Characterisation of CYP2C8, CYP2C9 and CYP2C19 polymorphisms in a Ghanaian population

<p>Abstract</p> <p>Background</p> <p>Genetic influences on drug efficacy and tolerability are now widely known. Pharmacogenetics has thus become an expanding field with great potential for improving drug efficacy and reducing toxicity. Many pharmacologically-relevant polymorphisms do show variability among different populations. Knowledge of allelic frequency distribution within specified populations can be useful in explaining therapeutic failures, identifying potential risk groups for adverse drug reactions (ADRs) and optimising doses for therapeutic efficacy. We sought to determine the prevalence of clinically relevant Cytochrome P450 (<it>CYP) 2C8</it>, <it>CYP2C9</it>, and <it>CYP2C19 </it>variants in Ghanaians. We compared the data with other ethnic groups and further investigated intra country differences within the Ghanaian population to determine its value to pharmacogenetics studies.</p> <p>Methods</p> <p>RFLP assays were used to genotype <it>CYP2C8 </it>(<it>*2</it>, <it>*3</it>, <it>*4</it>) variant alleles in 204 unrelated Ghanaians. <it>CYP2C9*2 </it>and <it>CYP2C19 </it>(<it>*2 </it>and <it>*3</it>) variants were determined by single-tube tetra-primer assays while <it>CYP2C9 </it>(<it>*3, *4, *5 </it>and <it>*11</it>) variants were assessed by direct sequencing.</p> <p>Results</p> <p>Allelic frequencies were obtained for <it>CYP2C8*2 </it>(17%), <it>CYP2C8*3 </it>(0%), <it>CYP2C8*4 </it>(0%), <it>CYP2C9*2 </it>(0%), <it>CYP2C9*3 </it>(0%), <it>CYP2C9*4 </it>(0%), <it>CYP2C9</it>*5 (0%), <it>CYP2C9*11 </it>(2%), <it>CYP2C19*2 </it>(6%) and <it>CYP2C19*3 </it>(0%).</p> <p>Conclusion</p> <p>Allele frequency distributions for <it>CYP2C8</it>, <it>CYP2C9 </it>and <it>CYP2C19 </it>among the Ghanaian population are comparable to other African ethnic groups but significantly differ from Caucasian and Asian populations. Variant allele frequencies for <it>CYP2C9 </it>and <it>CYP2C19 </it>are reported for the first time among indigenous Ghanaian population.</p

At the bottom of the differential diagnosis list: unusual causes of pediatric hypertension

Hypertension affects 1–5% of children and adolescents, and the incidence has been increasing in association with obesity. However, secondary causes of hypertension such as renal parenchymal diseases, congenital abnormalities and renovascular disorders still remain the leading cause of pediatric hypertension, particularly in children under 12 years old. Other less common causes of hypertension in children and adolescents, including immobilization, burns, illicit and prescription drugs, dietary supplements, genetic disorders, and tumors will be addressed in this review

Temporal Pattern of ICAM-I Mediated Regulatory T Cell Recruitment to Sites of Inflammation in Adoptive Transfer Model of Multiple Sclerosis

Migration of immune cells to the target organ plays a key role in autoimmune disorders like multiple sclerosis (MS). However, the exact underlying mechanisms of this active process during autoimmune lesion pathogenesis remain elusive. To test if pro-inflammatory and regulatory T cells migrate via a similar molecular mechanism, we analyzed the expression of different adhesion molecules, as well as the composition of infiltrating T cells in an in vivo model of MS, adoptive transfer experimental autoimmune encephalomyelitis in rats. We found that the upregulation of ICAM-I and VCAM-I parallels the development of clinical disease onset, but persists on elevated levels also in the phase of clinical remission. However, the composition of infiltrating T cells found in the developing versus resolving lesion phase changed over time, containing increased numbers of regulatory T cells (FoxP3) only in the phase of clinical remission. In order to test the relevance of the expression of cell adhesion molecules, animals were treated with purified antibodies to ICAM-I and VCAM-I either in the phase of active disease or in early remission. Treatment with a blocking ICAM-I antibody in the phase of disease progression led to a milder disease course. However, administration during early clinical remission aggravates clinical symptoms. Treatment with anti-VCAM-I at different timepoints had no significant effect on the disease course. In summary, our results indicate that adhesion molecules are not only important for capture and migration of pro-inflammatory T cells into the central nervous system, but also permit access of anti-inflammatory cells, such as regulatory T cells. Therefore it is likely to assume that intervention at the blood brain barrier is time dependent and could result in different therapeutic outcomes depending on the phase of CNS lesion development

Cocaine Serves as a Peripheral Interoceptive Conditioned Stimulus for Central Glutamate and Dopamine Release

Intravenous injections of cocaine HCl are habit-forming because, among their many actions, they elevate extracellular dopamine levels in the terminal fields of the mesocorticolimbic dopamine system. This action, thought to be very important for cocaine's strong addiction liability, is believed to have very short latency and is assumed to reflect rapid brain entry and pharmacokinetics of the drug. However, while intravenous cocaine HCl has almost immediate effects on behavior and extracellular dopamine levels, recent evidence suggests that its central pharmacological effects are not evident until 10 or more seconds after IV injection. Thus the immediate effects of a given intravenous cocaine injection on extracellular dopamine concentration and behavior appear to occur before there is sufficient time for cocaine to act centrally as a dopamine uptake inhibitor. To explore the contribution of peripheral effects of cocaine to the early activation of the dopamine system, we used brain microdialysis to measure the effects of cocaine methiodide (MI)—a cocaine analogue that does not cross the blood brain barrier—on glutamate (excitatory) input to the dopamine cells. IP injections of cocaine MI were ineffective in cocaine-naïve animals but stimulated ventral tegmental glutamate release in rats previously trained to lever-press for cocaine HCl. This peripherally triggered glutamate input was sufficient to reinstate cocaine-seeking in previously trained animals that had undergone extinction of the habit. These findings offer an explanation for short-latency behavioral responses and immediate dopamine elevations seen following cocaine injections in cocaine-experienced but not cocaine-naïve animals

A Central Role of Abscisic Acid in Stress-Regulated Carbohydrate Metabolism

Background: Abiotic stresses adversely affect plant growth and development. The hormone abscisic acid (ABA) plays a central role in the response and adaptation to environmental constraints. However, apart from the well established role of ABA in regulating gene expression programmes, little is known about its function in plant stress metabolism. Principal Findings: Using an integrative multiparallel approach of metabolome and transcriptome analyses, we studied the dynamic response of the model glyophyte Arabidopsis thaliana to ABA and high salt conditions. Our work shows that salt stress induces complex re-adjustment of carbohydrate metabolism and that ABA triggers the initial steps of carbon mobilisation. Significance: These findings open new perspectives on how high salinity and ABA impact on central carbohydrate metabolism and highlight the power of iterative combinatorial approaches of non-targeted and hypothesis-driven experiments in stress biology

New microdeletion and microduplication syndromes: a comprehensive review

Several new microdeletion and microduplication syndromes are emerging as disorders that have been proven to cause multisystem pathologies frequently associated with intellectual disability (ID), multiple congenital anomalies (MCA), autistic spectrum disorders (ASD) and other phenotypic findings. In this paper, we review the “new” and emergent microdeletion and microduplication syndromes that have been described and recognized in recent years with the aim of summarizing their main characteristics and chromosomal regions involved. We decided to group them by genomic region and within these groupings have classified them into those that include ID, MCA, ASD or other findings. This review does not intend to be exhaustive but is rather a quick guide to help pediatricians, clinical geneticists, cytogeneticists and/or molecular geneticists