Integrative Physiology B lood vessels consist of 2 major cell types, endothelial and mural cells, such as pericytes and vascular smooth muscle cells (VSMC), which surround the endothelium. Regulator of G-protein signaling 5 (RGS5) is expressed in mural cells and has emerged as a crucial modulator of vascular pathology in cancer. For instance, we have demonstrated that RGS5 is highly upregulated in angiogenic tumor pericytes.1 Loss of RGS5 results in pericyte maturation and normalization of tumor vasculature.2,3 Moreover, we showed a crucial role for RGS5 in regulating vascular barrier function in tumors and in brain capillaries during ischemia, and also provided the first genetic evidence that RGS5 is involved in vascular wall remodeling in adults. 2A striking feature of RGS5 expression is its dynamic nature in various physiological and pathological states, which indicates a role in adaptive processes. 1,[4][5][6] This is consistent with RGS5 being a member of the extended family of RGS molecules, which are modulators of G-protein-coupled receptors (GPCRs). G-protein signaling pathways rely on rapid on-off kinetics, and RGS molecules act as GTPaseactivating proteins (GAP) for heterotrimeric G proteins and, as such, regulate duration and intensity of signaling events. They contain a highly conserved carboxyl-terminal RGS domain that confers the catalytic function for active Gα subunits. Members of the R4/B subfamily, which include, among others, RGS 2, 4, and 5, are the smallest RGS Original received September 21, 2012; revision received January 7, 2013; accepted January 9, 2013. In December 2012, the average time from submission to first decision for all original research papers submitted to Circulation Research was 14.5 days.

Preeclampsia is a systemic vascular disorder of pregnancy and is associated with increased sensitivity to angiotensin II (AngII) and hypertension. The cause of preeclampsia remains unknown. We identified the role of regulator of G protein (heterotrimeric guanine nucleotide-binding protein) signaling 5 (RGS5) in blood pressure regulation during pregnancy and preeclampsia. RGS5 expression in human myometrial vessels is markedly suppressed in gestational hypertension and/or preeclampsia. In pregnant RGS5-deficient mice, reduced vascular RGS5 expression causes gestational hypertension by enhancing vascular sensitivity to AngII. Further challenge by increasing AngII results in preeclampsia-like symptoms, namely, more severe hypertension, proteinuria, placental pathology, and reduced birth weight. In pregnant heterozygote null mice, treatment with peroxisome proliferator-activated receptor (PPAR) agonists normalizes vascular function and blood pressure through effects on RGS5. These findings highlight a key role of RGS5 at the interface between AngII and PPAR signaling. Because preeclampsia is refractory to current standard therapies, our study opens an unrecognized and urgently needed opportunity for treatment of gestational hypertension and preeclampsia.

As the population of the world increases, there will be larger numbers of people with dementia and an emerging need for prompt diagnosis and treatment. Early dementia screening is the process by which a patient who might be in the prodromal phases of a dementing illness is determined as having, or not having, the hallmarks of a neurodegenerative condition. The concepts of mild cognitive impairment, or mild neurocognitive disorder, are useful in analyzing the patient in the prodromal phase of a dementing disease; however, the transformation to dementia may be as low as 10% per annum. The search for early dementia requires a comprehensive clinical evaluation, cognitive assessment, determination of functional status, corroborative history and imaging (including MRI, FDG-PET and maybe amyloid PET), cerebrospinal fluid (CSF) examination assaying Aβ1–42, T-τ and P-τ might also be helpful. Primary care physicians are fundamental in the screening process and are vital in initiating specialist investigation and treatment. Early dementia screening is especially important in an age where there is a search for disease modifying therapies, where there is mounting evidence that treatment, if given early, might influence the natural history—hence the need for cost-effective screening measures for early dementia.

The lack of an LPR, limited EPR and the absence of a link between the LPR and AHR highlight the limitations of this mouse model as a complete model of the lung dysfunction associated with asthma.

Burchell JT, Wikstrom ME, Stumbles PA, Sly PD, Turner DJ. Attenuation of allergen-induced airway hyperresponsiveness is mediated by airway regulatory T cells.

Summary The severity of allergic diseases may be modified by vitamin D. However, the immune pathways modulated by the active form of vitamin D, 1,25‐dihydroxyvitamin D3 [1,25(OH)2D3], are yet to be fully elucidated. In this study, naturally occurring CD4+ CD25+ cells from the skin‐draining lymph nodes (SDLN) of mice treated with topical 1,25(OH)2D3 had an increased ability to suppress T helper type 2 (Th2) ‐skewed immune responses. CD4+ CD25+ cells transferred from mice treated with topical 1,25(OH)2D3 into ovalbumin (OVA) ‐sensitized mice challenged intranasally with OVA 18 hr later, significantly suppressed the capacity of airway‐draining lymph node (ADLN) cells to proliferate and secrete cytokines in response to further OVA stimulation ex vivo. The CD4+ CD25+ cells from 1,25(OH)2D3‐treated mice also reduced airway hyperresponsiveness and the proportions of neutrophils and eosinophils in bronchoalveolar lavage fluid (BALF). To test the effect of 1,25(OH)2D3 on cells able to respond to a specific antigen, CD4+ CD25+ cells were purified from the SDLN of OVA‐T‐cell receptor (TCR) transgenic mice treated 4 days earlier with topical 1,25(OH)2D3. CD4+ CD25+ cells from OVA‐TCR mice treated with 1,25(OH)2D3 were able to alter BALF cell content and suppress ADLN responses to a similar degree to those cells from non‐transgenic mice, suggesting that the effect of 1,25(OH)2D3 was not related to TCR signalling. In summary, topical 1,25(OH)2D3 increased the regulatory capacity of CD4+ CD25+ cells from the SDLN to suppress Th2‐mediated allergic airway disease. This work highlights how local 1,25(OH)2D3 production by lung epithelial cells may modulate the suppressive activity of local regulatory T cells.

ABSTRACT:Mycoplasmas are an important cause of upper respiratory tract disease (URTD) in desert tortoises (Gopherus agassizii) and have been a main focus in attempts to mitigate diseasebased population declines. Infection risk can vary with an animal's population of origin, making screening tests popular tools for determining infection status in individuals and populations. To provide additional methods for investigating URTD we developed quantitative PCR (qPCR) assays specific for agents causing clinical signs of URTD: Mycoplasma agassizii, Mycoplasma testudineum, and Testudinid herpesvirus 2 (TeHV2) and tested necropsied desert tortoises housed at the Desert Tortoise Conservation Center in Las Vegas, Nevada, USA, as well as wild desert tortoises (n53), during 2010. Findings were compared with M. agassizii enzyme-linked immunosorbent assay (ELISA) data. Based on qPCR, the prevalence of M. agassizii was 75% (33/44) and the prevalence of TeHV2 was 48% (20/42) in the evaluated population. Both agents were also present in the wild tortoises. Mycoplasma testudineum was not detected. The M. agassizii ELISA and qPCR results did not always agree. More tortoises were positive for M. agassizii by nasal mucosa testing than by nasal flush. Our findings suggest that mycoplasmas are not the only agents of concern and that a single M. agassizii ELISA or nasal flush qPCR alone failed to identify all potentially infected animals in a population. Caution should be exercised in using these tests for disposition decisions.

MethodsMycobacteria isolated from more than 100 birds diagnosed with avian mycobacteriosis at the San Diego Zoo and its Safari Park were cultured postmortem and had their whole genomes sequenced. Computational workflows were developed and applied to identify the mycobacterial species in each DNA sample, to find single-nucleotide polymorphisms (SNPs) between samples of the same species, to further differentiate SNPs between as many as three different genotypes within a single sample, and to identify which samples are closely clustered genomically.ResultsNine species of mycobacteria were found in 123 samples from 105 birds. The most common species were Mycobacterium avium and Mycobacterium genavense, which were in 49 and 48 birds, respectively. Most birds contained only a single mycobacterial species, but two birds contained a mixture of two species. The M. avium samples represent diverse strains of M. avium avium and M. avium hominissuis, with many pairs of samples differing by hundreds or thousands of SNPs across their common genome. By contrast, the M. genavense samples are much closer genomically; samples from 46 of 48 birds differ from each other by less than 110 SNPs. Some birds contained two, three, or even four genotypes of the same bacterial species. Such infections were found in 4 of 49 birds (8%) with M. avium and in 11 of 48 birds (23%) with M. genavense. Most were mixed infections, in which the bird was infected by multiple mycobacterial strains, but three infections with two genotypes differing by ≤ 10 SNPs were likely the result of within-host evolution. The samples from 31 birds with M. avium can be grouped into nine clusters within which any sample is ≤ 12 SNPs from at least one other sample in the cluster. Similarly, the samples from 40 birds with M. genavense can be grouped into ten such clusters. Information about these genomic clusters is being used in an ongoing, companion study of mycobacterial transmission to help inform management of bird collections.