How should patients taking the discontinued diabetes drug troglitazone be managed?
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Biomedical subjects
Publications and source records attributed to S S Reddy.
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Outcome evaluation is of great interest throughout the healthcare field, but which outcomes are important depends on the viewpoint one holds. For the healthcare organisation costs and resource utilisation are paramount, whereas patients may be interested in being able to work and lead a productive life without long-term complications. Healthcare policy decisions are influenced by varying degrees of social forces, existing regulations and outcome research findings. Ideally, all three are in agreement but often they may be competitive or may not even be included in policy decision making. With respect to improving outcomes, much energy has been spent on developing diabetes care guidelines. However, these have had minimal impact on physician behaviour. Soon after onset or diagnosis of diabetes, we are most concerned with process measures such as micro-albumin levels, blood pressure monitoring, routine eye and foot examinations and lipid profiles. These process measures are related to the development of intermediate outcomes--proteinuria, retinopathy, foot ulcers and dyslipidaemia. Diabetes is an expensive disease but there is accumulating evidence that improved care can lead to better quality of life and reduction in health care resource utilisation. The UKPDS demonstrated that for one percentage point decrease in HbA1c there was a 35% reduction in the risk of complications. Preliminary data from various diabetes management programmes indicate that instituting standardised care may lead to cost savings and improved health. Rationing health care resources wisely requires consideration of multiple factors including quality of life years (QALYs) and healthy year equivalents (HYEs). Formal quantitative methods are used to measure overall desirability of a medical intervention. Questions to be answered include predictability of responsiveness or adverse events to drug therapy. Outcomes research will have a key role in future development of models of diabetes care.
AIMS: New approaches to continuing medical education will facilitate the implementation of clinical practice guidelines. This study assessed the short and long-term impact of a 7-h, small group workshop on family physicians' attitude, knowledge and self-reported practice patterns regarding diabetes mellitus. METHODS: One hundred and seventy-seven of 1807 family physicians who participated in this nationwide workshop, and 113 non-participant controls completed two validated questionnaires. Participants completed one questionnaire before the workshop and a second equivalent questionnaire 1 month later. Non-participant controls also completed the two questionnaires 1 month apart. Between 8 and 24 months later, these individuals were mailed the same questionnaire they completed on the first occasion; 143 participants and 50 controls returned this third questionnaire. RESULTS: Participants were more likely to be female (P = 0.03), not certified in family practice (P = 0.02), in a smaller centre (P = 0.0005), recent medical graduates (P = 0.001) and seeing fewer patients per month (P = 0.01) than controls. Compared to controls, participants had improved their attitude (P<0.0001), knowledge (P = 0.04) and self-reported practice patterns (P<0.002) regarding diabetes after 1 month but not after 1 year. CONCLUSIONS: An interactive, small group, diabetes continuing education programme effectively disseminates practice guidelines to family physicians. The impact of such a programme declines after 1 year.
The United Kingdom Prospective Diabetes Study (UKPDS) showed that intensive treatment (i.e., glucose-lowering drugs, with a goal fasting blood glucose level of 108 mg/dL) decreases the microvascular complications of type 2 diabetes mellitus. We summarize the key study results and their implications for clinical management of type 2 diabetes mellitus.
PURPOSE: To assess the policies and practices of nuclear medicine facilities as regards ventilation-perfusion (V-P) imaging in pregnant patients suspected of having pulmonary embolus. MATERIALS AND METHODS: Surveys were mailed to physician-directors of 1,000 randomly selected facilities at which nuclear imaging studies are performed. Information gathered included use of V-P imaging in pregnant patients, written policies, informed consent procedures, and modifications of standard protocols. RESULTS: Of the 1,000 surveys mailed, 327 (33%) completed surveys were returned. Of these 327 respondents, 220 (67%) reported that they perform V-P imaging in pregnant patients suspected of having pulmonary embolus. Of these 220 respondents, 115 (52%) routinely obtain informed consent, and 170 (77%) modify their standard V-P imaging protocol for pregnant patients. The most common modification (135 [79%] of 170 respondents) was reduction of the perfusion agent dose. Reported practice patterns for written policies, informed consent, and modifications did not show statistically significant trends among respondents in varying practice settings or geographic locations. CONCLUSION: Most respondents perform V-P imaging in pregnant patients suspected of having pulmonary embolus, with considerable variability in their policies and practices.
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The epidemiologic and pathologic evidence that fenfluramine and related drugs cause valvular heart disease is still speculative. However, at present, there is no alternative explanation for the cases of valvular disease found in patients taking these drugs, and there is evidence that similar substances can cause similar lesions. The manufacturer of fenfluramine and dexfenfluramine has prudently removed them from sale pending further studies.
Opportunistic infections are common after renal transplantation because of the use of immunosuppression. Nocardiosis is a rare but important cause of morbidity and mortality among renal transplant recipients. Depending upon the transplant center, the estimated incidence of nocardiosis among renal transplant recipients varies widely from 0 to 20%. We report the first case of nocardiosis in a recently transplanted renal patient maintained on tacrolimus, prednisone, and mycophenolate mofetil. It is likely that the nocardial infection in our patient was related to the development of her diabetes mellitus, and to her early episode of rejection and treatment which included high-dose steroids, and the addition of mycophenolate mofetil. Our case illustrates the importance of maintaining a heightened awareness so that nocardiosis may be diagnosed early and treated successfully.
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Troglitazone is the first of a new family of antihyperglycemic drugs. We review its use in clinical practice.
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Anger and hazardous driving were explored in two studies for their possible explanatory role in the low cholesterol-violent mortality association. In Study 1, we obtained fasting blood samples and indices of anger and driving habits from 102 healthy young adults. Among men (but not women), lower low-density lipoprotein (LDL) cholesterol levels were associated with significantly higher anger (r = 41, p < .01) and unsafe driving habits (r = -.30, p < .05), and although total cholesterol levels were correlated in the predicted direction, these were not significant. In Study 2, 78 healthy young men completed the same measures, and this time, both lower total and LDL-cholesterol were significantly related to increased anger and dangerous driving. Implications of these findings are discussed as are possible avenues for future research. Further scrutiny of the components of serum cholesterol and their relation to psychological factors may aid us in better understanding the reasons why men are at increased risk for hazardous behavior and violent death.
Epidermal growth factor (EGF) may either stimulate or inhibit cell growth. To elucidate the mechanism of these varied effects, we compared EGF action in parental A431 cells in which cell growth is inhibited, and clone 15, a mutant of these cells resistant to EGF growth inhibition. In both lines, EGF receptor was present in similar concentrations and underwent tyrosine phosphorylation to the same extent. Likewise, in both lines, acute exposure to EGF stimulated an increase in free cytoplasmic [Ca2+], as well as a similar increase in phosphorylation of lipocortin 1, a major substrate for the EGF receptor kinase whose phosphorylation is calcium-dependent. On the other hand, pretreatment of clone 15 cells with EGF for 72 h abolished EGF-induced phosphorylation of lipocortin 1 and led to a loss of the increase in cytoplasmic free [Ca2+], whereas no such desensitization was seen in the parental A431 cells. These data indicate a link between EGF-induced increase in cytoplasmic calcium, lipocortin phosphorylation, and cell growth and suggest that differences in mechanisms of desensitization to these immediate actions of EGF may lead to altered growth response to this hormone.
Leprechaunism is a rare genetic disorder characterized by severe growth retardation and insulin resistance. Maximal epidermal growth factor (EGF) binding was reduced in fibroblasts from three unrelated patients with leprechaunism (Ark-1, Can-1, and Minn-1) compared with control (0.8-2.2%/mg protein vs. 5.5%/mg protein). This was due to a decrease in receptor affinity in Ark-1 and Can-1 and a decrease in receptor number in Minn-1. In all cell lines, EGF-stimulated receptor autophosphorylation was also decreased to 18-60% of control, whereas EGF internalization and degradation was normal. Sphingosine (40 microM), a protein kinase C inhibitor, increased EGF receptor affinity twofold in control cells and six- to nine-fold in cells of leprechaunism. However, sphingosine did not enhance EGF-stimulated receptor autophosphorylation in either the controls or the patients' cells. By contrast, only one of the three cell lines of patients with the type A syndrome demonstrated a decrease in EGF binding and all demonstrated normal or near normal EGF-stimulated receptor autophosphorylation. These data indicate that in patients with leprechaunism, there are functional abnormalities of the EGF receptor, as well as of the insulin receptor, that may contribute to the severity of the syndrome. These data also suggest a role for the insulin receptor in maintaining normal EGF receptor function in these cells.
Leprechaunism is a genetic form of insulin resistance characterized by severe growth retardation and early death. To clarify the molecular basis of the insulin resistance, we investigated the insulin binding and kinase properties of the insulin receptor and the receptor gene in cultured skin fibroblasts of two patients (Ark-1 and Ark-2) with leprechaunism and in those of three of their parents. Specific insulin binding to fibroblasts was markedly reduced (less than 25% of control) in both patients with leprechaunism but was essentially normal in the parents. In contrast, insulin receptor autophosphorylation in 1% Triton X-100 cell lysates was reduced in both patients and parents. In Ark-1, the 70% reduction in autophosphorylation correlated with the decrease in binding, whereas in Ark-2 and in the three parents included in the study, autophosphorylation of the insulin receptor was reduced below the level accounted for by a change in receptor content. Analysis of the insulin receptor gene by hybridization with the receptor cDNA probes revealed no gross defect in either Ark-1 or Ark-2. Both parents of Ark-2 were heterozygous for a restriction fragment length polymorphism in the beta-subunit detected with Bam HI digestion (observed in 15% of controls). Ark-2 was homozygous for the more common allele of this polymorphism (observed in 84% of controls). Thus, we have biochemically characterized a new family of leprechaunism (Ark-2) and have found insulin receptor phosphorylation defects in their phenotypically normal parents.
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Insulin receptor function was examined in cultured skin fibroblasts from three patients with leprechaunism (Ark-1, Minn-1, and Can-1), a rare syndrome of severe insulin resistance and neonatal growth retardation. All three patients cell lines demonstrated insulin binding less than 15% of control. This was primarily due to reduced affinity of the receptor in Can-1 and due to reduced number of receptors in the other two cell lines (Ark-1 and Minn-1). When expressed as a fraction of total insulin bound, the percentage of cell-associated insulin internalized and degraded did not differ between the patient cell lines and the controls. However, chloroquine, which inhibited degradation by 50% in the control cells, had no effect in the cells from the patients. When normalized to insulin binding, insulin receptor autophosphorylation was normal in cells from Can-1, but reduced in those of Ark-1 and Minn-1. In contrast, the receptor-associated tyrosine kinase activity toward exogenous substrates was decreased in all three patient cell lines. These results suggest that leprechaunism is a biochemically heterogenous disease associated with a variety of alterations in receptor function. Cells from Ark-1 and Minn-1 exhibit parallel alterations in receptor autophosphorylation and kinase activity. Cells from Can-1 demonstrate normal receptor autophosphorylation but reduced kinase activity, thus displaying a unique form of a mutant insulin receptor. Despite reduced kinase activity, all three cell lines exhibit normal rates of insulin internalization, but decreased lysosomal-mediated degradation. Our data imply that receptor autophosphorylation and kinase activity may be regulated separately and that kinase activity may be linked to insulin degradation, but not necessarily internalization.