Cost-benefit analysis of walking to prevent coronary heart disease

OBJECTIVE: To quantify the cost-benefit relationship of walking to prevent coronary heart disease. DESIGN: Cost-benefit analysis. PARTICIPANTS: Hypothetical cohorts of sedentary men and women aged 35 to 74 years. MAIN OUTCOME MEASURES: Decision-analysis simulation was used to evaluate the cost-benefit relationship of walking, varying level of benefit from exercise, frequency of exercise to achieve benefit, participation rates, and costs of exercise and injury. RESULTS: At a relative risk of 1.9 for heart disease associated with sedentary behavior, $5.6 billion would be saved annually if 10% of adults began a regular walking program. A $4.3 billion savings is predicted if the entire sedentary population began walking regularly and the cost of the time an individual spends exercising is accounted for in those who dislike exercising. According to our baseline assumptions, walking is economically beneficial for men aged 35 to 64 years and for women aged 55 to 64 years. The threshold of relative risk at which economic benefit is found for walking in this population overall is estimated at 1.7, and under a volunteer model, most adults would benefit even at a relative risk of 1.15. CONCLUSIONS: There are significant sex and age differences in the economic benefits of walking to prevent heart disease. The value assigned to the time an individual spends exercising has a significant impact on the results. Overall, a substantial savings is predicted from encouraging sedentary individuals to participate in a regular walking program.     

Reduced beta-adrenergic sensitivity in patients with type 1 diabetes and hypoglycemia unawareness

OBJECTIVE: We tested the hypothesis that impaired tissue sensitivity to catecholamines contributes to hypoglycemia unawareness in subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 21 subjects with type 1 diabetes underwent a standardized insulin infusion protocol to produce a stepwise decrease in plasma glucose to 45-min plateaus of 4.3, 3.6, 3.0, and 2.3 mmol/l. Glycemic thresholds, maximum responses for adrenergic and neuroglycopenic symptoms, and counterregulatory hormones were determined. Patients were classified as hypoglycemia unaware if the initiation of adrenergic symptoms occurred at a plasma glucose level 2 SD below that of nondiabetic volunteers. beta-Adrenergic sensitivity was measured as the dose of isoproterenol required to produce an increment in heart rate of 25 beats per minute above baseline (I25) in resting subjects. RESULTS: Subjects with type 1 diabetes and hypoglycemia unawareness experienced the onset of adrenergic symptoms at a lower plasma glucose level than did those with awareness (2.5+/-0.1 vs. 3.7+/-0.1 mmol/l, P < 0.001), whereas neuroglycopenic symptoms occurred at similar glucose levels (2.7+/-0.2 vs. 2.8+/- 0.1 mmol/l). The plasma glucose levels for counterregulatory hormone secretion (epinephrine 2.9+/-0.2 vs. 4.1+/-0.2 mmol/l; norepinephrine 2.7+/-0.1 vs. 3.2+/-0.2 mmol/l; cortisol 2.5+/-0.2 vs. 3.3+/-0.2 mmol/l, P < 0.01) were also lower in subjects with unawareness. The maximal epinephrine (1,954+/-486 vs. 5,332+/- 1,059 pmol/l, P < 0.01), norepinephrine (0.73 +/- 0.14 vs. 1.47+/-0.21 nmol/l, P = 0.04), and cortisol (276+/-110 vs. 579+/-83 nmol/l, P < 0.01) responses were reduced in the unaware group. I25 was greater in unaware subjects than in subjects without unawareness (1.5+/-0.3 vs. 0.8+/-0.2 microg), where I25 was not different from that of controls (0.8 +/-0.2 microg). CONCLUSIONS: We conclude that subjects with type 1 diabetes and hypoglycemia unawareness have reduced beta-adrenergic sensitivity, which may contribute to their impaired adrenergic warning symptoms during hypoglycemia.     

The development and cross-validation of methods based on radioimmunoassay and LC/MS-MS for the quantification of the class III antiarrhythmic agent, MK-0499, in human plasma and urine

An analytical method based on radioimmunoassay (RIA) has been developed for the determination of the antiarrhythmic agent, MK-0499, in plasma and urine. Owing to the potency of the drug, the specificity of this assay in human plasma could not be adequately determined using conventional RIA procedures. A highly specific procedure, based on LC/MS-MS, was developed to cross-validate the RIA. The lower quantifiable limits of the RIA and LC/MS-MS-based methods were 0.05 and 0.013 ng ml-1, respectively. Cross-validation data, compared using paired student's t-test regression analysis, showed excellent correlation between methods. The mass spectrometric assay was also used to simultaneously measure plasma concentrations of unlabeled and 14C-labeled MK-0499 following administration of the drug at high specific activity to volunteers.     

Comparative evaluation of National Committee for Clinical Laboratory Standards broth macrodilution and agar dilution screening methods for testing fluconazole susceptibility of Cryptococcus neoformans

A simple screening method for fluconazole susceptibility of Cryptococcus neoformans using 2% dextrose Sabouraud dextrose agar (SabDex) with fluconazole was compared to the National Committee for Clinical Laboratory Standards (NCCLS) broth macrodilution method. By this method, fluconazole-susceptible C. neoformans isolates are significantly smaller on medium with fluconazole than on fluconazole-free medium. Isolates with decreased susceptibility have normal-size colonies on medium containing fluconazole. The 48-h NCCLS broth macrodilution MICs (NCCLS MICs) for isolates with normal-size colonies on 8- or 16-microg/ml fluconazole plates were predicted to be > or =8 or > or =16 microg/ml, respectively. On medium with 16 microg of fluconazole per ml, all strains (84 of 84) for which the NCCLS MICs were <16 microg/ml were correctly predicted, as were all isolates (7 of 7) for which the MICs were > or =16 microg/ml. Agar dilution appears to be an effective screening method for fluconazole resistance in C. neoformans.     

MR safety: past, present, and future from a historical perspective

This article focuses on both static field effects and oscillating magnetic fields associated with MR imaging and spectroscopy. Contemporary experiments and theories on health effects demonstrate that currently MR imaging is practiced in a safe manner. Technological capabilities and medical science objectives, however, will lead to procedures that will challenge the thresholds of physiological effects. Thus progress in this field will require continual surveillance and better definitions of guidelines which at present are considered prudent but too restrictive.     

Insulin-like growth factor-binding protein (IGFBP)-3 and IGFBP-5 share a common nuclear transport pathway in T47D human breast carcinoma cells

Insulin-like growth factor-binding proteins (IGFBPs) play an integral role in modifying insulin-like growth factor actions in a wide variety of cell types. Recent evidence suggests that IGFBP-3 and IGFBP-5 also have effects on cell growth that are insulin-like growth factor-independent. In investigating possible mechanisms for this effect, the intracellular trafficking of IGFBP-3 and IGFBP-5, both of which contain sequences with the potential for nuclear localization, was studied in T47D cells. Nuclear uptake of fluorescently labeled IGFBP-3 and IGFBP-5 was observed in a proportion of T47D cells that appeared to be rapidly dividing. IGFBP-1 and IGFBP-2, which do not possess the putative domain for nuclear translocation, were not transported to the nuclei of T47D cells. When T47D cells were preincubated with excess unlabeled IGFBP-3, nuclear localization of labeled IGFBP-3 or IGFBP-5 was not detected, indicating that their nuclear translocation involves a common pathway. Inhibition of receptor-mediated endocytosis did not affect nuclear uptake of IGFBP-3, suggesting that it uses an alternative non-classical import pathway for transport across the plasma membrane. In addition, a variant form of IGFBP-3 with a mutation in the putative nuclear localization sequence was unable to translocate to the nuclei of T47D cells, suggesting that nuclear translocation of IGFBP-3 was dependent on these carboxyl-terminal basic residues.     

Dual projection from the medial septum to the supramammillary nucleus in the rat

Hereditary inclusion body myopathies comprise autosomal recessive and autosomal dominant muscle disorders that have a variable clinical phenotype but share similar morphological features. These include rimmed vacuoles within muscle fibres and collections of intrasarcoplasmic and intranuclear tubulofilamentous inclusions, 16-18 nm in external diameter. The resemblances and the differences between the sporadic and the hereditary inclusion body myopathies are discussed. Recent advances in the identification of various proteins involved in these diseases are mentioned because they have provided better insight into their underlying pathophysiological mechanisms. Linkage studies have allowed the localization of the genetic defect of some hereditary inclusion body myopathies and related disorders, contributing to their individualization.