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Clayton South, Australia

Frohlich E.,Center for Medical Research
NeuroQuantology | Year: 2010

Nerve cells (neurons) are the basis for processing and propagation of information in the nervous system. The morphology of neurons, the generation of action potentials and intercellular communication by chemical and electrotonic synapses is described and illustrated by schematic and electron microscopic pictures. Neurotransmitters are described according to their mode of action and the action of pharmaceutics and drugs on receptors and neurotransmitter levels is explained.


Davis W.A.,University of Western Australia | Brown S.G.A.,Center for Medical Research | Bulsara M.,The University of Notre Dame Australia | Beilby J.,University of Western Australia | And 2 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Aims/hypotheses: The aim of this study was to determine whether the angiotensin-converting\ enzyme (ACE) gene I/D polymorphisms independently predict severe hypoglycemia in communitydwelling type 2 patients. Methods: Six hundred and two patients who were ACE genotyped at baseline and assessed in 1998 were followed up to the end of June 2006. Severe hypoglycemia was defined as that requiring documented health service use as the primary diagnosis. Cox proportional hazards modeling was used to determine the predictors of first episode and zero-inflated negative binomial regression modeling identified predictors of frequency. Results: Forty-nine patients (8.1%) experienced 63 episodes of severe hypoglycemia. After adjusting for previously identified significant independent predictors of time to first episode, both ACE DDgenotypeandACEinhibitor therapy, but not their interaction,addedto themodel[hazard ratio (95% confidence interval): 2.34 (1.29-4.26), P = 0.006, and 1.77 (0.99-3.13), P = 0.052, respectively]. Similarly, after adjusting for previously identified risk factors for multiple episodes of severe hypoglycemia, ACE DD genotype was independently associated with increased risk [incidence relative risk (95% confidence interval): 1.80 (1.00-3.24), P = 0.050]. Conclusions/interpretation: ACE DD genotype was associated with an approximately 2-fold increased risk of the first episode of severe hypoglycemia and its subsequent frequency in well-characterized patients with type 2 diabetes. Consistent with previous case-control studies, ACE inhibitor therapy was a weak predictor of severe hypoglycemia. ACE I/D genotyping might provide useful adjunctive prognostic information when intensive glycemic control measures are contemplated. Copyright © 2011 by The Endocrine Society.


Geng S.,Wuhan University | Gao Y.-D.,Wuhan University | Yang J.,Wuhan University | Zou J.-J.,Wuhan University | Guo W.,Center for Medical Research
International Immunopharmacology | Year: 2012

Store-operated calcium entry (SOCE) is the main Ca 2 + influx pathway of dendritic cells (DCs). DCs primed with histamine facilitate Th2 immune response via different types of histamine receptors. Histamine induces DCs to release Ca 2 + from internal store. Therefore, we wonder that whether histamine could activate SOCE in DCs through its receptors, and what's the functional relevance of the Ca 2 + influx through SOCE induced by histamine in Th 2 response. We certificate that histamine induced a transient Ca 2 + release followed by pronounced Ca 2 + influx after re-addition of external Ca 2 + which could be inhibited by SOCE blockers SKF-96365 and BTP-2. Moreover, the percentages of DCs that showed an obvious Ca 2 + release response to histamine were decreased in the presence of histamine 1 (H1) receptor antagonist pyridylethylamine (Pyr) or histamine 4 (H4) receptor antagonist JNJ7777120 (JNJ). Histamine up-regulated the mRNA expression of STIM1 in DCs, one of the two major proteins of SOCE channel. SOCE blocker BTP-2 and histamine receptor antagonists JNJ and Pyr inhibited the increase of CD86 induced by histamine on DCs. Histamine increased the level of IL-10 and decreased the level of IL-12p70 secreted by DCs. SOC blockers SKF and BTP-2 inhibited the level of both IL-10 and IL-12p70 secreted by DCs. Pretreatment of SOC blockers and H1, H4 receptor antagonists with DCs inhibited the Th2 polarization of T helper cells induced by histamine in mixed lymphocyte responses (MLR). We demonstrated that SOCE was involved in histamine-induced maturation and Th 2 response of DCs which was through histamine 1 and 4 receptor. © 2011 Elsevier B.V. All rights reserved.


Yeap B.B.,Center for Medical Research | Alfonso H.,Western Australian Center for Health and Ageing | Chubb S.A.P.,Center for Medical Research | Chubb S.A.P.,PathWest Laboratory Medicine | And 5 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Context: Testosterone (T) levels decline with increasing age. Controversy exists over the threshold for classifying T as low vs. normal in older men. The relevance of assessing dihydrotestosterone (DHT) and estradiol (E2) remains unclear. Objective: We assessed the associations of T, DHT, and E2 in men aged 70 yr or older and established reference ranges for these in healthy older men. Participants: Community-dwelling men aged 70-89 yr residing in Perth, Western Australia, Australia, participated in the study. Main Outcome Measures: Plasma T, DHT, and E2 were assayed using liquid chromatography-tandem mass spectrometry in early morning samples from 3690 men. Results: Increasing age, higher body mass index and waist to hip ratio, dyslipidemia, diabetes, and higher LH were independently associated with lower levels of T and DHT. Increasing age, diabetes, and higher LH were associated with lower E2. In a reference group of 394 men aged 76.1 ± 3.2 yr reporting excellent or very good health with no history of smoking, diabetes, cardiovascular disease, cancer, depression, or dementia, the 2.5th percentile for T was 6.4 nmol/liter (184 ng/dl); DHT, 0.49 nmol/liter; and E2, 28 pmol/liter. Applying these cutoffs to all 3690 men, those with low T or DHT had an increased odds ratio for frailty, diabetes, and cardiovascular disease. Men with both low T and DHT had a higher odds ratio for these outcomes. Conclusions: The 2.5th percentile in a reference group of healthy older men provides age-appropriate thresholds for defining low T, DHT, and E2. Additional studies are needed to test their potential applicability and clinical utility in older men. Copyright © 2012 by The Endocrine Society.


Warstat K.,Center for Regenerative Medicine | Hoberg M.,TU Munich | Rudert M.,TU Munich | Tsui S.,University of California at Los Angeles | And 8 more authors.
Annals of the Rheumatic Diseases | Year: 2010

Objectives: In synovial tissues of patients with rheumatoid arthritis (RA), strong expression of laminins and integrins co-localises with increased expression of inflammatory cytokines. Synovial fibroblasts (SF) contribute to the pathogenesis of RA through increased expression of cytokines and chemoattractant factors, one of which is interleukin-16 (IL16). A study was undertaken to investigate the regulatory pathways of IL16 in SF from patients with RA (RA-SF) and osteoarthritis (OA-SF). Methods: SF were seeded in laminin-coated flasks and activated by the addition of cytokines. The expression of IL16 was investigated by quantitative RT-PCR, immunoblotting and ELISA; its biological activity was determined by a cell migration assay. Cell-matrix interactions were investigated by cell binding and attachment assays. Relevant intracellular signalling pathways were studied by immunoblotting and with pharmacological blocking reagents. Results: Stimulation of SF with transforming growth factor β1 (TGF-β1) and growth on laminin-111 (LM-111) significantly increased the expression of IL16. Binding to LM-111 induced significantly more IL16 mRNA in RA-SF than in OA-SF (p<0.05). The IL16 cytokine was detected in supernatants of TGF-β1- activated and in LM-111+TGF-β1-activated RA-SF (38 to 62 pg/ml), but not in supernatants of OA-SF. This IL16 regulation involved p38MAPK, ERK1/2 and SMAD2 signalling, but not NFκB. Conclusions: Binding of RA-SF to LM-111 in the presence of TGF-β1 triggers a significant IL16 response and thus may contribute to the infiltration of CD4+ lymphocytes into synovial tissues. This mode of IL16 induction represents a novel pathway leading to IL16 production in RA-SF but not in OA-SF, which operates independently of NFκB signalling.

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