Functional Interleukin-17 Receptor A is Expressed in Central Nervous System Glia and Upregulated in Experimental Autoimmune Encephalomyelitis

Background: Interleukin-17A (IL-17A) is the founding member of a novel family of inflammatory cytokines that plays a critical role in the pathogenesis of many autoimmune diseases, including multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). IL-17A signals through its receptor, IL-17RA, which is expressed in many peripheral tissues; however, expression of IL-17RA in the central nervous system (CNS) and its role in CNS inflammation are not well understood. Methods: EAE was induced in C57Bl/6 mice by immunization with myelin oligodendroglial glycoprotein. IL-17RA expression in the CNS was compared between control and EAE mice using RT-PCR, in situ hybridization, and immunohistochemistry. Cell-type specific expression was examined in isolated astrocytic and microglial cell cultures. Cytokine and chemokine production was measured in IL-17A treated cultures to evaluate the functional status of IL-17RA. Results: Here we report increased IL-17RA expression in the CNS of mice with EAE, and constitutive expression of functional IL-17RA in mouse CNS tissue. Specifically, astrocytes and microglia express IL-17RA in vitro, and IL-17A treatment induces biological responses in these cells, including significant upregulation of MCP-1, MCP-5, MIP-2 and KC chemokine secretion. Exogenous IL-17A does not significantly alter the expression of IL-17RA in glial cells, suggesting that upregulation of chemokines by glial cells is due to IL-17A signaling through constitutively expressed IL-17RA. Conclusion: IL-17RA expression is significantly increased in the CNS of mice with EAE compared to healthy mice, suggesting that IL-17RA signaling in glial cells can play an important role in autoimmune inflammation of the CNS and may be a potential pathway to target for therapeutic interventions. © 2009 Sarma et al; licensee BioMed Central Ltd.

No or only population-specific effect of PON1 on human longevity: A comprehensive meta-analysis

Paraoxonase 1 (PON1) has been suggested as a plausible candidate gene for human longevity due to its modulation of cardiovascular disease risk, by preventing oxidation of atherogenic low-density lipoprotein. The role of the PON1 192 Q/R polymorphism has been analyzed for association with survival at old age in several populations, albeit with controversial results. To reconcile the conflicting evidence, we performed a large association study with two samples of 2357 Germans and 1025 French, respectively. We combined our results with those from seven previous studies in the largest and most comprehensive meta-analysis on PON1 192 Q/R and longevity to-date, to include a total of 9580 individuals. No significant association of PON1 192 Q/R with longevity was observed, for either R allele or carriership. This finding relied on very large sample sizes, is supported by different analysis methods and is therefore considered very robust. Moreover, we have investigated a potential interaction of PON1 192 Q/R with APOE epsilon4 using data from four populations. Whereas a significant result was found in the German sample, this could not be confirmed in the other examined groups. Our large-scale meta-analysis provided no evidence that the PON1 192 Q/R polymorphism is associated with longevity, but this does not exclude the possibility of population-specific effects due to the influence of, and interaction between, different genetic and/or environmental factors (e.g. diet).

Validity of a 1 minute walk test for children with cerebral palsy.

The concurrent validity of a 1 minute walk test at a child's maximum walking speed was assessed in children with bilateral spastic cerebral palsy (BSCP). The distance covered during the 1 minute walk test was compared with the children's gross motor function as assessed by the Gross Motor Function Measure (GMFM). Twenty-four male and 10 female children with CP (mean age 11y, range 4 to 16y) participated in the study. Gross Motor Function Classification System (GMFCS) levels were; level I (n=3), level II (n=17), level III (n=10), and level IV (n=4). Participants had clinical diagnoses of symmetrical diplegia (n=19), asymmetrical diplegia (n=14), and quadriplegia (n=1). Results showed a significant correlation between GMFM score and the distance covered during the 1 minute walk (r=0.92; p<0.001). There was also a significant decrease in the distance walked with increasing GMFCS level (p<0.001). We concluded that the 1 minute walk test is a valid measure for assessing functional ability in children with ambulatory BSCP. Its cost-effectiveness and user friendliness make it a potentially useful tool in the clinical setting. Further study needs to address its reliability and ability to detect change over time.

Persistent measles virus infection of mouse neural cells lacking known human entry receptors

Aims: Infection of the mouse central nervous system with wild type (WT) and vaccine strains of measles virus (MV) results in lack of clinical signs and limited antigen detection. It is considered that cell entry receptors for these viruses are not present on murine neural cells and infection is restricted at cell entry.

Methods: To examine this hypothesis, virus antigen and caspase 3 expression (for apoptosis) was compared in primary mixed, neural cell cultures infected in vitro or prepared from mice infected intracerebrally with WT, vaccine or rodent neuroadapted viruses. Viral RNA levels were examined in mouse brain by nested and real-time reverse transcriptase polymerase chain reaction.

Results: WT and vaccine strains were demonstrated for the first time to infect murine oligodendrocytes in addition to neurones despite a lack of the known MV cell receptors. Unexpectedly, the percentage of cells positive for viral antigen was higher for WT MV than neuroadapted virus in both in vitro and ex vivo cultures. In the latter the percentage of positive cells increased with time after mouse infection. Viral RNA (total and mRNA) was detected in brain for up to 20 days, while cultures were negative for caspase 3 in WT and vaccine virus infections.

Conclusions: WT and vaccine MV strains can use an endogenous cell entry receptor(s) or alternative virus uptake mechanism in murine neural cells. However, viral replication occurs at a low level and is associated with limited apoptosis. WT MV mouse infection may provide a model for the initial stages of persistent MV human central nervous system infections.

"To be accepted as normal": Public understanding and misconceptions concerning survivors of brain injury.

PRIMARY OBJECTIVE: To determine the views held by the general public in Northern Ireland towards survivors of brain injury. RESEARCH DESIGN: Qualitative semi-structured interviews. METHODS AND PROCEDURES: Interviews were conducted with 16 members of the general public. Ten questions addressed issues such as the role of survivors of brain injury in society, the challenges they face and the characteristics ascribed to them. MAIN OUTCOMES AND RESULTS: When asked to describe someone with a brain injury participants typically used negative labels and identified the most common problems as relating to physical, cognitive, emotional and social functioning. There was a general failure to recognize that brain injury was a 'hidden' disability, with most participants expecting some outward manifestation. Relatively few previous studies have employed a qualitative approach to explore how the public perceives survivors of brain injury. CONCLUSION: Members of the public have an increasing awareness of the challenges faced by survivors of brain injury. However, in spite of this, perceptions of aggressiveness, dependency and unhappiness were still evident, suggesting potential problems in reintegrating survivors of brain injury with their communities.

Oral Resveratrol Reduces Neuronal Damage in a Model of Multiple Sclerosis

Background: Neuronal loss in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), correlates with permanent neurological dysfunction. Current MS therapies have limited the ability to prevent neuronal damage. Methods: We examined whether oral therapy with SRT501, a pharmaceutical grade formulation of resveratrol, reduces neuronal loss during relapsing-remitting EAE. Resveratrol activates SIRT1, an NAD-dependent deacetylase that promotes mitochondrial function. Results: Oral SRT501 prevented neuronal loss during optic neuritis, an inflammatory optic nerve lesion in MS and EAE. SRT501 also suppressed neurological dysfunction during EAE remission, and spinal cords from SRT501-treated mice had significantly higher axonal density than vehicle-treated mice. Similar neuroprotection was mediated by SRT1720, another SIRT1-activating compound; and sirtinol, an SIRT1 inhibitor, attenuated SRT501 neuroprotective effects. SIRT1 activators did not prevent inflammation. Conclusions: These studies demonstrate that SRT501 attenuates neuronal damage and neurological dysfunction in EAE by a mechanism involving SIRT1 activation. SIRT1 activators are a potential oral therapy in MS. © 2010 by North American Neuro-Ophthalmology Society.

Attention deficits in Alzheimer's disease and vascular dementia

OBJECTIVE:

To compare the performance of patients with mild-moderate Alzheimer's disease (AD) and vascular dementia (VaD) on tests of information processing and attention.

METHOD:

Patients with AD (n=75) and VaD (n=46) were recruited from a memory clinic along with dementia-free participants (n=28). They underwent specific tests of attention from the Cognitive Drug Research battery, and pen and paper tests including Colour Trails A and B and Stroop. All patients had a CT brain scan that was independently scored for white-matter change/ischaemia.

RESULTS:

Attention was impaired in both AD and VaD patients. VaD patients had more impaired choice reaction times and were less accurate on a vigilance test measuring sustained attention. Deficits in selective and divided attention occurred in both patient groups and showed the strongest correlations with Mini Mental State Examination scores.

CONCLUSION:

This study demonstrates problems with the attentional network in mild-moderate AD and VaD. The authors propose that attention should be tested routinely in a memory clinic setting.

Interstitial Cells in the Urinary Bladder-Localization and Function

Aims: This review summarizes the currently available literature on the localization and proposed functions of a novel group of cells in the urinary bladder known as interstitial cells or interstitial cells of Cajal (ICC).

Methods: On-line searches of "Pubmed" for bladder, c-Kit, ICC, interstitial cell and myofibroblast were performed to identify relevant studies for the review.

Results: The literature contains substantial data that several sub-populations of ICC are present in the wall of the mammalian urinary bladder. These are located in the lamina propria and within the detrusor with distinctive cell shapes and morphological arrangements. Bladder ICC are identified with transmission electron microscopy or by immunohistochemical labeling using antibodies to the Kit receptor which is an established ICC marker. Lamina propria-ICC form a loose network connected via Cx43 gap junctions and are associated with mucosal nerves. Detrusor ICC track the smooth muscle bundles and make frequent contacts with intramural nerves. Both groups of ICC exhibit spontaneous electrical and Ca²⁺-signalling and also respond to application of neurotransmitter substances including ATP and carbachol. There is emerging evidence that the expression of ICC is upregulated in pathophysiological conditions including the overactive bladder.

Conclusions: There is now a convincing body of evidence that specialized ICC are present in the urinary bladder making important associations with other cells that make up the bladder wall and possessing physiological properties consistent with a role of bladder activity modulation. Neurourol. Urodynam. 29: 82–87, 2010. © 2009 Wiley-Liss, Inc.

A Multiple Indicators Multiple Causes (MIMIC) model of Behavioural and Psychological Symptoms in Dementia (BPSD)

Introduction: Although there is evidence for distinct behavioural sub-phenotypes in Alzheimer's disease (AD), their inter-relationships and the effect of clinical variables on their expression have been little investigated.