.60–0.92) were generally stable across datasets and across strata. Some variation in performance in the stratified analyses was observed but largely reflected changes in the composition of the strata. In Saskatchewan, the preferred algorithm had a sensitivity of 96%, specificity of 99%, positive predictive value of 99%, and negative predictive value of 96%. Conclusions: The performance of each algorithm was remarkably consistent across datasets. The preferred algorithm required ≥3 MS-related claims from any combination of inpatient, outpatient, or DMT use within 1 year. We recommend this algorithm as the standard AHC case definition for MS