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The majority of patients with ischaemic cerebrovascular disease (CVD) are not protected from further vascular events with antiplatelet therapy. Measurement of inhibition of platelet function ex vivo on antiplatelet therapy, using laboratory tests that correlate with the clinical effectiveness of these agents, would potentially enable physicians to tailor antiplatelet therapy to suit individuals. A systematic review of the literature was performed to collate all available data on ex vivo platelet function/reactivity in CVD patients, especially those treated with aspirin, dipyridamole or clopidogrel. Particular emphasis was paid to information from commonly available whole blood platelet function analysers (PFA-100®, VerifyNow® and Multiplate®). Data on pharmacogenetic mechanisms potentially influencing high on-treatment platelet reactivity (HTPR) on antiplatelet therapy in CVD were reviewed. Two-hundred forty-nine potentially relevant articles were identified; 93 manuscripts met criteria for inclusion. The prevalence of ex vivo HTPR in CVD varies between 3-62% with aspirin monotherapy, 8-61% with clopidogrel monotherapy and 56-59% when dipyridamole is added to aspirin in the early, subacute or late phases after TIA/stroke onset. The prevalence of HTPR on aspirin was higher on the PFA-100 than on the VerifyNow in one study (p < 0.001). Furthermore, the prevalence of HTPR on aspirin was lower when one used 'novel longitudinal' rather than 'cross-sectional, case-control' definitions of HTPR on the PFA early after TIA or stroke (p = 0.003; 1 study). Studies assessing the influence of genetic polymorphisms on HTPR in CVD patients are limited, and need validation in large multicentre studies. Available data illustrate that an important proportion of CVD patients have ex vivo HTPR on their prescribed antiplatelet regimen, and that the prevalence varies depending on the definition and assay used. Large, adequately-sized, prospective multicentre collaborative studies are urgently needed to determine whether comprehensive assessment of HTPR at high and low shear stress with a range of user-friendly whole blood platelet function testing platforms, in conjunction with pharmacogenetic data, improves our ability to predict the risk of recurrent vascular events in CVD patients, and thus enhance secondary prevention following TIA or ischaemic stroke.

Rationale: Aspergillus fumigatus (A. fumigatus) in cystic fibrosis (CF) is increasingly recognized. Although allergic bronchopulmonary aspergillosis (ABPA) leads to deterioration of pulmonary function, the effect of A. fumigatus colonization in the absence of ABPA remains unclear. Objectives: To address this, we examined individuals with CF with A. fumigatus who were ABPA negative to identify the effects of itraconazole therapy on Aspergillus-induced lung inflammation. Methods: The effect of A. fumigatus on nuclear vitamin D receptor (VDR) expression was investigated using qRT-PCR and Western blotting. IL-5 and IL-13 levels were quantified by ELISA. The effect of itraconazole was assessed by a combination of high-resolution computed tomography, lung function test, and microbiological analysis. Measurements and Main Results: We demonstrate that A. fumigatus down-regulates VDR in macrophages and airway epithelial cells and that the fungal metabolite gliotoxin (Gt) is the main causative agent. Gt overcame the positive effect of 1,25-OH vitamin D3 on VDR expression in vitro, resulting in increased IL-5 and IL-13 production. In vivo, A. fumigatus positivity was associated with increased Gt in CF bronchoalveolar lavage fluid and increased bronchoalveolar lavage fluid levels of IL-5 and IL-13. After airway eradication of A. fumigatus with itraconazole, we observed decreased Gt, IL-5 and IL-13, improved respiratory symptoms, and diminished high-resolution computed tomography mosaic pattern consistent with sustained pulmonary function. Conclusions: This study provides a rationale for the therapeutic effect of itraconazole and implied that the therapeutic potential of vitamin D supplementation in preventing ABPA is only feasible with concurrent elimination of A. fumigatus to permit VDR expression and its positive functional consequences.

Introduction Consistent adherence to treatment is essential for effective secondary prevention following TIA/ischaemic stroke. Representative data on long-term treatment continuation and adherence rates are limited. Methods This single centre study recruited patients attending our Rapid Access Stroke Prevention clinic in Ireland from 07/09/2006 → 30/11/2009. Demographic and clinical data, and prescribed medication regimens at initial assessment were recorded. All patients received copies of clinical correspondence containing clear ‘goal-directed treatment advice’ sent to their general practitioner or referring physician. Patients were subsequently interviewed with a standardised pro-forma to assess continuation and adherence rates; overall adherence rates with secondary prevention therapy were also assessed with a validated self-reporting tool (Morisky Scale). Recurrent vascular events during follow-up were recorded. Results One hundred and fourteen patients were recruited; mean age: 64.5 ± 13.8 years; median duration of follow-up: 630 days. Patients were prescribed aspirin (69.3%), alone (17.5%) or in combination with dipyridamole MR (51.8%), clopidogrel (18.2%), warfarin (16.7%), statins (76.3%) and anti-hypertensives (51.8%). During follow-up, the percentages of patients continuing treatment prescribed at the initial visit were: Aspirin (93.7%), dipyridamole MR (72.9%), clopidogrel (81%), warfarin (94.7%), statins (87.9%) and anti-hypertensives (89.8%). Overall, 99.1% reported taking their medication the preceding day. Morisky scale scores for all treatments revealed that 41.2% (N = 47) were high, 36.8% (N = 42) medium, and 12.3% (N = 14) low adherers; 9.7% (N = 11) had incomplete data. Two patients (1.8%) had recurrent cerebrovascular events, and two (1.8%) had myocardial infarctions. Discussion This novel study in European TIA/ischaemic stroke patients, who were provided with a goal-directed secondary prevention plan, showed high rates of medication-continuation and self-reported adherence with prescribed treatment, associated with a low incidence of recurrent vascular events during a median follow up of 1.7 years.

Cannabis use confers a two-fold increase in the risk for psychosis, with adolescent use conferring even greater risk. A high–low activity catechol-O-methyltransferase (COMT) polymorphism may modulate the effects of adolescent Δ-9-tetrahydrocannabinol (THC) exposure on the risk for adult psychosis. Mice with knockout of the COMT gene were treated chronically with THC (4.0 and 8.0 mg/kg over 20 days) during either adolescence (postnatal days (PDs) 32–52) or adulthood (PDs 70–90). The effects of THC exposure were then assessed in adulthood across behavioral phenotypes relevant for psychosis: exploratory activity, spatial working memory (spontaneous and delayed alternation), object recognition memory, social interaction (sociability and social novelty preference), and anxiety (elevated plus maze). Adolescent THC administration induced a larger increase in exploratory activity, greater impairment in spatial working memory, and a stronger anti-anxiety effect in COMT knockouts than in wild types, primarily among males. No such effects of selective adolescent THC administration were evident for other behaviors. Both object recognition memory and social novelty preference were disrupted by either adolescent or adult THC administration, independent of genotype. The COMT genotype exerts specific modulation of responsivity to chronic THC administration during adolescence in terms of exploratory activity, spatial working memory, and anxiety. These findings illuminate the interaction between genes and adverse environmental exposures over a particular stage of development in the expression of the psychosis phenotype.

Background 1,25-Dihydroxycholecalciferol (1,25(OH) 2 D 3 ) has been shown to mitigate epithelial inflammatory responses after antigen exposure. Patients with cystic fibrosis (CF) are at particular risk for vitamin D deficiency. This may contribute to the exaggerated inflammatory response to pulmonary infection in CF. Methods CF respiratory epithelial cell lines were exposed to Pseudomonas aeruginosa lipopolysaccharide (LPS) and Pseudomonas conditioned medium (PCM) in the presence or absence of 1,25(OH) 2 D 3 or a range of vitamin D receptor (VDR) agonists. Levels of IL-6 and IL-8 were measured in cell supernatants, and cellular total and phosphorylated IκBα were determined. Levels of human cathelicidin antimicrobial peptide (hCAP18) mRNA and protein were measured in cells after treatment with 1,25(OH) 2 D 3 . Results Pretreatment with 1,25(OH) 2 D 3 was associated with significant reductions in IL-6 and IL-8 protein secretion after antigen exposure, a finding reproduced with a range of low calcaemic VDR agonists. 1,25(OH) 2 D 3 treatment led to a decrease in IκBα phosphorylation and increased total cellular IκBα. Treatment with 1,25(OH) 2 D 3 was associated with an increase in hCAP18/LL-37 mRNA and protein levels. Conclusions Both 1,25(OH) 2 D 3 and other VDR agonists significantly reduce the pro-inflammatory response to antigen challenge in CF airway epithelial cells. VDR agonists have significant therapeutic potential in CF.