P-624: Changes in plasma renin match the antihypertensive effects of aliskiren in patients with hypertension: Placebo/irbesartan-controlled trial with the orally active renin inhibitor aliskiren

For several decades, the lack of oral availability and poor antihypertensive effects of renin inhibitors (RI), despite seemingly powerful inhibition of conventionally measured plasma renin activity (PRA), have discredited RI as cardiovascular drugs. Aliskiren is a novel orally effective RI with antihypertensive potency comparable to losartan or irbesartan. The present study investigated the effects of aliskiren and irbesartan on PRA, measured by the reliable antibody trapping technique, as well as on plasma active renin concentration (ARC) and sitting systolic blood pressure (SBP). In 569 patients with mild to moderate hypertension (baseline sphygmomanometric sitting blood pressure 152±12/99±4 mmHg, mean±SD), PRA and ARC, as well as SBP were measured before and after 8 weeks of treatment with once daily oral doses of aliskiren (150, 300 or 600mg), irbesartan 150mg or placebo. The effects of study treatments on PRA, ARC and SBP are summarized in the Table. Treatment N PRA (ng/mL/h) ARC (pg/mL) SBP (mmHg) Baseline Week 8 Baseline Week 8 Baseline Week 8 Placebo 111 0.72 0.64 6.2 5.6 152 ± 12 147 ± 18 Aliskiren 150mg 112 0.66 0.20 6.0 15.3 151 ± 11 140 ± 14 Aliskiren 300mg 115 0.59 0.17 6.1 21.0 152 ± 10 137 ± 14 Aliskiren 600mg 113 0.64 0.16 5.8 34.9 153 ± 12 137 ± 16 Irbesartan 150mg 118 0.64 1.33 5.5 11.3 153 ± 11 140 ± 16 PRA and ARC values are geometric means; SBP values are mean ± SD Aliskiren reduced PRA by 69%, 71% and 75% at 150, 300 and 600mg respectively, while irbesartan doubled PRA. Most of the antihypertensive effect of aliskiren was obtained with the lowest dose, but higher doses slightly further decreased SBP. Aliskiren 150mg and irbesartan 150mg provided similar increases in ARC and hence comparably blocked the renin-angiotensin system (RAS), and the achieved SBP was also the same. Aliskiren 300mg and 600mg caused greater increases in ARC compared with irbesartan 150mg (p<0.05), and further decreases in SBP. The dose-dependent increases in ARC observed with aliskiren document increasing blockade of the RAS. In conclusion, aliskiren provides a parallel reduction in PRA and SBP, a dose-dependent blockade of the RAS and is at least as effective as irbesartan at comparable dosages (150mg

Switching the Interpenetration of Confined Asymmetric Polymer Brushes

The interpenetration of two polymer brushes on approaching flat surfaces has been investigated. When compacting polymer brushes with an asymmetric charge on each surface, one neutral and the other weakly charged, we find that the brush interpenetration becomes a parameter that can be controlled by the pH of the hydrating solution. The switching between high and low degrees of brush interpenetration was investigated with numerical self-consistent field theory (nSCF) and experimentally using a sample environment which combines neutron reflectometry with a surface force type apparatus. Initially, a pair of uncharged poly(ethylene oxide), PEO, brushes are examined, where one of the brushes is deuterated to distinguish it from a hydrogenous counterpart. We find in both nSCF and these experiments that there is no significant overlap between the brushes as both compact into polymer blocks with little hydration. However, when a weak polyelectrolyte poly(2-(dimethylamino)ethyl methacrylate), PDMAEMA, brush is confined against a deuterated neutral PEO brush and the pH of the hydrating solution is below the polycation’s pKa of 7.5, then the presence of charged groups on the PDMAEMA allows significant interpenetration to occur between the two polymer brushes on contact. This interpenetration remains once the polymer brushes dehydrate due to the confining pressure that is applied. Raising the pH to a value above the pKa, removes the charges from the polyelectrolyte brush resulting in little to no interpenetration between the two brushes. Therefore, by simply adjusting the pH of the hydrating solution the interpenetration state between polymer brush pairs can be switched when one brush is a weak polyelectrolyte. Since polymer brushes are widely investigated and used to reduce friction between solid surfaces, this effect may have significant implications in the design and operation of polymer brushes with controllable friction properties

An efficient semiparametric maxima estimator of the extremal index

The extremal index $\theta$, a measure of the degree of local dependence in the extremes of a stationary process, plays an important role in extreme value analyses. We estimate $\theta$ semiparametrically, using the relationship between the distribution of block maxima and the marginal distribution of a process to define a semiparametric model. We show that these semiparametric estimators are simpler and substantially more efficient than their parametric counterparts. We seek to improve efficiency further using maxima over sliding blocks. A simulation study shows that the semiparametric estimators are competitive with the leading estimators. An application to sea-surge heights combines inferences about $\theta$ with a standard extreme value analysis of block maxima to estimate marginal quantiles.Comment: 17 pages, 7 figures. Minor edits made to version 1 prior to journal publication. The final publication is available at Springer via http://dx.doi.org/10.1007/s10687-015-0221-

Warming seas increase cold-stunning events for Kemp’s ridley sea turtles in the northwest Atlantic

Since the 1970s, the magnitude of turtle cold-stun strandings have increased dramatically within the northwestern Atlantic. Here, we examine oceanic, atmospheric, and biological factors that may affect the increasing trend of cold-stunned Kemp’s ridleys in Cape Cod Bay, Massachusetts, United States of America. Using machine learning and Bayesian inference modeling techniques, we demonstrate higher cold-stunning years occur when the Gulf of Maine has warmer sea surface temperatures in late October through early November. Surprisingly, hatchling numbers in Mexico, a proxy for population abundance, was not identified as an important factor. Further, using our Bayesian count model and forecasted sea surface temperature projections, we predict more than 2,300 Kemp’s ridley turtles may cold-stun annually by 2031 as sea surface temperatures continue to increase within the Gulf of Maine. We suggest warmer sea surface temperatures may have modified the northerly distribution of Kemp’s ridleys and act as an ecological bridge between the Gulf Stream and nearshore waters. While cold-stunning may currently account for a minor proportion of juvenile mortality, we recommend continuing efforts to rehabilitate cold-stunned individuals to maintain population resiliency for this critically endangered species in the face of a changing climate and continuing anthropogenic threats

Cell-associated bacteria in the human lung microbiome

Abstract Background Recent studies have revealed that bronchoalveolar lavage (BAL) fluid contains previously unappreciated communities of bacteria. In vitro and in vivo studies have shown that host inflammatory signals prompt bacteria to disperse from cell-associated biofilms and adopt a virulent free-living phenotype. The proportion of the lung microbiota that is cell-associated is unknown. Results Forty-six BAL specimens were obtained from lung transplant recipients and divided into two aliquots: ‘whole BAL’ and ‘acellular BAL,’ the latter processed with a low-speed, short-duration centrifugation step. Both aliquots were analyzed via bacterial 16S rRNA gene pyrosequencing. The BAL specimens represented a wide spectrum of lung health, ranging from healthy and asymptomatic to acutely infected. Bacterial signal was detected in 52% of acellular BAL aliquots, fewer than were detected in whole BAL (96%, p ≤ 0.0001). Detection of bacteria in acellular BAL was associated with indices of acute infection [BAL neutrophilia, high total bacterial (16S) DNA, low community diversity, p < 0.01 for all] and, independently, with low relative abundance of specific taxonomic groups (p < 0.05). When whole and acellular aliquots from the same bronchoscopy were directly compared, acellular BAL contained fewer bacterial species (p < 0.05); whole and acellular BAL similarity was positively associated with evidence of infection and negatively associated with relative abundance of several prominent taxa (p < 0.001). Acellular BAL contained decreased relative abundance of Prevotella spp. (p < 0.05) and Pseudomonas fluorescens (p < 0.05). Conclusions We present a novel methodological and analytical approach to the localization of lung microbiota and show that prominent members of the lung microbiome are cell-associated, potentially via biofilms, cell adhesion, or intracellularity.http://deepblue.lib.umich.edu/bitstream/2027.42/111056/1/40168_2014_Article_75.pd

Evidence for natural products as alternative wound-healing therapies

Chronic, non-healing wounds represent a significant area of unmet medical need and are a growing problem for healthcare systems around the world. They affect the quality of life for patients and are an economic burden, being difficult and time consuming to treat. They are an escalating problem across the developed world due to the increasing incidence of diabetes and the higher prevalence of ageing populations. Effective treatment options are currently lacking, and in some cases chronic wounds can persist for years. Some traditional medicines are believed to contain bioactive small molecules that induce the healing of chronic wounds by reducing excessive inflammation, thereby allowing re-epithelisation to occur. Furthermore, many small molecules found in plants are known to have antibacterial properties and, although they lack the therapeutic selectivity of antibiotics, they are certainly capable of acting as topical antiseptics when applied to infected wounds. As these molecules act through mechanisms of action distinct from those of clinically used antibiotics, they are often active against antibiotic resistant bacteria. Although there are numerous studies highlighting the effects of naturally occurring small molecules in wound-healing assays in vitro, only evidence from well conducted clinical trials can allow these molecules or the remedies that contain them to progress to the clinic. With this in mind, we review wound-healing natural remedies that have entered clinical trials over a twenty-year period to the present. We examine the bioactive small molecules likely to be in involved and, where possible, their mechanisms of action

A Period Seroprevalence (SARS-CoV-2) Survey in MHCCN Cancer Healthcare Workers (HCWs) Providing Patient Care during the Height of the Outbreak: A Registry Study (Initial Progress)

Introduction: There is little information on the basic epidemiologic and serologic profile(s) of the novel SARSCoV- 2 coronavirus especially in HCWs employed in rural settings. We embarked on a period seroprevalence study in the MaineHealth Cancer Network (MHCCN) to document Covid-19 exposure in our rural cancer care workforce. Our fundamental hypothesis is that despite implementing procedures to safeguard patients and the use of appropriate PPE in the care of known source patients/PUIs in both the inpatient and outpatient cancer care settings a small, but not insignificant number of cancer care providers (hereafter referred to as cancer HCWs) will have evidence of exposure by virtue of plasma antibody seroconversion.https://knowledgeconnection.mainehealth.org/lambrew-retreat-2021/1001/thumbnail.jp

Clinical Significance of Bronchodilator Responsiveness Evaluated by Forced Vital Capacity in COPD: SPIROMICS Cohort Analysis.

ObjectiveBronchodilator responsiveness (BDR) is prevalent in COPD, but its clinical implications remain unclear. We explored the significance of BDR, defined by post-bronchodilator change in FEV1 (BDRFEV1) as a measure reflecting the change in flow and in FVC (BDRFVC) reflecting the change in volume.MethodsWe analyzed 2974 participants from a multicenter observational study designed to identify varying COPD phenotypes (SPIROMICS). We evaluated the association of BDR with baseline clinical characteristics, rate of prospective exacerbations and mortality using negative binomial regression and Cox proportional hazards models.ResultsA majority of COPD participants exhibited BDR (52.7%). BDRFEV1 occurred more often in earlier stages of COPD, while BDRFVC occurred more frequently in more advanced disease. When defined by increases in either FEV1 or FVC, BDR was associated with a self-reported history of asthma, but not with blood eosinophil counts. BDRFVC was more prevalent in subjects with greater emphysema and small airway disease on CT. In a univariate analysis, BDRFVC was associated with increased exacerbations and mortality, although no significance was found in a model adjusted for post-bronchodilator FEV1.ConclusionWith advanced airflow obstruction in COPD, BDRFVC is more prevalent in comparison to BDRFEV1 and correlates with the extent of emphysema and degree of small airway disease. Since these associations appear to be related to the impairment of FEV1, BDRFVC itself does not define a distinct phenotype nor can it be more predictive of outcomes, but it can offer additional insights into the pathophysiologic mechanism in advanced COPD.Clinical trials registrationClinicalTrials.gov: NCT01969344T4

The Incidence of Highly-Obscured Star-Forming Regions in SINGS Galaxies

Using the new capabilities of the Spitzer Space Telescope and extensive multiwavelength data from the Spitzer Infrared Nearby Galaxies Survey (SINGS), it is now possible to study the infrared properties of star formation in nearby galaxies down to scales equivalent to large HII regions. We are therefore able to determine what fraction of large, infrared-selected star-forming regions in normal galaxies are highly obscured and address how much of the star formation we miss by relying solely on the optical portion of the spectrum. Employing a new empirical method for deriving attenuations of infrared-selected star-forming regions we investigate the statistics of obscured star formation on 500pc scales in a sample of 38 nearby galaxies. We find that the median attenuation is 1.4 magnitudes in H-alpha and that there is no evidence for a substantial sub-population of uniformly highly-obscured star-forming regions. The regions in the highly-obscured tail of the attenuation distribution (A_H-alpha > 3) make up only ~4% of the sample of nearly 1800 regions, though very embedded infrared sources on the much smaller scales and lower luminosities of compact and ultracompact HII regions are almost certainly present in greater numbers. The highly-obscured cases in our sample are generally the bright, central regions of galaxies with high overall attenuation but are not otherwise remarkable. We also find that a majority of the galaxies show decreasing radial trends in H-alpha attenuation. The small fraction of highly-obscured regions seen in this sample of normal, star-forming galaxies suggests that on 500pc scales the timescale for significant dispersal or break up of nearby, optically-thick dust clouds is short relative to the lifetime of a typical star-forming region.Comment: Accepted for publication in ApJ; emulateapj style, 30 pages, 18 figures (compressed versions), 3 table