A Candidate Gene Association Study Identifies DAPL1 as a Female-Specific Susceptibility Locus for Age-Related Macular Degeneration (AMD)

Age-related macular degeneration (AMD) is the leading cause of blindness among white caucasians over the age of 50 years with a prevalence rate expected to increase markedly with an anticipated increase in the life span of the world population. To further expand our knowledge of the genetic architecture of the disease, we pursued a candidate gene approach assessing 25 genes and a total of 109 variants. Of these, synonymous single nucleotide polymorphism (SNP) rs17810398 located in death-associated protein-like 1 (DAPL1) was found to be associated with AMD in a joint analysis of 3,229 cases and 2,835 controls from five studies [combined P ADJ = 1.15 × 10(-6), OR 1.332 (1.187-1.496)]. This association was characterized by a highly significant sex difference (P diff = 0.0032) in that it was clearly confined to females with genome-wide significance [P ADJ = 2.62 × 10(-8), OR 1.541 (1.324-1.796); males: P ADJ = 0.382, OR 1.084 (0.905-1.298)]. By targeted resequencing of risk and non-risk associated haplotypes in the DAPL1 locus, we identified additional potentially functional risk variants, namely a common 897-bp deletion and a SNP predicted to affect a putative binding site of an exonic splicing enhancer. We show that the risk haplotype correlates with a reduced retinal transcript level of two, less frequent, non-canonical DAPL1 isoforms. DAPL1 plays a role in epithelial differentiation and may be involved in apoptotic processes thereby suggesting a possible novel pathway in AMSaveD pathogenesis.

Positive and negative contractile effects of somatostatin-14 on rat ventricular cardiomyocytes.

Somatostatin-14 elicits negative inotropic and chronotropic actions in atrial myocardium. Less is known about the effects of somatostatin-14 in ventricular myocardium. The direct contractile effects of somatostatin-14 were assessed using ventricular cardiomyocytes isolated from the hearts of adult rats. Cells were stimulated at 0.5 Hz with CaCl2 (2 mM) under basal conditions and in the presence of the -adrenoceptor agonist, isoprenaline (1 nM), or the selective inhibitor of the transient outward current (Ito), 4-aminopyridine (500 M). Somatostatin-14 did not alter basal contractile response but it did inhibit (IC50 13 nM) the response to isoprenaline (1 nM). In the presence of 4-aminopyridine (500 M), somatostatin-14 stimulated a positive contractile response (EC50 118 fM) that was attenuated markedly by diltiazem (100 nM). These data indicate that somatostatin-14 exerts dual effects directly in rat ventricular cardiomyocytes: (1) a negative contractile effect, observed in the presence of isoprenaline (1 nM), coupled to activation of Ito; and (2) a previously unreported and very potent positive contractile effect, unmasked by 4-aminopyridine (500 M), coupled to the influx of calcium ions via L-type calcium channels. The greater potency of somatostatin-14 for producing the positive contractile effect indicates that the peptide may exert a predominantly stimulatory influence on the resting contractility of ventricular myocardium in vivo, whereas the negative contractile effect, observed at much higher concentrations, could indicate that localized elevations in the concentration of the peptide may serve as a negative regulatory influence to limit the detrimental effects of excessive stimulation of cardiomyocyte contractility.

The relationship of clinical and inflammatory markers to outcome in stable patients with cystic fibrosis

Decreased survival in patients with cystic fibrosis has been related to FEV1, BMI, and infection with Burkholderia cepacia complex (BCC). We have assessed the relationship of blood, sputum, and urine inflammatory markers to lung function, BMI, colonization with B cenocepacia (Bc), and patient survival. Thirty-nine stable cystic fibrosis (CF) patients (10 with Bc) were enrolled in a study to determine the effect of alpha-1-antitrypsin on airways inflammation. Pre-treatment measurements were used in this study. Demographics, sputum microbiology, heart rate, oxygen saturation, lung function were recorded. Blood samples were obtained for white blood count (WBC), C-Reactive Protein (CRP), and plasma neutrophil elastase/AAT complexes (pNEC). Neutrophil elastase (NE), neutrophil elastase/AAT complexes (sNEC), interleukin-8 (IL-8), TNF-receptor 1 (sTNFr), and myeloperoxidase (MPO) were measured in sputum and urinary desmosine concentration determined. Patients with Bc had significantly higher levels of pNEC, 332?±?91.4 ng/ml (mean?±?SEM) versus 106?±?18.2 ng/ml (P?=?0.0005) and sNEC, 369?±?76.6 ng/ml versus 197?±?36.0 ng/ml compared to those who were not. Five deaths were reported at the end of 1 year, (four with Bc) (P?=?0.011). Patients who subsequently died had significantly lower lung function FEV1, 1.2?±?0.2 L versus 2.0?±?0.1 L (P?=?0.03) and FVC, 2?±?0.3 L versus 3.1?±?0.2 L (P?=?0.01), compared to those that survived. There was significantly higher NE activity, 3.6?±?1.6 U/ml versus 1.5?±?0.6 U/ml (P?=?0.03), pNEC, 274?±?99 ng/ml versus 142?±?30 ng/ml (P?=?0.05), MPO, 163?±?62 mcg/ml versus 54?±?6.9 mcg/ml (P?=?0.03), and urinary desmosines 108?±?19.9 pM/mg creatinine versus 51.1?±?3.3 pM/mg creatinine (P?=?0.001), in those patients who subsequently died compared to those that survived. These data suggest there is increased neutrophil degranulation in patients infected with Bc and these patients have a poor outcome.

Perceived and reported access to the general practitioner: an international comparison of universal access and mixed private/public systems.

Timely and convenient access to primary healthcare is essential for the health of the population as delays can incur additional health and financial costs. Access to health care is under increasing scrutiny as part of the drive to contain escalating costs, while attempting to maintain equity in service provision. The objective was to compare primary care services in Republic of Ireland and Northern Ireland, and to report on perceived and reported access to GP services in universal access and mixed private/public systems. A questionnaire study was performed in Northern Ireland (NI) and the Republic of Ireland (ROI). Patients of 20 practices in the ROI and NI were contacted (n = 22,796). Main outcome measures were overall satisfaction and the access to GP services. Individual responses and scale scores were derived using the General Practice Assessment Questionnaire (G-PAQ). The response rate was 52% (n = 11,870). Overall satisfaction with GP practices was higher in ROI than in NI (84.2% and 80.9% respectively). Access scores were higher in ROI than in NI (69.2% and 57.0% respectively) Less than 1 in 10 patients in ROI waited two or more working days to see a doctor of choice (8.1%) compared to almost half (45.0%) in NI. In NI overall satisfaction decreased as practice size increased; 82.8%, 80.4%, and 75.8%. In both systems, in large practices, accessibility is reduced when compared to smaller practices. The faster access to GP services in ROI may be due to the deterrent effect of the consultation charge freeing up services although, as it is the poorest and sickest who are deterred by the charge this improved accessibility may come at a significant cost in terms of equity. The underlying concern for policy makers centres around provision of equitable services.