A new development in the British National Health Service is fundholding, whereby certain general practitioners are given budgets from which they purchase services for patients. Our knowledge about fundholding is rudimentary. Many important questions remain unanswered. These include: the impact of fundholding on the efficiency of overall resource utilisation; its effect on strategic planning; its effect on equity; its impact on the role of the doctor and the doctor-patient relationship; and its consequences for practice organisation and the culture of primary care. Even the scant results we do have must be interpreted cautiously. Fundholding was introduced during a period of great turbulence for general practice. Its strategic function was uncertain and its impact has been confounded by the effects of a series of earlier and concurrent policy changes. Few reliable conclusions about fundholding, either positive or negative, can be drawn from existing research.

The pathogenesis of acute pancreatitis is poorly understood, despite well-recognised precipitating factors. Current evidence suggests that the earliest abnormalities of acute pancreatitis arise within acinar cells, but the key intracellular trigger has yet to be identified. Within the pancreas, physiological concentrations of secretagogues bind to G-protein-linked cell-surface receptors on acinar cells, evoking short, oscillatory spikes of acinar cytosolic-free ionised calcium ([Ca2+]i), an ubiquitous intracellular messenger. Specific effects within acinar cells include initiation of enzyme release through the phosphorylation cascades of stimulus-secretion coupling. Low resting levels of [Ca2+]i are restored by Ca(2+)-ATPase, which pumps calcium into the endoplasmic reticulum and out of the cell. If high concentrations of [Ca2+]i persist, toxicity results, intracellular signalling is disrupted, and cell damage occurs. Sustained elevations in acinar [Ca2+]i result from exposure to high concentrations of secretagogues, high doses of which also induce acute pancreatitis. Similarly, sustained elevations of [Ca2+]i may result from ductal hypertension, alcohol, hypoxia, hypercalcaemia, hyperlipidaemia, viral infection, and various drugs--all factors known to precipitate acute pancreatitis. We suggest that these factors precipitate acute pancreatitis by causing either excessive release of acinar [Ca2+]i, or damage to the integrity of mechanisms that restore low resting levels of [Ca2+]i, and that the consequent calcium toxicity is the key trigger in the pathogenesis of acute pancreatitis.

In a complex organism, somatic cells are under intermittent selection pressure for the emergence of mutants that can survive environmental insults and that can grow autonomously despite adverse conditions. Repeated rounds of mutation, selection, and proliferation may lead to cancer. The organism prevents malignant transformation by assuring accurate DNA repair before cell division, by forcing the death of cells with excessive DNA damage, and by placing limits on the replicative lifespans of most somatic cells. The p53 gene is a "guardian of the genome"--it regulates multiple components of the DNA damage control response and promotes cellular senescence. Disabling mutations and deletions of p53 occur in 50% of human tumours. p53-deficient cancers are often unstable, aggressive, and resistant to therapy.

The observation of an exponential increase in senile dementia prevalence with age has led to the conclusion that this disease may be inevitable in those who live long enough. The alternative view is that at very high ages the prevalence rate levels off. Studies conducted to date have not included sufficient numbers of very old people to resolve this difference of opinion. The question is important both to our understanding of the biological mechanisms involved and for public health planning. We have carried out a meta-analysis of nine epidemiological studies of senile dementia that used DSM III diagnostic criteria and that included samples of elderly people over age 80. The resulting curve was best described as a flattened S curve that fitted a modified logistic function rather than an exponential pattern. The rate of increase in senile dementia prevalence was found to fall in the age range 80-84, and at around the age of 95 prevalence was seen to level off to about 40%. It seems that senile dementia is better conceptualised as an "age-related" (ie, occurring within a specific age range) rather than as an "ageing-related" disorder (that is, caused by the ageing process itself). Very elderly survivors may be at diminishing risk of dementia and this has implications for public health policy.

Infection with specific viruses has a role in the pathogenesis of some cancers in human beings. However, the incidence of such cancers is much lower than the frequency of virus infection, suggesting either that infection alone does not result in cancer and that cellular events in addition to the presence of the virus must occur, or that cancer occurs only if viral proteins are expressed in an appropriate cell type or in an immunocompromised host. Molecular analysis of viruses found in association with cancer has revealed that they function, at least in part, by encoding proteins which can associate with and subvert the function of host cell-encoded tumour suppressor proteins which regulate pathways of growth arrest and apoptosis. Better understanding of the mechanisms underlying this association will have diagnostic, prognostic, and therapeutic implications in the near future.

Clinical management of acute myocardial infarction has been strongly influenced by large, simple trials (mega-trials) with unrestrictive protocols and limited data collection. The design has been adopted to increase statistical power to a maximum. Its validity rests on an effective randomisation procedure and intention-to-treat analysis of deaths. Experience has shown that mega-trials tend to generate effect-estimates nearer the null than those from conventional trials or meta-analyses. When a small or absent observed treatment effect (or subgroup effect) in a mega-trial contrasts with the results of conventionally designed trials, it is necessary to assess both null bias and failure to increase the true treatment effect to a maximum in the mega-trial. Null bias will arise when the contrast between treatment and no-treatment, or between subgroups, is blunted either by non-protocol therapy or by inaccuracy of data, including misclassification between subgroups. Each is more likely with an unrestrictive design. To increase the true treatment effect to a maximum, trial conditions must be specified with insight into mechanism, dose-dependence, and time-dependence. The mega-trial design is therefore unsuited to an exploratory role. These issues are illustrated by the examples of nitrates, angiotensin-converting-enzyme inhibitors, and magnesium in acute myocardial infarction but have general relevance to the validity and generalisability of simple trials.

The myometrium is usually thought of as a homogeneous mass of smooth muscle fibres. However, magnetic resonance studies of the uterus have revealed two distinct zones--the subendometrial myometrium or junctional zone and the outer myometrium. The junctional zone is not only structurally but also functionally different from the outer myometrium. For instance, myometrial contractions in a non-pregnant woman originate exclusively from the junctional zone, and their amplitude, frequency, and direction depend on the phase of the cycle. Irregular thickening of the junctional zone has been proposed as the magnetic resonance criterion for the diagnosis of diffuse adenomyosis. However, this magnetic resonance appearance relies on the disruption of the inner myometrial architecture secondary to smooth muscle hyperplasia but does not provide proof of mucosal invasion of the myometrium. We postulate that adenomyosis is a dichotomous disease characterised primarily by disruption of the inner myometrial architecture and function, with secondary infiltration of endometrial elements into the myometrium under certain circumstances. This hypothesis focuses on the inner myometrium and may explain the high incidence of superficial adenomyosis in dysfunctional uterine bleeding.