The activation of red blood cell transketolase in groups of patients especially at risk from thiamin deficiency

Erythrocyte transketolase activation by thiamin diphosphate has been studied in elderly patients with moderate or severe chronic dementia, acute alcoholic admissions and chronic alcoholics with evidence of brain damage, mostly of the Wernicke-Korsakoff type. Significantly more patients in each group than controls showed abnormal activation of transketolase, not only by 0.3 mM thiamin diphosphate (TDP) but also in further activation by increase to 3 mM. This indicated the presence in a proportion of the alcoholic and the demented patients of an abnormal enzyme variant, similar to that previously found in vitro. The modified transketolase activation test may warn not only of marginal thiamin deficiency but also independently, of susceptibility to brain damage in patients at risk.     

Defibrination with ancrod in experimental chronic immune complex nephritis

The role of fibrin deposition in experimental (crescentic) nephritis in rabbits, due to chronic immune complex deposition induced by BSA, has been studied. Fibrin deposition was prevented and in such animals crescent formation inhibited, suggesting that, as in experimental nephritis due to anti-GBM antibodies, fibrin deposition plays a major pathogenetic role in epithelial cell proliferation. However, in defibrinated animals, mesangial and endothelial cell proliferation, polymorpho-nuclear leucocyte infiltration and impairment of renal function could still occur. These studies are further evidence that defibrination may be of benefit in the treatment of rapidly progressive glomerulonephritis in man.     

Molecular epidemiology of HIV-1 variants in the global AIDS pandemic: an update

The picture of HIV-1 genetic diversity in the global pandemic continues to evolve. Identification of new variants, including circulating and unique recombinant forms, recognition of new outbreaks and of changes in established epidemics, and characterization of growing numbers of full-length genomes provide a view of high dynamism and increasing complexity. The pervasive role of recombination as a major driving force in the generation of diversity in the HIV-1 pandemic is becoming evident, and is particularly visible in areas in which different genetic forms meet, referred to as "geographic recombination hotspots". The importance of superinfection and its impact on HIV-1 diversification and propagation is surfacing, although restrictions to superinfection are also apparent. Genetic diversity within subtypes is increasing over time and new geographically localized lineages deriving from point introductions are being recognized. Characterization of such variants may be of relevance to vaccine development and may allow the detection of intrasubtype recombination and superinfection. Recent studies supporting the correlation of HIV-1 clades to immune responses and to drug resistance-associated mutations lend increasing relevance to the role of molecular epidemiology as an essential tool in combating the AIDS pandemic. However, knowledge on the global HIV-1 genetic diversity and its implications is still far from adequate and a major scaling up of efforts is needed.     

Identification of 21 novel glucokinase (GCK) mutations in UK and European Caucasians with maturity-onset diabetes of the young (MODY)

Maturity-onset diabetes of the young (MODY) resulting from mutations in the glucokinase (GCK) gene accounts for approximately 20% of MODY in the UK. We have performed fluorescent single stranded conformation polymorphism (F-SSCP) analysis or direct sequencing of the GCK gene in 212 patients referred as part of a research cohort or for diagnostic molecular genetic testing. Mutation screening has identified 43 different mutations in 61 individuals, of which 21 are novel. This report details the mutations identified and their associated clinical features.     

The role of polymorphonuclear leucocytes in the autologous phase of nephrotoxic nephritis.

The role of polymorphonuclear leucocytes (PMN) in the autologous phase of nephrotoxic nephritis (NTN) in the rabbit has been investigated. Depletion of circulating PMN by nitrogen mustard protected renal function and immunofluorescent examination showed reduction in glomerular fibrin deposition. Depletion of circulating PMN using a highly specific goat anti-PMN serum (APS) provided similar protection of renal function, highly significant reduction in proteinuria and histological and immunofluorescent examination showed reduced glomerular PMN infiltration, extracapillary cell proliferation and virtual absence of fibrin deposition. Although protection by nitrogen mustard may have been partly due to immunosuppression, no reduction in antibody response was detected in the APS-treated rabbits. The results implicate the polymorph as the principal injurious agent in this model of NTN, responsible directly or indirectly for both proteinuria and glomerular fibrin deposition.     

Missed opportunities for the prevention of cardiovascular disease among British hypertensives in primary care.

BACKGROUND: High-risk strategies for the prevention of cardiovascular disease (CVD) among hypertensive patients require knowledge of the prevalence and interaction of modifiable risk factors to ensure effective targeting of interventions. Comparatively little is known of risk-factor profiles and their modification among hypertensives in primary care. AIM: The present study was designed to explore relationships between patients' knowledge of CVD risk factors, their perception of personal risk and health behaviours, and their use of lifestyle interventions. METHOD: A cross-sectional survey of 2676 men and women with mild to moderate hypertension (diastolic blood pressure 95-115 mmHg), and their general practitioners, recruited from 1044 general practices throughout the UK, was conducted. RESULTS: Levels of modifiable risk factors were high, although there was considerable variation by age and sex; most (98.5%) patients had at least one additional CVD risk factor. A lower standard of living was associated with a higher prevalence of 'unhealthy' behaviours. Out of those with a current lifestyle problem, 85% of obese patients, 59% of smokers, 47% of excess drinkers, 49% of those with dietary risk factors and 32% of inactive patients claimed to have adopted healthier behaviours within the past 3 months. Older subjects and those with a lower standard of living were less likely to acknowledge risks, and those who did were less likely to report improving their lifestyles. While 71% of patients recalled receiving lifestyle advice, the coverage and targeting of specific interventions was generally poor. Overall, 60% of the sample had received advice on weight control, 47% on diet, 38% on exercise, 38% on smoking and 36% on alcohol. Women and older people were less likely to be given relevant counseling, and there was no evidence of targeting with respect to subjects' social class, level of hypertension or duration of diagnosis. CONCLUSION: Lifestyle interventions are welcomed and are viewed as helpful by patients receiving them. Potential health gains among high-risk hypertensives are being lost because of poor targeting and coverage of those at greatest risk.     

Platelet aggregation and strenuous exercise

1. Platelet aggregation in the Chandler's tube has been found to be increased in a group of normal male and female volunteers who undertook strenuous physical exercise. This coincided with acceleration of the ;intrinsic' blood clotting system and a rise in fibrinogen. The rise in fibrinogen occurred despite increased fibrinolysis.2. The study confirms the sensitivity of the platelet aggregation system to changes in the ;intrinsic' clotting mechanism. Acceleration of this system in this study resulted from a physiological cause and produced accelerated aggregation in the coagulation-affected phase.     

The influence of FK-506 on the thymus: an immunophenotypic and structural analysis.

The influence of the powerful new immunosuppressant FK-506 on the thymus was investigated in Sprague-Dawley rats that were immunized with sheep erythrocytes and treated with FK-506 (1 mg/kg/day i.m.) for 7 days. Suppression of humoral immunity in drug-treated animals was accompanied by reductions in circulating lymphocytes bearing activation markers (interleukin-2 receptor beta-chain and OX40, activated CD4+ cells) and by striking thymic medullary atrophy. There were, however, no significant differences in thymic weights or in thymocyte numbers between experimental and control groups during the period of FK-506 administration. Reduction of the medullary compartment was visualized immunohistochemically, by decreases in major histocompatibility complex (MHC) class I- and MHC class II-positive cells and in CD37+ (mature medullary) thymocytes. Flow cytometric analysis of thymocytes showed that FK-506 induced increases in bright, Thy-1.1+ cells and in numbers of CD4+ and CD8+ thymocytes, whilst CD37+ cells were less numerous than in controls. Percentages of MHC class I- and MHC class II-positive cells varied little throughout the course of FK-506 administration. Evidence of selective damage to medullary epithelial cells, attributable to FK-506, was found at both the light and electron microscopic levels, whilst thymic macrophages in drug-treated rats displayed features of enhanced phagocytic activity, including ingestion of damaged epithelial cells. These FK-506-induced abnormalities were reversed within 14 days of drug withdrawal. These findings suggest that, like cyclosporin A, FK-506 reversibly disrupts the thymic microenvironment and may interfere with the function/maturation of T lymphocytes.