Angiotensin-converting enzyme activity and inhibition in dogs with cardiac disease and an angiotensin-converting enzyme polymorphism

OBJECTIVE The objective of this study was to evaluate angiotensin-converting enzyme (ACE) activity in dogs and with and without an ACE polymorphism in the canine ACE gene, before and after treatment with an ACE inhibitor. METHODS Thirty-one dogs (20 wild-type, 11 ACE polymorphism) with heart disease were evaluated with ACE activity measurement and systolic blood pressure before and after administration of an ACE inhibitor (enalapril). RESULTS Median pre-treatment ACE activity was significantly lower for ACE polymorphism dogs than for dogs with the wild-type sequence ( P=0.007). After two weeks of an ACE inhibitor, ACE activity was significantly reduced for both genotypes (wild-type, P<0.0001; ACE polymorphism P=0.03); mean post-therapy ACE activity was no different between the groups. CONCLUSION An ACE polymorphism is associated with lower levels of ACE activity. Dogs with the polymorphism still experience suppression of ACE activity in response to an ACE inhibitor. It is possible that the genetic status and ACE activity of dogs may impact the response of dogs with this variant to an ACE inhibitor

Carboxylic acids in clouds at a high-elevation forested site in central Virginia

During September 1990 we sampled coarse (>18-μm diameter) and fine (18- to 5.5-μm diameter) droplets and liquid-water content (LWC) in cloud from a tower on a forested ridge top in Shenandoah National Park, Virginia. Cloud-water pH and aqueous- and vapor-phase concentrations of carboxylic acids (HCOOH and CH3COOH) and formaldehyde (HCHO) were measured in parallel over 1- to 1.5-hour intervals. Both size fractions of cloud droplets contained similar concentrations of carboxylic species and H+ during most sampling; most cloud water was in coarse droplets. The pH of coarse (3.27–4.76) and fine (3.22–4.70) droplets coupled with total LWC of 0.04–0.56 g m−3 STP (standard m3 at 0°C and 1 atm) resulted in the partitioning of carboxylic acids primarily in the vapor phase. The observed phase partitioning for CH3COOH was within the uncertainty range of thermodynamic data. However, HCOOH exhibited significant phase disequilibria, which could not be explained by artifacts from variable LWC or from mixing droplets of different acidities. We hypothesize that the large volume of liquid water deposited on the forest canopy interacted with the near-surface cloud leading to apparent disequilibria based on time-integrated samples. HCOOH was selectively depleted relative to CH3COOH in cloud, particularly at higher pH, suggesting rapid removal of HCOOH by cloud-water deposition. We saw no evidence for significant production of HCOOH from the aqueous-phase oxidation of HCHO.Engineering and Applied Science

Carboxylic acids in the rural continental atmosphere over the eastern United States during the Shenandoah Cloud and Photochemistry Experiment

The Shenandoah Cloud and Photochemistry Experiment (SCAPE) was conducted during September 1990 in the rural continental atmosphere at a mountain top site (1014 m) in Shenandoah National Park, Virginia. We report here the extensive set of trace gas measurements performed during clear sky periods of SCAPE, with particular focus on the carboxylic acids, formic, acetic, and pyruvic. Median mixing ratios were 5.4 and 2.1 parts per billion by volume (ppbv) for formic and acetic acid, respectively, and they did not exhibit the diurnal variation characteristic of low-elevation sites. Mixing ratios of formic acid often approached or exceeded 10 ppbv, which are the largest values yet reported for the nonurban troposphere. Over the rural eastern United States, formic and acetic acid appear to have significant nonphotochemical sources. Secondary production from suspected pathways appears to be relatively unimportant. The observed lack of correlation between formic and acetic acid with peroxide species argues against a significant source from permutation reactions of peroxy radicals. In addition, model calculations using the SCAPE data indicate minimal production of carboxylics from olefin/O3 oxidation reactions. The tight correlation (r2 = 0.88) between mixing ratios of formic and acetic acid is strongly suggestive of a commonality in their sources. The seasonal cycle of carboxylic acids in the atmosphere and precipitation over the eastern United States is evidence that combustion emissions are not a principal source of these species. It appears that direct biogenic emissions from vegetation and soils cannot be ruled out as important sources. In particular, the correlation between the seasonal variation of formic and acetic acid and the ambient temperature is consistent with a soil microbial source. Similar conclusions were reached for pyruvic acid, with its mixing ratio ranging 4–266 parts per trillion by volume (pptv) (median = 63) and most likely supported by biogenic emissions and possibly photochemical sources.Engineering and Applied Science

Temporal changes in clinical and radiographic variables in dogs with preclinical myxomatous mitral valve disease: The EPIC study

The Evaluation of pimobendan in dogs with cardiomegaly caused by preclinical myxomatous mitral valve disease (EPIC) study monitored dogs with myxomatous mitral valve disease (MMVD) as they developed congestive heart failure (CHF)

Canine models of Duchenne muscular dystrophy and their use in therapeutic strategies

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder in which the loss of dystrophin causes progressive degeneration of skeletal and cardiac muscle. Potential therapies that carry substantial risk, such as gene and cell-based approaches, must first be tested in animal models, notably the mdx mouse and several dystrophin-deficient breeds of dogs, including golden retriever muscular dystrophy (GRMD). Affected dogs have a more severe phenotype, in keeping with that of DMD, so may better predict disease pathogenesis and treatment efficacy. We and others have developed various phenotypic tests to characterize disease progression in the GRMD model. These biomarkers range from measures of strength and joint contractures to magnetic resonance imaging. Some of these tests are routinely used in clinical veterinary practice, while others require specialized equipment and expertise. By comparing serial measurements from treated and untreated groups, one can document improvement or delayed progression of disease. Potential treatments for DMD may be broadly categorized as molecular, cellular, or pharmacologic. The GRMD model has increasingly been used to assess efficacy of a range of these therapies. While some of these studies have largely provided general proof-of-concept for the treatment under study, others have demonstrated efficacy using the biomarkers discussed. Importantly, just as symptoms in DMD vary among patients, GRMD dogs display remarkable phenotypic variation. While confounding statistical analysis in preclinical trials, this variation offers insight regarding the role that modifier genes play in disease pathogenesis. By correlating functional and mRNA profiling results, gene targets for therapy development can be identified

International collaborative study to assess cardiovascular risk and evaluate long-term health in cats with preclinical hypertrophic cardiomyopathy and apparently healthy cats:The REVEAL Study

Background: Hypertrophic cardiomyopathy is the most prevalent heart disorder in cats and principal cause of cardiovascular morbidity and mortality. Yet, the impact of preclinical disease is unresolved. Hypothesis/Objectives: Observational study to characterize cardiovascular morbidity and survival in cats with preclinical nonobstructive (HCM) and obstructive (HOCM) hypertrophic cardiomyopathy and in apparently healthy cats (AH). Animals: One thousand seven hundred and thirty client-owned cats (430 preclinical HCM; 578 preclinical HOCM; 722 AH). Methods: Retrospective multicenter, longitudinal, cohort study. Cats from 21 countries were followed through medical record review and owner or referring veterinarian interviews. Data were analyzed to compare long-term outcomes, incidence, and risk for congestive heart failure (CHF), arterial thromboembolism (ATE), and cardiovascular death. Results: During the study period, CHF, ATE, or both occurred in 30.5% and cardiovascular death in 27.9% of 1008 HCM/HOCM cats. Risk assessed at 1, 5, and 10 years after study entry was 7.0%/3.5%, 19.9%/9.7%, and 23.9%/11.3% for CHF/ATE, and 6.7%, 22.8%, and 28.3% for cardiovascular death, respectively. There were no statistically significant differences between HOCM compared with HCM for cardiovascular morbidity or mortality, time from diagnosis to development of morbidity, or cardiovascular survival. Cats that developed cardiovascular morbidity had short survival (mean \ub1 standard deviation, 1.3 \ub1 1.7 years). Overall, prolonged longevity was recorded in a minority of preclinical HCM/HOCM cats with 10% reaching 9-15 years. Conclusions and Clinical Importance: Preclinical HCM/HOCM is a global health problem of cats that carries substantial risk for CHF, ATE, and cardiovascular death. This finding underscores the need to identify therapies and monitoring strategies that decrease morbidity and mortality

A Morphometric Assessment of the Intended Function of Cached Clovis Points

A number of functions have been proposed for cached Clovis points. The least complicated hypothesis is that they were intended to arm hunting weapons. It has also been argued that they were produced for use in rituals or in connection with costly signaling displays. Lastly, it has been suggested that some cached Clovis points may have been used as saws. Here we report a study in which we morphometrically compared Clovis points from caches with Clovis points recovered from kill and camp sites to test two predictions of the hypothesis that cached Clovis points were intended to arm hunting weapons: 1) cached points should be the same shape as, but generally larger than, points from kill/camp sites, and 2) cached points and points from kill/camp sites should follow the same allometric trajectory. The results of the analyses are consistent with both predictions and therefore support the hypothesis. A follow-up review of the fit between the results of the analyses and the predictions of the other hypotheses indicates that the analyses support only the hunting equipment hypothesis. We conclude from this that cached Clovis points were likely produced with the intention of using them to arm hunting weapons

Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms

Type 2 diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype spanning SLC16A11 that explains ∼20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly linked variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreasing SLC16A11 expression in liver and (2) disrupting a key interaction with basigin, thereby reducing cell-surface localization. Both independent mechanisms reduce SLC16A11 function and suggest SLC16A11 is the causal gene at this locus. To gain insight into how SLC16A11 disruption impacts T2D risk, we demonstrate that SLC16A11 is a proton-coupled monocarboxylate transporter and that genetic perturbation of SLC16A11 induces changes in fatty acid and lipid metabolism that are associated with increased T2D risk. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D. Video Abstract [Figure presented] Keywords: type 2 diabetes (T2D); genetics; disease mechanism; SLC16A11; MCT11; solute carrier (SLC); monocarboxylates; fatty acid metabolism; lipid metabolism; precision medicin

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

The stigma turbine:A theoretical framework for conceptualizing and contextualizing marketplace stigma

Stigmas, or discredited personal attributes, emanate from social perceptions of physical characteristics, aspects of character, and “tribal” associations (e.g., race; Goffman 1963). Extant research emphasizes the perspective of the stigma target, with some scholars exploring how social institutions shape stigma. Yet the ways stakeholders within the socio-commercial sphere create, perpetuate, or resist stigma remain overlooked. We introduce and define marketplace stigma as the labeling, stereotyping, and devaluation by and of commercial stakeholders (consumers, companies and their employees, stockholders, institutions) and their offerings (products, services, experiences). We offer the Stigma Turbine (ST) as a unifying conceptual framework that locates marketplace stigma within the broader sociocultural context, and illuminates its relationship to forces that exacerbate or blunt stigma. In unpacking the ST, we reveal the critical role market stakeholders can play in (de)stigmatization, explore implications for marketing practice and public policy, and offer a research agenda to further our understanding of marketplace stigma and stakeholder welfare