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PubMed1999

The World Health Organization International Consortium in Psychiatric Epidemiology (ICPE): initial work and future directions -- the NAPE Lecture 1998. Nordic Association for Psychiatric Epidemiology.

OBJECTIVE: To provide an overview of the World Health Organization (WHO) International Consortium in Psychiatric Epidemiology (ICPE), to introduce the World Mental Health 2000 (WMH2000) Initiative and to discuss methodological issues that the ICPE is grappling with in planning the WMH2000 Initiative. METHOD: We review the history, mission and organization of the ICPE and the rationale behind the WMH2000 Initiative. We review methodological research underlying major design and implementation decisions regarding the WMH2000 surveys. RESULTS: The ICPE is an international consortium created to facilitate cross-national comparative epidemiological research using the WHO Composite International Diagnostic Interview (CIDI). The first-phase core ICPE surveys, which we are currently analysing, include over 33 000 interviews in seven countries, with an additional set of over 30 000 interviews in seven countries ready to be added to the master file within the next year. The WMH2000 Initiative will include a third series of CIDI surveys that include an anticipated 100000 additional interviews in 10 countries. A series of complex methodological challenges confront us in designing and implementing the WMH2000 surveys. These include issues in the conceptualization and measurement of impairment and disablement, the implementation of standardized quality control procedures across countries, and the blending of epidemiological and clinical interviewing methods to obtain a valid cross-national characterization of disorder prevalences. Our current plans regarding these issues are discussed. CONCLUSION: Valid and representative general population epidemiological data on patterns, predictors and adverse consequences of psychiatric disorders are needed as a foundation for public health initiatives. The efforts of the ICPE promise to provide data of this sort for many regions in the world. Formidable methodological and logistical challenges arise in implementing this agenda, but we are confident that these challenges can be met by building on the firm foundation already established in the ongoing ICPE collaboration.

Data Collection↗
PubMed2006

Developmental psychopathology in adolescence: findings from a Swiss study--the NAPE Lecture 2005.

OBJECTIVE: Presentations of selective findings coming from the Zurich Adolescent Psychology and Psychopathology Study with two major aims: i) the study of the prevalence, course, and correlates of mental disorders in adolescence, and ii) the study of the determinants and processes of mental disorders in adolescence. METHOD: A representative sample of n = 1964 children and adolescents was studied in the canton of Zurich in 1994. Additional waves of data collection took place in 1997 and 2000/2001. Mean ages at these three assessments were 13, 16, and 20 years. Each wave contained a two-stage procedure of assessment with screening by questionnaires and consecutive interviewing. The main constructs used were general and specific measures of psychopathology, life events, coping styles, self-related cognitions, and quality of the social network. RESULTS: Prevalence rates of any mental disorder in school-age at the time of assessment was 22.5% fitting into a transcultural range of 18-26% based on DSM-III-R criteria. Furthermore, the derivation and validation of a four-group adolescent drinker typology was demonstrated. Additionally, the prevalence and continuity of functional-somatic symptoms from adolescence to young adulthood was shown. Another piece of the research tested for the identification of risk, compensatory, vulnerability, and protective factors influencing behaviour problems and found remarkably different frequencies across the four types of moderating factors. CONCLUSION: The presented findings provide further understanding of the developmental psychology and psychopathology of adolescence and the service, intervention, and prevention needs of this age-group.

Adolescent↗
PubMed2005

The John Ultmann Lecture--the role of radiation therapy in the treatment of Hodgkin's disease: past, present, and future.

Radiation therapy has been used in the treatment of Hodgkin's disease for more than a century. At first it was demonstrated to provide significant palliation. As advances in technology permitted a more controlled delivery of radiation to defined regions, long lasting responses of disease were demonstrated. Beginning in the mid-1960s, Vera Peters and Henry Kaplan demonstrated the curative potential of high dose extended field irradiation in the treatment of stage I-II Hodgkin's disease. As effective programs of chemotherapy evolved, combined modality therapy with intensive chemotherapy and extensive radiation was applied for patients with early stage disease, resulting in significant morbidity and some mortality. More recently, combined modality programs of brief chemotherapy and limited radiation have been extremely successful in managing patients with stage I-II disease. In addition to its utility in early disease, radiation therapy is an integral component of treatment programs for patients with large mediastinal adenopathy. It has also proved useful in patients with stage III-IV who achieve only a partial response to chemotherapy and may also have a role to play as a component of high-dose therapy hematopoietic stem cell transplant programs. Radiation therapy remains the most effective single agent for the treatment of Hodgkin's disease.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Theodor Bücher Lecture. Metabolomics, modelling and machine learning in systems biology - towards an understanding of the languages of cells. Delivered on 3 July 2005 at the 30th FEBS Congress and the 9th IUBMB conference in Budapest.

The newly emerging field of systems biology involves a judicious interplay between high-throughput 'wet' experimentation, computational modelling and technology development, coupled to the world of ideas and theory. This interplay involves iterative cycles, such that systems biology is not at all confined to hypothesis-dependent studies, with intelligent, principled, hypothesis-generating studies being of high importance and consequently very far from aimless fishing expeditions. I seek to illustrate each of these facets. Novel technology development in metabolomics can increase substantially the dynamic range and number of metabolites that one can detect, and these can be exploited as disease markers and in the consequent and principled generation of hypotheses that are consistent with the data and achieve this in a value-free manner. Much of classical biochemistry and signalling pathway analysis has concentrated on the analyses of changes in the concentrations of intermediates, with 'local' equations - such as that of Michaelis and Menten v=(Vmax x S)/(S+K m) - that describe individual steps being based solely on the instantaneous values of these concentrations. Recent work using single cells (that are not subject to the intellectually unsupportable averaging of the variable displayed by heterogeneous cells possessing nonlinear kinetics) has led to the recognition that some protein signalling pathways may encode their signals not (just) as concentrations (AM or amplitude-modulated in a radio analogy) but via changes in the dynamics of those concentrations (the signals are FM or frequency-modulated). This contributes in principle to a straightforward solution of the crosstalk problem, leads to a profound reassessment of how to understand the downstream effects of dynamic changes in the concentrations of elements in these pathways, and stresses the role of signal processing (and not merely the intermediates) in biological signalling. It is this signal processing that lies at the heart of understanding the languages of cells. The resolution of many of the modern and postgenomic problems of biochemistry requires the development of a myriad of new technologies (and maybe a new culture), and thus regular input from the physical sciences, engineering, mathematics and computer science. One solution, that we are adopting in the Manchester Interdisciplinary Biocentre (http://www.mib.ac.uk/) and the Manchester Centre for Integrative Systems Biology (http://www.mcisb.org/), is thus to colocate individuals with the necessary combinations of skills. Novel disciplines that require such an integrative approach continue to emerge. These include fields such as chemical genomics, synthetic biology, distributed computational environments for biological data and modelling, single cell diagnostics/bionanotechnology, and computational linguistics/text mining.

Artificial Intelligence↗
PubMed2001

Chemoprevention with antiestrogens: the beginning of the end for breast cancer. Daniel G. Miller Lecture.

In the 1960s, compounds known as nonsteroidal antiestrogens were identified as potential contraceptives, but the drugs caused the induction of ovulation in subfertile women. Tamoxifen and clomiphene were marketed for this indication. However, tamoxifen was advanced for the treatment of breast cancer in the 1970s through a close cooperation between the laboratory and the clinical trials community. The extensive use of long-term adjuvant tamoxifen has resulted in saving the lives of 400,000 women with breast cancer. Tamoxifen is a selective estrogen receptor modulator (SERM) that produces antiestrogenic actions in the breast but estrogen-like actions in bone and lowers serum cholesterol. These properties not only allowed the application of tamoxifen as the first chemopreventive in high-risk pre- and postmenopausal women but also the development of raloxifene to prevent osteoporosis with the potential to prevent breast cancer in postmenopausal women. The future development of SERMs holds the promise of preventing osteoporosis and coronary heart disease as well as breast and endometrial cancer.

Amino Acid Substitution↗
PubMed1990

The physiological basis of training the skeleton. The Sir Frederick Smith Memorial Lecture.

The skeleton consists of a series of elements with a variety of functions. In locations such as the skull, where shape or protection are of prime importance, the bone's architecture is achieved during growth under predominant genetic control. In locations such as the limbs, where the ability to withstand repetitive loading is important, only the general form of the bone will be achieved as a result of growth alone, the remaining characteristics resulting from an adaptive response to functional load bearing. In the horse, this functional load-bearing will be provided by the animal's natural activity pattern in box or paddock supplemented by the specific activities of the training regimen. It is the adaptive response to the total activity pattern that influences bone modelling and remodelling and so determines the bone's architecture. The objective of the training regimen is to ensure that this response achieves an appropriate match between bone architecture and the loads it is required to withstand during both training and athletic performance. We propose that for the match between architecture and load-bearing to be established, and maintained, subsequently, bone cells must be able to 'assess' directly or indirectly the functional strains produced within the bone tissue. Because these strains are used as feedback they are both the objective of functionally adaptive modelling and remodelling, and the stimulus for its control. The mechanisms whereby bone cells control skeletal modelling and remodelling to produce a functionally competent skeleton are unknown although some of the factors and sequence of events involved are presented here. The extent to which variation in training regimen affects bone architecture has not been studied systematically in any species.

Adaptation, Physiological↗
PubMed2001

Hormones and calcium: mechanisms controlling uterine smooth muscle contractile activity. The Litchfield Lecture.

The regulation of myometrial contraction is of paramount importance for the maintenance of pregnancy and for parturition. Understanding this regulation involves delineating the pathways that control myometrial contraction and relaxation and defining the regulation of these pathways. The pathways can be broken down further into those signalling cascades controlling the concentration of intracellular free calcium (Ca(2+)(i)) and those controlling the contractile apparatus itself. This discussion focuses primarily on the former and their regulation during pregnancy. In particular, cross-talk between the contractant and relaxant signalling pathways mediated through cyclic AMP is markedly changed at the end of pregnancy. Experimental Physiology (2001) 86.2, 223-237.

Animals↗
PubMedDate not supplied

1997 Whitaker Distinguished Lecture: Models to solve mysteries in biomechanics at the cellular level; a new view of fiber matrix layers.

Three different fundamental cellular level transport models are presented to explore current or recently solved mysteries in what appear to be three unrelated problem areas: (i) Starling's hypothesis for lymph formation in the microcirculation; (ii) the cellular level transduction and transmission mechanisms for sensing and communicating mechanical strain in bone; and (iii) the growth of cellular level macromolecular leakage spots in the arterial intima and their relation to the formation of subendothelial liposomes. This trilogy of what appear to be unrelated problems is shown to have a common link, the thin layer of specialized matrix that cells produce at the surface of their plasmalemma membranes in part to regulate the water and solute transport that surrounds them. In each case unexpected model predictions have led to new hypotheses and the design of new experiments which have helped explain long-standing fundamental questions in biomechanics.

Adaptation, Physiological↗