A history and overview of phenotypic variability in CYP2D6 activity

CYP2D6 is a human cytochrome P450 that is responsible for the metabolism of a large number of drugs and chemicals. Interest in CYP2D6 has largely centered on the wide interindividual variability in its catalytic activity that stems from a common genetic polymorphism in the CYP2D6 gene. Two major phenotypes exist, extensive metabolizer (EM) and poor metabolizer (PM), together with the two less studied phenotypes of ultrarapid metabolizer (UM) and intermediate metabolizer. These phenotypes are the expression of an underlying allelomorphism in CYP2D6 and are also context dependent. Several drugs that are CYP2D6 substrates display polymorphic metabolism, that is, the existence in the population of multiple phenotypes, in particular EM and PM. The most notable drugs in this regard are debrisoquine and sparteine, although there are also data for a few others, in particular, dextromethorphan and metoprolol. Many nongenetic factors can alter the expression of CYP2D6 phenotypes, the most significant of which is the presence of other drugs. In this context, the EM phenotype may not be immutable, with potential conversion into a PM phenocopy, due to significantly impaired CYP2D6 metabolism in the presence of other CYP2D6 substrates and inhibitors. This phenotype interconversion generated great concern and helped drive the movement away from phenotyping based upon drug administration to genotyping of acquired DNA samples. However, ascertaining the presence of CYP2D6 alleles in a DNA sample does not determine the metabolism and pharmacokinetics of CYP2D6 substrates in that subject: it is a forecast, much like the weather forecast and, as we all know regarding the weather, the forecast can be inaccurate at times.

Psychological adaptation to spousal bereavement in old age. The role of trait resilience, marital history, and context of death

This research examined the effect of marital status and gender on various indicators of psychological adaptation, namely depressive symptoms, loneliness, and life satisfaction. It further explores the role of trait resilience, marital history, and context of death for predicting These outcomes in bereaved individuals. Four hundred eighty widowed individuals aged between 60 and 89 were compared with 759 married peers. Main effects were found for marital status and gender for all indicators. The regression analyses illustrate the multifaceted structure of psychological adaptation. Trait resilience is a key factor in adapting to spousal bereavement, whereas marital history and the context are secondary.

The history and literature of the Israelites according to the Old Testament and the Apocrypha

by C[onstance] and A[nna] de Rothschild

Web Classroom Application. Digital technologies to study theory, history and criticism of architecture at Escuela Superior de Arquitectura UPMadrid. The search for some guides to direct the inquiry learning

xxx

Journal of researches into the natural history and geology of the countries visited during the voyage of H.M.S. Beagle round the world, under the command of Capt. Fitz Roy, R.N.

(1878 printing)

The brown-tail moth, Euproctis chrysorrhcea (L.). A report on the life history and habits of the imported brown-tail moth, together with a description of the remedies best suited for destroying it. By Charles H. Fernald ... and Archie H. Kirkland ... Pub. under the direction of the State board of agriculture by authority of the legislature.

1903

The brown-tail moth, Euproctis chrysorrhcea (L.). A report on the life history and habits of the imported brown-tail moth, together with a description of the remedies best suited for destroying it. By Charles H. Fernald ... and Archie H. Kirkland ... Pub. under the direction of the State board of agriculture by authority of the legislature.

1903

The History and Challenges of Cohesion Policies. Jean Monnet/Robert Schuman Paper Series Vol. 14 No. 2, February 2014

From Introduction. Regional economic disequilibria was viewed as both an obstacle to and result of integration (European Commission 1965; European Commission 1962; European Commission 1969). Even within the Treaty of Rome, the Community tried to establish mechanisms to alleviate regional inequality. However, it was not until 1975 that the main mechanism of regional policy was established as a result of British and Irish enlargement: the European Regional Development Fund (ERDF). Since then, cohesion policy has become a significant EU expenditure accounting for €347bn, or 35.7% of the total EU budget for 2007-13(European Commission Regional Policy-Info Regio 2012). It has also become a key policy linked to enlargement. The underlying principle of cohesion policy assumes that the market alone cannot solve development problems and therefore government intervention is needed. This notion is in direct contrast to the underlying principle of EU competition policy, which asserts that the free market can solve economic development problems (Meadows, interview by author, 2003). The logic underlying cohesion policy is not only counter to EU competition policy, but also regulatory policies. Unlike other EU policies, cohesion policy is not a sectoral policy, but rather territorial in nature (Leonardi, 2006). Thus at times EU regulatory policy has also unintentionally worked counter to the goals of regional policy, sometimes disadvantaging poorer regions (Dudek, 2005). As the Community has sought to ameliorate regional disparities, it meant that all levels of government: local, regional, national and supranational would need to be involved, however, member states have different territorial governance and European regional development programs have to varying degrees impacted the relationship and policy responsibility of different levels of government (Leonardi, 2006; Bachtler and Michie 1993; Marks, 1993). The very nature of regional development policy has provoked a re-examination of subsidiarity, or which level of government is the lowest and most appropriate level. The discussion of policy formulation and implementation at the lowest level possible also addresses the issue of the democratic deficit. Some argue that the closer government is to the people the more responsive and representative it is. Democracy, however, also implies that public funds are used in a transparent way and for public rather than private good. Yet, as we examine the history and current situation of EU regional funds we find that corruption and misuse still abound. Thus, to understand the history of regional policy it is imperative to look at the major transformations of the policy, how regional policy has impacted subsidiarity and the quality of democracy, become an important instrument of enlargement and contradicted or conflicted with other EU policies.