Neuregulin-1 attenuates mortality associated with experimental cerebral malaria.

BackgroundCerebral Malaria (CM) is a diffuse encephalopathy caused by Plasmodium falciparum infection. Despite availability of antimalarial drugs, CM-associated mortality remains high at approximately 30% and a subset of survivors develop neurological and cognitive disabilities. While antimalarials are effective at clearing Plasmodium parasites they do little to protect against CM pathophysiology and parasite-induced brain inflammation that leads to seizures, coma and long-term neurological sequelae in CM patients. Thus, there is urgent need to explore therapeutics that can reduce or prevent CM pathogenesis and associated brain inflammation to improve survival. Neuregulin-1 (NRG-1) is a neurotrophic growth factor shown to protect against brain injury associated with acute ischemic stroke (AIS) and neurotoxin exposure. However, this drug has not been tested against CM-associated brain injury. Since CM-associated brain injuries and AIS share similar pathophysiological features, we hypothesized that NRG-1 will reduce or prevent neuroinflammation and brain damage as well as improve survival in mice with late-stage experimental cerebral malaria (ECM).MethodsWe tested the effects of NRG-1 on ECM-associated brain inflammation and mortality in P. berghei ANKA (PbA)-infected mice and compared to artemether (ARM) treatment; an antimalarial currently used in various combination therapies against malaria.ResultsTreatment with ARM (25 mg/kg/day) effectively cleared parasites and reduced mortality in PbA-infected mice by 82%. Remarkably, NRG-1 therapy (1.25 ng/kg/day) significantly improved survival against ECM by 73% despite increase in parasite burden within NRG-1-treated mice. Additionally, NRG-1 therapy reduced systemic and brain pro-inflammatory factors TNFalpha, IL-6, IL-1alpha and CXCL10 and enhanced anti-inflammatory factors, IL-5 and IL-13 while decreasing leukocyte accumulation in brain microvessels.ConclusionsThis study suggests that NRG-1 attenuates ECM-associated brain inflammation and injuries and may represent a novel supportive therapy for the management of CM

Towards Understanding Apparent South Australian GP Resistance to Adopting Health Informatics Systems

This paper reports on a qualitative study of the attitudes of 23 South Australian practitioners in General Practice (GP) towards adopting an unspecified data amalgamating Health Informatics (HI) system. Findings suggest key areas of concern are associated with the potential for diminution of control over change and adoption was primarily influenced by a perceived need to protect the role and value of GPs. If change was seen as involuntary, uncertain or without demonstrable benefit to relevant patient outcomes, the prospect of change tended to manifest as passive or active GP resistance. Findings suggest increased exposure to use of HI systems influences GP perception of both the importance and certainty of potential implementation outcomes. It was concluded that discrete attitudes towards the use of HIS technology could be identified. Determined by contextual GP perceptions of competing managerial, technological and political factors, they are not mutually exclusive and more appropriately seen as a series of developmental and co-existing perspectives

Understanding South Australian GP Attitudes Towards Health Informatics Systems

This paper reports on the attitudes of 20 practitioners in South Australian General Practice towards adopting Health Informatics (HI) systems. HI systems are aimed at improving the overall quality and management of healthcare, but adoption of the technology may require a change in the General Practitioner’s (GP) approach to the way they perform their healthcare delivery role. This qualitative study found HI adoption was primarily influenced by the perceived potential for change in the professional’s value and role. While GPs were generally reluctant to consider technological innovation that was not perceived to demonstrate potential for improvement in patient health outcomes, increased exposure to HI systems positively influenced perceptions of both the importance and the certainty of potential implementation outcomes. It was concluded that GP attitudes could be characterised by four different perspectives of HI systems use in general practice medicine delivery

Heme Mediated STAT3 Activation in Severe Malaria

The mortality of severe malaria [cerebral malaria (CM), severe malaria anemia (SMA), acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)] remains high despite the availability associated with adequate treatments. Recent studies in our laboratory and others have revealed a hitherto unknown correlation between chemokine CXCL10/CXCR3, Heme/HO-1 and STAT3 and cerebral malaria severity and mortality. Although Heme/HO-1 and CXCL10/CXCR3 interactions are directly involved in the pathogenesis of CM and fatal disease, the mechanism dictating how Heme/HO-1 and CXCL10/CXCR3 are expressed and regulated under these conditions is still unknown. We therefore tested the hypothesis that these factors share common signaling pathways and may be mutually regulated.We first clarified the roles of Heme/HO-1, CXCL10/CXCR3 and STAT3 in CM pathogenesis utilizing a well established experimental cerebral malaria mouse (ECM, P. berghei ANKA) model. Then, we further determined the mechanisms how STAT3 regulates HO-1 and CXCL10 as well as mutual regulation among them in CRL-2581, a murine endothelial cell line.The results demonstrate that (1) STAT3 is activated by P. berghei ANKA (PBA) infection in vivo and Heme in vitro. (2) Heme up-regulates HO-1 and CXCL10 production through STAT3 pathway, and regulates CXCL10 at the transcriptional level in vitro. (3) HO-1 transcription is positively regulated by CXCL10. (4) HO-1 regulates STAT3 signaling.Our data indicate that Heme/HO-1, CXCL10/CXCR3 and STAT3 molecules as well as related signaling pathways play very important roles in the pathogenesis of severe malaria. We conclude that these factors are mutually regulated and provide new opportunities to develop potential novel therapeutic targets that could be used to supplement traditional prophylactics and treatments for malaria and improve clinical outcomes while reducing malaria mortality. Our ultimate goal is to develop novel therapies targeting Heme or CXCL10-related biological signaling molecules associated with development of fatal malaria

Evolving Adult ADHD Care: Preparatory Evaluation of a Prototype Digital Service Model Innovation for ADHD Care

Background: Given the prevalence of ADHD and the gaps in ADHD care in Australia, this study investigates the critical barriers and driving forces for innovation. It does so by conducting a preparatory evaluation of an ADHD prototype digital service innovation designed to help streamline ADHD care and empower individual self-management. Methods: Semi-structured interviews with ADHD care consumers/participants and practitioners explored their experiences and provided feedback on a mobile self-monitoring app and related service innovations. Interview transcripts were double coded to explore thematic barriers and the enablers for better ADHD care. Results: Fifteen interviews (9 consumers, 6 practitioners) revealed barriers to better ADHD care for consumers (ignorance and prejudice, trust, impatience) and for practitioners (complexity, sustainability). Enablers for consumers included validation/empowerment, privacy, and security frameworks, tailoring, and access. Practitioners highlighted the value of transparency, privacy and security frameworks, streamlined content, connected care between services, and the tailoring of broader metrics. Conclusions: A consumer-centred approach to digital health service innovation, featuring streamlined, private, and secure solutions with enhanced mobile tools proves instrumental in bridging gaps in ADHD care in Australia. These innovations should help to address the gaps in ADHD care in Australia. These innovations should encompass integrated care, targeted treatment outcome data, and additional lifestyle support, whilst recognising the tensions between customised functionalities and streamlined displays

Pharmacologic inhibition of CXCL10 in combination with anti-malarial therapy eliminates mortality associated with murine model of cerebral malaria.

Despite appropriate anti-malarial treatment, cerebral malaria (CM)-associated mortalities remain as high as 30%. Thus, adjunctive therapies are urgently needed to prevent or reduce such mortalities. Overproduction of CXCL10 in a subset of CM patients has been shown to be tightly associated with fatal human CM. Mice with deleted CXCL10 gene are partially protected against experimental cerebral malaria (ECM) mortality indicating the importance of CXCL10 in the pathogenesis of CM. However, the direct effect of increased CXCL10 production on brain cells is unknown. We assessed apoptotic effects of CXCL10 on human brain microvascular endothelial cells (HBVECs) and neuroglia cells in vitro. We tested the hypothesis that reducing overexpression of CXCL10 with a synthetic drug during CM pathogenesis will increase survival and reduce mortality. We utilized atorvastatin, a widely used synthetic blood cholesterol-lowering drug that specifically targets and reduces plasma CXCL10 levels in humans, to determine the effects of atorvastatin and artemether combination therapy on murine ECM outcome. We assessed effects of atorvastatin treatment on immune determinants of severity, survival, and parasitemia in ECM mice receiving a combination therapy from onset of ECM (day 6 through 9 post-infection) and compared results with controls. The results indicate that CXCL10 induces apoptosis in HBVECs and neuroglia cells in a dose-dependent manner suggesting that increased levels of CXCL10 in CM patients may play a role in vasculopathy, neuropathogenesis, and brain injury during CM pathogenesis. Treatment of ECM in mice with atorvastatin significantly reduced systemic and brain inflammation by reducing the levels of the anti-angiogenic and apoptotic factor (CXCL10) and increasing angiogenic factor (VEGF) production. Treatment with a combination of atorvastatin and artemether improved survival (100%) when compared with artemether monotherapy (70%), p<0.05. Thus, adjunctively reducing CXCL10 levels and inflammation by atorvastatin treatment during anti-malarial therapy may represent a novel approach to treating CM patients

The table displays biological processes or functions enhanced by Atorvastatin treatment identified by Ingenuity Pathway Analysis as significantly (p<0.05) associated with the dataset.

<p>The column ‘# of gene products’ gives the number of cytokines/chemokines from the dataset obtain from the network</p

Chlamydial infection in vitamin D receptor knockout mice is more intense and prolonged than in wild-type mice

Vitamin D hormone (1,25-dihydroxyvitamin D) is involved in innate immunity and induces host defense peptides in epithelial cells, suggesting its involvement in mucosal defense against infections. Chlamydia trachomatis is a major cause of bacterial sexually transmitted disease worldwide. We tested the hypothesis that the vitamin D endocrine system would attenuate chlamydial infection. Vitamin D receptor knock-out mice (VDR(−/−)) and wild-type mice (VDR(+/+)) were infected with 10(3) inclusion forming units of Chlamydia muridarum and cervical epithelial cells (HeLa cells) were infected with C. muridarum at multiplicity of infection 5:1 in the presence and absence of 1,25-dihydroxyvitamin D(3).VDR(−/−) mice exhibited significantly higher bacterial loading than wild-type VDR(+/+) mice (P<0.01) and cleared the chlamydial infection in 39 days, compared with 18 days for VDR(+/+) mice. Monocytes and neutrophils were more numerous in the uterus and oviduct of VDR(−/−) mice than in VDR(+/+) mice (P< 0.05) at d 45 after infection. Pre-treatment of HeLa cells with 10nM or 100nM 1,25-dihydroxyvitamin D(3) decreased the infectivity of C. muridarum (P< 0.001). Several differentially expressed protein spots were detected by proteomic analysis of chlamydial-infected HeLa cells pre-treated with 1,25-dihydroxyvitamin D(3). Leukocyte elastase inhibitor (LEI), an anti-inflammatory protein, was up-regulated. Expression of LEI in the ovary and oviduct of infected VDR(+/+) mice was greater than that of infected VDR(−/−) mice. We conclude that the vitamin D endocrine system reduces the risk for prolonged chlamydial infections through regulation of several proteins and that LEI is involved in its anti-inflammatory activity