Deposition of amyloid beta-protein in the brain has been regarded as the central event in Alzheimer's disease; however, amyloid beta-protein precursor is an endogenous protein, probably with neurotrophic functions. An alternative hypothesis is that amyloid beta-protein is involved in the disease process secondarily, as a protective reactant when brain cells are injured. Insufficiency of amyloid beta-protein precursor, whether because of a genetic defect or in relation to the action of environmental factors, then allows development of Alzheimer changes.

Non-insulin-dependent diabetes mellitus (NIDDM) is an important health problem in the black population of southern Africa. Whether the primary cause of NIDDM is insulin secretory dysfunction or peripheral insulin resistance is unknown. In westernised populations it is believed that insulin resistance and hyperinsulinaemia occur in the early stages of disease, followed later by progressive impairment of insulin secretion. However, we suggest that in the southern African black population a decrease in the mass of functioning beta cells is an important event, making these people vulnerable to the deleterious effects of insulin resistance induced by obesity and other factors. These abnormalities are, in turn, associated with insulin receptor down-regulation. An accelerated decline in beta-cell function then follows in susceptible individuals, ultimately producing striking insulinopenia. Insulinopenic NIDDM in black southern Africans may partly explain why this population has a comparatively low incidence of macrovascular complications and also predicts a short-lived therapeutic response to oral sulphonylureas in most patients.

There is growing interest in screening to detect symptomless hepatocellular carcinoma (HCC), which should be easier to treat than symptomatic tumours. Combined alpha-fetoprotein and ultrasound monitoring can detect HCCs of 1 cm, and Lipiodol retention can be detected in tumours smaller than 1 cm. A number of treatment options are available. Surgical resection may be curative in selected patients with a single small tumour, but the cirrhotic patient is left with a diseased liver and the risk of tumour recurrence or death from underlying liver dysfunction. Orthotopic liver transplantation is a rational treatment for patients with decompensating cirrhosis and a small HCC, but it is expensive and necessitates immunosuppression. A variety of targeted or local therapies, either individually or in combination, can be used to treat HCC. These include percutaneous alcohol injection into an HCC, which may be an alternative to surgical resection. Tumour necrosis can be seen after targeted Lipiodol chemotherapy or radiotherapy. Transcatheter arterial embolisation selectively embolises the feeding artery, and can be combined with Lipiodol chemotherapy. Small tumours are thus amenable to treatment, even in patients who cannot have surgery. Screening and treatment for symptomless HCC seems justified, unless controlled trials teach us differently.

A little recognised feature of neurons is their large complement of lysosomes. Studies of the accumulation of the abnormal isoform of the prion protein (PrPSC) in the prion encephalopathies and the formation of beta/A4 protein from its precursor in Alzheimer's disease suggest that generation of these key proteins takes place in lysosome-related organelles. The release of hydrolytic enzymes from lysosomes may be a primary cause of neuronal damage. Although molecular genetic approaches have identified protein mutations central to the main neurodegenerative disease, cell biological observations are now beginning to unravel the intracellular pathways involved in the molecular pathogenesis of neurodegeneration: as a result, it is now appropriate to consider therapeutic manipulation of the lysosomal system as an approach to treatment.

The molecular basis of cancer is now understood to involve activation of dominant oncogenes and inactivation of tumour suppressor genes, and these genetic events may represent novel targets for cancer therapy. This review focuses on the potential use and ethical implications of gene transfer to alter the behaviour of somatic cells in cancer patients. Antisense nucleic acids and ribozymes represent informational drugs that may be used to modulate the expression of selected genes and suppress malignant behaviour in cancer cells. Genetic immunomodulation by introducing genes for cytokines into cancer cells or lymphocytes can stimulate a cytotoxic immune response against the tumour. Gene transfer techniques can be applied to target prodrug activation specifically to tumour cells and also to protect normal tissues against toxic chemotherapy. Gene replacement therapy could even be used to restore the function of defective tumour suppressor genes.