Epidemiology of insulin-using commercial motor vehicle drivers. Major variability of state licensing requirements in the U.S.

Licensing agencies in many areas, including the U.S., prohibit insulin-using individuals from driving CMVs or large trucks. This study examined the debate over the risks of licensing insulin-using individuals to drive CMVs as an occupation, and the variations in regulations of different states. As part of an ongoing review of the regulations governing interstate commerce in the U.S., we surveyed all 50 states and Washington, D.C. to determine the regulations concerning intrastate driving. We received responses from 48 states and D.C., representing 95% of the U.S. population. Only 9 states reported preventing insulin users from acquiring a CMV license, whereas 39 states and D.C. permitted licensing within state boundaries. Of the states allowing insulin users to drive, 26 placed special requirements on CMV licensing. The results indicate that, despite a standardized U.S. federal law for driving across states, enormous variability exists in the policies for driving within states, ranging from no restrictions to a complete ban on CMV driving for insulin users.


Metabolic effects of dietary fructose in diabetic subjects.

To assess the metabolic effects of chronic dietary fructose consumption in diabetic subjects. Six type I and 12 type II diabetic subjects consumed, in random order, two isocaloric study diets for 28 days. In one diet, 20% of energy was derived from fructose. In the other diet, < 3% of energy came from fructose, and carbohydrate energy was derived primarily from starch. Both study diets were composed of common foods. All meals were prepared in a metabolic kitchen where all foods were weighed during meal preparation. Mean plasma glucose, urine glucose, and serum glycosylated albumin values were lower during the fructose diet than during the starch diet, but the differences achieved only marginal statistical significance. The day-28 value for mean plasma glucose was 12.5% lower (P = 0.03) during the fructose diet than during the starch diet. At days 14, 21, and 28, fasting serum cholesterol and LDL cholesterol were both significantly higher during the fructose diet than during the starch diet. The day-28 values for serum cholesterol and LDL cholesterol during the fructose diet were 6.9% (P = 0.008) and 10.9% (P = 0.002) higher, respectively, than the corresponding values during the starch diet. No differences were observed between the study diets in fasting serum HDL cholesterol, fasting serum triglycerides, peak postprandial serum triglycerides, or fasting serum lactate. Peak postprandial serum lactate was significantly higher during the fructose diet. Type I and type II diabetic subjects responded to the diets in a consistent way, but type I subjects experienced significantly more hypoglycemia during the fructose diet than during the starch diet. A high-fructose diet may result in reduced glycemia in diabetic subjects but at the expense of increased fasting serum total and LDL cholesterol.


Dropout and relapse during diabetes care.

To determine factors associated with dropout and relapse during chronic diabetes care. Private practice outpatient treatment-education program for adult diabetes was surveyed. Retrospective analysis was done, involving 422 patients for up to 3 yr. Of the patients in the study, 12% dropped out after the initial visit, and 33% of the residual cohort dropped out during each subsequent 6-mo period. Factors associated with dropout included distance from home to clinic > 100 miles, lack of insulin treatment, and cigarette smoking. In patients who remained in follow-up, a significant decrease in HbA1C occurred during the first 6 mo, but 40% of the patients relapsed between 6 and 12 mo. Frequency of relapse declined as time passed. Relapse was more frequent in women. Dropout from treatment and relapse after temporary improvement account for a substantial amount of uncontrolled diabetes, and overcoming the obstacles of dropout and relapse has potential for significant improvement in diabetes care.


A multisite physician's office laboratory evaluation of an immunological method for the measurement of HbA1c.

To evaluate the clinical performance of a new immunological HbA1c method in physicians' office laboratories. Three physicians' offices participated in the evaluations. The clinicians routinely use HbA1c test results to monitor their patients' long-term blood glucose control. Precision and interlaboratory variability were assessed using three levels of lyophilized controls. Correlation of the method's results to currently available laboratory methods was made. Comparison of finger-stick (capillary) results to venous EDTA whole blood results was made on 134 patients. Physician and laboratory personnel input was evaluated with regard to the clinical utility of the system. The CVW and CVB were a maximum of 4.5 and 4.4% for the immunoassay system on three levels of control materials at the three sites. Interlaboratory variability among the control means was found to be 4.9-5.4, 8.0-8.3, and 11.7-12.0% HbA1c. Correlation coefficients (r) ranged from 0.95 to 0.99. There was a positive bias by the DCA 2000 compared with the in-house method at site 1. Minimal negative biases were seen by the DCA 2000 with comparative methods used at sites 2 and 3. Median percentage differences with the comparative methods were 12, -1.4, and -5.6%. Comparison of capillary to venous sample results, from the DCA 2000, showed no clinically significant differences. Operator and physician feedback were positive with respect to technical ease in performance of the test and accuracy of results. Precision was acceptable and interlaboratory variability was low. The immunological method correlated well with manual ion-exchange and automated HPLC methods. The small sample size and good comparison between capillary and venous sample results make fingerstick sampling acceptable. The method provided immediate test results (within 9 min) to the clinicians.


Short-term effects of alterations in dietary fat on metabolic control in IDDM.

Two experimental diets were evaluated to investigate the hypothesis that dietary fat has an independent influence on metabolic control in IDDM. The diets had similar CHO contents (26 and 22% of energy intake) but differed markedly in fat (53 vs. 16% energy) and protein (20 vs. 62% energy). We had 10 subjects follow the low-CHO, high-fat diet, and 8 subjects follow the low-CHO, low-fat, high-protein diet. In each case, markers of glycemic and lipid control obtained after adherence to the experimental diet for 2 wk were compared with corresponding data from a preceding control period during which subjects had followed their usual diet (protein 18-19%, CHO 41-46%, fat 33-37%). Despite the low CHO content of the high-fat diet, insulin requirements were unchanged relative to the control diet. Moreover, the glycemic response to a standard breakfast was elevated significantly (P < 0.001), suggesting that insulin resistance had either been induced or exacerbated. The small rise in total cholesterol concentration in response to the high-fat diet was accounted for by a rise in HDL cholesterol. Glycemic control and lipid metabolism were unchanged after the low-CHO, low-fat diet, although insulin requirements fell by an average of 6 U/day (P < 0.05) relative to those recorded during the 2-wk control period. Diets high in fat are deleterious to glycemic control in IDDM, but general applicability is limited by the small sample size and short duration of this study.


Nitrate levels in community drinking waters and risk of IDDM. An ecological analysis.

To investigate whether higher IDDM incidence rates occurred in areas with high nitrate levels in their potable water supplies. Incidence rates for the 63 counties in Colorado were calculated using the Colorado IDDM Registry of children diagnosed < 18 yr of age between 1978 and 1988 (n = 1280). A weighted average of the nitrate levels from each water district within each county was calculated using data collected by the Colorado Department of Health between 1984 and 1988. The rs between nitrate levels and IDDM incidence was 0.26 (P = 0.03). After controlling for differences in ethnicity, counties with water nitrate levels in the third tertile (0.77-8.2 mg/L) had a significantly increased risk of IDDM compared with those in the first tertile (0.0-0.084 mg/L) (rp = 0.29, P = 0.02). This ecological analysis suggests that low-level nitrate exposure through drinking water may play a role in the etiology of IDDM, perhaps as a promoter through the generation of free radicals.


Multicenter study of the prevalence of diabetes mellitus and impaired glucose tolerance in the urban Brazilian population aged 30-69 yr. The Brazilian Cooperative Group on the Study of Diabetes Prevalence.

To assess the prevalence of diabetes and IGT in the urban adult Brazilian population. We used a two-stage, multicenter, cross-sectional survey in a random sample of 21,847 individuals aged 30-69 yr from nine large cities. Subjects were first screened by FCG. All positive screenees (FCG > or = 5.6 mM/L) and every sixth consecutive negative screenee were administered a 75 g OGTT and classified as diabetic, IGT, or normal (nondiabetic) according to WHO recommendations. OGTT findings from the negative screenees were extrapolated to all negative screenees after adjustments for potential biases. The overall rates were 7.6 and 7.8% for diabetes and IGT, respectively. Men (7.5%) and women (7.6%) had similar rates of diabetes. Similar rates resulted with whites (7.8%) and nonwhites (7.3%). Diabetes prevalence increased from 2.7% in the 30-39-yr age-group to 17.4% in the 60-69-yr age-group. Diabetes was more prevalent among less educated people, but this difference disappeared after adjusting for age. Family history of diabetes was associated with a twofold increase in diabetes prevalence (12.5 vs. 5.8%); the same increase occurred with obesity (11.6 vs. 5.2%). Undiagnosed diabetes accounted for 46% of the total prevalence. Among previously diagnosed cases, 22.3% were not under treatment, 7.9% were on insulin, 40.7% were on oral agents, and 29.1% were on dietary treatment only. Self-reported diabetes prevalence was 0.1, 3.2, and 11.6% in the age groups < 30, 30-69, and > 70 yr, respectively. The prevalence of diabetes in Brazil is comparable with that of more developed countries, where it is considered a major health problem.


Analysis of early-phase insulin responses in nonobese subjects with mild glucose intolerance.

To study the possible contribution of a B-cell defect in the development of glucose intolerance in nonobese subjects. There were 41 normal, nondiabetic subjects; 18 subjects with IGT; and 21 patients with NIDDM. All subjects were nonobese (BMI < 27 kg/m2). Insulin secretory responses to an OGTT, IVGTT, and GST were studied. Early-phase insulin responses to OGTT and IVGTT were decreased in subjects with IGT to levels comparable with those in NIDDM patients, whereas the response to GST was preserved in the subjects with IGT compared with NIDDM patients. The insulinogenic index of OGTT correlated well (r = 0.78) with early-phase insulin response to IVGTT, suggesting that the insulinogenic index in OGTT is related to the early-phase insulin response to IVGTT in nonobese subjects. Impaired early-phase insulin response to glucose was associated with mild glucose intolerance, suggesting the importance of impaired insulin secretion in the development of glucose intolerance in nonobese subjects.


Residual left ventricular pump function after acute myocardial infarction in NIDDM patients.

Left ventricular remodeling occurs immediately after MI, involving structural changes in noninfarcted segment. However, the residual left ventricular pump function in NIDDM patients after acute MI has not been clarified. The purpose of this study was to evaluate the difference in the process of left ventricular remodeling between NIDDM and nondiabetic patients. Left ventricular regional EF images obtained by radionuclide angiography were investigated in 20 NIDDM and 29 nondiabetic patients the 3rd wk after acute MI. Regional EF of the noninfarcted area and P/V had a significant hyperbolic relation with left ventricular EDV in both groups of patients. Despite no difference in the extent of myocardial necrosis and the number of coronary vessels diseased between NIDDM and nondiabetic patients, regional EF of the noninfarcted area and P/V were significantly lower when left ventricular EDV increased in NIDDM patients compared with nondiabetic patients. Pathogenetic changes of the residual myocardium associated with NIDDM may adversely influence the process of left ventricular remodeling after MI, especially in patients with increased left ventricular EDV.


Leukocyte scanning with 111In is superior to magnetic resonance imaging in diagnosis of clinically unsuspected osteomyelitis in diabetic foot ulcers.

To compare the accuracies of MRI and leukocyte scanning in diagnosing clinically unsuspected osteomyelitis in diabetic foot ulcers. A prospective study of 16 diabetic foot ulcers in 12 patients, including both ambulatory and hospitalized patients, was performed at a university medical center. Pedal images were obtained by leukocyte scanning with [111In]oxyquinoline and MRI. Definitive diagnosis of osteomyelitis then was determined by bone biopsy for culture and histology. Biopsy-proven osteomyelitis was present in 7 (44%) of the 16 foot ulcers. The diagnosis was suspected clinically in 0%. Leukocyte scanning was 100% sensitive, whereas MRI was only 29% sensitive in diagnosing osteomyelitis in diabetic foot ulcers. Specificities were 67 and 78%, respectively. The positive and negative predictive values (70 and 100%, respectively) for the leukocyte scan also were greater than those of MRI (50 and 58%, respectively). Leukocyte scanning is superior to MRI in detecting clinically unsuspected osteomyelitis in diabetic foot ulcers.


Prevalence of Corynebacteria in diabetic foot infections.

Microbiological flora of diabetic foot infections are usually polymicrobial and frequently include bacteria of the Corynebacterium sp. (diphtheroids). The purpose of this study was to determine the prevalence of these bacteria in both deep and superficial cultures in diabetic patients with foot infections. The charts of 50 patients of successive admissions to the Orthopedic-Diabetes Service at our hospital were reviewed to obtain the following data: age, sex, ethnic origin, method of treatment of diabetes, blood glucose level, prior antibiotics, and reports of cultures taken from bedside and intraoperative sites. Data were analyzed to compare the prevalence of diphtheroids in reliable versus nonreliable cultures and the influence of other parameters on the presence of these organisms. Fourteen of 19 (74%) of the intraoperative specimens grew diphtheroids compared with 25 of 65 (39%) of the bedside cultures, a highly significant difference. In addition, there was a somewhat greater occurrence of diphtheroids in women compared with men. The likelihood that contamination is the cause for the presence of diphtheroids is highly unlikely, because one arm of the study included cultures derived from deep tissue at the time of the surgical procedure (i.e., the intraoperative cultures). Cultures always grew at least one other organism in addition to the diphtheroid. Corynebacteria, commonly known as diphtheroids, are present as a part of the polymicrobial flora in a large percentage of diabetic patients with foot infections. Because the diphtheroids were identified in culture material taken in the operating room or at the time of incision and drainage in a higher percentage of patients than in specimens from superficial cultures, it is highly unlikely that they are contaminants.


Chronic sulfonylurea therapy augments basal and meal-stimulated insulin secretion while attenuating insulin responses to sulfonylurea per se.

To examine changes in glycemia and insulin secretion in response to SU per se and in response to a standard diet plus OD or TD SU therapy during chronic GP and GB therapy. Randomized (between agents and in order of dosing regimens), prospective, open, crossover study among 14 NIDDM patients to compare glucose, insulin, and C-peptide responses to a standard diet and to 10 mg of oral GP or GB taken without food 1) after 2 wk without therapy, 2) after 4 wk of either GP (n = 7) or GB (n = 7) treatment OD, and 3) after 4 wk of TD therapy with the same agent. Each patient received the same drug for maintenance therapy and for assessment of the response to the drug alone. We observed a comparable reduction in overall glycemia with both agents, with more marked postprandial effects for GP. Similar glucose, insulin, and C-peptide profiles for both agents during OD and TD therapy. Augmented insulin secretion in response to meals contrasting with reduced insulinotropic effects of the drugs per se with chronic therapy. Therapeutic equivalence of OD and TD dosing with GP and GB during chronic therapy. In view of the improved insulin secretion in response to nutrient stimuli, the attenuation of responses to SU per se during chronic therapy does not imply impairment of beta-cell secretory capacity or represent a therapeutic disadvantage.


Impact of NIDDM on mortality and causes of death in Pima Indians.

To compare overall and cause-specific death rates for diabetic and nondiabetic Pima Indians. This community-based study determined overall and cause-specific death rates in persons with and without NIDDM in the Pima population. Underlying causes of death for the 10-yr period from 1975 to 1984 were derived from review of death certificates and medical records. Diabetes diagnoses were based on an ongoing diabetes study initiated by the National Institutes of Health in 1965. Of the 512 deaths, 241 were in Pima Indians with NIDDM; 203 (84%) of the deaths in diabetic subjects were attributed to natural causes (46 diabetic nephropathy, 35 IHD, 29 infections, 20 malignant neoplasms, 20 alcoholic liver disease, 18 stroke, 35 other causes). For natural causes, the overall age-sex-adjusted death rate in diabetic subjects was 1.7 times (95% CI 1.4-2.2) that in nondiabetic subjects. Longer duration of diabetes was significantly related to mortality, an association that was stronger in women than in men. Rates of death from diabetic nephropathy, IHD, and infections (but not stroke) were each significantly related to longer diabetes duration. Together, diabetic nephropathy and IHD accounted for 90% of the excess death rate among diabetic, compared with nondiabetic, Pimas. In Pima Indians, NIDDM has a significant adverse effect on death rates that is directly related to diabetes duration, especially for deaths from diabetic nephropathy, IHD, or infections. Among the Pima, diabetic nephropathy is the leading cause of death, and IHD ranks second--a variation from other populations (in which IHD ranks first), probably partly attributable to a much younger age of onset of diabetes among the Pima than in the U.S. white population.


Mexiletine in the treatment of diabetic neuropathy.

To prove the efficacy of mexiletine in painful diabetic neuropathy. Treatment was provided in three dosages. For pain measurements, a VAS and McGill's verbal rating scale were chosen. Ninety-five patients were included in the study. A global assessment of the VAS among patients showed no differences between mexiletine treatment and placebo. The total evaluation (PRIT) of the McGill scale fell just below the level of significance. More specific exploratory evaluations of subclasses of the McGill scale, representing different degrees of pain, gave remarkable differences between mexiletine and placebo in sensory and miscellaneous items. In special subgroups, which were formed according to types and courses of complaints compiled at the beginning of this evaluation, the substantial advantages of the mexiletine treatment were shown with both the VAS and the McGill scale. Evidence strongly indicates that, in particular, those patients with stabbing or burning pain, heat sensations, or formication will benefit most by mexiletine therapy. Concerning the dosage, a medium regimen of 450 mg/day seems to be appropriate. With an increase in the antiarryhthmic dosage level, the efficacy does not rise proportionally. Mexiletine proved to be a safe therapy with negligible side effects at the medium dose range, even less than placebo; and remarkably, no cardiovascular side effects were noted. Further studies should avoid global assessments and pay more attention to the variety of complaints and quality of life.


Epidemiology of childhood type I diabetes in Sudan, 1987-1990.

To determine the incidence of type I diabetes in children 0-14 yr of age in Khartoum, Sudan. Prospective registration of newly diagnosed patients in a hospital-based registry with independent validation of completeness of case ascertainment. Eligible patients were Sudanese children < 15 yr of age, who developed type I diabetes during the period 1 January 1987 through 31 December 1990, and who were living in Khartoum city at the time of diagnosis. The denominator is the stable childhood population of Khartoum city, as estimated by the National Bureau of Statistics. In 4 yr, 239 cases were notified in the primary source and 268 in the secondary source. Some 196 patients were registered in both sources. Using the capture-recapture method to correct for underascertainment, the estimated total number of cases was 327, and the overall degree of ascertainment was 95%. The incidence of type I diabetes in children 0-14 yr of age increased from 5.9/10(5) in 1987 to 10.1/10(5) in 1990 (P < 0.001). Girls exhibited slightly higher incidence rates than boys in the 10-14-yr age-group throughout the 4 yr, but the differences were not statistically significant. The age distribution at onset was bimodal with a clear peak at age 12 yr in girls and age 14 yr in boys and another smaller peak at age 7 yr in both sexes. The number of new cases was markedly higher in the cooler months of the year, with a peak in January and a nadir in June (P < 0.01). This trend was consistent over the period of observation. Childhood diabetes is increasing in Sudan. Our incidence figures are higher than those reported from other Arab countries and is similar to reports from France and Italy.


Effect of high carbohydrate intake on hyperglycemia, islet function, and plasma lipoproteins in NIDDM.

To study effects of high carbohydrate intake on hyperglycemia, islet functions, and plasma lipoproteins in patients with NIDDM. An attempt was made to induce hyperglycemia in 10 men with NIDDM by feeding them an isocaloric high-carbohydrate diet (65% of energy as simple carbohydrates [31% as glucose] and 20% as fat) for 28 days in a metabolic ward. Response to the high-carbohydrate diet was compared with that of feeding a diet rich in monounsaturated fat (45% of energy as fat [31% as monounsaturated fat] and 38% as carbohydrates) for 28 days in a cross-over manner. Islet functions were assessed by evaluating plasma glucose, insulin, C-peptide and glucagon responses to standard meal tolerance tests on days 0, 14, 21, and 28 of each dietary period. Fasting plasma lipoproteins were determined during the last week of each dietary period. The high-carbohydrate diet caused significant but modest accentuation of hyperglycemia, particularly in patients with moderately severe diabetes mellitus, whereas no change was observed with the high-monounsaturated fatty-acid diet. Accentuation of hyperglycemia was accompanied by an increase in plasma glucagon levels, but no significant change in insulin and C-peptide responses. In 1 patient, feeding the high-carbohydrate diet for 68 days produced marked hyperglycemia and caused definite suppression of insulin and C-peptide responses along with an increase in glucagon levels. Compared with the high-monounsaturated fat diet, the high-carbohydrate diet also raised plasma triglyceride and VLDL cholesterol concentrations. High-carbohydrate diets may cause accentuation of hyperglycemia and a rise in plasma glucagon levels in NIDDM patients. High-carbohydrate diets also adversely affect lipoproteins and therefore may not be desirable in all NIDDM patients.


Screening for microalbuminuria. A comparison of single sample methods of collection and techniques of albumin analysis.

To evaluate single-sample urine collections to determine their ability to screen patients for the presence of microalbuminuria. Microalbuminuria in patients with type I diabetes predicts the development of diabetic renal disease. Cross-sectional analysis of single-sample urine collection techniques (first morning void, random upright void) and methods of albumin analysis (RIA, reagent tablet) were compared with conventional 24-h urine collections (RIA). The study included 94 patients (45 males, 49 females; mean serum creatinine 88 microM) with type I diabetes, selected from a screened population of 301 patients from the University Hospital Subspecialty Clinics. A 24-hour urine collection RIA analysis for albumin revealed 36 normal patients (< 30 mg), 27 with microalbuminuria (30-300 mg), and 31 with albuminuria (> 300 mg). Random upright urine samples were more sensitive (RIA 89%, tablets 78%) for the detection of microalbuminuria than first morning void specimens (RIA 70%, tablets 60%). Specificity was > 80% with both random and first morning voids. Screening for microalbuminuria can be performed in the clinic by random upright single-sample urine collections. When reagent tablets were used, these results are available immediately. Patients who screen positive should be confirmed by 24-h or other timed urine collections.


Contraception in women with IDDM. An epidemiological study.

To study whether suitable contraceptive methods to women with diabetes mellitus in fact are applied. A questionnaire survey on the use of contraceptives in all 18-to-49-yr-old women (n = 261) with IDDM in Funen County, Denmark, and an age-comparable control group, (n = 287) was performed. Data were collected from 1987 to 1990. Response was achieved from 94% diabetic women and 88% control subjects. The overall use of contraception in diabetic women (77.1%) was almost identical to that of control subjects (73.6%). Compared with control subjects, significantly fewer diabetic women were using the OCP (P < 0.005) and partner sterilization (P < 0.05), whereas more diabetic women were sterilized (P < 0.0005). Among diabetic contraceptive users, the IUD, female sterilization, condoms, and the OCP each accounted for roughly 20%. Diabetic women using the OCP were predominantly young, and most had never been pregnant; approximately 20% of them used high-dose formulations. Sterilization was frequently used by older diabetic women, and most of these women had 2 or more children; 27% of the diabetic women using an IUD were nulligravidae. Further, 18% used a method with an unsuitable high failure rate. Our study demonstrates that diabetic women are not sufficiently advised concerning use of contraception.


Renal hemodynamics and albumin excretion rate in patients with diabetes secondary to acquired pancreatic disease.

OBJECTIVE--To assess kidney function and AER in patients with PD. RESEARCH DESIGN AND METHODS--Thirty-three patients with PD (age 52 +/- 7 yr, duration of disease 11 +/- 6 yr, BMI 24 +/- 3 kg/m2) and 33 patients with IDDM were matched for sex, BMI, and duration of disease. GFR and RPF were determined by single injection of [51Cr]EDTA and [125I]hippurate. AER was measured by radioimmunoassay in a single timed overnight urine collection. RESULTS--GFR and RPF were, respectively, 113 +/- 35 and 441 +/- 145 ml.min-1.73 m2 in patients with PD and 123 +/- 30 and 549 +/- 94 (P < 0.001) in IDDM. FF was significantly higher in patients with PD (0.26 +/- 0.05 vs. 0.22 +/- 0.03; P < 0.001). Prevalence of hyperfiltration (GFR > 135 ml.min-1.1.73 m2) was similar in both groups (30% in patients with PD vs. 28% in those with IDDM). Geometric mean of urinary AER was 10.4 micrograms/min (range 1-186) in patients with PD and 11.2 (1-198) in IDDM patients. Some 30.3% of patients with PD and 18% of those with IDDM were microalbuminuric (AER > 20 micrograms/min). By multiple regression analysis, AER was significantly related to systolic (P < 0.04) and diastolic blood pressure (P < 0.01) and to BMI (P < 0.03) in patients with PD. Retinopathy was more frequent in microalbuminuric patients with PD than in those without elevated AER. CONCLUSIONS--We suggest that early renal abnormalities occur similarly in patients with PD and IDDM.


Randomized prospective double-blind trial in healing chronic diabetic foot ulcers. CT-102 activated platelet supernatant, topical versus placebo.

To assess the efficacy of topically applied CT-102 APST for treating diabetic neurotrophic foot ulcers. Thirteen patients entered a randomized, double-blind trial of topically applied CT-102 APST vs. placebo (normal saline) gauze dressings for the treatment of nonhealing diabetic neurotrophic foot ulcers. CT-102 APST (Curative Technologies, Setauket, NY) was prepared from homologous platelets and contained multiple growth factors including PDGF, PDAF, EGF, PF-4, TGF-beta, aFGF, and bFGF. Inclusion criteria for subjects included diabetes, ulcer of > 8 wk duration, peri-wound transcutaneous oxygen tension > 30 mmHg, platelet count > 100,000/mm3, and no wound infection. Wounds were excised before entry and were > 700 mm3 but < 50,000 mm3 in volume, < 100 cm2 in area, and involved subcutaneous tissue. In the CT-102 group, 5 of 7 ulcers were healed (100% epithelialized) by 15 wk, but only 1 of 6 ulcers was healed by 20 wk with placebo (P < 0.05). Average percent reduction in ulcer area at 20 wk was 94% for CT-102 vs. 73% for placebo. Daily reduction in ulcer volume was 73.8 +/- 42.4 mm3/day (mean +/- SE) for CT-102 vs. 21.8 +/- 8.1 mm3/day for placebo (P < 0.05). Daily reduction in ulcer area was 6.2 +/- 1.8 mm2/day for CT-102 vs. 1.8 +/- 0.4 mm2/day for placebo (P < 0.05). CT-102 significantly accelerated wound closure in diabetic leg ulcers when administered as part of a comprehensive program for the healing of chronic ulcers.


Prediction of infant birth weight by GDM screening tests. Importance of plasma triglyceride.

We measured plasma glucose, GHb, GPro, IRI and TG at 24-28-wk gestation to determine the extent of elevations in GDM and relationships to glucose intolerance and infant macrosomia. Plasma samples were obtained 1 h after ingestion of 50 g glucose after an overnight fast in 521 randomly selected negative screenees, 264 positive screenees with GTT-, and 96 positive screenees with GTT+ (GDM). Screening test values in GDM subjects exceeded the GTT- group, whose values exceeded those of negative screenees: glucose, 9.6*, 8.7*, 6.3 mM; GHb, 5.2*, 4.9*, 4.7%; GPro, 3.1*, 3.0*, 2.8%; IRI, 791*, 662*, 410 pM; and TG, 2.3*, 1.9, 1.9 mM, (*P < 0.005 vs. negative screenees). TG was the only test elevated in the GDM but not in the GTT- groups. Screening test values correlated with GTT values in the following order (strongest to weakest): glucose* > TG* > GHb* > IRI > GPro (*statistical significance). Plasma TG was the only screening test significantly associated with birth weight corrected for gestational age (birth-weight ratio) (r = 0.09-0.16) (P < 0.05 to < 0.01) and was of the same order as 1- and 2-h GTT associations with birth weight (r = 0.13 and 0.14, respectively) (P < 0.05 to < 0.01). Plots of TG/birth-weight ratio increased linearly to the 80-90th TG percentile in negative screenees and GTT- subjects. GDM subjects followed this trend but with more variation. Above the 90th percentile for TGs, birth-weight ratio trended lower, significantly so when the groups were combined (P < 0.05). In multivariate analysis, TG was associated with birth-weight ratio even when maternal prepregnancy weight and pregnancy weight gain associations with TG and birth-weight ratio were controlled (P < 0.019). Of the five screening tests evaluated, all were elevated in GDM, but TG is the best discriminator of GDM from the GTT- group, and it is the only test significantly related to birth-weight ratio--and to glucose intolerance besides glucose itself. The TG association with birth weight is not explained fully by maternal weight. The results suggest that plasma TG may be a physiological contributor to infant birth weight. Further evaluation of plasma TG in GDM screening is justified, but GHb, GPro, and IRI appear to hold less promise.


Early disturbances of ambulatory blood pressure load in normotensive type I diabetic patients with microalbuminuria.

To compare 24-h ABP in normotensive type 1 diabetic patients with and without microalbuminuria. The study was a retrospective comparison of cases and matched control subjects. The first phase included 35 type 1 diabetic patients, normotensive by OMS criteria. The 23 patients with normoalbuminuria (< 15 micrograms/min) were compared with 12 patients with microalbuminuria (> or = 15 micrograms/min). In the second phase, the 12 microalbuminuric patients were paired by sex- and age-matched with 12 normoalbuminuric patients and 12 nondiabetic healthy control subjects. We measured casual systolic and diastolic BP and HR, 24-h ABP and AHR (recorded with a Spacelabs automatic recorder), and microalbuminuria. No correlation between microalbuminuria and casual BP was observed. Microalbuminuria was correlated significantly with diastolic 24-h APR and nocturnal systolic and diastolic ABP (r = 0.35, 0.38, and 0.33, respectively; P < 0.05) and with AHR during all time periods (24-h, r = 0.46; day, r = 0.39; night, r = 0.39; P < 0.05). Normo- and microalbuminuric patients did not differ in casual BP and HR. However, microalbuminuric patients had a significant increase in systolic 24-h ABP (119.1 +/- 8.2 vs. 113.1 +/- 8.1, P = 0.05), diastolic 24-h ABP (74.9 +/- 7.5 vs. 70.2 +/- 5.7, P = 0.04), nocturnal systolic ABP (112.8 +/- 7.1 vs. 105.8 +/- 7.9, P = 0.01), and AHR during all time periods. The same results were observed when patients were paired by age and sex. Normotensive microalbuminuric type 1 patients, although strictly comparable with normoalbuminuric patients for casual BP and HR, have an increased ABP and HR, especially during the night. This difference might reflect dysautonomia. Ambulatory measurement of BP and HR is more appropriate than casual measurements in hemodynamic studies of incipient diabetic nephropathies and could be proposed as an interesting tool for an early prediction of diabetic nephropathy.


Diabetic retinopathy in Oklahoma Indians with NIDDM. Incidence and risk factors.

To determine the incidence rates and risk factors for development of diabetic retinopathy in Oklahoma Indians. Cohort follow-up study with baseline examination between 1972 and 1980 and follow-up examination between 1987 and 1991. Mean +/- SD follow-up time was 12.8 +/- 1.7 yr. Eleven Indian Health Service facilities (clinics and hospitals) in Oklahoma participated in the study. Study participants were a quasirandom sample of 1012 American Indians (379 men, 633 women) in Oklahoma with NIDDM, 927 of whom received a detailed eye examination at baseline. The mean age of participants was 52 yr with a duration of diabetes of 6.9 yr at baseline. The average quantum of Indian blood was 92% (77% full blood). At follow-up, 515 (55.6%) were alive, 408 (44.0%) were deceased, and 4 (0.4%) could not be traced. Of the living participants, 380 (73.8%) underwent an ophthalmoscopic examination. The incidence of retinopathy among the participants who were free of disease at baseline and who survived the follow-up interval was 72.3%. By multivariate analysis, significant independent predictors of retinopathy recorded at baseline were FPG level, therapeutic regimen, systolic blood pressure, and duration of diabetes. FPG levels > or = 11.1 mM (200 mg/dl) increased the risk of retinopathy 1.7 times that for levels < 7.8 mM (140 mg/dl). Insulin use was associated with a 20% greater incidence. Hypertension was a particularly significant risk factor for those with lower FPG levels. Given that NIDDM is reaching epidemic proportions in Oklahoma Indians and that most may be afflicted with retinopathy, frequent ophthalmological examinations are clearly indicated for this high-risk population. The role of intervention, namely glycemic and hypertensive control, deserves further study.


Use of premixed insulin among the elderly. Reduction of errors in patient preparation of mixtures.

To evaluate the accuracy of elderly patients in their mixing of regular and intermediate insulins, to assess the safety and efficacy of premixed insulins compared with extemporarily mixed insulins, and to determine patients' preferences. We conducted a crossover multicenter study of 5 mo duration. Premixed insulins and patient-mixed, human biosynthetic (rDNA) insulins were used among 64 insulin-treated patients with NIDDM. After a 4-wk run-in period, eligible patients were randomly assigned to treatment 1 (extemporarily mixed insulins) or treatment 2 (premixed insulins) for 8 wk. After that period, the two treatments were crossed for an additional 8-wk period. A blood glucose profile was recorded monthly and HbA1c was measured at the beginning and at the end of each treatment period. An in vitro skills test was performed to assess the accuracy and reproducibility of the patient preparation of insulin doses, and a questionnaire was used to determine their personal preferences for premixed versus extemporarily mixed insulin. In our study, the quality of the metabolic control was the same whether patients used self-mixed or premixed insulin. The differences in blood glucose profiles and HbA1c were negligible between type and periods of treatment. The overall number of hypoglycemic episodes increased during the trial in both groups, but the difference between treatments was not significant. The in vitro skills test, however, indicated that the accuracy in the preparation of insulin doses was significantly higher when patients aspirated from one vial compared with preparation from two vials (P < 0.001). The CVs were 3.7% when drawing up a single dose and 5.0% when preparing a mixture, but the ranges were rather elevated (0.1-20.7 and 0.6-35.8%, respectively). Forty-two patients described the preparation of their daily insulin dose as very easy and 21 described it as easy when using premixed insulins versus 11 and 43, respectively, when using extemporarily mixed insulins (P < 0.001). While the quality of the metabolic control was the same whether patients used self-mixed or premixed insulin, the in vitro skills test indicated that insulin preparation by elderly patients is highly inaccurate. In some patients, a modification of the contents of the insulin is likely to occur in a few days. The use of premixed insulins should lessen the errors that occur in mixing insulins and from the contamination of the second insulin vial. Draw-up errors could partially account for the lack of improvement of glucose control during the period when patients received premixed insulins. A longer observation period probably is needed to assess appreciable changes in the quality of diabetes control.


Depression in adults with diabetes.

Depression in diabetes is a prevalent and chronic condition. The etiology is unknown but is probably complex; and biological, genetic, and psychological factors remain as potential contributors. Several neuroendocrine and neurotransmitter abnormalities common to both depression and diabetes have been identified, adding to etiological speculations. Pharmacotherapy of depression may improve both mood and glucose regulation in diabetes, although controlled studies of the efficacy of psychotherapy and pharmacotherapy for depression in diabetes are not yet available. Depression has potential interactions with diabetes on multiple levels and remains an important clinical focus independent of the medical disease.


Psychosocial problems and interventions in diabetes. A review of the literature.

This article reviews and organizes the recent literature on psychosocial problems and interventions in diabetes to see if it is possible to identify effective modes of treatment for numerous different psychosocial problems. An attempt was made to review extensively the references on psychosocial problems and to review exhaustively the references on psychosocial interventions. The review was organized under four major headings: psychological sequelae of medical crises, psychopathology in diabetes, stress and hassles in living with diabetes, and family dysfunctions. Results of the literature review were similar for all areas: although some studies suggested that these problems are especially severe for people with diabetes, the best-designed studies suggested that this was not so. Regardless of the prevalence of these problems in the diabetic population at large, individuals who suffer from these problems are at special risk for reduced physical and emotional well-being, so they need psychosocial interventions that effectively resolve their difficulties. Unfortunately, the literature on psychosocial interventions in diabetes is meager, and it lacks the systematic, quantitative evaluations necessary to identify effective modes of treatment for different psychosocial problems. It is possible to state tentatively that certain interventions have been used for specific problems with some indication that they can be effective. Issues for future research are identified. Addressing these issues might provide a foundation for making decisions about areas ripe for clinical trials, and ultimately determining which intervention is best suited for treating any given psychosocial problem.


Methodological issues in diabetes research. Measuring adherence.

The prevalence of nonadherence in IDDM and NIDDM populations and conceptual and methodological issues relevant to measuring diabetes regimen adherence are reviewed. The prevalence of nonadherence varies across the different components of the diabetes regimen, during the course of the disease, and across the patient's life span. Although prevalence rates might be expected to differ between IDDM and NIDDM populations, this rarely has been evaluated. Conceptual problems in defining and measuring adherence include: the absence of explicit adherence standards against which the patient's behavior can be compared; inadvertent noncompliance attributable to patient-provider miscommunication and patient knowledge/skill deficits; the behavioral complexity of the diabetes regimen; and the confounding of compliance with diabetes control. Methods for measuring adherence include: health status indicators, provider ratings, behavioral observations, permanent products, and patient self-reports, including behavior ratings, diaries, and 24-h recall interviews. A measurement method should be selected on the basis of reliability, validity, nonreactivity, sensitivity to the complexity of diabetes regimen behaviors, and measurement independence from the patient's health status. The timing of measurements should be based on the stability of adherence behaviors and temporal congruity with other measures of interest (e.g., indexes of metabolic control). Directions for future research and suggestions for clinical practice are provided.


Interaction of insulin and exercise on glucose transport in muscle.

Glucose transport is the rate-limiting step for glucose utilization in muscle. In muscle and adipose tissue, glucose transport is acutely regulated by such factors as insulin and exercise. Translocation of glucose transporters (GLUT4) from an intracellular domain to the cell surface is the major mechanism for this regulation. Using immunocytochemistry, the intracellular distribution of GLUT4 under resting conditions is similar in adipocytes and myocytes. GLUT4 is concentrated in tubulovesicular structures either in the trans-Golgi region or in the cytosol, often close to the cell surface but not on the cell surface. After stimulation, cell surface GLUT4 labeling is increased by as much as 40-fold. GLUT4 is chronically regulated by altered gene expression. Neural and/or contractile activity regulates GLUT4 expression in muscle: 1) GLUT4 levels differ among muscles of different fiber type; 2) GLUT4 levels in muscle are increased with exercise training and decreased with denervation; and 3) cultured muscle cells, which lack an intact nerve supply, express very low levels of GLUT4. GLUT4 expression appears to be regulated in parallel with many oxidative enzymes in muscle, suggesting that there may be a unified developmental program that determines the overall metabolic properties of a particular muscle. Preliminary evidence suggests that impaired GLUT4 expression in muscle is not the primary defect associated with insulin resistance. Nevertheless, it is conceivable that the adaptive increase in muscle GLUT4 that is found with exercise training may have beneficial effects in insulin-resistant states such as non-insulin-dependent diabetes.


Effects of exercise on insulin sensitivity in humans.

Physical exercise is promoted as one of the primary therapeutic strategies available to increase insulin sensitivity in individuals deemed at risk from insulin resistance and its attendant hyperinsulinism. Subjects with non-insulin-dependent diabetes mellitus (NIDDM) and impaired glucose tolerance (IGT) represent the major clinical population in which physical training is promoted as a treatment modality to improve insulin sensitivity. This manuscript reviews both the acute effects of muscular contractions and the effects of physical training on insulin sensitivity in NIDDM and insulin-dependent diabetic (IDDM) human subjects. Additionally, the effects of localized (regional) muscular contractions on insulin-mediated glucose disposal in previously exercised and nonexercised muscle groups will be discussed briefly.


Persistence of glucose metabolism after exercise in trained and untrained soleus muscle.

We tested the hypothesis that increments in glucose metabolism in muscles from trained animals are caused by training adaptations in skeletal muscle and not by the residual effects of the last training session. The effects of a single bout of exercise on glucose metabolism (glycolysis and glycogenesis) were compared, against appropriate controls, in untrained (experiment 1) and trained (experiment 2) rat soleus muscles immediately (t = 0) and 3, 6, 24, 48, and 96 h after a standardized bout of exercise. [3H]Glucose incorporation into glycogen and glycolysis was measured in vitro in the absence and presence of insulin (0.1 and 10 nM). Experiment 1: A single bout of exercise provoked an increase in glycogenesis in the exercised, untrained muscles compared with the nonexercised, untrained muscles (0-96 h; P = 0.006). Glycolysis was not altered (0-96 h; P > 0.05). Experiment 2: In the exercised trained soleus, rates of glycolysis were greater than in the exercised, untrained soleus, at insulin concentrations of 0.1 nM (0-96 h; P = 0.005) and 10 nM (0-96 h; P = 0.01), but not in the absence of insulin (0-96 h; P > 0.05). No differences were observed in the rates of glycogenesis (0-96 h; P > 0.05). Therefore, acute exercise provokes increments in glycogenesis, whereas training increases glycolysis, in the presence of insulin, for some time after exercise. We speculate that insulin-dependent increments in glycolysis in trained muscles are a consequence of increased glucose transport caused by a greater pool of insulin-translocatable, intracellular glucose transporters.


Effects of physical training on the metabolism of skeletal muscle.

With moderate training (30-60 min daily at 70-80% of VO2 max, 3-5 times weekly), the trained muscles display a 40-50% increase in the content of mitochondrial oxidative enzymes. Concomitantly, the total number of muscle capillaries may increase by 50%, whereas the content of glycolytic enzymes is not, or only marginally, affected. The oxidative enzyme increase, which occurs over 6-8 wk, is lost in 4-6 wk if training is stopped. This loss occurs faster than the decrease in muscle capillarization and in the whole-body VO2 max. Trained muscles of athletes have 3-4 times higher oxidative enzyme levels and two- to threefold more capillaries per muscle fiber than untrained muscle. Extensive endurance training results in an enhanced percentage of slow-twitch fibers, but the time course of this change is not known. More extensive changes are observed in chronically stimulated rabbit muscle. In this case, enzymes of oxidation display large increases (6- to 12-fold), whereas there is a decrease of 70-90% in enzymes of glycolysis, glycogenolysis, gluconeogenesis, and high-energy phosphate transfer. There is a normal training response in mitochondrial enzyme activities in individuals with insulin-dependent and non-insulin-dependent diabetes, but the ability to form new skeletal muscle capillaries in response to physical training may be deficient in insulin-dependent diabetes. Training-induced changes in the metabolic character of skeletal muscle leads to an increased reliance on fat metabolism during exercise, with a lowered blood lactate concentration and a sparing of muscle glycogen.


Does training spare insulin secretion and diminish glucose levels in real life?

Compared with untrained subjects, in trained subjects the increased insulin sensitivity and decreased glucose induced insulin secretion will tend to promote health by decreasing glucose levels and insulin secretion, whereas the increased food intake will tend to increase these variables. To evaluate the net effect of training, we administered oral glucose loads making up identical fractions of daily carbohydrate intake (i.e., same relative glucose loads) to 8 athletes and 7 sedentary subjects (age: 25 +/- 1 vs. 24 +/- 1 yr [mean +/- SE] [NS]; body weight: 76.0 +/- 1.3 vs. 79.3 +/- 2.3 kg [NS]; maximal oxygen uptake: 76 +/- 2 vs. 48 +/- 1 ml O2.kg-1.min-1 [2P < 0.05], respectively). Furthermore, 24 h plasma concentration profiles of glucose, C-peptide, and insulin were determined during ordinary living conditions. Daily carbohydrate intake was higher (2P < 0.05) in athletes compared with sedentary subjects (678 +/- 34 vs. 294 +/- 18 g.day-1, respectively). In response to same relative oral glucose loads, glucose and C-peptide responses were similar in athletes compared to sedentary subjects. Twenty-four hour integrated glucose and C-peptide concentrations did not differ between athletes and sedentary subjects (7.4 +/- 0.2 vs. 7.3 +/- 0.6 mol.L-1.1440 min [2P > 0.05] and 923 +/- 99 vs. 1047 +/- 175 pM.ml-1.1440 min [2P > 0.05], respectively), and insulin concentrations tended to be lower in athletes compared with sedentary subjects (124 +/- 13 vs. 175 +/- 38 pM.ml-1.1440 min [2P > 0.05]).(ABSTRACT TRUNCATED AT 250 WORDS)


Recent developments in metabolism that impinge on research into the nature and treatment of diabetes mellitus.

It has been established that adenosine, its agonists, or antagonists can cause dramatic changes in insulin sensitivity in isolated soleus muscle and, moreover, can modify changes in sensitivity caused by pathophysiological conditions. Addition of adenosine deaminase to the incubation medium, which is known to lower the concentration of adenosine, increases the sensitivity of glycolysis to insulin. Addition of an adenosine-receptor agonist decreases sensitivity by about 10-fold, whereas addition of an adenosine-receptor antagonist increases sensitivity by about 10-fold. The latter totally removes the resistance of glucose utilization to insulin in the isolated soleus muscle obtained from either the genetically obese rat or from the rat fed a high sucrose diet. These findings strongly support the view that changes in insulin sensitivity in muscle can be brought about either by acute changes in the local concentration of adenosine or in the affinity or number of receptors for adenosine in muscle. However, in many of the conditions investigated, in which insulin sensitivity in muscle is changed, there was no correlation between the change in the adenosine content of the muscle and altered insulin sensitivity. It has also been shown that prostaglandin E1 can increase dramatically the sensitivity of glycolysis to insulin and that this is a specific effect of prostaglandins of the E series. It is not produced by prostacyclins, thromboxanes, or leukotrienes. It is unclear if there is a relationship between the effects of adenosine and prostaglandins. Chronic elevation of catecholamines may increase the sensitivity of glucose utilization to insulin and also increase the rate of thermogenesis by substrate cycling.(ABSTRACT TRUNCATED AT 250 WORDS)


Glucose turnover in type I diabetic subjects during exercise. Effect of selective and nonselective beta-blockade and insulin withdrawal.

To assess the effect of selective beta 1-blockade (atenolol and betaxolol) and nonselective beta-blockade (propranolol) on glucose turnover in subjects with insulin-dependent (type I) diabetes mellitus during moderate exercise. Five subjects with type I diabetes were infused with insulin and then exercised for 1 h, after pretreatment with each of the three drugs or saline and, on a separate day, after withdrawal of insulin. Glucose turnover was measured using tritiated glucose. Plasma glucose, initially 9.2 +/- 0.5 mmol/L (mean +/- SE) when insulin infused and 14.0 +/- 0.8 when insulin was withdrawn, fell on exercise by 3.4 +/- 1.1 mmol/L (P < 0.05) saline, 4.0 +/- 0.8 mmol/L (P < 0.01) with betaxolol, 3.8 +/- 0.7 mmol/L (P < 0.01) with atenolol, 5.0 +/- 0.6 mmol/L (P < 0.005) with propranolol, and 1.7 +/- 1.0 mmol/L (NS) when insulin was withdrawn. Propranolol, but not the other beta-blockers, caused a significantly greater fall in glucose on exercise than during the control study. Glucose appearance rate (Ra) was similar basally and rose to an almost identical level in all five groups during exercise. Glucose disappearance rate (Rd) rose similarly during exercise, except after propranolol when the rise was significantly greater than with saline (P < 0.01). Failure of glucose to change significantly during exercise when insulin had been withdrawn was associated with the smallest rise in Rd and the highest nonesterified fatty acid concentrations. Propranolol and betaxolol, but not atenolol, reduced nonesterified fatty acids. We conclude that the greater fall in glucose on exercise after beta-blocking drugs is probably largely a direct effect of beta 2-blockade on muscle, increasing the exercise-induced rise in Rd glucose. This offers support to the use of beta 1-specific drugs, where beta-blockade is necessary in type I diabetes.


Habitual physical activity in adult IDDM patients. A study with portable motion meters.

The objective of this study was to assess the habitual physical activity of insulin-dependent diabetes mellitus (IDDM) patients on intensive insulin therapy. This case-control study consisted of 34 IDDM patients (14 on multiple injection therapy, 20 on continuous subcutaneous insulin infusion [CSII], and control subjects matched for sex, age, weight, height, body mass index, smoking behavior, and occupational status). Seven IDDM patients were studied before and after changing from multiple injection to CSII therapy. All patients were well controlled according to HbA1c. Portable motion meters were used to assess habitual physical activity during 7 consecutive days with appreciable reproducibility (coefficient of variation 1.24%) and agreement to standardized activity protocols (r = 0.96, P < 0.001). Habitual physical activity was similar in IDDM patients on injection treatment and in controls, respectively. CSII-treated patients exhibited on the average 17% less habitual physical activity than control subjects (P < 0.05). Changing from multiple injection therapy to CSII lowered habitual physical activity insignificantly in seven patients. There was no indication of decreasing physical exercise (e.g., sports) by CSII in this patient group. No correlations were found between habitual physical activity and HbA1c or body mass index, respectively. Habitual physical activity is similar in IDDM patients on multiple injection therapy and control subjects, but may decrease by CSII therapy.


Prevention of hypoglycemia during exercise in type I diabetes.

Insulin-dependent (type I) diabetic subjects who exercise for whatever reason do this at the risk of hypoglycemia. To enjoy physical activities without major metabolic complications, diabetic patients can take measures to prevent exercise-induced hypoglycemia. These measures basically include preventing accelerated insulin absorption, mimicking physiological insulin secretion during exercise, supplying additional carbohydrates during exercise, and providing effective diabetes education. When adapting the insulin dose, duration and intensity of the work load, time of day, prevailing insulin levels, and the state of nutrition must be considered. Additional carbohydrates can prevent hypoglycemia when exercise is spontaneous and insulin dose reduction is impossible. Prevention of exercise-induced hypoglycemia may be best achieved if patients participate in intensive and comprehensive teaching programs for self-management of diabetes.


Fuel and fluid homeostasis during long-term exercise in healthy subjects and type I diabetic patients.

This study was designed to examine metabolic and hormonal effects of long-term exercise in healthy subjects and insulin-dependent (type I) diabetic patients. Two studies were performed. First, 16 healthy males (32 +/- 3 yr) were studied during a semitriathlon competition (2 km swimming, 90 km biking, and 21 km running). Second, 9 type I diabetic males (41 +/- 2 yr) and 17 healthy matched control subjects were studied during a 75 km cross-country skiing race. Blood samples were taken before and immediately after exercise, and also during the ski race. During the semitriathlon race, serum insulin, C-peptide, glucagon cortisol, growth hormone ACTH, prolactin, and plasma renin activity increased two- to ninefold, whereas serum testosterone fell. Apart from a fall in magnesium, serum electrolyte concentrations remained unchanged. Before long-term skiing, patients reduced their insulin dose by 30-40%. They were hyperglycemic during the initial part of the race, but near normoglycemic thereafter. There were large interindividual variations in the increments of counterregulatory hormones, whereas serum testosterone and luteinizing hormone fell quite uniformly. Plasma renin activity and aldosterone concentrations rose similarly in diabetic and healthy subjects, whereas the rise in antidiuretic hormone was slightly greater in diabetic patients. During the initial part of the race, serum atrial natriuretic peptide fell in both groups. Severalfold increments in hormone concentrations contribute to the maintenance of fuel and fluid homeostasis during long-term exercise. With an appropriate adjustment of insulin dose and diet, also type I diabetic patients can participate in competitive long-term exercise.


Moderate exercise increases platelet function in type I diabetic patients without severe angiopathy and in good control.

The aim of this study was to investigate whether a 45-min moderate exercise, performed postprandially with a timing that partially prevented the risk of hypoglycemia, was able to modify platelet function in patients affected by insulin-dependent (type I) diabetes mellitus without severe late complications and in a good metabolic control. We submitted 6 male type I diabetic patients (27.2 +/- 3.4 yr; body mass index, 21.4 +/- 0.6 kg/m2; HbA1c, 7.6 +/- 0.9%) on a daily three-insulin injection regimen, without severe late complications of diabetes, to a 45-min moderate exercise (about 50% of maximal oxygen consumption) with a cycle ergometer, beginning 180 min after breakfast and 195 min after a subcutaneous shot of regular insulin. Serial venous blood samples were conducted to measure plasma glucose, free insulin, counterregulatory hormones (glucagon, growth hormone, cortisol, and catecholamines), platelet sensitivity to ADP, platelet activating factor and collagen, and plasma concentrations of the platelet-specific protein beta-thromboglobulin (a marker of the platelet release reaction in vivo). Exercise was accompanied by a decrease of plasma glucose (from 5.9 +/- 1.2 to 4.6 +/- 1 mmol/L, P = 0.067) and free insulin (from 180 +/- 36 to 114 +/- 30 pmol/L, P = 0.003), and by a significant increase of growth hormone (from 5 +/- 1 to 15 +/- 4 micrograms/L, P = 0.045), cortisol (from 240 +/- 30 to 406 +/- 69 nmol/L, P = 0.018), epinephrine (from 1005 +/- 240 to 5143 +/- 1753 pmol/L, P = 0.077), and norepinephrine (from 5.04 +/- 1.08 to 13.48 +/- 2.98 nmol/L, P = 0.009). Platelet sensitivity to the agonists and plasma concentrations of beta-thromboglobulin increased during the exercise period. In particular, ADP ED50 reached during exercise 61 +/- 16% of basal values (P = 0.048), platelet activating factor ED50 reached 73 +/- 11% (P = 0.043), and collagen ED50 reached 68 +/- 9% (P = 0.008). beta-Thromboglobulin rose from 24 +/- 2 to 32 +/- 3 micrograms/L (P = 0.007). Moderate exercise enhances platelet function in type I diabetic patients without severe angiopathy and in a good metabolic control.


Effect of diabetes on glucoregulation. From glucose transporters to glucose metabolism in vivo.

Peripheral resistance to insulin is a prominent feature of both insulin-dependent and non-insulin-dependent diabetes. Skeletal muscle is the primary site responsible for decreased insulin-induced glucose utilization in diabetic subjects. Glucose transport is the rate-limiting step for glucose utilization in muscle, and that cellular process is defective in human and animal diabetes. The transport of glucose across the muscle cell plasma membrane is mediated by glucose transporter proteins, and two isoforms (GLUT1 and GLUT4) are expressed in muscle. Insulin acutely increases glucose transport in muscle by selectively stimulating the recruitment of the GLUT4 transporter (but not GLUT1) from an intracellular pool to the plasma membrane. In skeletal muscles of streptozocin-induced diabetic rats, there is a decreased GLUT4 protein content in intracellular and plasma membranes. In these rats, insulin induced the mobilization of GLUT4 from the internal pool, but the incorporation of the transporter protein into the plasma membrane is diminished. Conversely, the content of the GLUT1 transporter increases in the plasma membrane of these diabetic rats. Normalization of glycemia with phlorizin fully restores the amount of GLUT1 and GLUT4 proteins to normal levels in the plasma membrane without altering insulin levels. This suggests that glycemia regulates the number of glucose transporters at the cell surface, GLUT1 varying directly and GLUT4 inversely, to glycemia. The regulatory role of glycemia also can be seen in diabetic dogs in vivo, where correction of hyperglycemia with phlorizin restores, at least in part, the defective metabolic clearance rate of glucose seen in these animals. In addition to acutely stimulating glucose transport in muscle, insulin controls exercise- and possibly stress-mediated glucose uptake in vivo, by preventing hyperglycemia and by restraining the effects of catecholamines on lipolysis and/or muscle glycogenolysis. Finally, we postulated a neural pathway that requires the permissive effect of insulin to increase glucose uptake by the muscle. Thus, insulin, glucose, and neural pathways regulate muscle glucose utilization in vivo and are, therefore, important determinants of glucoregulation in diabetes.


Metabolic responses to exercise. Effects of endurance training and implications for diabetes.

In this study, some important metabolic responses to exercise will be discussed, and aspects of particular interest for patients with diabetes mellitus will be emphasized. Alterations in the metabolic responses to exercise induced by physical endurance training and consequences of training for metabolism of plasma lipids and lipoproteins will be discussed. Glucoregulation during exercise is not perfect in normal subjects and is less so in patients with diabetes mellitus. For instance, during intense exercise, large increases in the plasma glucose concentration occur and a state of insulin resistance exists for a few hours after intense exercise. Even so, increased sensitivity to insulin is found the day after intense exercise and also shortly after more moderate intensity exercise, both in healthy subjects and in patients with diabetes mellitus. Increased sensitivity to insulin is also found after endurance training, whereas insulin sensitivity is decreased after inactivity. Exercise training increases the ability of muscle to take up and oxidize free fatty acids during exercise and also increases the activity of the enzyme lipoprotein lipase in muscle. The activity of lipoprotein lipase in muscle correlates with muscle insulin sensitivity. This might explain why insulin resistance is often associated with hypercholesterolemia, hypertriglyceridemia, and low high-density lipoprotein cholesterol.


Interaction of exercise and insulin in type II diabetes mellitus.

In skeletal muscle, at the level of glucose transport, insulin resistance appears to be a major alteration responsible for decreased glucose disposal rates in non-insulin-dependent (type II) diabetes mellitus. This study focuses on in vitro studies of the glucose transport process in human and rat skeletal muscle. Muscle strips from a group of lean type II diabetic patients demonstrated a 50% decrease in insulin responsiveness for glucose transport when compared with nondiabetic subjects. These findings indicate the presence of postreceptor defects in type II diabetic muscles. Furthermore, in an isolated muscle preparation, it could be demonstrated that epitrochlearis muscles from streptozocin-induced diabetic rats were not only resistant to insulin, but also to exercise-induced increase in glucose transport. However, both regular physical exercise and insulin therapy normalized the decreased capacity for glucose transport in the diabetic rat muscles. Therefore, it appears that regular physical exercise and, in some cases insulin therapy, would be advisable for type II diabetic patients with marked muscular insulin resistance to improve peripheral glucose disposal rates.


Efficacy of training in obese diabetic patients.

The consensus of studies in non-insulin-dependent diabetes mellitus (NIDDM) seems to be that exercise has beneficial effects not only on glucose metabolism and insulin sensitivity, but also on elevated plasma lipids, blood pressure, and obesity frequently following NIDDM. Feasibility of effective physical training programs in subjects suffering from NIDDM seems, however, questionable on a large scale because NIDDM is found mainly in physically inactive subjects over the age of 50. In such individuals, cardiovascular complications may also prevent physical activity of sufficient intensity. Although direct information is limited, the possibility remains that regular exercise may prevent or postpone clinical NIDDM, particularly by preventing the development of obesity.


Diabetes, exercise, and atherosclerosis.

Regular exercise may diminish the risk for atherosclerotic vascular disease in patients with non-insulin-dependent (type II) diabetes and in the general population. The basis for this effect of exercise may be its ability to diminish or prevent hyperinsulinemia, insulin resistance, and/or increases in intra-abdominal adipose mass. These abnormalities are associated with premature atherosclerotic vascular disease, essential hypertension, type II diabetes, and certain dyslipoproteinemias, and most likely precede them. They also have been implicated in the pathogenesis of these disorders. We propose that the high prevalence of hyperinsulinemia and insulin resistance in individuals leading a western life-style accounts for the reported benefit of physical activity in preventing coronary heart disease in the general population. We also propose that exercise (and diet) are most likely to be effective when initiated in young individuals, before the onset of irreversible vascular alterations, and when life-style changes may be more acceptable. Early identification of such individuals may be possible on the basis of family history, the presence of components of the hyperinsulinemia-insulin resistance syndrome, and/or central obesity. One such group that may already have been identified is women with gestational diabetes.


Prevention of type II diabetes by physical training. Epidemiological considerations and study methods.

Disease prevention may be considered at three levels: primary (avoiding disease occurrence), secondary (early detection and reversal), and tertiary (prevention or delay of complications). Physical exercise could potentially contribute to all of these. Metabolic studies suggest the major effect of exercise is at the level of insulin sensitivity/resistance. Therefore, it may have the greatest benefit in primary prevention and in the early stages of the disease. Studies of migrants and of active and inactive professions support this notion. There is also provisional support for the benefit of exercise on metabolic control and prevention or delay of chronic complications in non-insulin-dependent (type II) diabetic patients. In designing a trial of exercise, aspects such as single/multifactorial intervention, the age range of subjects, and choice of outcome measures must be considered. The most widely used methodological tool in assessing physical activity levels in population studies is the activity questionnaire, which is nonreactive, practical, applicable, and accurate relative to other methods. A positive approach to exercise training for both the patient with type II diabetes and the general community appears to be warranted. However, trials examining the efficacy of activity intervention, with independent evaluation of both short- and long-term outcomes, are still needed.


Ten-year experience with an exercise-based outpatient life-style modification program in the treatment of diabetes mellitus.

Exercise is frequently recommended in the treatment of diabetes mellitus. Nevertheless, its use has been limited in clinical practice, and concerns about safety and efficacy persist. We have reviewed a 10-yr experience with 255 patients enrolled in a comprehensive diabetes program that emphasized physical training. A low maximal oxygen uptake (VO2max) was found in patients with non-insulin-dependent diabetes mellitus compared with sedentary control subjects. This was not accounted for by autonomic neuropathy and is unlikely to be due to subtle differences in life-style. Exercise-related proteinuria was common and occurred in 29% of patients and was associated with higher blood pressure levels at rest and during exercise, impaired VO2max, and decreased R-R interval variation. Regular exercise was associated with a modest decrease in resting and exercise blood pressure. Glycosylated hemoglobin levels and plasma triglycerides improved only in patients with non-insulin-dependent diabetes mellitus. Insulin requirements were significantly reduced in patients with insulin-dependent diabetes mellitus. Compliance for up to 3 mo in the program was acceptable but longer-term compliance was poor. Serious complications during the program were rare. Our experience suggests a program of regular aerobic training can be safely and effectively used in an outpatient population with diabetes mellitus for up to 3 mo.


I'm running on insulin. Summary of the history of the International Diabetic Athletes Association.

The changes that physical activity brings in the functioning of the human body have a special interest to active individuals with diabetes. Certain adjustments in dosing are necessary. Even today, with such an emphasis on healthy life-style, little information is available to assist an individual with diabetes to exercise safely. Granted, no easy formula exists. Many different factors influence blood glucose. Most often, individuals with diabetes learn by trial and error how to best manage their favorite activity. In 1985, Paula Harper founded the International Diabetic Athletes Association (IDAA) in hopes of educating people with diabetes about the benefits of regular exercise. For most individuals with insulin-dependent (type I) diabetes mellitus, it is not encouragement, but safety that is the issue. The IDAA offers great opportunities for sharing ideas at its annual meetings. These meetings attract an exceptional faculty of speakers and offer a mix of workshops led by experienced diabetic athletes on various sports. A quarterly newsletter is published that presents new information and recognizes success stories. IDDA chapters exist in the U.S., Canada, U.K., Germany, France, Luxembourg, Switzerland, Belgium, the Netherlands, and Spain.


Fine-needle aspiration cytology of malignant nerve sheath tumors.

Precise preoperative diagnosis of three malignant nerve sheath tumors (MNST) was based on their remarkably uniform and highly characteristic cytologic appearance. The differential diagnosis with benign nerve sheath tumors and other spindle cell sarcomas is addressed, and the possibility of achieving confident diagnosis on cytologic material from at least some soft-tissue sarcomas is confirmed.


Helicobacter (Campylobacter) pylori in gastric brushing cytology.

Helicobacter (formerly Campylobacter) pylori is frequently associated with chronic gastritis and peptic ulcer and has been implicated as an etiologic agent. Identification of H. pylori is important for specific treatment with antibiotics and bismuth compounds. We studied 27 patients who presented with symptoms of gastritis or peptic ulcer on whom paired gastric biopsies and gastric brushings for cytology had been performed. Biopsies were stained with H & E and Warthin-Starry or Giemsa for H. pylori. Previously, Papanicolaou-stained brushings were restained with Giemsa and reviewed blindly by two cytologists. Cytologic examination revealed the characteristic 1-3 mu curved or spiral gram-negative bacilli embedded in mucus in 12 of 27 (44%) of cases. Biopsies showed H. pylori in 13 of 27 (48%) of cases. Cytology and histology were concordant in 22 of 27 (81%) of cases. Three cases were positive on biopsy, negative on cytology; two of these were unsatisfactory cytology specimens. Two cases were positive on cytology, negative on biopsy, apparently sampling artifacts. Papanicolaou-stained slides were scored for several morphologic parameters; numbers of acute and chronic inflammatory cells and degree of cytologic atypia. None of these were predictive of the presence of H. pylori. We conclude that Giemsa-stained gastric brushings are a useful complement to gastric biopsies in establishing the diagnosis of H. pylori.


Should we report cervical smears lacking endocervical component as unsatisfactory?

The purpose of the study is to correlate the accuracy of diagnosis of cervical smears with the presence/absence of an endocervical component. The referral smears and the smears obtained during colposcopic examination of 84 patients with biopsy-proven squamous lesions were evaluated for the presence of an endocervical component, and the cytologic interpretations were compared with the histologic findings. Of the 136 smears containing an endocervical component, 111 (81.6 percent) had good correlation with histology and 25 (18.4%) showed a discrepancy. Of the 30 smears lacking an endocervical component, 24 (80%) had good histologic correlation and 6 (20%) were discrepant. Our data showed no significant difference in the detection of squamous lesions in those smears with an endocervical component from those without. We conclude that, although the presence or absence of an endocervical component should be documented in the cytology report, its absence should not be an indication to report the cervical smears as unsatisfactory.


Pulmonary mycetomas in immunocompetent patients: diagnosis by fine-needle aspiration.

Mycetomas usually grow within preexisting cavities and frequently lead to pulmonary hemorrhage. We describe four males, aged 38 to 72 years, in whom myceotomas were diagnosed by FNA. Preexisting cavitary lesions resulted from tuberculosis, anaerobic abscess, and bullous lung disease (two cases). Fine needle aspiration yielded tangled mats of fungal hyphae (large and grossly visible in three cases) and acute inflammatory cells. The atypical cells often seen in the walls of such lesions were not identified. Cultures showed Aspergillus (3 cases) Pseudoallescheria boydii (1 case). The diagnosis was surgically confirmed in two cases. Two patients were too ill for surgery and the fourth refused. At 7 and 10 months, the two remaining individuals have pulmonary hemorrhage but no evidence of progression or malignancy. In poor surgical candidates, conservative management of mycetomas diagnosed by fine needle aspiration is appropriate. Excluding mycetoma secondary to cavitary lung carcinoma requires careful correlation of historical, clinical, radiographic, cytologic, and follow-up data.


Aspiration biopsy cytology of malignant papillary breast neoplasms.

Papillary carcinoma of the breast is a rare neoplasm characterized by a low grade of malignancy. From the files of the Department of Histopathology of Conegliano Veneto City Hospital, Conegliano Veneto, Italy, 16 cases of papillary breast carcinoma diagnosed by fine-needle aspiration cytology have been selected. A multiparametric morphologic study has been performed in order to contribute to the cytologic characterization of this rare group of breast malignancies. The authors believe that aspiration biopsy cytology is able to provide an accurate preoperative diagnosis.


Pulmonary aspergillosis: an unusual cytologic presentation.

Cytologic identification of Aspergillus is usually based on recognition of hyphal elements; conidia are rarely seen. We report a case of autopsy-proven pulmonary Aspergillosis which was studied antemortem by bronchoalveolar lavage. This mass arose in the clinical setting of chronic necrotizing pulmonary aspergillosis. The specimen contained numerous conidia, some of which exhibited germination. No hyphae were seen. This unusual cytologic expression of clinically significant fungal disease could be easily overlooked. Distinction of Aspergillus conidia from contaminating pollen is discussed.


Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): cytomorphologic analysis on fine-needle aspirates.

Cytomorphologic characteristics of smears from fine-needle aspirates (FNA) of three cases of sinus histiocytosis with massive lymphadenopathy (SHML) (Rosai-Dorfman disease) are described. All aspirates showed mature lymphocytes, plasma cells, and large pale histiocytes with well-preserved lymphocytes within the cytoplasm (lymphocytophagocytosis). The cases were confirmed by surgical biopsy, and the immunohistochemical findings suggested a macrophage origin for this lesion. The value of FNA analysis as an aid to diagnosis of SHML is discussed.


Fine-needle aspiration cytology of metastatic breast tumor originating from leukemia.

Two cases of metastatic breast tumor originating from leukemia are reported. Fine-needle aspiration (FNA) specimens showed a large number of isolated small-to-medium-sized atypical lymphocytic cells. It is difficult to distinguish metastatic breast tumors and primary breast cancers by physical findings alone. FNA cytology is an effective method for qualitative diagnosis. When atypical lymphocytic cells are obtained in aspiration materials of the breast, past history and general examination are necessary for diagnosis. In some cases of leukemia with breast involvement, good outcomes are obtained. Therefore, earlier detection is necessary in order to begin suitable therapy earlier and to avoid unnecessary excisional biopsy in patients with leukemia and breast tumors. To achieve this it is also necessary to first take into consideration the possibility of metastasis or infiltration of leukemia, and second to prepare two types of specimen for Papanicolaou stain and Giemsa stain before operation.


Leiomyosarcoma of the orbit: diagnosis of its recurrence by fine-needle aspiration cytology.

An 8 1/2-yr-old boy with proptosis was diagnosed to have low-grade leiomyosarcoma of the orbit following lateral orbitotomy and histology of an incompletely excised intraconal mass. He received chemotherapy but had recurrence of proptosis at the age of 12 yr. Ultrasonography revealed a solid mass and its fine-needle aspiration cytology features were consistent with recurrence of leiomyosarcoma. A year later, the cytodiagnosis was confirmed by histology of the excised tumor from a second lateral orbitotomy. Masson's trichrome stain confirmed the smooth muscle nature of the neoplasm and ultrastructural features were in favor of leiomyosarcoma. The patient received intermittent chemotherapy, and is clinically free from disease at the age of 17 yr.


Fine-needle aspiration of a periurethral Teflon-filled cyst following radical prostatectomy.

Periurethral Teflon injections are being used increasingly for the treatment of urinary incontinence after radical prostatectomy. We report a case of a man who developed increasing obstructive urinary symptoms and stress incontinence following radical retropubic prostatectomy. Six months earlier, he had undergone periurethral Teflon injections. On transrectal ultrasound and magnetic resonance imaging, a 3.2-cm cystic lesion was noted at the prostatic bed near the bladder neck where the Teflon had been injected. Ultrasound-guided transperineal fine-needle aspiration of the cyst yielded a specimen with numerous birefringent crystalline Teflon particles. Although previous reports have described granulomatous tissue reaction, no multinucleated giant cells were present to suggest granuloma formation. To our knowledge, this is the first reported case of Teflon cyst formation following periurethral Teflon injections. The patient's history, imaging studies, cytopathology, and review of the literature are presented in this report.


Rounded atelectasis: diagnosis by fine-needle aspiration cytology.

Rounded atelectasis, a rare, benign mass lesion, is most often seen in association with asbestos-related pleural changes. Often a presumptive diagnosis can be made on the basis of characteristic CT and chest radiographic findings. However, not infrequently radiographic imaging fails to differentiate rounded atelectasis from primary bronchogenic carcinoma, a disease which is seen with increased frequency in patients with asbestos exposure. We describe two cases where the diagnosis of rounded atelectasis was made by fine-needle aspiration (FNA) cytology. The cytologic features included abundant pulmonary parenchymal material with thickened alveolar walls containing pulmonary macrophages and connective tissue. It is important to realize that this is a useful positive finding indicating rounded atelectasis, rather than a negative finding suggesting the absence of neoplasm. Needles with a cutting action may be necessary to obtain sufficient material to make the diagnosis of rounded atelectasis.


Infantile cutaneous rhabdomyosarcoma (Li-Fraumeni syndrome): cytological presentation of fine-needle aspirate biopsy, report of a case.

We describe the cytopathological picture of a cutaneous rhabdomyosarcoma located in the left nasal furrow of a 4-mo-old girl, some of whose close relatives have died or suffered from different types of neoplasias (Li-Fraumeni syndrome). We believe that the cytological picture is highly characteristic and rules out other round cell tumours of childhood. We underline the usefulness of FNAC in dermatology and strongly advocate the introduction of this technique into the diagnostic armoury of every dermatologist.


Detection of numerical chromosomal abnormalities in malignant cells on body fluids by fluorescence in situ hybridization of interphase cell nuclei with chromosome-specific probes.

To detect numerical chromosomal abnormalities (NCA) in malignant cells on body fluids, Fluorescence in situ hybridization (FISH) technique was tested in clinical specimens from patients with metastatic disease. Directly labeled DNA probes specific for chromosomes 8, 12, X, and Y (Imagenetics, Naperville, IL) were used for in situ hybridization to interphase cell nuclei. Fifteen body fluids (BF) from various sites were studied. Based initially on the Papanicolaou-stained slides, there were seven malignant and eight benign samples. Blind analysis (200 cells/sample) showed that all benign samples had a normal number of chromosomes, whereas six of seven malignant samples showed different NCA comprising 5-60% of the cell population ranging from three to 10 chromosome signals per cell. We conclude that interphase cytogenetic cell analysis of BF by FISH is: (1) feasible and gives superior signals for detection of NCA, (2) helpful in detecting malignant cells, (3) relatively simple with a turnaround time of less than 24 hr. This method may have diagnostic and prognostic application in the study of the biologic behavior of malignant neoplasms.


Peritoneal washing cytology in women: diagnostic pitfalls and clues for correct diagnosis.

The significance of peritoneal washing cytology in the management of patients with gynecologic cancer is well established. Its microscopic evaluation, however, is not always straightforward. Previous studies have identified some of the conditions that may result in misinterpretation of cytologic results. This report reviews the literature and describes other sources of diagnostic difficulties and clues for correct diagnosis. In addition, an outline for distinguishing endosalpingiosis from borderline and well-differentiated serous carcinoma is proposed.


Fibroadenoma of the breast: diagnostic pitfalls of fine-needle aspiration.

On fine-needle aspiration (FNA), fibroadenomas have a characteristic cytological appearance, although occasional cases are misinterpreted as carcinomas and vice versa. In a review of 521 breast aspirates correlated with the subsequent histology, six of 87 fibroadenomas (7%) were malignant or suspicious of malignancy on FNA (false positives). Following cytological review, four were still suspicious of malignancy because of cellular dyscohesion and prominent nucleoli, while two were fibroadenomas. On FNA, four of 145 carcinomas (3%) were diagnosed as fibroadenomas (false negatives). On review, three were malignant or suspicious of malignancy, while one was consistent with a fibroadenoma. Three false negative diagnoses were due to underappreciation of single malignant cells present between epithelial groupings typical of a fibroadenoma, while one was due to undersampling of the carcinoma. Cytologically, some fibroadenomas are sufficiently atypical that histological confirmation is necessary to exclude a malignancy. Misinterpreting carcinomas as fibroadenomas could be avoided by careful study of the morphology of isolated cells.


Management of hypertension.

To provide maximal protection against the cardiovascular complications that accompany hypertension, the disease must be managed in ways to minimize the total cardiovascular risk burden. These involve five major steps: (1) careful monitoring of the blood pressure in response to appropriate therapy; (2) assessment of concomitant cardiovascular risk factors; (3) institution of life-style modifications needed to control both hypertension and other risk factors; (4) use of antihypertensive drugs, chosen to best manage the individual patient's overall risk burden and provided in a manner that will lower the pressure gently while avoiding adverse reactions; and (5) identifying and reaching the goal of therapy: levels of blood pressure that are neither too high to avoid increased risks for cerebral and renal damage nor too low to avoid increased risks for coronary ischemia. This monograph builds on the 30-year experience of one of the leading clinical investigators in the field to translate the multiple advances made in the management of hypertension into practical guidelines for improved care of the many millions of patients with this disease. Particular emphasis is directed toward certain therapeutic challenges, including the elderly, diabetic patients, and resistant hypertensive patients.


Studies on the stability of the clinical electro-oculogram.

The electro-oculogram is variable as a clinical test, but the recording technique has not been standardized, and differences in the protocols for adaptation and stimulation among laboratories may contribute to the variability. To analyze some of these factors, we performed more than 100 electro-oculograms on a single subject under different conditions. Both the Arden ratio and the ratio of light peak amplitude to a stable dark-adapted baseline were independent of pupillary dilation but linearly related to retinal illumination measured in trolands. Between 3.0 and 4.0 log trolands, the values began to level off, but they were difficult to interpret because of subject discomfort above 3.5 log trolands. The Arden ratios were influenced by preadaptation light levels and were roughly 20% higher above 90 cd/m2 than below 45 cd/m2. There was a circadian rhythm in dark trough, baseline and light peak values, but the composite Arden ratio and light peak/baseline ratio showed little circadian effect. The light peak/baseline ratios were slightly more stable than the Arden ratios; the variability (defined as [standard deviation x 100]/mean) was 6.6% and 12.5%, respectively. Our results suggest that stimulus intensities for clinical electro-oculographic testing should be between 3.0 and 3.5 log trolands; pupil dilation is optional. This translates into light levels of 141-447 cd/m2 for a 3-mm pupil and 20-63 cd/m2 for an 8-mm pupil. The reduction in variability and independence from preadaptation achieved by using the light peak/baseline ratio instead of the Arden ratio must be weighed against the time required to achieve a stable dark baseline.


Electroretinographic oscillatory potentials in diabetic retinopathy. An analysis in the domains of time and frequency.

The oscillatory potentials of the electroretinogram in dark and light adaptation were evaluated by Fourier transform in 87 diabetics and 74 age-matched controls. The study consisted of four groups: normal control, no observable diabetic retinopathy, background diabetic retinopathy and proliferative diabetic retinopathy. A reduction in the amplitude of each oscillatory potential, the summed amplitudes, the area and the total power of the oscillatory potentials as well as delayed implicit time of each oscillatory potential peak in dark and light adaptation could be found in patients with background diabetic retinopathy and proliferative diabetic retinopathy. The amplitude of oscillatory potential 4 in dark adaptation and the total power of the oscillatory potentials in light adaptation seemed to be affected in patients with no observable diabetic retinopathy. The implicit time of oscillatory potential 2 in dark adaptation was valuable to distinguish between patients with no observable diabetic retinopathy and background diabetic retinopathy.


Comparison of preoperative 10-Hz visual evoked potentials to contrast sensitivity and visual acuity after cataract extraction.

Cataract patients whose surgical outcomes were in question were referred for testing by visual evoked potentials, elicited through closed eyelids by a luminance stimulus (flash) that appeared 10 times per second. Visual evoked potentials were rated as normal (predicted acuity of 20/50 or better) or abnormal (predicted acuity of 20/60 or worse). Postoperative Arden and Optronix contrast sensitivities and visual acuities were determined in 37 patients who had no intraoperative or early postoperative complications. Arden grating scores of less than 100 were rated as normal. The optimal and cutoff spatial frequency values were determined for the Optronix scores. Optimal and cutoff values of greater or equal to 1 c/deg and 12 c/deg, respectively, were rated as normal. Visual acuities were considered normal at 20/50 or better. Preoperative visual evoked potentials were quantitatively compared to the postoperative contrast sensitivities and visual acuities by 2 x 2 contingency tables. The accuracy of prediction was 79% for the visual acuities, 62% for the Optronix optimal values, 70% for the Optronix cutoff values and 62% for the Arden gratings.


Averaged steady-state visual evoked cortical potentials at artificially raised intraocular pressure.

By recording steady-state visual evoked cortical potentials while intraocular pressure is artificially increased, information can be obtained on the pressure tolerance of the optic nerve head. Such experiments have previously been performed by a vector voltmeter technique. We studied the visual evoked cortical potentials in 30 healthy volunteers with artificially increased intraocular pressure, but we used an averager instead of a vector voltmeter. The results were similar except that the noise level in averaging was higher than with the vector voltmeter technique. This observation confirms that the signal-to-noise ratio is much better with the vector voltmeter technique than with the averaging technique. Our results show that averaging can be used in pressure tolerance testing, but the amplitude cannot be observed as far down as in the vector voltmeter technique. This limits the clinical value of averagers in this application.


Visual evoked potentials during the early phase of optic nerve compression in the orbital cavity.

We obtained case histories and electrophysiologic recordings from four patients with transient vision impairment due to acute orbital compression. The visual evoked potentials (VEPs) displayed alterations that depended on the size and consistency of the compressing pathology and also on the duration of the compression. This study provides evidence of the utility of the VEP in the assessment of the severity and reversibility of optic nerve lesions. The case histories also emphasized the necessity to elucidate the pathologic process of compressive lesions of the optic nerve.


Clinical application of motion-onset visual evoked potentials.

The results of motion-onset visual evoked potentials and pattern-reversal visual evoked potentials were compared in 5 adults with amblyopia, in 13 patients with unilateral retrobulbar neuritis and in 62 patients with multiple sclerosis. While the pattern-reversal visual evoked potentials had reduced amplitudes and prolonged latencies in all amblyopic eyes, the motion-onset visual evoked potentials were normal. Thus, motion-onset visual evoked potentials cannot be used for diagnosis of amblyopia. In patients with retrobulbar neuritis, both types of visual evoked potentials were delayed on stimulation of the affected eye. The latency increase was, however, greater for pattern-reversal visual evoked potentials than for motion-onset visual evoked potentials. Examination of the patients with multiple sclerosis showed that the additional use of motion-onset visual evoked potentials increased the sensitivity of the investigation. In some patients, only the motion-onset visual evoked potentials had pathologic latency increases, whereas the pattern-reversal visual evoked potentials stayed within normal limits.


An optical stimulator for studying the topography of electrical and magnetic visual evoked responses.

Visual processing areas cover more than 50% of the cortex in primates, but in humans only about half of this area is projected on gyral crests and thus readily accessible to investigation by evoked potential mapping. However, neuromagnetometry does not reflect the activity of these radial dipoles, but instead it strongly represents tangential dipoles, which may arise from activity within the sulci. It follows that the full exploration of the visual areas can only be achieved by combining these complementary techniques. Software-controlled video stimulators are almost universally used for evoked potential recording, but they generate troublesome interference during neural magnetometry. A simple optical stimulator was therefore designed to project a stimulus into magnetically shielded rooms from a remote situation. The system is capable of providing a wide variety of visual stimuli, including pattern reversal, onset, movement and progressive adjustment of chromatic and achromatic contrast. Evoked responses to complex images and isoluminant colored gratings were studied to demonstrate the performance of this type of system.


Light-emitting diodes and half-cell electrodes in experimental recording of electroretinogram c-wave.

A method of electroretinogram c-wave recording in the rat was developed that uses a contact lens electrode connected through a saline bridge with a silver-silver chloride half-cell. A cluster of light-emitting diodes, regulated by an electronic light-emitting diode stimulator, was used as a light source. The method enables recordings of c-waves of 0.4-1.6 mV amplitude as well as other electroretinogram components in narrow limits of variation. The two main sources of response variability are voltage shunting and eyeball protrusion.


Scotopic versus photopic pattern onset-offset electroretinograms.

We investigated the contribution of rods and cones to the human pattern electroretinogram to onset and offset checkerboards of different spatial frequency and wavelength in a 39 degrees x 39 degrees field. Under strictly scotopic conditions, there was a negative potential at onset and a positive potential at offset, whereas under photopic conditions, there was a positive potential at onset and a negative/positive potential at offset. Thus, the waveform to pattern onset (offset) was that of the luminance electroretinogram to decreasing (increasing) luminances. For pattern onset, the sensitivity difference 486-601 nm under scotopic and photopic conditions closely followed the luminosity function of rods and cones. The amplitude of the scotopic onset response increased with check size up to 3 degrees 30' and that of the photopic onset response, up to 30'. With larger checks, the scotopic and photopic onset response markedly decreased. This indicates antagonistic center-surround organization of the receptive fields under both scotopic and photopic conditions. By contrast, the offset response monotonically increased with check size under scotopic and photopic conditions, which suggests a luminance component in the pattern electroretinogram. Consequently, the pattern electroretinogram to reversing checkerboards has to be regarded as a mixture of both pattern- (contrast) and luminance-specific components.