Dextromethorphan hydrobromide, 25 mg po, was given to 268 unrelated Swiss subjects to study urinary drug and metabolite profiles. Rates of O-demethylation yielding the main metabolite dextrorphan were expressed by the urinary dextromethorphan/dextrorphan metabolic ratio. We found a bimodal distribution of this parameter in our population study, which indicates that there are two phenotypes for dextromethorphan O-demethylation. The antimode at a metabolic ratio of 0.3 separated the poor metabolizer (PM; n = 23; prevalence of 9%) from extensive metabolizer (EM) phenotypes. Urinary output of dextrorphan was less than 6% of the dose in all PMs and was 50% in the 245 EMs. Pedigree analysis of 14 family studies revealed an autosomal-recessive transmission of deficient dextromethorphan O-demethylation. In these families, 37 heterozygous genotypes could be identified; however, through use of the urinary drug and metabolite analysis it was not possible to identify the heterozygous genotypes within the EM phenotype group. Co-segregation of dextromethorphan O-demethylation with debrisoquin 4-hydroxylation was also studied. Complete concordance of the two phenotypic assignments was obtained, with a Spearman rank correlation coefficient of rs = 0.78 (n = 62; P less than 0.0001) for dextromethorphan and debrisoquin metabolic ratios. Presumably the two drug oxidation polymorphisms are under the same genetic control. Thus the innocuousness and ubiquitous availability of dextromethorphan render it attractive for worldwide pharmacogenetic investigations in man.

A multifactorial and growing crisis of health care systems in the developed world has affected medicine. In order to provide rational responses, some central concepts of the past, such as the definitions of health and disease, need to be updated. For this purpose physicians should initiate a new debate. As a point of departure the following definitions are proposed: Health is a dynamic state of wellbeing characterized by a physical, mental and social potential, which satisfies the demands of a life commensurate with age, culture, and personal responsibility. If the potential is insufficient to satisfy these demands the state is disease. This term includes sickness, illness, ill health, and malady. The described potential is divided into a biologically given and a personally acquired partial potential. Their proportions vary throughout the life cycle. The proposed definitions render it empirically possible to diagnose persons as healthy or diseased and to apportion some of the responsibility for their state of health to individuals themselves. Treatment strategies should always consider three therapeutic routes: improvements of the biologically given and of the personally acquired partial potentials and adaptations of the demands of life. These consequences favourably contrast with those resulting from the WHO-definition of health.

To evaluate the prognostic value of quantitative liver function tests in comparison with established prognostic variables, the data of 47 patients with liver cirrhosis were analysed. A total of 16 variables, comprising the galactose elimination capacity and the indocyanine green clearance, the Child-Pugh classification, and several clinical and biochemical variables were subjected to Kaplan-Meier life-table analysis and Cox proportional hazards regression analysis. As independent variables, poor prognosis was associated significantly with increasing Child-Pugh score (p less than 0.00001), whereas the galactose elimination capacity (p = 0.03) and the indocyanine green clearance (p less than 0.001) were less sensitive indicators. The regression analysis showed prognostic value in decreasing sequence for Child-Pugh classification, age, sex, history of upper GI haemorrhage, and alkaline phosphatase activity. The quantitative liver function tests evaluated in the present work have less prognostic value than routinely accessible variables.

The Millennium Development Goals (MDGs) mobilized global commitments to promote health, socioeconomic, and sustainable development. Trends indicate that the health MDGs may not be achieved by 2015, in part because of insufficient coordination across related health, socioeconomic, and environmental initiatives. Explicitly acknowledging the need for such collaboration, the Meikirch Model of Health posits that: Health is a state of wellbeing emergent from conducive interactions between individuals' potentials, life's demands, and social and environmental determinants. Health results throughout the life course when individuals' potentials – and social and environmental determinants – suffice to respond satisfactorily to the demands of life. Life's demands can be physiological, psychosocial, or environmental, and vary across contexts, but in every case unsatisfactory responses lead to disease. This conceptualization of the integrative nature of health could contribute to ongoing efforts to strengthen cooperation across actors and sectors to improve individual and population health – leading up to 2015 and beyond.

Health is an adaptive state unique to each person. This subjective state must be distinguished from the objective state of disease. The experience of health and illness (or poor health) can occur both in the absence and presence of objective disease. Given that the subjective experience of health, as well as the finding of objective disease in the community, follow a Pareto distribution, the following questions arise: What are the processes that allow the emergence of four observable states—(1) subjective health in the absence of objective disease, (2) subjective health in the presence of objective disease, (3) illness in the absence of objective disease, and (4) illness in the presence of objective disease? If we consider each individual as a unique biological system, these four health states must emerge from physiological network structures and personal behaviors. The underlying physiological mechanisms primarily arise from the dynamics of external environmental and internal patho/physiological stimuli, which activate regulatory systems including the hypothalamic-pituitary-adrenal axis and autonomic nervous system. Together with other systems, they enable feedback interactions between all of the person's system domains and impact on his system's entropy. These interactions affect individual behaviors, emotional, and cognitive responses, as well as molecular, cellular, and organ system level functions. This paper explores the hypothesis that health is an emergent state that arises from hierarchical network interactions between a person's external environment and internal physiology. As a result, the concept of health synthesizes available qualitative and quantitative evidence of interdependencies and constraints that indicate its top-down and bottom-up causative mechanisms. Thus, to provide effective care, we must use strategies that combine person-centeredness with the scientific approaches that address the molecular network physiology, which together underpin health and disease. Moreover, we propose that good health can also be promoted by strengthening resilience and self-efficacy at the personal and social level, and via cohesion at the population level. Understanding health as a state that is both individualized and that emerges from multi-scale interdependencies between microlevel physiological mechanisms of health and disease and macrolevel societal domains may provide the basis for a new public discourse for health service and health system redesign.