Propentofylline Targets TROY, a Novel Microglial Signaling Pathway

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain cancer, with a median survival of less than 2 years after diagnosis with current available therapies. The tumor microenvironment serves a critical role in tumor invasion and progression, with microglia as a critical player. Our laboratory has previously demonstrated that propentofylline, an atypical methylxanthine with central nervous system glial modulating and anti-inflammatory actions, significantly decreases tumor growth in a GBM rodent model by preferentially targeting microglia. In the present study, we used the CNS-1 rat glioma model to elucidate the mechanisms of propentofylline. Here we demonstrate that propentofylline targets TROY, a novel signaling molecule up-regulated in infiltrating microglia, and not macrophages, in response to CNS-1 cells. We identify Pyk2, Rac1 and pJNK as the downstream signaling molecules of TROY through western blot analysis and siRNA transfection. We demonstrate that inhibition of TROY expression in microglia by siRNA transfection significantly inhibits microglial migration towards CNS-1 cells similar to 10 µM propentofylline treatment. These results identify TROY as a novel molecule expressed in microglia, involved in their migration and targeted by propentofylline. Furthermore, these results describe a signaling molecule that is differentially expressed between microglia and macrophages in the tumor microenvironment

Evaluating the Connect with Pharmacy web-based intervention to reduce hospital readmission for older people

YesBackground The patient transition from a hospital to a post-discharge healthcare setting has potential to disrupt continuity of medication management and increase the risk of harm. “Connect with Pharmacy” is a new electronic web-based transfer of care initiative employed by Leeds Teaching Hospitals NHS Trust. This allows the sharing of discharge information between the hospital and a patient’s chosen community pharmacy. Objective We investigated whether the timely sharing of discharge information with community pharmacies via “Connect with Pharmacy” reduced hospital readmission rates in older patients. Method To evaluate intervention efficacy, hospital admission data was retrospectively collected. For primary analysis, admission rates were tracked 6-months prior (baseline) and 6-months post-intervention. Secondary measures included effect on total length of stay if readmitted, emergency department attendance and duration, and impact of polypharmacy. Main outcome measure The rate of non-elective hospital readmissions, 6-months post-intervention. Results In the sample (n = 627 patients; Mean age = 81 years), emergency readmission rates following the intervention (M = 1.1, 95% CI [0.98, 1.22]) reduced by 16.16% relative to baseline (M = 1.31, 95% CI [1.21, 1.42]) (W = 54,725; p < 0.001). There was no reduction in total length of stay. Subsidiary analysis revealed a post-intervention reduction in number of days spent in hospital lasting more than three days (χ2 = 13.37, df = 1, p < 0 .001). There were no statistically reliable differences in the remaining secondary measures. Conclusion The results showed a reduction in readmissions and potential post-intervention length of stay, indicating there may be further benefits for our older patients’ experiences and hospital flow

Can working with the private for-profit sector improve utilization of quality health services by the poor? A systematic review of the literature

BACKGROUND: There has been a growing interest in the role of the private for-profit sector in health service provision in low- and middle-income countries. The private sector represents an important source of care for all socioeconomic groups, including the poorest and substantial concerns have been raised about the quality of care it provides. Interventions have been developed to address these technical failures and simultaneously take advantage of the potential for involving private providers to achieve public health goals. Limited information is available on the extent to which these interventions have successfully expanded access to quality health services for poor and disadvantaged populations. This paper addresses this knowledge gap by presenting the results of a systematic literature review on the effectiveness of working with private for-profit providers to reach the poor. METHODS: The search topic of the systematic literature review was the effectiveness of interventions working with the private for-profit sector to improve utilization of quality health services by the poor. Interventions included social marketing, use of vouchers, pre-packaging of drugs, franchising, training, regulation, accreditation and contracting-out. The search for published literature used a series of electronic databases including PubMed, Popline, HMIC and CabHealth Global Health. The search for grey and unpublished literature used documents available on the World Wide Web. We focused on studies which evaluated the impact of interventions on utilization and/or quality of services and which provided information on the socioeconomic status of the beneficiary populations. RESULTS: A total of 2483 references were retrieved, of which 52 qualified as impact evaluations. Data were available on the average socioeconomic status of recipient communities for 5 interventions, and on the distribution of benefits across socioeconomic groups for 5 interventions. CONCLUSION: Few studies provided evidence on the impact of private sector interventions on quality and/or utilization of care by the poor. It was, however, evident that many interventions have worked successfully in poor communities and positive equity impacts can be inferred from interventions that work with types of providers predominantly used by poor people. Better evidence of the equity impact of interventions working with the private sector is needed for more robust conclusions to be drawn

Patient preferences and treatment safety for uncomplicated vulvovaginal candidiasis in primary health care

<p>Abstract</p> <p>Background</p> <p>Vaginitis is a common complaint in primary care. In uncomplicated candidal vaginitis, there are no differences in effectiveness between oral or vaginal treatment. Some studies describe that the preferred treatment is the oral one, but a Cochrane's review points out inconsistencies associated with the report of the preferred way that limit the use of such data. Risk factors associated with recurrent vulvovaginal candidiasis still remain controversial.</p> <p>Methods/Design</p> <p>This work describes a protocol of a multicentric prospective observational study with one year follow up, to describe the women's reasons and preferences to choose the way of administration (oral vs topical) in the treatment of not complicated candidal vaginitis. The number of women required is 765, they are chosen by consecutive sampling. All of whom are aged 16 and over with vaginal discharge and/or vaginal pruritus, diagnosed with not complicated vulvovaginitis in Primary Care in Madrid.</p> <p>The main outcome variable is the preferences of the patients in treatment choice; secondary outcome variables are time to symptoms relief and adverse reactions and the frequency of recurrent vulvovaginitis and the risk factors. In the statistical analysis, for the main objective will be descriptive for each of the variables, bivariant analysis and multivariate analysis (logistic regression).. The dependent variable being the type of treatment chosen (oral or topical) and the independent, the variables that after bivariant analysis, have been associated to the treatment preference.</p> <p>Discussion</p> <p>Clinical decisions, recommendations, and practice guidelines must not only attend to the best available evidence, but also to the values and preferences of the informed patient.</p

Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics

In December 2016, a panel of experts in microbiology, nutrition and clinical research was convened by the International Scientific Association for Probiotics and Prebiotics to review the definition and scope of prebiotics. Consistent with the original embodiment of prebiotics, but aware of the latest scientific and clinical developments, the panel updated the definition of a prebiotic: a substrate that is selectively utilized by host microorganisms conferring a health benefit. This definition expands the concept of prebiotics to possibly include non-carbohydrate substances, applications to body sites other than the gastrointestinal tract, and diverse categories other than food. The requirement for selective microbiota-mediated mechanisms was retained. Beneficial health effects must be documented for a substance to be considered a prebiotic. The consensus definition applies also to prebiotics for use by animals, in which microbiota-focused strategies to maintain health and prevent disease is as relevant as for humans. Ultimately, the goal of this Consensus Statement is to engender appropriate use of the term ‘prebiotic’ by relevant stakeholders so that consistency and clarity can be achieved in research reports, product marketing and regulatory oversight of the category. To this end, we have reviewed several aspects of prebiotic science including its development, health benefits and legislation

Tissue transglutaminase induction in the pressure-overloaded myocardium regulates matrix remodelling

Aims Tissue transglutaminase (tTG) is induced in injured and remodelling tissues, and modulates cellular phenotype, while contributing to matrix cross-linking. Our study tested the hypothesis that tTG may be expressed in the pressure-overloaded myocardium, and may regulate cardiac function, myocardial fibrosis and chamber remodelling. Methods and results In order to test the hypothesis, wild-type and tTG null mice were subjected to pressure overload induced through transverse aortic constriction. Moreover, we used isolated cardiac fibroblasts and macrophages to dissect the mechanisms of tTG-mediated actions. tTG expression was upregulated in the pressure-overloaded mouse heart and was localized in cardiomyocytes, interstitial cells, and in the extracellular matrix. In contrast, expression of transglutaminases 1, 3, 4, 5, 6, 7 and FXIII was not induced in the remodelling myocardium. In vitro, transforming growth factor (TGF)-beta 1 stimulated tTG synthesis in cardiac fibroblasts and in macrophages through distinct signalling pathways. tTG null mice had increased mortality and enhanced ventricular dilation following pressure overload, but were protected from diastolic dysfunction. tTG loss was associated with a hypercellular cardiac interstitium, reduced collagen cross-linking, and with accentuated matrix metalloproteinase (MMP) 2 activity in the pressure-overloaded myocardium. In vitro, tTG did not modulate TGF-beta-mediated responses in cardiac fibroblasts; however, tTG loss was associated with accentuated proliferative activity. Moreover, when bound to the matrix, recombinant tTG induced synthesis of tissue inhibitor of metalloproteinases (TIMP)-1 through transamidase-independent actions. Conclusions Following pressure overload, endogenous tTG mediates matrix cross-linking, while protecting the remodelling myocardium from dilation by exerting matrix-preserving actions