Platelet phenotype changes associated with breast cancer and its treatment

Platelets and their granular contents influence both angiogenesis and breast cancer progression. This study was performed to assess the effect of breast cancer and its treatment on platelet biology and the response to inhibition of the platelet P2Y12 receptor. Receptor-specific platelet activation and inhibition was studied for three platelet-associated proteins important in cancer angiogenesis and progression, vascular endothelial growth factor (VEGF), thrombospondin1 (TSP1), and transforming growth factor beta 1 (TGF-β1).

Twenty-four women with active breast cancer and 10 healthy controls not receiving antiplatelet therapy participated in the study. Ex vivo activation of platelets in whole blood was accomplished using PAR1AP, PAR4AP, convulxin, and ADP. Platelet inhibition was accomplished using the P2Y12 receptor antagonist cangrelor (the in vitro equivalent of clopidogrel). VEGF, TSP1, and TGF-β1 were measured using standard ELISA.

Platelet activation by ADP, PAR1, PAR4, and collagen receptors increased VEGF, TSP1, and TGF-β1 secretion in patients with breast cancer. Agonist-induced release of VEGF was greater in cancer patients as compared to healthy controls (p = 0.02 for ADP, p < 0.001 for PAR1AP, PAR4AP, and convulxin) despite a decrease in the efficiency of VEGF secretion in patients with breast cancer. These differences were not observed for TSP1 and TGF-β1 secretion. P2Y12 receptor inhibition decreased VEGF, TSP1, and TGF-β1 secretion. In patients with cancer, cangrelor inhibited TSP1 release to a greater extent than VEGF and TGF-β1 release. In patients with breast cancer, the magnitude of platelet inhibition achieved by cangrelor was greater than that achieved with healthy controls for all agonists and platelet proteins studied.

While platelets are known to influence progression of breast cancer, our results show that breast cancer and its treatment influence the platelet phenotype by increasing the secretion of pro-angiogenic proteins following platelet activation, modulating the efficiency of platelet protein release as well as increasing the response to antiplatelet therapy.     

TGF-β1 enhances cardiomyogenic differentiation of skeletal muscle-derived adult primitive cells

The optimal medium for cardiac differentiation of adult primitive cells remains to be established. We quantitatively compared the efficacy of IGF-1, dynorphin B, insulin, oxytocin, bFGF, and TGF-β1 in inducing cardiomyogenic differentiation. Adult mouse skeletal muscle-derived Sca1+/CD45-/c-kit-/Thy-1+ (SM+) and Sca1-/CD45-/c-kit-/Thy-1+ (SM-) cells were cultured in basic medium (BM; DMEM, FBS, IGF-1, dynorphin B) alone and BM supplemented with insulin, oxytocin, bFGF, or TGF-β1. Cardiac differentiation was evaluated by the expression of cardiac-specific markers at the mRNA (qRT-PCR) and protein (immunocytochemistry) levels. BM+TGF-β1 upregulated mRNA expression of Nkx2.5 and GATA-4 after 4 days and Myl2 after 9 days. After 30 days, BM+TGF-β1 induced the greatest extent of cardiac differentiation (by morphology and expression of cardiac markers) in SM- cells. We conclude that TGF-β1 enhances cardiomyogenic differentiation in skeletal muscle-derived adult primitive cells. This strategy may be utilized to induce cardiac differentiation as well as to examine the cardiomyogenic potential of adult tissue-derived stem/progenitor cells. Electronic supplementary material  The online version of this article (DOI:) contains supplementary material, which is available to authorized users. Returned for 1. Revision: 8 January 2008 1. Revision received: 8 April 2008 Ahmed Abdel-Latif and Ewa K. Zuba-Surma contributed equally to this work.     

Geoepidemiology of systemic vasculitis: comparison of the incidence in two regions of Europe

OBJECTIVE: The aetiopathogenesis of the primary systemic vasculitides (PSV) is unknown but includes both environmental and genetic factors. The development of classification criteria/definitions for PSV allows comparison of the epidemiology between different regions. METHODS: The same methods and the American College of Rheumatology (1990) criteria or Chapel Hill definitions were used to compare the epidemiology of Wegener's granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis, and polyarteritis nodosa in Norwich (east England population 413 500) and Lugo (northwest Spain population 204 100). Patients with PSV were identified between 1 January 1988 and 31 December 1998. RESULTS: Overall, the incidence of PSV in adults was almost equal in Norwich (18.9/million) and Spain (18.3/million). The incidence of Wegener's granulomatosis in Norwich (10.6/million) was greater than in Spain (4.9/million). There was a marked age-specific increase in incidence in Norwich with a peak age 65-74 years (52.9/million), but a virtually equal age distribution between ages 45 and 74 in Lugo (34.1/million). There was no significant increase with time in either population, or evidence of cyclical changes in incidence. CONCLUSION: These data support the suggestion that environmental factors may be important in the pathogenesis of PSV.     

The organic solute transporter alpha-beta, Ostalpha-Ostbeta, is essential for intestinal bile acid transport and homeostasis

The apical sodium-dependent bile acid transporter (Asbt) is responsible for transport across the intestinal brush border membrane; however, the carrier(s) responsible for basolateral bile acid export into the portal circulation remains to be determined. Although the heteromeric organic solute transporter Ostalpha-Ostbeta exhibits many properties predicted for a candidate intestinal basolateral bile acid transporter, the in vivo functions of Ostalpha-Ostbeta have not been investigated. To determine the role of Ostalpha-Ostbeta in intestinal bile acid absorption, the Ostalpha gene was disrupted by homologous recombination in mice. Ostalpha(-/-) mice were physically indistinguishable from wild-type mice. In everted gut sac experiments, transileal transport of taurocholate was reduced by >80% in Ostalpha(-/-) vs. wild-type mice; the residual taurocholate transport was further reduced to near-background levels in gut sacs prepared from Ostalpha(-/-)Mrp3(-/-) mice. The bile acid pool size was significantly reduced (>65%) in Ostalpha(-/-) mice, but fecal bile acid excretion was not elevated. The decreased pool size in Ostalpha(-/-) mice resulted from reduced hepatic Cyp7a1 expression that was inversely correlated with ileal expression of fibroblast growth factor 15 (FGF15). These data indicate that Ostalpha-Ostbeta is essential for intestinal bile acid transport in mice. Unlike a block in intestinal apical bile acid uptake, genetic ablation of basolateral bile acid export disrupts the classical homeostatic control of hepatic bile acid biosynthesis.     

Geriatrics training in general internal medicine fellowship programs: current practice, barriers, and strategies for improvement

To ensure its growth and prosperity, general internal medicine will need to embrace care of the elderly, research on aging, and geriatrics education as components of its core mission. Experts agree that general internal medicine fellows could benefit from increased opportunities in research on aging and geriatrics education; however, important barriers will hamper efforts to integrate geriatrics training into general internal medicine fellowship programs. This article reviews the barriers to integration and proposes solutions for overcoming those barriers. As a result of interviews and meetings with a broad representation of general internists, geriatricians, funding agencies, and policymakers, we propose 2 interventions: 1) the development of institutional program grants to foster collaboration between general internal medicine and geriatrics faculty in the training of general internal medicine fellows and 2) the creation of a 3-year fellowship program combining general internal medicine and geriatrics. This article discusses the importance of evaluating these and other programs intended to increase the geriatrics experience of general internal medicine fellows, and it describes the potential implications of these changes for a broad array of stakeholder institutions.     

Latent learning of spatial information is impaired in middle‐aged rats

The present study determined if the middle age related impairment that occurs with nonspatial latent learning also occurs in spatial latent learning. Thirty young (3‐months‐old) and 30 middle‐aged (12‐months‐old) male Sprague–Dawley rats were given either pre‐exposure to spatial cues surrounding a Barnes maze (SpatialPX), or pre‐exposure to just the maze (MazePX). They were then given 10 training trials in which they had to find a hidden escape box while experiencing an aversive environment produced by bright lights and wind. Results showed that young rats given the SpatialPX condition demonstrated faster escape latencies and fewer errors than young rats given the MazePX condition. However, middle‐aged rats given the SpatialPX condition did not show this improved performance. These findings indicate that the middle age learning deficit is not task specific, but rather is a general impairment in latent learning, possibly due to the early degeneration of the entorhinal cortex. © 2012 Wiley Periodicals, Inc. Dev Psychobiol 55: 309–315, 2013     

Illness and infection in elite full-contact football-code sports: A systematic review

ObjectivesFull-contact football-code team sports offer a unique environment for illness risk. During training and match-play, players are exposed to high-intensity collisions which may result in skin-on-skin abrasions and transfer of bodily fluids. Understanding the incidence of all illnesses and infections and what impact they cause to time-loss from training and competition is important to improve athlete care within these sports. This review aimed to systematically report, quantify and compare the type, incidence, prevalence and count of illnesses across full-contact football-code team sports.Design/methodsA systematic search of Cochrane Library, MEDLINE, SPORTDiscus, PsycINFO and CINAHL electronic databases was performed from inception to October 2019; keywords relating to illness, athletes and epidemiology were used. Studies were excluded if they did not quantify illness or infection, involve elite athletes, investigate full-contact football-code sports or were review articles.ResultsTwenty-eight studies met the eligibility criteria. Five different football-codes were reported: American football (n = 10), Australian rules football (n = 3), rugby league (n = 2), rugby sevens (n = 3) and rugby union (n = 9). One multi-sport study included both American football and rugby union. Full-contact football-code athletes are most commonly affected by respiratory system illnesses. There is a distinct lack of consensus of illness monitoring methodology.ConclusionsFull-contact football-code team sport athletes are most commonly affected by respiratory system illnesses. Due to various monitoring methodologies, illness incidence could only be compared between studies that used matching incidence exposure measures. High-quality illness surveillance data collection is an essential component to undertake effective and targeted illness prevention in athletes.     

A Review of Neuroimaging Studies in Persistent Postural-Perceptual Dizziness (PPPD)

Persistent postural-perceptual dizziness (PPPD) is a functional vestibular disease characterized by persistent dizziness, unsteadiness, and/or non-spinning vertigo, and is the most common vestibular syndrome in young adults. A stiffened postural control strategy, shift to reliance on visual over vestibular information, and hypervigilance to the environment have been suggested as possible pathophysiological mechanisms of PPPD. However, the exact mechanisms remain unclear. Recently, neuroimaging studies using magnetic resonance imaging and single photon emission computed tomography have provided pivotal insights into the pathophysiology of PPPD. The aim of this review was to evaluate and summarize the existing data on neuroimaging studies in PPPD. In summary, these studies fairly consistently reported decreased brain structure, function, and connectivity among the areas involved in multisensory vestibular processing and spatial cognition, and increased function and connectivity in the visual processing areas in patients with PPPD. The detected brain changes might reflect maladaptive and compensatory mechanisms including dysfunctional integration of multisensory vestibular information and visual dependence. Notably, various factors including personality traits (i.e., neuroticism), psychiatric comorbidities (i.e., anxiety and depression), and triggering factors (i.e., peripheral vestibular lesions) seem to modulate brain functional activity and connectivity patterns, possibly accounting for some differences across the results. Future studies should carefully control for these confounding effects in order to draw firm conclusions.