CYP2C19*2 and prognosis after an acute coronary syndrome: Insights from a Portuguese center.

BACKGROUND: Clopidogrel requires oxidation dependent on the cytochrome P450 enzyme 2C19 (CYP2C19) to form its active metabolite. The importance of loss-of-function alleles (particularly CYP2C19*2, 681G>A) in poor platelet response to clopidogrel is well recognized. OBJECTIVE: To investigate the prevalence and prognostic impact of the CYP2C19*2 allele in a local acute coronary syndrome (ACS) population. METHODS: We performed a prospective, longitudinal study of 95 patients admitted for an ACS between March and October 2009 to a single coronary care unit. Patients aged under 75 who survived hospital stay and for whom clopidogrel was prescribed were included. At discharge, CYP2C19 was genotyped using a commercially available kit. Patients were divided into two groups: Group A (non-carriers, normal metabolizers, CYP2C19*1/*1), n=69; and Group B (carriers, slow metabolizers, CYP2C19*2/*1 or *2/*2), n=26. The primary endpoint was a combined outcome of cardiovascular death, non-fatal myocardial infarction or re-admission for unstable angina; median follow-up was 136.0 (79.0-188.0) days. RESULTS: The median age of the population was 62.0 (51.0-68.0) years, and 83.2% were male. The CYP2C19*2 (A) allele had a frequency of 14.2%. There were no differences between the groups with respect to demographic data or history of cardiovascular disease. Coronary anatomy, left ventricular ejection fraction and renal function were also similar. The groups were also homogenous with respect to GRACE risk score (118.0 (95.0-136.5) vs. 115.0 (96.0-133.0), p=0.68), medical treatment and percutaneous revascularization during hospital stay. Event-free survival was higher for Group A (94.0% vs. 75.0%, log-rank p=0.010). Three readmissions for MI were documented, all in the slow metabolizers group. CONCLUSION: In our ACS population, the CYP2C19*2 allele was a medium-term prognostic marker.

Platelet aggregation at discharge: a useful tool in acute coronary syndromes?

INTRODUCTION: Inhibition of platelet aggregation appears two hours after the first dose of clopidogrel, becomes significant after the second dose, and progresses to a steady-state value of 55% by day seven. Low response to clopidogrel has been associated with increased risk of stent thrombosis and ischemic events, particularly in the context of stable heart disease treated by percutaneous coronary intervention. OBJECTIVE: To stratify medium-term prognosis of an acute coronary syndrome (ACS) population by platelet aggregation. METHODS: We performed a prospective longitudinal study of 70 patients admitted for an ACS between May and August 2009. Platelet function was assessed by ADP-induced platelet aggregation using a commercially available kit (Multiplate(®) analyzer) at discharge. The primary endpoint was a combined outcome of mortality, non-fatal myocardial infarction, or unstable angina, with a median follow-up of 136.0 (79.0-188.0) days. RESULTS: The median value of platelet aggregation was 16.0U (11.0-22.5U) with a maximum of 41.0U and a minimum of 4.0U (normal value according to the manufacturer: 53-122U). After ROC curve analysis with respect to the combined endpoint (AUC 0.72), we concluded that a value of 18.5U conferred a sensitivity of 75.0% and a specificity of 68% to that result. We therefore created two groups based on that level: group A - platelet aggregation <18.5U, n=44; and group B - platelet aggregation ≥18.5U, n=26. The groups were similar with respect to demographic data (age 60.5 [49.0-65.0] vs. 62.0 [49.0-65.0] years, p=0.21), previous cardiovascular history, and admission diagnosis. There were no associations between left ventricular ejection fraction, GRACE risk score, or length of hospital stay and platelet aggregation. The groups were also similar with respect to antiplatelet, anticoagulant, proton pump inhibitor (63.6 vs. 46.2%, p=0.15) and statin therapy. The variability in platelets and hemoglobin was also similar between groups. Combined event-free survival was higher in group A (96.0 vs. 76.7%, log-rank p<0.01). Platelet aggregation higher than 18.5U was an independent predictor of the combined event (HR 6.75, 95% CI 1.38-32.90, p=0.02). CONCLUSION: In our ACS population platelet aggregation at discharge was a predictor of medium-term prognosis.

Parenting of Children with Autism Spectrum Disorder: A Grounded Theory Study.

BACKGROUND: Parenting a child with an autism spectrum disorder (ASD) involves several processes and emotions during this transition. In addition to the family's natural transition when a child is born, the family of a child with ASD has to deal with the particularities of the disability, its characteristics, and its evolution. METHODS: This is a qualitative grounded theory study aiming to deepen the knowledge about the process of parenting children with ASD. Data were collected using interviews and observations of nine couples and one single mother. RESULTS: Coding and analysis led to the main theme, which is as follows: parenting of children with ASD as representative of the parents' transformation while caring for the child, also based on adaptation throughout this experience. CONCLUSIONS: Parenting is a dynamic process, grounded on the interaction of different contexts, such as family, education, health, and society, and on the co-construction of different times and episodes. These characteristics underline the complex and individual nature of parenting children with autism, which requires specific assessments and interventions by nurses when caring for these families, whether in a family nursing context, community nursing, and pediatric nursing or midwifery.

Pharmacogenetics of advanced lung cancer: Predictive value of functional genetic polymorphism AGXT Pro11Leu in clinical outcome?

INTRODUCTION: AGXT gene codes for the enzyme alanine glyoxylate aminotransferase, which is involved in hepatic peroxisomal metabolism of platinum-based chemotherapeutic agents. The association of genetic variant AGXT rs34116584 on the clinical outcome and response to chemotherapy of patients with non-small cell lung cancer (NSCLC) remains to be established. Our aim was to evaluate the association of functional AGXT gene polymorphism in NSCLC progression, considering as primary and secondary endpoint, progression free survival (PFS) and overall survival (OS), respectively. METHODS: Genotyping of theAGXT rs34116584 genetic polymorphism was performed by mass spectrometry on 168 DNA samples from patients with NSCLC (stages IIIA-IVB). Univariate survival analysis included the study of Kaplan-Meier curves with the Log-Rank test, while Cox regression was used as a multivariate analysis. RESULTS: Multivariate analysis showed shorter PFS for T carriers [HR=2.0, 95% CI, 1.4-3.0, p<0.0001] and shorter OS [HR=1.8, 95% CI, 1.1-3.0, p=0.017] globally, as well as in a subgroup of patients (n=144) treated with first line platinum-based chemotherapy [HR=2.0, 95% CI, 1.3-3.1, p=0.001] and [HR=1.8, 95% CI, 1.1-3.1, p=0.026], respectively. CONCLUSION: This polymorphism seems to have an impact on NSCLC progression, opening new perspectives for its inclusion as a pharmacogenetic predictor of response to platinum-based chemotherapy.

Genetic characterization of warfarin sensitivity in a population of cardiovascular patients on chronic anticoagulation.

BACKGROUND: Genetic factors account for 35-40% of the interindividual variation observed in response to warfarin. The most important genes involved are CYP2C9 (cytochrome P450 2C9) and VKORC1 (vitamin K epoxide reductase complex subunit 1). OBJECTIVES: To determine the prevalence of the different genotypes influencing response to oral anticoagulants in a population of cardiovascular patients on chronic anticoagulation and to investigate the correlation between genotype and the warfarin dose required for optimal anticoagulation. METHODS: A total of 91 chronically anticoagulated consecutive patients were genotyped for CYP2C9 and VKORC1, using PCR and reverse hybridization. RESULTS: Of the 91 patients, 57.1% were male and mean age was 67.4 +/- 13.1 years. most frequent indication for warf was atrial fibrillation (56.8%). We analyzed the prevalence of the different CYP2C9 and VKORC1 genotypes in this population and found that the warfarin doses required to maintain patients at their desired anticoagulation target were significantly different among carriers of the different genotypes. CONCLUSIONS: Our study highlights the importance of genetic study in the clinical management of patients on chronic anticoagulation, increasing the safety and efficacy of warfarin therapy.

Platelet hyperactivation in maintained growth hormone-deficient childhood patients after therapy withdrawal as a putative earlier marker of increased cardiovascular risk.

GH deficiency (GHD) is associated with a higher risk of vascular disease, whose pathophysiological mechanisms remains not yet fully elucidated. This study aimed to assess the main cardiovascular risk indexes, plasma catecholamines content, and the platelet function in childhood-onset GHD patients. Some of the main clinical examinations related with cardiovascular risk, plasma catecholamines content, as well as platelet intracellular free calcium concentration ([Ca(2+)](i)), whole-blood aggregation, and morphology were evaluated in childhood-onset GHD patients treated with GH for a variable period and off GH therapy for at least 2 yr before entry into study and in sex-, age-, and body mass index-matched control groups. Among the patients, group 1 (GHD-1) has recovered GH levels after withdrawal, whereas group 2 (GHD-2) has remained GH deficient. Minor differences on the cardiovascular risk indexes were observed between the groups. Plasma catecholamine concentrations in the GHD groups did not statistically differ from the control group, but higher adrenaline content was observed in the GHD-2 group when compared with the GHD-1 one. Basal and thrombin-evoked [Ca(2+)](i) and platelet aggregation were identical between the GHD-1 group and the matched control. However, the GHD-2 group has increased thrombin-evoked [Ca(2+)](i) (297.0 +/- 15.7 Deltanmol/liter; P < 0.01), collagen, and ADP-induced platelet aggregation (33.3 +/- 4.3 and 12.5 +/- 2.1 Omega, respectively; P < 0.05) vs. the control-2 group (Delta[Ca(2+)](i): 102.1 +/- 13.6 Deltanmol/liter; aggregation: 19.6 +/- 2.9 and 6.2 +/- 0.8 Omega). The platelet hyperreactivity state in the GHD-2 was reinforced by morphologic studies of electron microscopy. In conclusion, there were minor differences between the GHD-1 group and the controls, which might be due to the recovery of GH levels after therapy withdrawal. However, the maintained GHD group, despite minor cardiovascular risk index differences, has increased [Ca(2+)](i) and aggregation, which could indicate a hyperactivation state that might be viewed as an earlier marker of cardiovascular disturbances.

Isosorbide-5-mononitrate treatment prevents cyclosporin A-induced platelet hyperactivation and the underlying nitric oxide-cyclic guanosine-3',5'-monophosphate disturbances.

INTRODUCTION: The clinical use of cyclosporin A (CsA) is commonly associated with the development of hypertension and increased risk of thromboembolic events. Decreased endothelium-dependent relaxation and increased platelet activation seems to be involved on those side effects, but the underlying mechanisms are not yet elucidated. The present study aimed to evaluate the CsA effect on the platelet NO-cyclic guanosine-3',5'-monophosphate (cGMP) pathway and the putative benefits of concomitant isosorbide-5-mononitrate (IS-5-MN) administration on CsA-induced hypertension and on platelet hyperactivation. MATERIALS AND METHODS: Blood pressures, platelet NO synthase activity and cGMP content, intracellular free calcium concentration ([Ca2+]i) and whole blood platelet aggregation were assessed in three rat groups orally treated, during 7 weeks, with the following diets: orange juice (control group), 5 mg/kg/day of CsA (CsA group) and 150 mg/kg/day, b.i.d., of IS-5-MN for 2 weeks and IS-5-MN plus 5 mg/kg/day of CsA for 7 weeks (IS-5-MN+CsA group). RESULTS: IS-5-MN treatment has prevented hypertension development obtained in the solely CsA-treated rats. CsA treatment has inhibited NOS activity, which was reverted by the concomitant IS-5-MN and CsA administration. On the contrary, platelets from CsA-treated rats had cGMP content increased when compared with the control rats. The variation obtained when ISMN was present was less predominant. Therefore, the organic nitrate treatment has prevented platelet hyperactivation, namely, by decreasing thrombin-evoked [Ca2+]i and collagen-evoked platelet aggregation, when compared with the solely CsA-treated group. The preventive effect of IS-5-MN was reinforced by electron microscopy studies of platelet activation. CONCLUSIONS: By increasing [Ca2+]i and aggregation, CsA induces platelet hyperactivation and simultaneously increases cGMP content, which might represent a compensatory inhibitory mechanism. The concomitant IS-5-MN treatment prevents the above-mentioned platelet hyperreactivity and tends to normalize the NO-cGMP pathway as well as the development of hypertension.