Local activation of cannabinoid CB1 receptors in the urinary bladder reduces the inflammation-induced sensitization of bladder afferents

<p>Abstract</p> <p>Background</p> <p>Systemic administration of cannabinoid agonists is known to reduce pain induced by bladder inflammation and to modulate cystometric parameters <it>in vivo</it>. We have previously reported that intravesical administration of a cannabinoid agonist reduces the electrical activity of bladder afferents under normal conditions. However, the effects of local activation of bladder cannabinoid receptors on afferent activity during inflammation are unknown. This study was aimed to assess the effects of intravesical administration of a cannabinoid agonist on the discharges of afferent fibers in inflamed bladders <it>ex vivo</it>. We also characterized the expression of CB₁receptors in the bladder and their localization and co-expression with TRPV1, a marker of nociceptive afferents.</p> <p>Results</p> <p>Compared to untreated animals, afferent fiber activity in inflamed bladders was increased for intravesical pressures between 10 and 40 mmHg. Local treatment with a non selective cannabinoid agonist (AZ12646915) significantly reduced the afferent activity at intravesical pressures above 20 mmHg. This effect was blocked by AM251 but not by AM630 (selective for CB₁and CB₂respectively). Finally, CB₁was co-expressed with TRPV1 in control and inflamed bladders.</p> <p>Conclusion</p> <p>These results demonstrate that sensitization of bladder afferents induced by inflammation is partly suppressed by intravesical activation of cannabinoid receptors, an effect that appears to be mediated by CB₁receptors. Also, TRPV1 positive fibers were found to co-express CB₁, supporting the hypothesis of a direct action of the cannabinoid agonist on nociceptive afferents. Taken together, these results indicate a peripheral modulation by the cannabinoid system of bladder hypersensitivity during inflammation.</p

Immunological characterization and transcription profiling of peripheral blood (PB) monocytes in children with autism spectrum disorders (ASD) and specific polysaccharide antibody deficiency (SPAD): case study

<p>Abstract</p> <p>Introduction</p> <p>There exists a small subset of children with autism spectrum disorders (ASD) characterized by fluctuating behavioral symptoms and cognitive skills following immune insults. Some of these children also exhibit specific polysaccharide antibody deficiency (SPAD), resulting in frequent infection caused by encapsulated organisms, and they often require supplemental intravenous immunoglobulin (IVIG) (ASD/SPAD). This study assessed whether these ASD/SPAD children have distinct immunological findings in comparison with ASD/non-SPAD or non-ASD/SPAD children.</p> <p>Case description</p> <p>We describe 8 ASD/SPAD children with worsening behavioral symptoms/cognitive skills that are triggered by immune insults. These ASD/SPAD children exhibited delayed type food allergy (5/8), treatment-resistant seizure disorders (4/8), and chronic gastrointestinal (GI) symptoms (5/8) at high frequencies. Control subjects included ASD children without SPAD (N = 39), normal controls (N = 37), and non-ASD children with SPAD (N = 12).</p> <p>Discussion and Evaluation</p> <p>We assessed their innate and adaptive immune responses, by measuring the production of pro-inflammatory and counter-regulatory cytokines by peripheral blood mononuclear cells (PBMCs) in responses to agonists of toll like receptors (TLR), stimuli of innate immunity, and T cell stimulants. Transcription profiling of PB monocytes was also assessed. ASD/SPAD PBMCs produced less proinflammatory cytokines with agonists of TLR7/8 (IL-6, IL-23), TLR2/6 (IL-6), TLR4 (IL-12p40), and without stimuli (IL-1ß, IL-6, and TNF-α) than normal controls. In addition, cytokine production of ASD/SPAD PBMCs in response to T cell mitogens (IFN-γ, IL-17, and IL-12p40) and candida antigen (Ag) (IL-10, IL-12p40) were less than normal controls. ASD/non-SPAD PBMDs revealed similar results as normal controls, while non-ASD/SPAD PBMCs revealed lower production of IL-6, IL-10 and IL-23 with a TLR4 agonist. Only common features observed between ASD/SPAD and non-ASD/SPAD children is lower IL-10 production in the absence of stimuli. Transcription profiling of PB monocytes revealed over a 2-fold up (830 and 1250) and down (653 and 1235) regulation of genes in ASD/SPAD children, as compared to normal (N = 26) and ASD/non-SPAD (N = 29) controls, respectively. Enriched gene expression of TGFBR (p < 0.005), Notch (p < 0.01), and EGFR1 (p < 0.02) pathways was found in the ASD/SPAD monocytes as compared to ASD/non-SPAD controls.</p> <p>Conclusions</p> <p>The Immunological findings in the ASD/SPAD children who exhibit fluctuating behavioral symptoms and cognitive skills cannot be solely attributed to SPAD. Instead, these findings may be more specific for ASD/SPAD children with the above-described clinical characteristics, indicating a possible role of these immune abnormalities in their neuropsychiatric symptoms.</p

cis-Urocanic Acid Attenuates Acute Dextran Sodium Sulphate-Induced Intestinal Inflammation

On exposure to sunlight, urocanic acid (UCA) in the skin is converted from trans to the cis form and distributed systemically where it confers systemic immunosuppression. The aim of this study was to determine if administration of cis-UCA would be effective in attenuating colitis and the possible role of IL-10. Colitis was induced in 129/SvEv mice by administering 5% dextran sodium sulfate (DSS) for 7 days in drinking water. During this period mice received daily subcutaneously injections of cis-UCA or vehicle. To examine a role for IL-10, 129/SvEv IL-10−/− mice were injected for 24 days with cis-UCA or vehicle. Clinical disease was assessed by measurement of body weight, stool consistency, and presence of blood. At sacrifice, colonic tissue was collected for histology and measurement of myeloperoxidase and cytokines. Splenocytes were analyzed for CD4+CD25+FoxP3+ T-regulatory cells via flow cytometry. Murine bone-marrow derived antigen-presenting cells were treated with lipopolysaccharide (LPS) ± UCA and cytokine secretion measured. Our results demonstrated that cis-UCA at a dose of 50 µg was effective in ameliorating DSS-induced colitis as evidenced by reduced weight loss and attenuated changes in colon weight/length. This protection was associated with reduced colonic expression of CXCL1, an increased expression of IL-17A and a significant preservation of splenic CD4+CD25+FoxP3+ T-regulatory cells. cis-UCA decreased LPS induced CXCL1, but not TNFα secretion, from antigen-presenting cells in vitro. UCA reduced colonic levels of IFNγ in IL-10−/− mice but did not attenuate colitis. In conclusion, this study demonstrates that cis-urocanic acid is effective in reducing the severity of colitis in a chemically-induced mouse model, indicating that pathways induced by ultraviolet radiation to the skin can influence distal sites of inflammation. This provides further evidence for a possible role for sunlight exposure in modulating inflammatory disorders

The Phrenic Component of Acute Schizophrenia – A Name and Its Physiological Reality

Decreased heart rate variability (HRV) was shown for unmedicated patients with schizophrenia and their first-degree relatives, implying genetic associations. This is known to be an important risk factor for increased cardiac mortality in other diseases. The interaction of cardio-respiratory function and respiratory physiology has never been investigated in the disease although it might be closely related to the pattern of autonomic dysfunction. We hypothesized that increased breathing rates and reduced cardio-respiratory coupling in patients with acute schizophrenia would be associated with low vagal function. We assessed variability of breathing rates and depth, HRV and cardio-respiratory coupling in patients, their first-degree relatives and controls at rest. Control subjects were investigated a second time by means of a stress task to identify stress-related changes of cardio-respiratory function. A total of 73 subjects were investigated, consisting of 23 unmedicated patients, 20 healthy, first-degree relatives and 30 control subjects matched for age, gender, smoking and physical fitness. The LifeShirt®, a multi-function ambulatory device, was used for data recording (30 minutes). Patients breathe significantly faster (p<.001) and shallower (p<.001) than controls most pronouncedly during exhalation. Patients' breathing is characterized by a significantly increased amount of middle- (p<.001), high- (p<.001), and very high frequency fluctuations (p<.001). These measures correlated positively with positive symptoms as assessed by the PANSS scale (e.g., middle frequency: r = 521; p<.01). Cardio-respiratory coupling was reduced in patients only, while HRV was decreased in patients and healthy relatives in comparison to controls. Respiratory alterations might reflect arousal in acutely ill patients, which is supported by comparable physiological changes in healthy subjects during stress. Future research needs to further investigate these findings with respect to their physiological consequences for patients. These results are invaluable for researchers studying changes of biological signals prone to the influence of breathing rate and rhythm (e.g., functional imaging)

Reliability of self-reported health risk factors and chronic conditions questions collected using the telephone in South Australia, Australia

Extent: 10p.Background: Accurate monitoring of health conditions and behaviours, and health service usage in the population, using an effective and economical method is important for planning and evaluation. This study examines the reliability of questions asked in a telephone survey by conducting a test/retest analysis of a range of questions covering demographic variables, health risk factors and self-reported chronic conditions among people aged 16 years and over. Methods: A Computer Assisted Telephone Interviewing (CATI) survey on health issues of South Australians was re-administered to a random sub-sample of 154 respondents between 13-35 days (mean 17) after the original survey. Reliability between questions was assessed using Cohen’s kappa and intraclass correlation coefficients. Results: Demographic questions (age, gender, number of adults and children in the household, country of birth) showed extremely high reliability (0.97 to 1.00). Health service use (ICC = 0.90 95% CI 0.86-0.93) and overall health status (Kappa = 0.60 95% CI 0.46-0.75) displayed moderate agreement. Questions relating to self-reported risk factors such as smoking (Kappa = 0.81 95% CI 0.72-0.89) and alcohol drinking (ICC 0.75 = 95% CI 0.63-0.83) behaviour showed good to excellent agreement, while questions relating to self-reported risk factors such as time spent walking for physical activity (ICC 0.47 = 95% CI 0.27-0.61), fruit (Kappaw = 0.60 95% CI 0.45-0.76) and vegetable consumption (Kappaw = 0.50 95% CI 0.32-0.69) showed only moderate agreement. Self-reported chronic conditions displayed substantial to almost perfect agreement (0.72 to 1.00) with the exception of moderate agreement for heart disease (Kappa = 0.82 95% CI 0.57-0.99). Conclusion: These results show the questions assessed to be reliable in South Australia for estimating health conditions and monitoring health related behaviours using a CATI survey.Eleonora Dal Grande, Simon Fullerton and Anne W Taylo

25th Annual Computational Neuroscience Meeting: CNS-2016

Abstracts of the 25th Annual Computational Neuroscience Meeting: CNS-2016 Seogwipo City, Jeju-do, South Korea. 2–7 July 201