Search

Background & Aims: TG4040 is a modified vaccinia Ankara (MVA) virus that expresses the hepatitis C virus (HCV) proteins NS3, NS4, and NS5B. We performed a phase II open-label study to determine the efficacy, safety, and immunotherapeutic properties of TG4040 in combination with pegylated interferon α-2a and ribavirin (PEG-IFNα/RBV) in patients with chronic HCV infection., Methods: Treatment-naive patients with HCV genotype 1 infection were assigned randomly to 1 of the following groups: PEG-IFNα/RBV for 48 weeks (group A, n = 31), PEG-IFNα/RBV for 4 weeks followed by PEG-IFNα/RBV for 44 weeks with 6 injections of TG4040 (group B, n = 63), or TG4040 for 12 weeks (7 injections) followed by PEG-IFNα/RBV for 48 weeks with 6 injections of TG4040 (group C, n = 59). The primary end point was complete early virologic response (cEVR), defined as HCV-RNA level less than 10 IU/mL after 12 weeks of PEG-IFNα/RBV treatment., Results: In group C, 64.2% of evaluable patients achieved cEVR, compared with 30.0% in group A and 45.9% in group B (P = .0003 for group C vs A). A higher percentage of patients achieved a sustained virologic response 24 weeks after therapy ended in group C (58.2%) than in groups A (48.4%) or B (50.8%). HCV- and MVA-specific T-cell responses were observed predominantly in group C. As expected, most patients given injections of TG4040 developed anti-MVA antibodies. The combination of TG4040 and PEG-IFNα/RBV was reasonably well tolerated. However, PEG-IFNα-associated thrombocytopenia developed in 3 patients who carried the class II HLA allele DRB01*04., Conclusions: A higher percentage of patients with chronic HCV infection who received immunotherapy with TG4040 followed by TG4040 and PEG-IFNα/RBV achieved a cEVR compared with patients who received only PEG-IFNα/RBV therapy. These findings show that immunotherapies that activate T cells are effective in patients with chronic HCV infection. ClinicalTrials.gov number, NCT01055821., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Unfractionated heparin, derived from porcine intestine, is the prototype of a rapidly acting anticoagulant. It has been used for over 60 years to arrest or prevent thrombus growth. Low-molecular-weight heparins, available in the last 20 years, are manufactured from unfractionated heparin and have superior dose-response relationships because of fewer nonspecific reactions with plasma proteins and cells. Fondaparinux is a recently approved five-saccharide synthetic molecule that carries the evolution of heparin further. It is a pure Xa inhibitor, with minimal nonspecific interactions. It does not appear to elicit the antibody that leads to heparin-induced thrombocytopenia (HIT). All of these agents are given either intravenously or subcutaneously. They act indirectly by activating the natural plasma inhibitor, antithrombin III. Direct thrombin inhibitors bind directly to thrombin's active site without interaction with the cofactor, antithrombin III. Lepirudin (Refludan; Berlex, Wayne, NJ) and argatroban (Argatroban; GlaxoSmithKline, Research Triangle Park, NC) are given intravenously and are usually used in HIT and thrombosis associated with HIT. Bivalirudin (Angiomax; The Medicines Company, Parsippany, NJ) is a parenteral direct thrombin used in place of heparin in percutaneous coronary interventions. Ximelagatran (Exanta; AstraZeneca, Wilmington, DE) is an oral direct thrombin inhibitor under development for both acute and chronic anticoagulation.

Insulin induces transcription of the hepatic apolipoprotein AI (apo AI) gene by increasing Sp1 binding to the promoter. To determine the effect of fatty acids on this process, HepG2 cells cotransfected with the plasmid pAI.474.CAT containing the full-length apo AI promoter and the Sp1-expressing plasmid, pCMV-Sp1, were studied. Chloramphenicol acetyl transferase (CAT) activity (% acetylation) increased 1.98-fold in cells receiving the Sp1 expression construct relative to control cells (46.4% +/- 0.6% v 23.4% +/- 1.3%, P < .05). Treatment of cells with 3 saturated fatty acids, stearic, myristic, and palmitic acid, repressed the ability of exogenous Sp1 to induce apo AI reporter gene expression (15.2% +/- 1.7%, 22.5% +/- 0.3%, 22.9% +/- 0.1%, 23.5% +/- 0.8%, respectively, P < .05). Unsaturated fatty acids, oleic, linoleic, or linolenic acid had no effect on Sp1-mediated induction of the apo AI promoter. In the presence of the trans fatty acids, CAT activity in the Sp1-transfected cells was similar to control cells (16.7% +/- 3.3%, 19.3% +/- 0.5%, and 21.0% +/- 2.1% acetylation in cells exposed to elaidic acid, linolelaidic, or linolenelaidic acid, respectively). In cells treated with an equimolar mixture of oleic acid and stearic acid, apo AI promoter activity was suppressed in a manner similar to that observed in stearic acid-treated cells. Insulin (100 microU/mL) induced apo AI promoter activity 2.9-fold (22.4% +/- 1.7% v 7.8% +/- 2.4%, P < .05). However, in the presence of stearic acid, insulin was unable to induce apo AI promoter (6.3% +/- 1.6%). Stearic acid treatment did not alter Sp1-DNA binding as measured by gel shift analysis. Therefore, saturated fatty acids blunt Sp1 induction of apo AI promoter probably at a step beyond DNA binding.

Although calcitriol has been shown to have an important role in the pathogenesis of hyperparathyroidism, its use as a therapeutic agent often has been limited by calcemic and phosphatemic toxicity. Vitamin D analogs and the synthetic prohormones, with the potential to have lesser effects on calcium and phosphorus, have been introduced and shown to be effective therapeutic agents. Paricalcitol is used widely in the United States and may be associated with improved clinical outcomes. Further studies on the effects of these vitamin D sterols on the skeleton and further studies of potential differential effects on calcification processes will be forthcoming, and as the mechanisms of their lesser toxicity become understood, perhaps this will pave the way for a future generation of vitamin D analogs with even greater specificity for the suppression of hyperparathyroidism with lesser toxicity.

Prostanoids have been implicated in the transcriptional control of several genes. Since prostanoid synthesis inhibitors are commonly used in subjects with coronary heart disease we studied the effect of cyclooxygenase (COX) inhibition on apolipoprotein AI (apoAI) expression in a human hepatoma cell line (HepG2) transfected with full-length apoAI promoter attached to the chloramphenicol acetyl transferase (CAT) reporter gene. To control for transfection efficiency, the cells were cotransfected with the plasmid pCMV.SPORT-beta-gal containing the beta-galactosidase gene driven by the cytomegalovirus promoter. Treatment of these cells with varying concentrations of indomethacin (INDO, 0, 50, 100, and 300 micromol/L) resulted in a dose-dependent decrease in apoAI promoter activity (% acetylation corrected for beta-galactosidase activity: were 46.1 +/- 2.6, 29.9 +/- 1.2, 25.2 +/- 2.9, and 17.2 +/- 2.8, respectively, P <.001). INDO treatment did not cause significant changes in beta-galactosidase activity. A similar reduction in apoAI promoter activity was found after treating the cells with 50 micromol/L acetylsalicylic acid (ASA) (31.8 +/- 1.8%, P <.001), suggesting that the effect of INDO is related to COX inhibition rather than a peculiar effect of INDO. Nuclear run-off assays indicated that treatment of cells with 50 micromol/L INDO resulted in 31.4% reduction in apo A1 transcription rate (P <.0002). Northern blot analysis of RNA from HepG2 cells treated with 50 micromol/L of INDO for 72 hours showed that the apoAI mRNA concentration relative to G3PDH mRNA was 4,043.0 +/- 84.6 and 3,064.0 +/- 49.8 in control and INDO-treated cells, respectively (P <.0006). Kinetic studies of apoAI mRNA in HepG2 cells indicated that the half-life of apoAI mRNA was not significantly altered with 50 micromol/L INDO treatment. Apo AI mRNA half-life was 25.3 hours in control cells and 26.9 hours in INDO-treated cells. Western blot analysis of culture media of HepG2 cells treated with 50 micromol/L of INDO for 72 hours showed a significant reduction in apoAI protein (6,760.0 +/- 318.1 v 4,773.0 +/- 112.0 arbitrary units, P <.004). Treatment of cells with either arachidonic acid (COX substrate) or various prostanoids including prostaglandin I(2), thromboxane B(2), (+/-)5-HETE, or (+/-)12-HETE did not significantly alter apoAI promoter activity. However, prostaglandin E(1) and E(2) at the highest concentration tested (50 nmol/L) significantly repressed apoAI promoter activity. COX activity measurements in HepG2 cells verified the efficacy of COX inhibition by INDO. It is concluded that COX inhibition with INDO or ASA downregulates apoAI expression at the transcriptional level. This effect could not be attributed to either arachidonic acid excess or to a deficiency in various prostanoids tested.

Normeperidine, a major metabolite of meperidine, is half as potent as meperidine as an analgesic but two to three times more potent as a convulsant. Renal failure significantly increases the plasma half-life of normeperidine. The intensity of the central nervous system excitation is highly correlated with the plasma concentration of normeperidine. Moreover, normeperidine toxicity is not reversed by naloxone, which may exacerbate it. We report a patient with end-stage renal disease undergoing maintenance continuous cycler peritoneal dialysis who had been receiving meperidine for pain control. The patient subsequently developed myoclonic contractions and a grand mal seizure. The patient was successfully treated with hemodialysis (using an F8 dialyzer) for presumed normeperidine-induced seizure. During hemodialysis, normeperidine average blood clearance was 73 mL/min, average plasma clearance was 50 mL/min, and average percentage of plasma extraction was 24%. There also was a 26% reduction in plasma concentration of normeperidine over 3 hours of hemodialysis. In conclusion, our findings suggest that hemodialysis may be used effectively for treating patients with suspected normeperidine-induced neurotoxicity.

Surgery and radiation for advanced head and neck cancer are debilitating and associated with poor survival. If outpatient preoperative chemotherapy could be used such that smaller surgical resections are needed, organs might be preserved and patients' quality of life enhanced. Accordingly, we are conducting a phase I trial of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin in previously untreated patients with advanced head and neck cancer. Study goals include identifying the maximum tolerated paclitaxel dose, evaluating response, and enhancing organ preservation. Newly diagnosed patients with stage III/IV head and neck cancer, measurable disease, and Zubrod performance status < or =2 were eligible. Of 33 patients treated thus far, four (12%) had stage III and 29 (88%) stage IV disease. Their median age was 58 years (range, 17 to 76 years). Treatment was repeated at 21-day intervals for two courses. Patients who achieved clinical partial or complete responses (CRs) received a third course of treatment. If patients were found to have a histologic CR at restaging, radiation was substituted for surgery. Carboplatin was dosed by the Calvert formula to an area under the concentration-time curve of 7.5. Cohorts received escalating doses of paclitaxel (150 to 265 mg/m2) over 3 hours until dose-limiting toxicity was encountered. Five patients were treated at 150 mg/m2, three at 170 mg/m2, eight at 200 mg/m2, six at 230 mg/m2, four at 250 mg/m2, and seven at 265 mg/m2. At present, 26 patients are evaluable for primary tumor response. Thus far, we have seen seven CRs (27%) and seven partial responses (27%), for an overall response rate of 54%. Of 25 patients assessable pathologically, seven (28%) had a CR. Grade 3/4 toxicity at paclitaxel 265 mg/m2 included neurosensory toxicity in 17%, mucositis in 17%, neutropenia in 67%, and thrombocytopenia in 17%. We conclude that paclitaxel 230 mg/m2 and carboplatin area under the curve 7.5 can be administered safely to this patient population. The dose-limiting toxicity that occurred at paclitaxel 265 mg/m2 comprised grade 3/4 neutropenia and thrombocytopenia with associated cumulative grade 2 neuropathy. The maximum tolerated dose of paclitaxel with the combination will be between 230 and 265 mg/m2. This combination has activity in head and neck cancer.

To determine if dietary carbohydrates modulate apolipoprotein A1 (ApoA1) expression, plasma ApoA1 protein and hepatic ApoA1 mRNA levels were measured in young and aged rats maintained on a high-fructose (60% of diet weight consisting of fructose), or high-glucose (60% glucose) diet or fed regular rat chow for 10 days. Aged rats on regular chow had significantly higher plasma ApoA1 concentrations and hepatic ApoA1 mRNA than young rats maintained on this diet. Plasma ApoA1 and hepatic ApoA1 mRNA levels in young rats or aged rats maintained on the 60% fructose diet were significantly higher than in rats within the same age group maintained on regular rat chow (P < .01). Similar induction of ApoA1 protein and mRNA was found in rats maintained on the 60% glucose diet (P < .01). It is concluded that ApoA1 expression in rats is modulated by factors related to the nature of dietary carbohydrates rather than insulin resistance associated with high-fructose feeding.

The surgical options for heart transplant recipients who develop obstructive coronary artery disease in their allograft have historically been limited to retransplantation. Given the worse outcome in recipients of second grafts, often caused by recurrence of coronary disease, coupled with the significant increase in the number of patients on the transplantation waiting lists, has made retransplantation a limited option. However, as heart transplant recipients continue to live longer, there are an increasing number of patients who develop allograft coronary disease. Coronary bypass surgery has not been offered to these patients because of numerous pathology reports describing uniform involvement of the coronary vessel from its origin to the distal intramural branches, thereby eliminating any reasonable runoff vascular bed to handle increased flow that might be delivered with bypass conduits. However, new diagnostic techniques such as measurement of coronary flow reserve by Doppler flow wire can define the physiological vasodilating capacity or reserve which, if normal, should allow conventional bypass surgery if adequate target epicardial vessels are present. This approach would allow a more reasonable alternative to many patients who otherwise would die of this disease without any intervention. Other alternatives such as transmyocardial laser revascularization are discussed.

Retinoids are synthetic derivatives of vitamin A. They are administered primarily for dermatological conditions, such as psoriasis, acne, and disorders of keratinization. Toxicity has proven a significant problem with long-term administration of the retinoids. Bone abnormalities mimicking seronegative spondyloarthropathy or diffuse idiopathic skeletal hyperostosis have been described in many cases, as well as other rheumatologic manifestations such as arthritis, myopathy, and vasculitis. These retinoid-related adverse effects are reviewed.

Background/aims: In the past, nonalcoholic steatohepatitis has been described mostly in obese women with diabetes. The aim of this study was to describe a series of patients with nonalcoholic steatohepatitis with a different clinical profile., Methods: The clinical, biochemical, and histological features of 33 patients with nonalcoholic steatohepatitis seen from July 1990 to June 1993 were analyzed., Results: The mean age was 47 years. All patients were antibody to hepatitis C virus-negative. Nineteen of 33 (58%) were men, 20 of 33 (61%) were nonobese, 26 of 33 (79%) had normal glucose levels, and 26 of 33 (79%) had normal lipid levels. Fourteen of 33 (42%) had normal glucose and lipid levels and were not obese. Thirteen of 33 (39%) had pathological increases in fibrosis, 5 of whom had micronodular cirrhosis. Of these 13 with severe, progressive disease, 8 (62%) were women, 8 (62%) were obese, 4 (31%) were diabetic or had an elevated glucose level, and 3 (23%) had hyperlipidemia. Although serum iron studies (transferrin saturation and ferritin) were abnormal in 18 of 31 (58%), no patient had hemochromatosis., Conclusions: Nonalcoholic steatohepatitis can be a severe, progressive liver disease leading to the development of cirrhosis. It should no longer be considered a disease predominantly seen in obese women with diabetes.

Background/aims: Determination of hepatic iron concentration (HIC) is essential for the evaluation of hereditary hemochromatosis. Occasionally, only paraffin-embedded liver biopsy specimens are available, or fresh biopsy specimens have been placed in saline for transport. This study aimed to describe a method for extraction of liver tissue from paraffin blocks, determine the accuracy of measurement of HIC in recovered tissue compared with fresh tissue, and determine the effect of immersion in saline on HIC., Methods: HIC was measured in both fresh and deparaffinized liver specimens (n = 41). Accurate measurements were defined as either a normal result in both specimens or a result in the deparaffinized specimen that was within 30% of the fresh measurement., Results: Measurements of HIC in fresh and deparaffinized tissue showed an excellent linear relationship (r = 0.95). In deparaffinized samples > or = 0.4 mg, accurate measurements were seen in 24 out of 29 specimens, compared with 6 out of 12 specimens weighing < 0.4 mg (P < 0.01). The hepatic iron index calculated from results in deparaffinized samples > or = 0.4 mg correctly classified all patients. Immersion of fresh biopsy specimens in saline for 1 hour resulted in up to 50% iron loss (P < 0.05)., Conclusions: Accurate measurement of HIC in deparaffinized liver biopsy specimens is possible. Calculation of the hepatic iron index from deparaffinized liver tissue can facilitate diagnosis of hemochromatosis when fresh tissue is not available. Samples should not be transported in saline.

We describe a 75-year-old male patient who developed end-stage renal failure secondary to scleroderma renal crisis. The patient had cutaneous involvement limited to his fingers and feet, and had repeatedly negative serologic tests for antinuclear antibodies. This case illustrates that scleroderma renal crisis should be considered in the differential diagnosis of unexplained acute renal failure in patients with suspected systemic sclerosis, even if they lack the typical extensive cutaneous changes and the expected serologic findings.

Background: Iron overload results in impaired hepatic mitochondrial oxidative metabolism. The current experiments evaluated the effects of iron overload on enzyme activities in the mitochondrial electron transport chain, on hepatic adenine nucleotide levels, and on hepatocellular oxygen consumption., Methods: Hepatic iron overload was produced in rats using dietary carbonyl iron. Hepatic adenine nucleotides were assessed after freeze-clamping, mitochondrial enzyme activities and oxygen consumption were measured in isolated mitochondria, and oxygen consumption in isolated hepatocytes was determined., Results: At a mean hepatic iron concentration of 4630 micrograms/g, there were no changes in reduced nicotinamide adenine dinucleotide (NADH)-cytochrome c reductase activity (complex I-III), but there was a 35% reduction in succinate-cytochrome c reductase activity (complex II-III), and a 70% decrease in cytochrome c oxidase activity (complex IV). With mild iron loading (2060 micrograms/g), there was a 28% decrease in hepatic adenosine 5'-triphosphate (ATP) levels with no change in adenosine 5'-diphosphate (ADP) or adenosine 5'-monophosphate (AMP) levels, whereas, at a higher hepatic iron concentration (3170 micrograms/g), there was a 40% reduction in ATP levels, a 22% decrease in ADP levels, with no change in AMP levels. There was a 48% reduction in oxygen consumption in isolated iron-loaded hepatocytes., Conclusions: Chronic iron overload decreases hepatic mitochondrial cytochrome c oxidase activity, hepatocellular oxygen consumption, and hepatic ATP levels.

Early studies showed few immunologic abnormalities in juvenile rheumatoid arthritis (JRA) patients. There were no specific laboratory markers useful for diagnosis and assessment of the course of disease in JRA. Previous work showed an association of antinuclear antibodies (ANA) with early-onset pauciarticular disease and iridocyclitis. Similarly, the presence of 19S immunoglobulin (Ig) M rheumatoid factors (RF) was associated with late-onset polyarticular disease in girls. More recent studies have detected many unique autoantibodies. Newer assays show 19S IgM RF in up to 35% of JRA patients, although still mainly in girls with late-onset polyarticular disease. Hidden 19S IgM RF can be shown in up to 75% of JRA patients using different procedures, primarily in those with active polyarticular-or pauciarticular-onset disease. Immune complexes have been detected in JRA patients by means of different techniques; their presence usually correlates with active disease. Studies on a specific ANA in JRA have shown no common extractable nuclear antigen, but antihistone antibodies have been found in up to 75% of cases, again mainly in those with pauciarticular onset and iritis. Finally, a variety of unusual immunologic proteins have also been detected, including anti-ocular, anti-cellular, anti-cardiolipin, anti-perinuclear factor, and anti-collagen antibodies. This review evaluates the significance of these antibodies that can now be found in JRA.

A direct effect of calcitriol on the regulation of the secretion of parathyroid hormone (PTH) has been shown in vitro and in vivo. In patients with renal failure on maintenance hemodialysis, it has been shown that intravenous (IV) administration of calcitriol appears to be superior to continuous oral administration. This may be due to the higher levels of calcitriol obtained in blood with consequent improved delivery of calcitriol to peripheral target tissues including the parathyroid glands. However, IV administration of calcitriol, is not practical for patients with end-stage renal disease (ESRD) who are maintained on continuous ambulatory peritoneal dialysis (CAPD). The present studies were designed to investigate whether intermittent administration of large doses of calcitriol orally ("pulse therapy") could mimic the effects of IV calcitriol in hemodialysis patients and achieve suppression of PTH secretion. Studies were performed in five patients who had been maintained on CAPD for more than 6 months. After basal determinations of calcium, phosphorus, and PTH, therapy was begun with calcitriol administered orally in a dose of 5 micrograms given twice per week. Calcium carbonate was continued as a phosphate binder. Dialysate calcium concentration was 1.75 mmol/L (3.5 mEq/L). With this therapy, PTH levels decreased rapidly, and, after 4 to 6 weeks of therapy, reached values 60% lower than pretreatment values. Mean values for serum calcium did not change significantly (2.29 +/- 0.12 mmol/L [9.6 +/- 0.5 mg/dL] before treatment compared with 2.32 +/- 0.08 mmol/L [9.7 +/- 0.25 mg/dL] after therapy). Mean serum phosphorus was also unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Asbestos is a heterogeneous mineral fiber with considerable heat resistance and sound-abatement properties. It is relatively easily mined and processed and has been applied in a number of forms to ships and buildings. Unfortunately, respirable asbestos fibers have significant pathologic effects on the human lung and other organs. These effects can result in characteristic pleuropulmonary diseases, which become manifest after a latency period of 10 to 40 years from first exposure. This brief review will outline some major current controversies in the clinical approach to evaluation of asbestos-induced lung diseases.

In diabetic animals, there is a decrease in serum 1,25-dihydroxyvitamin D [1,25(OH)2D] and in renal production of 1,25(OH)2D. In nondiabetic animals, renal 1,25(OH)2D production is markedly stimulated by parathyroid hormone (PTH) and calcitonin (CT). There is evidence that diabetes impairs the responsiveness of the kidney to PTH. The effect of diabetes on responsiveness to CT is unknown. The studies reported here determined the effect of streptozotocin-induced diabetes on renal responsiveness to PTH and CT. Experiments were performed in 7- to 8-week-old rats that were fed a diet sufficient in calcium and vitamin D and were thyroparathyroidectomized (TPTX) 5 days before hormone treatment. PTH (0.33 U/g body weight at 24, 12, and 2 hours before death) significantly increased renal 1,25(OH)2D production by threefold in nondiabetic rats. This effect was markedly attenuated by diabetes. On the other hand, CT (20 U/100 g body weight at 12 and 2 hours before death) produced a maximal response in both groups of animals. In diabetic rats, CT stimulated renal 1,25(OH)2D production fivefold, whereas PTH stimulated production only 1.5-fold. Diabetes did not affect the capacity of PTH to increase serum calcium or decrease renal tubular reabsorption of phosphorus (TRP). These findings suggest that the decrease in renal 1,25(OH)2D production seen in experimental diabetes may be due to decreased renal responsiveness to PTH, but not to decreased responsiveness to CT.

Since androgens may increase the sensitivity of the erythroid progenitors to erythropoietin, the present studies were designed to investigate the effect of administration of androgens on the actions of exogenous erythropoietin (EPO) in hemodialysis patients. Studies were performed in a group of 15 adult male hemodialysis patients. Seven patients were treated with EPO alone at a dose of 2,000 U intravenously (IV) three times a week. An additional group of eight patients was treated with 2,000 U of EPO three times a week and also received 100 mg of nandrolone decanoate intramuscularly (IM) each week. After 12 weeks of therapy, hematocrit values increased slightly in the group receiving EPO alone, from 25.3 +/- 0.8 to 27.4 +/- 1.5. In contrast, EPO in combination with nandrolone decanoate resulted in a greater increase in hematocrit values, from 24.4 +/- 1.4 to 32.9 +/- 1.8 (P less than 0.001). The results show that the groups receiving low-dose EPO alone had a poor erythropoietic response. In contrast, patients receiving androgen in addition to EPO had a significantly greater increase in hematocrit values with treatment. Transfusions were eliminated in both groups of patients. These data show that androgen therapy significantly augments the action of exogenous EPO such that lower doses of EPO are sufficient for an adequate hematopoietic response.

Limited guidelines exist for rehabilitation programs for individuals with diabetes mellitus, blindness, and associated autonomic neuropathy. Abnormalities in autonomic function have been postulated to interfere with exercise conditioning and may predispose individuals to exercise-induced hypoglycemia. Twenty-nine individuals with diabetes mellitus underwent standardized noninvasive testing for the evaluation of cardiovascular autonomic function and graded exercise before entering a rehabilitation program. Inadequate responses of heart rate to respiratory variation were observed in 28 patients, abnormal heart rate responses to postural maneuvers were seen in 23, and postural hypotension was noted in nine. Individuals with symptomatic postural hypotension were able to exercise using a stationary bicycle, but developed hypotensive episodes on walking or prolonged standing. Blood glucose consistently decreased by a mean of 76 (+/- 9) mg/dl after each exercise session, even though low levels of exercise were performed (2.9 +/- 0.2 metabolic equivalents, for 28 +/- 1 min). There was no relationship between the degree of autonomic neuropathy and the level of blood glucose fall. There was, however, a significant correlation (r = -0.59, p = 0.001) between the decrease in blood glucose level and the amount of regular insulin used in the routine morning dose. Precautions were taken to avoid hypoglycemia, and insulin and diet were adjusted accordingly to prevent severe hypoglycemic reactions.