This two-part review is intended principally for practising clinicians who want to know why some types of evidence about the effects of treatment on survival, and on other major aspects of chronic disease outcome, are much more reliable than others. Although there are a few striking examples of treatments for serious disease which really do work extremely well, most claims for big improvements turn out to be evanescent. Unrealistic expectations about the chances of discovering large treatment effects could misleadingly suggest that evidence from small randomised trials or from non-randomised studies will suffice. By contrast, the reliable assessment of any more moderate effects of treatment on major outcomes--which are usually all that can realistically be expected from most treatments for most common serious conditions--requires studies that guarantee both strict control of bias (which, in general, requires proper randomisation and appropriate analysis, with no unduly data-dependent emphasis on specific parts of the overall evidence) and strict control of random error (which, in general, requires large numbers of deaths or of some other relevant outcome). Past failures to produce such evidence, and to interpret it appropriately, have already led to many premature deaths and much unnecessary suffering.

Pre-eclampsia is usually defined on the basis of new onset hypertension and albuminuria developing after 20 weeks of pregnancy. There are difficulties with measurement of these variables. Conventional sphygmomanometry remains the gold standard for blood-pressure measurement. The value of ambulatory blood-pressure measurement has yet to be established. Oedema is now omitted from all definitions of preeclampsia, although the finding of widespread severe oedema of sudden onset should not be ignored for clinical purposes. Definitions of pre-eclampsia based solely on hypertension and proteinuria ignore the wide clinical variability in this syndrome. Women with no proteinuria but who do have hypertension and other features such as severe headache or other symptoms, thrombocytopenia, hyperuricaemia, disordered liver function, and fetal compromise are likely to have pre-eclampsia. This notion is accepted in the new Australasian definition of pre-eclampsia and more than hinted at in the new American College of Obstetricians and Gynecologists' definition. Definitions used for clinical purposes should be as safe as practical; they are likely to include a considerable number of false positives. Most research studies are weakened if patients without the disease are included. Therefore, a separate stringent research definition of pre-eclampsia we also suggest.

After more than a century of intensive research, pre-eclampsia and eclampsia remain an enigmatic set of conditions. Aberration of the interaction between placental and maternal tissue is probably the primary cause, but the exact nature of the differences from normal pregnancy remain elusive. In this review attempts to understand the sequence of physiological changes have concentrated on vascular endothelium and oxidative stress issues. There are genetic components to susceptibility, but the relative contributions of maternal and fetal genotypes are still unclear. Whole-genome mapping could ultimately define the causative genes.

A major goal of antidepressant development is to improve on preceding drug classes with agents with greater specificity (and therefore fewer unwanted side-effects) and with more rapid onset of antidepressant action. To this end, four antidepressants with significantly distinct pharmacological characteristics have been recently introduced: venlafaxine, nefazodone, mirtazapine, and reboxetine. Venlafaxine is the first antidepressant in a new drug class referred to as the serotonin noradrenergic reuptake inhibitors (SNaRIs). Nefazodone is a weaker serotonin and norepinephrine reuptake inhibitor, but a potent serotonin 5-HT2 receptor antagonist. Mirtazapine is a potent antagonist of central 2alpha-adrenergic autoreceptors, and heteroreceptors and is an antagonist of serotonin 5-HT2 and 5-HT3 receptors. The result of these actions is to increase both noradrenergic and specific (5-HT1) serotonergic transmission, and mirtazapine has therefore been termed a noradrenergic and specific serotonergic antidepressant (NaSSA). Reboxetine is the first selective noradrenaline reuptake inhibitor (NaRI) to be introduced since the tricyclics, and lacks immediate serotonergic effects.

Previous meta-analysis of outcome trials in hypertension have not specifically focused on isolated systolic hypertension or they have explained treatment benefit mainly in function of the achieved diastolic blood pressure reduction. We therefore undertook a quantitative overview of the trials to further evaluate the risks associated with systolic blood pressure in treated and untreated older patients with isolated systolic hypertension

This programme of overviews of randomised trials was established to investigate the effects of angiotensin-converting-enzyme (ACE) inhibitors, calcium antagonists, and other blood-pressure-lowering drugs on mortality and major cardiovascular morbidity in several populations of patients. We did separate overviews of trials comparing active treatment regimens with placebo, trials comparing more intensive and less intensive blood-pressure-lowering strategies, and trials comparing treatment regimens based on different drug classes.

Several observational studies and individual randomised trials in hypertension have suggested that, compared with other drugs, calcium antagonists may be associated with a higher risk of coronary events, despite similar blood-pressure control. The aim of this meta-analysis was to compare the effects of calcium antagonists and other antihypertensive drugs on major cardiovascular events.

The supremacy of combined oral contraceptives (OCs) is being challenged. For too long combined OCs have been seen as synonymous with contraception, helping to maintain ignorance of alternative methods. Further, the efficacy of these OCs and condoms is often compromised by incorrect or inconsistent use. We particularly welcome developments in male systemic methods, that allow men to share not only in conception but also in contraception, and methods that are completely forgettable once instituted, especially if usable by adolescents.

It is too soon for a verdict on the health risks from cellular telephones, especially in view of changing technology. From the Interphone project and some other large studies in progress, better information may emerge. Based on the epidemiological evidence available now, the main public-health concern is clearly motor vehicle collisions, a behavioural effect rather than an effect of radiofrequency exposure as such. Neither the several studies of occupational exposure to radiofrequencies nor the few of cellular telephone users offer any clear evidence of an association with brain tumours or other malignancies. Even if the studies in progress were to find large relative effects for brain cancer, the absolute increase in risk would probably be much smaller than the risk stemming from motor vehicle collisions. Cellular telephones affect the quality of our lives in myriad ways, for good and ill; the health risk is just one part of a picture that is slowly coming into focus.

Although safety guidelines--to which mobile telephones and their base-stations conform--do protect against excessive microwave heating, there is evidence that the low intensity, pulsed radiation currently used can exert subtle non-thermal influences. If these influences entail adverse health consequences, current guidelines would be inadequate. This review will focus on this possibility. The radiation used is indeed of very low intensity, but an oscillatory similitude between this pulsed microwave radiation and certain electrochemical activities of the living human being should prompt concern. However, being so inherently dependent on aliveness, non-thermal effects cannot be expected to be as robust as thermal ones, as is indeed found; nor can everyone be expected to be affected in the same way by exposure to the same radiation. Notwithstanding uncertainty about whether the non-thermal influences reported do adversely affect health, there are consistencies between some of these effects and the neurological problems reported by some mobile-telephone users and people exposed longterm to base-station radiation. These should be pointers for future research.

Proteomics-based approaches, which examine the expressed proteins of a tissue or cell type, complement the genome initiatives and are increasingly being used to address biomedical questions. Proteins are the main functional output, and the genetic code cannot always indicate which proteins are expressed, in what quantity, and in what form. For example, post-translational modifications of proteins, such as phosphorylation or glycosylation, are very important in determining protein function. Similarly, the effects of environmental factors or multigenic processes such as ageing or disease cannot be assessed simply by examination of the genome alone. This review describes the underlying technology and illustrates several areas of biomedical research, ranging from pathogenesis of neurological disorders to drug and vaccine design, in which potential clinical applications are being explored.

Polymorphisms in the genes that code for drug-metabolising enzymes, drug transporters, drug receptors, and ion channels can affect an individual's risk of having an adverse drug reaction, or can alter the efficacy of drug treatment in that individual. Mutant alleles at a single gene locus are the best studied individual risk factors for adverse drug reactions, and include many genes coding for drug-metabolising enzymes. These genetic polymorphisms of drug metabolism produce the phenotypes of "poor metabolisers" or "ultrarapid metabolisers" of numerous drugs. Together, such phenotypes make up a substantial proportion of the population. Pharmacogenomic techniques allow efficient analysis of these risk factors, and genotyping tests have the potential to optimise drug therapy in the future.

No one can question the remarkable contribution of US public health to understanding the causes and consequences of illness, disability, and death. However, some commentators question the agenda: the endless pursuit of individual risk factors and the cursory attention to social determinants of disease. We attempt to illustrate some limitations of US public health by focusing on type-2 diabetes (adult-onset non-insulin-dependent diabetes)--an increasingly prevalent but still poorly understood medical condition with devastating complications and implications for quality of life. A more theoretically based multilevel approach to diabetes, outlined for the 21st century, has an almost exclusive downstream curative focus, that ranges from midstream preventive programmes to upstream healthy public policy.

Cardiogenic shock remains the major cause of death among patients with all types of acute coronary syndromes. Thus, there is a growing interest in the identification of patients who are at risk for developing cardiogenic shock, in the exploration of different therapeutic approaches to preventing its development, and in the improvement of outcome when it occurs. This article reviews the aetiology and pathophysiology of cardiogenic shock, its epidemiology, its treatment (including pharmaceutical agents, counterpulsation, and revascularisation), and its outcome. Algorithms are presented that predict its occurrence in both ST-segment-elevation myocardial infarction and unstable angina or non-ST-elevation myocardial infarction, and that predict its mortality in patients with ST-segment-elevation acute myocardial infarction. Such new areas as metabolic therapy and glycoprotein IIb/IIIa inhibitors are discussed, as are the economic implications of shock.

Exercise-induced changes in the electrocardiogram have been used to identify coronary artery disease for almost a century. Over the past decade, however, clinicians have increasingly focused on more expensive diagnostic tools believing them to offer improved diagnostic accuracy. In fact, by incorporating historical data, the simple exercise test can in most cases outperform the newer tests. The use of prediction equations and non-staged exercise protocols can improve the test still further, while advances in the use of the test for prognosis, with the discovery of novel risk factors and the addition of gas analysis, may in the future shift the primary emphasis away from diagnosis. Brief, inexpensive, and done in most cases without the presence of a cardiologist, the exercise test offers the highest value for predictive accuracy of any of the non-invasive tests for coronary artery disease.

Idiosyncratic drug reactions are unpredictable reactions that can result in significant morbidity and mortality. Severe reactions are often characterised by fever and internal organ involvement. Despite progress in the identification of reactive metabolites believed to be the cause of idiosyncratic reactions, the basic mechanisms remain elusive. Furthermore, because of the lack of consensus regarding definition of these syndromes, reporting, and therefore epidemiological data, are often unreliable. Research is needed to explore further the pathophysiology of these reactions, so that better diagnostic tests and treatment methods can be developed.

Adverse reactions are a potential concern for physicians when they prescribe or recommend drugs. Epidemiological principles, when combined with clinical judgment, can be of help in this situation, starting with an appreciation of the strengths and weaknesses of different sources of information on adverse reactions--clinical trials, case reports, and formal epidemiological studies. The latter studies generally provide the most comprehensive information on the risks of serious adverse drug reactions. An understanding of the different types of risk estimates, relative and absolute, is also needed--we stress the value of the absolute risk as the best measure of the impact of an adverse reaction. Rare serious reactions, although striking, have little impact on individual risk, whereas more common reactions, even with much lower fatality rates, are more likely to lead to adverse outcomes for patients. The importance of balancing risks and benefits, taking into account all the information about an individual patient's risk profile, is also highlighted.

Pre-eclampsia is associated with significant morbidity and mortality for mother and baby, but it resolves completely post partum. Despite a steady reduction in maternal mortality from the disorder in more developed countries, it remains one of the most common reasons for a woman to die during pregnancy. The disorder starts with a placental trigger followed by a maternal systemic response. Because both this systemic response and the woman's reaction to it are inconsistent, the clinical presentation varies in time and substance, with many different organ systems affected. With the increasing understanding of the disease process, there have been advances in management, such as antihypertensive therapy, magnesium sulphate, and fluid restriction.