Interaction between insulin sensitivity and muscle perfusion on glucose uptake in human skeletal muscle: evidence for capillary recruitment.

Insulin and glucose delivery (muscle perfusion) can modulate insulin-mediated glucose uptake. This study was undertaken to determine 1) to what extent insulin sensitivity modulates the effect of perfusion on glucose uptake and 2) whether this effect is achieved via capillary recruitment. We measured glucose disposal rates (GDRs) and leg muscle glucose uptake (LGU) in subjects exhibiting a wide range of insulin sensitivity, after 4 h of steady-state (SS) euglycemic hyperinsulinemia (>6,000 pmol/l) and subsequently after raising the rate of leg blood flow (LBF) 2-fold with a superimposed intrafemoral artery infusion of methacholine chloride (Mch), an endothelium-dependent vasodilator. LBF was determined by thermodilution: LGU = arteriovenous glucose difference (AVGdelta) x LBF. As a result of the 114+/-12% increase in LBF induced by Mch, the AVGdelta decreased 32+/-4%, and overall rates of LGU increased 40+/-5% (P < 0.05). We found a positive relationship between the Mch-modulated increase in LGU and insulin sensitivity (GDR) (r = 0.60, P < 0.02), suggesting that the most insulin-sensitive subjects had the greatest enhancement of LGU in response to augmentation of muscle perfusion. In separate groups of subjects, we also examined the relationship between muscle perfusion rate and glucose extraction (AVGdelta). Perfusion was either pharmacologically enhanced with Mch or reduced by intra-arterial infusion of the nitric oxide inhibitor N(G)-monomethyl-L-arginine during SS euglycemic hyperinsulinemia. Over the range of LBF, changes in AVGdelta were smaller than expected based on the noncapillary recruitment model of Renkin. Together, the data indicate that 1) muscle perfusion becomes more rate limiting to glucose uptake as insulin sensitivity increases and 2) insulin-mediated increments in muscle perfusion are accompanied by capillary recruitment. Thus, insulin-stimulated glucose uptake displays both permeability- and perfusion-limited glucose exchange properties.

Screening and treatment of diabetic nephropathy by primary care physicians.

OBJECTIVE: To describe the practices of Indiana primary care physicians related to diabetic nephropathy screening and management. DESIGN: Cross-sectional, observational. SETTING: The state of Indiana. PARTICIPANTS: Active primary care physicians (defined as general internists, family practitioners, and general practitioners) in Indiana who provided care for diabetic patients at the time of the survey (n = 1,018) MEASUREMENTS AND MAIN RESULTS: Practice patterns relevant to microalbuminuria and overt albuminuria screening and management were assessed along two dimensions: the percentage of patients to whom the practices were applied and the frequency with which the practices were performed. Of 1,141 physicians who responded to the survey, 1,018 were eligible for analysis. Eighty-six percent of physicians reported screening more than half of their patients with type 1 diabetes for overt albuminuria, as did 82% of physicians for their patients with type 2 diabetes. Only 17% of physicians indicated performing microalbuminuria testing on more than half of their type 1 patients. Angiotensin-converting enzyme inhibitor agents were used frequently to treat abnormal urinary albumin excretion when hypertension was present, but less often when hypertension was absent. Physician specialty, year of graduation from medical school, practice location, and familiarity with the results of the Diabetes Control and Complications Trial were significant predictors of screening and treatment practice patterns. CONCLUSIONS: Primary care physicians report practices that allow them to detect overt albuminuria but not microalbuminuria. Angiotensin-converting enzyme inhibitors are frequently used by physicians who test for microalbuminuria, but efforts to increase the detection of early renal damage are needed so that these agents and other therapeutic strategies may be employed at the earliest opportunity.

Autologous transplantation of mobilized peripheral blood CD34+ cells selected by immunomagnetic procedures in patients with multiple myeloma.

In the use of autologous PBPC transplantation in patients with multiple myeloma, contamination of PBPC with myeloma cells is commonly observed. Enrichment for CD34+ cells has been employed as a method of reducing this contamination. In this study the reduction of myeloma cells in PBPC was accomplished by the positive selection of CD34+ cells using immunomagnetic bead separation (Isolex 300 system). PBPC were mobilized from 18 patients using cyclophosphamide (4.5 g/m2) and G-CSF (10 microg/kg/day). A median of two leukaphereses and one selection was performed per patient. The median number of mononuclear cells processed was 3.50 x 10(10) with a recovery of 1.11 x 10(8) cells after selection. The median recovery of CD34+ cells was 48% (range 17-78) and purity was 90% (29-99). The median log depletion of CD19+ cells was 3.0. IgH rearrangement, assessed by PCR, was undetectable in 13 of 24 evaluable CD34+ enriched products. Patients received 200 mg/m2 of melphalan followed by the infusion of a median of 2.91 x 10(6)/kg CD34+ cells (1.00-16.30). The median time to absolute neutrophil count >0.5 x 10(9)/l was 11 days, and sustained platelet recovery of >20 x 10(9)/l was 14 days. We conclude that immunomagnetic-based enrichment of CD34+ cells results in a marked reduction in myeloma cells without affecting engraftment kinetics.

Nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mouse as a model system to study the engraftment and mobilization of human peripheral blood stem cells.

Mobilized CD34(+) cells from human peripheral blood (PB) are increasingly used for hematopoietic stem-cell transplantation. However, the mechanisms involved in the mobilization of human hematopoietic stem and progenitor cells are largely unknown. To study the mobilization of human progenitor cells in an experimental animal model in response to different treatment regimens, we injected intravenously a total of 92 immunodeficient nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice with various numbers of granulocyte colony-stimulating factor (G-CSF) -mobilized CD34(+) PB cells (ranging from 2 to 50 x 10(6) cells per animal). Engraftment of human cells was detectable for up to 6.5 months after transplantation and, depending on the number of cells injected, reached as high as 96% in the bone marrow (BM), displaying an organ-specific maturation pattern of T- and B-lymphoid and myeloid cells. Among the different mobilization regimens tested, human clonogenic cells could be mobilized from the BM into the PB (P = .019) with a high or low dose of human G-CSF, alone or in combination with human stem-cell factor (SCF), with an average increase of 4.6-fold over control. Therefore, xenotransplantation of human cells in NOD/SCID mice will provide a basis to further study the mechanisms of mobilization and the biology of the mobilized primitive human hematopoietic cell.

Beneficial and harmful effects of augmented feedback on physicians' clinical-teaching performances.

PURPOSE: To evaluate whether clinical-teaching skills could be improved by providing teachers with augmented student feedback. METHOD: A randomized, controlled trial in 1994 included 42 attending physicians and 39 residents from the Department of Medicine at the Indiana University School of Medicine who taught 110 students on medicine ward rotations for one-month periods. Before teaching rotations, intervention group teachers received norm-referenced, graphic summaries of their teaching performances as rated by students. At mid-month, intervention group teachers received students' ratings augmented by individualized teaching-effectiveness guidelines based on the Stanford Faculty Development Program framework. Linear models were used to analyze the students' mean ratings of teaching behaviors at mid-month and end-of-month. Independent variables included performance ratings, intervention status, teacher status, teaching experience, and interactions with baseline ratings. RESULTS: Complex interactions with baseline performance were found for most teaching categories at mid-month and end-of-month. The intervention-group teachers who had high baseline performance scores had higher student ratings than did the control group teachers with similar baseline scores; the intervention group teachers who had low baseline performance scores were rated lower than were the control group teachers with comparable baseline scores. The residents who had medium or high baseline scores were rated higher than were the attending physicians with comparable baseline scores; the performance of the residents who had low baseline scores was similar to that of the attending physicians with comparable baseline scores. CONCLUSION: Baseline performance is important for targeting those teachers most likely to benefit from augmented student feedback. Potential deterioration in teaching performance warrants a reconsideration of distributing students' ratings to teachers with low baseline performance scores.

Continuously monitored stopping boundary methodologies: the issues of sensitivity, association and trial suspension.

Thall et al. consider a continuous monitoring strategy for multiple discrete outcomes to determine whether a trial should terminate early. We evaluate important issues raised in the application of a continuous monitoring strategy for multiple outcomes. Specifically, we evaluate: (i) the sensitivity of such a methodology to small perturbations in the stopping boundaries; (ii) the need to employ accrual buffers when a trial approaches a stopping boundary-a large buffer implying that temporary suspension is unwarranted; and (iii) the role of association among the multiple outcomes of interest. Simulation studies demonstrate that the methodology is sensitive to small perturbations in the stopping boundaries, that the size of an accrual buffer can vary widely over the course of a trial, and that the extent of association among multiple outcomes plays a large role in determining the stopping properties of a trial. We illustrate these issues using the HLA non-identical donor bone marrow transplant trial, with two discrete outcomes.

Same eyes, different doctors: differences in primary care physician referrals for diabetic retinopathy screening.

OBJECTIVE: To analyze eye care specialist referral patterns for the diabetic patients of primary care physicians. RESEARCH DESIGN AND METHODS: In 1993, we conducted a census of primary care physicians to evaluate practice patterns relating to diabetes care in the state of Indiana. Using a logistic regression model and data from this census, we compared 1) physicians' odds of referring type II diabetic patients to an optometrist, as opposed to an ophthalmologist, with those of type I diabetic patients and 2) the referral odds ratios of type II to type I diabetic patients between metropolitan and nonmetropolitan counties. RESULTS: Overall, 10% of the physicians in our study most often refer some patients to an optometrist. Physicians are more likely to refer their type II diabetic patients to an optometrist, as opposed to an ophthalmologist, than they are to refer type I diabetic patients, both before and after adjustment for covariates. Physicians who practice in metropolitan counties are 1.55 times more likely to refer their type II diabetic patients than their type I diabetic patients to an optometrist. In nonmetropolitan counties, physicians are 2.5 times more likely to refer their type II diabetic patients to an optometrist. The difference between metropolitan and nonmetropolitan physicians is significant (P = 0.027). CONCLUSIONS: Some physicians mostly refer their diabetic patients to optometrists, instead of ophthalmologists, for eye examinations intended to discover early signs of diabetic eye disease. Type II diabetic patients are more likely to be referred to an optometrist, instead of an ophthalmologist, than are type I diabetic patients. In nonmetropolitan areas, the difference in referral patterns becomes even more marked.

Primary care physicians' practice patterns and diabetic retinopathy. Current levels of care.

BACKGROUND: Diabetic retinopathy is a costly and prevalent complication of diabetes mellitus. OBJECTIVE: To assess primary care physicians' self-reported practice patterns for the screening and detection of diabetic retinopathy relative to published guidelines. PARTICIPANTS AND METHODS: All primary care physicians (defined as general internists, family practitioners, and general practitioners) in Indiana were identified and surveyed using a mailed questionnaire. Of 2390 physicians, 1508 (63%) responded and were determined to be eligible. Of these 1508 physicians, 1058 (70%) completed all or some of the eye care-related questions. For each eye care practice, physicians were asked to specify the proportion of patients to which the practice was applied and the frequency (eg, every 3 months) with which the behavior was performed, if appropriate. Physicians were also asked to distinguish between patients with type I (insulin-dependent) and type II (non-insulin-dependent) diabetes mellitus for each practice behavior. RESULTS: Physicians' responses were classified as "high," "moderate," or "low" based on the American Diabetes Association guidelines. Forty-five percent of the physicians' responses were classified as high for referring all of their patients with type I diabetes mellitus to an eye care specialist annually as were 35% of the physicians' responses for referring their patients with type II diabetes mellitus. Fewer physicians reported high levels of routine in-office funduscopic examination. No relationship was found between the extent to which physicians performed an in-office funduscopic examination and patterns of referral to eye care specialists. Logistic regression analysis suggested that recent graduates and general internists are most likely to report behavior that is considered high (P < .05). CONCLUSION: The diabetic retinopathy-related practice patterns of primary care physicians in Indiana differ significantly from published guidelines.

Do activities of daily living have a hierarchical structure? An analysis using the longitudinal study of aging.

BACKGROUND: It has long been thought that individual activities of daily living (ADLs) can be combined to form a hierarchy or Guttman scale. The purpose of this study is to determine if ADLs fit into a single hierarchical structure, and to examine how such a hierarchy should be evaluated. METHODS: We use data from the baseline year of the Longitudinal Study of Aging, a nationally representative survey of noninstitutionalized persons 70 years of age and older. For each of the 360 permutations of the ADLs within the Katz hierarchy, we calculate the standard measures of fit of ordered data to a Guttman scale: the coefficient of reproducibility, the minimum marginal reproducibility, the percentage improvement, and the coefficient scalability. RESULTS: We find that although the Katz hierarchy does satisfy the traditional requirements for scalability, many other ADL hierarchies also satisfy these criteria. Specifically, our analysis shows that there are 4 hierarchies at least as good as the Katz hierarchy, and 103 hierarchies which satisfy the minimum standard for scalability. CONCLUSIONS: We conclude that the typical scalogram methodology may not be sufficient to summarize data, and that a multiplicity of disability profiles may exist.