Changing bone marrow micro-environment during development of acute myeloid leukaemia in rats

The high incidence of serious chest infections in patients with Parkinson's disease is unexplained, but an impairment in cough reflex may have a role. Maximal voluntary cough (MVC) and reflex cough (RC) to inhalation of ultrasonically nebulized distilled water were analyzed in patients with Parkinson's disease and age-matched control subjects by monitoring the integrated electromyographic activity (IEMG) of abdominal muscles. The peak amplitude of IEMG activity (IEMGP) was expressed as a fraction of the highest IEMGP value observed during MVC corrected to account for possible losses in abdominal muscle force due to reduced central muscle activation. Cough intensity was indexed in terms of both the IEMGP and the ratio of IEMGP to the duration of the expiratory ramp (TEC), i.e., the rate of rise of IEMG activity. Cough threshold was slightly higher in patients than in control subjects, but the difference failed to reach statistical significance. Compared with control subjects, patients displayed a lower IEMGP during maximal expiratory pressure maneuvers (PEmax), MVC, and RC (p always < 0.01); TEC during RC was longer (p < 0.01) than in controls. Consequently, the rate of rise of IEMG activity during cough was always lower in patients (p < 0. 01), especially during RC. Finally, PEmax, and both the peak and rate of rise of IEMG activity during RC were inversely related to the level of clinical disability (Spearman rank correlation coefficient, rs = -0.88, -0.86, and -0.85, respectively, p always < 0.01). The results indicate that the central neural mechanisms subserving the recruitment of motor units and/or the increase in their frequency of discharge during voluntary and, even more markedly, RC are impaired in patients with Parkinson's disease.     

Treatment of advanced breast cancer with sterically stabilized liposomal doxorubicin: results of a multicenter phase II trial

PURPOSE: A multicenter phase II study to determine the activity and toxicity of Caelyx (Doxil; Sequus Pharmaceuticals Inc, Menlo Park, CA) in patients with metastatic breast cancer. PATIENTS AND METHODS: Seventy-one patients with stage IV breast cancer were treated with Caelyx at doses of 45 to 60 mg/m2 every 3 to 4 weeks for a maximum of six cycles. Twenty-eight patients had received prior chemotherapy with a nonanthracycline regimen. Fifty-two patients had disease at multiple sites. Hepatic and pulmonary disease were the predominant metastatic site in 50 patients. Response was assessable in 64 cases. RESULTS: Sixteen patients achieved a partial response and a complete response (overall response rate, 31%; (95% confidence interval, 20% to 43%). Twenty patients (31%) had stable disease on treatment. Neutropenia > or = grade 3 occurred in 10% of cycles (27% of patients) and mucositis > or = grade 3 in 10% of cycles (32% of patients). Significant alopecia was rare and routine prophylactic antiemetics were not required. At doses of 60 mg/m2 every 3 weeks, seven of 13 patients had > or = grade 3 skin toxicity; overall, this toxicity complicated 25% of treatment cycles. The incidence of > or = grade 3 skin toxicity was greatly reduced at doses of 45 mg/m2 every 4 weeks, occurring in five of 32 patients and affecting only 5% of 126 treatment cycles. CONCLUSION: Caelyx is an active agent in advanced breast cancer with a safety profile that differs markedly from nonliposomal doxorubicin. A regimen of 45 mg/m2 every 4 weeks was well tolerated in this cohort of women with advanced poor-prognosis breast cancer. The mild myelosuppression seen with this regimen would favor its use in combination chemotherapy.     

Reinfection with Schistosoma japonicum after treatment with praziquantel in Poyang lake region, China

The study on reinfection with Schistosoma japonicum after treatment was carried out in a cohort of subjects in a heavy endemic village of Poyang lake region, China. After mass treatment with praziquantel in non-transmission time, detailed observations of water contact were estimated using the mean area of skin exposed daily. One year after treatment, the prevalence of infection in study subjects was 54.48%, returning to 83% of initial prevalence. The peak prevalence occurred the 11-15 year age class, but intensity of exposure also varies with age and that age group supporting the higher prevalence of reinfection had high levels of exposure. Among groups of subjects with a similar exposure stratum, young subjects under the age of 21 years were more heavily reinfected, while no heavy reinfection was observed in adults (> or = 25 years). These observations suggest that subjects in this area slowly acquire an increasing degree of immunity to lighten the intensity of infection with S. japonicum.     

Bone density and skeletal metabolism in patients with orthotopic ileal neobladder

The interposition of a bowel segment as a bladder substitute into the urinary tract may result in impaired calcium metabolism. We studied 25 male patients (aged 45 to 77 yr) who had undergone a Vescica Ileale Padovana (VIP) reconstruction following cystectomy 29 to 75 mo before. Bone mineral density of the spine and femur was measured by dual x-ray absorptiometry. Blood and 24-h urine samples were analyzed for the main parameters of bone metabolism. Sixteen healthy men were enrolled as a control group. Although blood pH did not differ between patients and control subjects, VIP subjects showed lower levels of plasma HCO3- (P < 0.005) and higher serum chloride (P < 0.001). Bone alkaline phosphatase was higher (P < 0.001), and urine calcium, phosphate, and creatinine levels were lower in VIP patients (P < 0.01, P < 0.01, and P < 0.05, respectively). Bone mineral density at the femoral neck (P < 0.03) and Ward's triangle (P < 0.05) was decreased in VIP patients. When subdivided according to time since operation, patients who had the ileal neobladder implanted for a shorter period of time showed lower blood pH (P < 0.03) and urine calcium (P < 0.05) levels and higher urinary hydroxyproline (P < 0.02). Duration of the ileal neobladder was positively correlated with PTH (r = 0.46, P < 0.03) and blood pH (r = 0.47, P < 0.02). Furthermore, pH values were positively correlated with urine calcium (r = 0.48, P < 0.02). In conclusion, in patients with ileal neobladder, a mild metabolic acidosis is responsible for an increased bone turnover and lower bone mass. Moreover, a decrease over time in the absorption capacity of the ileal pouch might result in calcium malabsorption, which represents an additional risk factor for reduced bone mass in these patients.     

Complex demodulation of cardiorespiratory dynamics preceding vasovagal syncope

BACKGROUND: The dynamic autonomic processes leading to vasovagal syncope are poorly understood. METHODS AND RESULTS: We used complex demodulation to continuously assess changes in respiration, R-R interval, and arterial pressure (blood pressure) variability during 60 degree head-up tilt in 25 healthy subjects with tilt-induced vasovagal syncope and 25 age-matched nonsyncopal control subjects. Coherence and transfer function analyses were used to examine the relation between respiration and R-R interval variability before syncope. Baseline blood pressure, R-R, and ventilation were similar between syncope subjects and control subjects. Syncope subjects experienced an increase in tidal volume and decrease in BP beginning 3 minutes before impending syncope (systolic blood pressure <80 mm Hg) necessitated termination of tilt. Approximately 90 seconds before syncope there was a sudden prolongation of R-R interval and increase in amplitude of high and low frequency R-R interval variability, indicating an abrupt enhancement of vagal tone. The increase in respiratory amplitude between 180 and 90 seconds before syncope was not accompanied by changes in R-R interval or R-R variability, suggesting a dissociation between respiration and the respiratory sinus arrhythmia. The coherence analysis showed fewer syncope subjects with coherence between respiratory and R-R interval variabilities and lower transfer magnitudes in syncope subjects compared with control subjects. Nonsyncopal subjects had no change in respiratory, R-R interval, or blood pressure dynamics during matched time periods before the time of syncope. CONCLUSIONS: Vasovagal syncope is preceded by a period of hyperpnea and cardiorespiratory decoupling followed by an abrupt increase in cardiovagal tone. Respiratory pumping without inspiratory cardiac slowing may partially counteract preload reduction until sudden bradycardia precipitates syncope.     

Metabolic bone disease of total parenteral nutrition

We compared the clinical course of pediatric patients (n = 25) with acetaminophen poisoning treated with an investigational intravenous preparation of N-acetylcysteine (IV-NAC) with that of historical control subjects (n = 29) treated with conventional oral NAC (O-NAC) therapy. Patients received IV-NAC for 52 hours; historical control subjects received O-NAC (72 hours). There were no significant intergroup differences between treatment groups in age (15.5 vs 15.9 years), gender (88% vs 90% female) or distribution of risk categories (probable risk, 12 vs 15; high risk; 13 vs 14). The peak prothrombin time was significantly higher in the IV-NAC group (14.2 vs 13.6 seconds; p = 0.048). Mean treatment delay was significantly longer in the IV-NAC group (14.4 vs 10.4 hours; p = 0.001). Hepatoxicity was noted in two (8.0%) patients in the IV-NAC treatment group and two (6.9%) patients in the O-NAC group. All patients recovered. Our results indicate that 52 hours of intravenous NAC is as effective as 72 hours of oral NAC.     

Diagnostic value of postexercise systolic blood pressure response for detecting coronary artery disease in patients with or without hypertension

To evaluate the diagnostic value of the postexercise systolic blood pressure (SBP) response for detecting and evaluating the presence of coronary artery disease (CAD), treadmill testing was conducted in 130 subjects with normal blood pressure and 51 patients with hypertension, each of whom underwent selective coronary angiography. A total of 48 subjects with normal blood pressure and 27 patients with hypertension had no significant narrowing of the coronary artery (control subjects), whereas 82 subjects with normal blood pressure and 24 patients with hypertension had significant narrowing (patients with CAD). The postexercise SBP response was defined on the basis of the SBP ratio (i.e., the SBP at 3 minutes of recovery divided by that at peak exercise). An SBP ratio that exceeded 0.90 (cutoff point for discriminating control subjects from patients with CAD) was considered to be an abnormal SBP response. In the subjects with normal blood pressure, the abnormal SBP response identified CAD as accurately as did ST-segment depression. In the patients with hypertension, the diagnostic accuracy was increased significantly by combining the abnormal SBP response and ST-segment depression (p < 0.01). The SBP ratio increased with the number of diseased coronary arteries. Ten of the 14 patients with a narrowing of the left main coronary artery had an SBP ratio higher than 1.00. The postexercise SBP response may be useful for detecting CAD in patients with and without hypertension and for evaluating the severity of CAD.     

Glucose infusion partially attenuates glucose production and increases uptake during intense exercise

Glucose infusion can prevent the increase in glucose production (Ra) and increase glucose uptake (Rd) during exercise of moderate intensity. We postulated that 1) because in postabsorptive intense exercise (>80% maximal O2 uptake) the eightfold increase in Ra may be mediated by catecholamines rather than by glucagon and insulin, exogenous glucose infusion would not prevent the Ra increment, and 2) such infusion would cause greater Rd. Fit young men were exercised at >85% maximal O2 uptake for 14 min in the postabsorptive state [controls (Con), n = 12] or at minute 210 of a 285-min glucose infusion. In seven subjects, the infusion was constant (CI; 4 mg . kg-1 . min-1), and in seven subjects it was varied (VI) to mimic the exercise Ra response in Con. Although glucose suppressed Ra to zero (with glycemia approximately 6 mM and insulin approximately 150 pM), an endogenous Ra response to exercise occurred, to peak increments two-thirds those in Con, in both CI and VI. Glucagon was unchanged, and very small increases in the glucagon-to-insulin ratio occurred in all three groups. Catecholamine responses were similar in all three groups, and correlation coefficients of Ra with plasma norepinephrine and epinephrine were significant in all. In all CI and VI, Rd at rest was 2x Con, increased earlier in exercise, and was higher for the 1 h of recovery with glucose infusion. Thus the Ra response was only partly attenuated, and the catecholamines are likely to be the regulators. This suggests that an acute endogenous Ra rise is possible even in the postprandial state. Furthermore, the fact that more circulating glucose is used by muscle during exercise and early recovery suggests that muscle glycogen is spared.     

Muscle oxygenation kinetics measured by near-infrared spectroscopy during recovery from exercise in chronic heart failure

The aim of the present study was to determine the kinetics of recovery of muscle oxygenation (MO) from comparable levels of exercise in chronic heart failure (CHF) patients and normal subjects and to relate MO kinetics to the level of exercise intolerance. The rationale is based on the observation that the O2 debt is increased in patients with heart failure and repayment of the debt is relatively slow. Ten patients with stable CHF (mean age 47 +/- 10 years) and nine healthy control subjects (47 +/- 6 years) were studied. All patients had ischemic cardiomyopathy (ejection fraction 33 +/- 7%). On different days, all subjects performed an upright incremental cycle ergometer exercise test with gas-exchange analysis to determine peak VO2, and a 6-minute constant work-rate (CWR) protocol at 60% of peak VO2. Oxygenation of the vastus lateralis muscle was continuously monitored during exercise and recovery using near-infrared spectroscopy (NIRS). Both MO and VO2 responses to recovery were described by a monoexponential model with a time delay. The time constant and time delay were combined to calculate a mean response time (MRT). Recovery VO2 and MO MRTs for the incremental and constant work rate exercise test were longer in CHF patients than in control subjects (p < 0.05). Both VO2 and MO MRTs were inversely related to peak VO2 (r = -0.73 and -0.52, respectively; p < 0.05 for both). However, both kinetics were not significantly different within each group between the two exercise intensities. In conclusion, the greater the cardiac dysfunction, as assessed by peak VO2, the more the recovery of muscle and total body oxygenation from both maximal and submaximal exercise is delayed.     

Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension

BACKGROUND: Patients with essential hypertension have abnormal endothelium-dependent vasodilation. Because the endothelium exerts its action on the vascular smooth muscle through the release of several substances, it is important to identify which of these factors is involved in the abnormal response of hypertensive arteries. METHODS AND RESULTS: To investigate the role of endothelium-derived nitric oxide in this abnormality, we studied the vascular effect of the arginine analogue NG-monomethyl-L-arginine, an inhibitor of the endothelial synthesis of nitric oxide, under baseline conditions and during infusion of acetylcholine, an endothelium-dependent vasodilator, and sodium nitroprusside, a direct smooth muscle dilator. The study included 11 hypertensive patients (seven men; age, 46.5 +/- 9 years) and 10 normal control subjects (seven men; age, 45.7 +/- 7 years). Drugs were infused into the brachial artery, and the response of the forearm vasculature was measured by strain-gauge plethysmography. Basal blood flow was similar in normal control subjects and hypertensive patients (2.97 +/- 0.7 versus 2.86 +/- 1.1 mL.min-1.100 mL-1, respectively). NG-monomethyl-L-arginine produced a significantly greater decrease in blood flow in control subjects than in patients (1.08 +/- 0.6 versus 0.32 +/- 0.4 mL.min-1.100 mL-1; p < 0.004). The vasodilator response to acetylcholine was reduced in patients compared with control subjects (maximum flow, 8.2 +/- 4 versus 16.4 +/- 8 mL.min-1.100 mL-1; p < 0.001). NG-monomethyl-L-arginine blunted the vasodilator response to acetylcholine in control subjects (maximum flow decreased from 16.4 +/- 8 to 7.01 +/- 3 mL.min-1.100 mL-1; p < 0.004); however, the arginine analogue did not significantly alter the response to acetylcholine in hypertensive patients (maximum flow, 8.2 +/- 4 versus 8.01 +/- 5 mL.min-1.100 mL-1). NG-monomethyl-L-arginine did not modify the vasodilator response to sodium nitroprusside in either control subjects or patients. CONCLUSIONS: These findings indicate that patients with essential hypertension have a defect in the endothelium-derived nitric oxide system that may at least partly account for both the increased vascular resistance under basal conditions and the impaired response to endothelium-dependent vasodilators.     

Morpho-functional study of the kidney in patients with kidney disease and liver disease with magnetic resonance

INTRODUCTION: We studied renal function and perfusion after the i.v. injection of Gd-DTPA-BMA, a nonionic paramagnetic contrast agent, to assess renal morphology and function in normal subjects, in renal insufficiency patients and in patients with hepatic failure and normal renal function. The latter were chosen because some patients with advanced hepatic failure may suffer from the hepatorenal syndrome, characterized by severe vasoconstriction in the renal cortical vessels. We investigated if dynamic MRI can detect early renal perfusion abnormalities in the patients who will eventually develop this syndrome. MATERIAL AND METHODS: Thirty MR examinations were carried out on 30 subjects after the i.v. injection of Gd-DTPA-BMA. Our series consisted of: 10 normal subjects; 10 renal insufficiency patients; 10 patients with hepatic failure and normal renal function. MR examinations were performed on a Philips ACS II scanner operating at 1.5 T. Two sequences were carried out in all cases: T1-weighted SE and T1-weighted TGE sequences after the bolus injection of .1 mmol/kg contrast agent. Renal longitudinal diameter and parenchymal thickness were measured in all cases and signal intensity time curves were always made. The signal intensity of the cortex, corticomedullary junction, medulla and pyelocaliceal system of each kidney was measured using a region of interest (ROI). The signal intensity curves were made considering quantitative parameters, including the area below the curve (ASC), the peak (P) and the time to peak (T-P). RESULTS: Longitudinal diameter and parenchymal thickness values were significantly lower in renal insufficiency patients than in normal subjects. Four phases were demonstrated after i.v. contrast agent injection in normal subjects, namely A) the cortical phase, B) the corticomedullary junction phase, C) the medullary phase, D) the pyelocaliceal phase. No signal intensity decrease in the medullary and pyelocaliceal curves was observed in renal insufficiency patients. Signal intensity curves values were lower in hepatic failure patients than in those with normal renal function. Hepatic failure patients could be divided into two groups: 5 patients had low P and ASC values and 4 had normal P and ASC values. The patients with lower P and ASC values developed the hepatorenal syndrome within a few months of the MR examination. DISCUSSION: Signal intensity decreased in the pyelocaliceal system phase in normal subjects because of the high paramagnetic contrast agent concentration. The lack of signal intensity decrease in renal insufficiency patients was caused by the reduced capability of concentrating Gd-DTPA-BMA. Lower signal intensity values in hepatic failure patients may be considered an early sign of the hepatorenal syndrome.     

Endothelium-dependent dilatation is impaired in young healthy subjects with a family history of premature coronary disease

BACKGROUND: A family history of premature coronary artery disease (CAD) in a first-degree relative is an independent risk factor for coronary disease. Both genetic and environmental influences are likely to be responsible and may interact, but their relative importance is unclear. METHODS AND RESULTS: We studied endothelial function in 50 first-degree relatives (31 men, 19 women; mean age, 25+/-8 years) of patients (men < or = 45 years, women < or = 55 years) with proven CAD. All subjects were well, lifelong nonsmokers, not diabetic, and not hypertensive and took no medications. Using high-resolution external vascular ultrasound, we measured brachial artery diameter at rest and in response to reactive hyperemia (with increased flow causing an endothelium-dependent vasodilatation) and to sublingual glyceryltrinitrate (GTN, an endothelium-independent dilator). Vascular responses were compared with those of 50 healthy control subjects matched for age and sex. Flow-mediated dilatation (FMD) was impaired in the family history group (4.9+/-4.6% versus 8.3+/-3.5% in control subjects, P<.005). In contrast, GTN caused dilatation in all subjects (family history, 17.1+/-8.8%; control subjects, 19.0+/-6.3%; P=NS), suggesting that reduced FMD was due to endothelial dysfunction. When the family history subjects were subdivided, those found to have a serum cholesterol > 4.2 mmol/L (group A, n=10) had mildly impaired FMD compared with control subjects (5.5+/-5.1% versus 8.3+/-3.5%). In others whose affected relative had coronary risk factors (group B, n=24), FMD was also only slightly reduced (6.2+/-4.8% versus 8.3+/-3.5%). In contrast, subjects with no risk factors and whose affected relative had a normal cardiovascular risk factor profile (group C, n=16) had markedly impaired FMD (2.9+/-3.7% versus 8.3+/-3.5%). Although ANOVA of the three family history subgroups did not reach statistical significance (F=2.55, P=.09), pairwise analysis showed that FMD in group C was significantly impaired compared with group B (P=.026). CONCLUSIONS: Healthy young adults with a family history of premature coronary disease may have impaired endothelium-dependent dilatation, even in the absence of other cardiovascular risk factors. Those subjects, who were free of risk factors and whose affected first-degree relative was free of risk factors, had the most impaired endothelial function, suggesting a genetic influence on early arterial physiology that may be relevant to later clinical disease.     

Effect of physical training on exercise-induced hyperkalemia in chronic heart failure. Relation with ventilation and catecholamines

BACKGROUND: The exercise-induced rise in arterial potassium concentration ([K+]a) may contribute to exercise hyperpnea and could play a role in exertional fatigue. This study was designed to determine whether the exercise-induced rise in [K+]a is altered in patients with chronic heart failure (CHF) and whether physical training affects K+ homeostasis. METHODS AND RESULTS: We evaluated 10 subjects with CHF (ejection fraction, 23 +/- 3.9%) and 10 subjects with normal left ventricular function (NLVF) who had undergone previous coronary artery graft surgery (ejection fraction, 63 +/- 8.6%). Subjects performed an incremental cycle ergometer exercise test before and after a physical training or detraining program. Changes in [K+]a and ventilation (VE) during exercise were closely related in both groups. Subjects with CHF did less absolute work and had reduced maximal oxygen consumption (VO2max) compared with subjects with NLVF (P < .01). Exercise-induced rises in [K+]a, VE, norepinephrine, lactate, and heart rate were greater at matched absolute work rates in subjects with CHF than in subjects with NLVF (P < .01). However, when the rise in [K+]a was plotted against percentage of VO2max to match for relative submaximal effort, there were no differences between the two groups. Physical training resulted in reduced exercise-induced hyperkalemia at matched submaximal work rates in both groups (P < .01) despite no associated change in the concentration of arterial catecholamines. At maximal exercise when trained, peak increases in [K+]a were unaltered, but peak concentrations of catecholamines were raised (P < .05). The decrease in VE at submaximal work rates after training was not significant with this incremental exercise protocol, but both groups had an increased peak VE when trained (P < .01). CONCLUSIONS: Exercise-induced rises in [K+]a, catecholamines, and VE are greater at submaximal work rates in subjects with CHF than in subjects with NLVF. Physical training reduces the exercise-induced rise in [K+]a but does not significantly decrease VE during submaximal exercise with this incremental cycle ergometry protocol. The reduction in exercise-induced hyperkalemia after training is not the result of altered concentrations of arterial catecholamines. The pathophysiological significance of the increased exercise-induced hyperkalemia in CHF and the mechanisms of improved K+ homeostasis with training have yet to be established.     

Effect of acute pharmacological reduction of plasma free fatty acids on growth hormone (GH) releasing hormone-induced GH secretion in obese adults with and without hypopituitarism

In obesity, there is a markedly decreased GH secretion. The diagnosis of GH deficiency (GHD) in adults is based on peak GH responses to stimulation tests. In the severely obese, peak GH levels after pharmacological stimulation are often in the range that is observed in hypopituitary patients. To distinguish obese subjects from GHD patients, it will be necessary to demonstrate that reduced GH responsiveness to a given test is reversible in the former, but not in the latter, group. Recent studies have shown that reduction of plasma free fatty acids (FFA) with acipimox in obese patients restores their somatotrope responsiveness. There are no data evaluating GH responsiveness to acipimox plus GHRH in obese adults with hypopituitarism. The aim of the present study was to evaluate the effect of acute pharmacological reduction of plasma FFA on GHRH-mediated GH secretion in obese normal subjects and obese adults with hypopituitarism. Eight obese patients with a body mass index of 34.2+/-1.2; eight obese adults with hypopituitarism, with a body mass index of 35.5+/-1.9; and six control subjects were studied. All the patients showed an impaired response to an insulin-tolerance test (0.15 U/kg, i.v.), with a peak GH secretion of less than 3 microg/L. Two tests were carried out. On one day, they were given GHRH (100 microg, i.v., 0 min), preceded by placebo; and blood samples were taken every 15 min for 60 min. On the second day, they were given GHRH (100 microg, i.v., 0 min), preceded by acipimox (250 mg, orally, at -270 min and -60 min); and blood samples were taken every 15 min for 60 min. The administration of acipimox induced a FFA reduction during the entire test. Normal control subjects had a mean peak (microg/L) of 23.8+/-4.8 after GHRH-induced GH secretion; previous acipimox administration increased GHRH-induced GH secretion, with a mean peak of 54.7+/-14.5. In obese patients, GHRH-induced GH secretion was markedly reduced, with a mean peak (microg/L) of 3.9+/-1; previous administration of acipimox markedly increased GHRH-mediated GH secretion, with a mean peak of 16.0+/-3.2 (P < 0.05). In obese adults with hypopituitarism, GHRH-induced GH secretion was markedly reduced, with a mean peak (microg/L) of 2+/-0.7; previous acipimox administration did not significantly modify GHRH-mediated GH secretion, with a mean peak of 3.3+/-1.1 (P < 0.05). The GH response of obese patients and obese adults with hypopituitarism was similar after GHRH alone. In contrast, the GH response after GHRH plus acipimox, was markedly decreased in obese adults with hypopituitarism (mean peak, 3.3+/-1.1), compared with obese patients (mean peak, 16.0+/-3.2) (P < 0.05) and control subjects (mean peak, 54.7+/-14.5) (P < 0.01). In conclusion, GH secretion, after GHRH-plus-acipimox administration, is reduced in obese adults with hypopituitarism patients, when compared with obese normal patients. Testing with GHRH plus acipimox is safe and is free from side effects and could be used for the diagnosis of GHD in adults.     

Multiple metachronous metastasis of adenocarcinoma of the kidneys in crossed ectopy with fusion

OBJECTIVE: Hyperandrogenism in patients with polycystic ovary syndrome has been shown to correlate with hyperinsulinaemia of insulin resistance. We have investigated if basal levels of insulin and the response to the intravenous administration of glucagon can reveal insulin resistance in patients with polycystic ovary syndrome. PATIENTS: Nine obese (BMI > 25 kg/m2) and nine non-obese (BMI 19-25 kg/m2) women with PCOS, chosen from a population of 91 women attending the infertility clinic, and 19 normally cycling women (seven obese, 12 non-obese) were studied. Oligo or amenorrhoea, hirsutism, and 12 or more follicles in a given ovary were selection criteria. MEASUREMENTS: Glucagon, 1 mg, was given intravenously to 18 of the 91 women and to the control subjects. Blood was taken at -5, 0, 5, 10 and 15 minutes for measurements of integrated areas under the response curve for insulin, C-peptide and glucose, respectively. Basal blood samples were drawn for fasting insulin, C-peptide, glucose, testosterone, sex hormone-binding globulin (SHBG), free fatty acids and IGF-I measurements. The free androgen index was calculated according to the formula FAI = testosterone x 100/SHBG. RESULTS: There were no significant differences in maximal increment and area under the response curve for glucose, C-peptide and insulin. FAI was significantly higher in all patients with features of polycystic ovary syndrome. However, fasting insulin levels were significantly higher only in obese patients when compared with obese control subjects and lean patients. CONCLUSIONS: The administration of 1 mg glucagon i.v. did not distinguish patients with polycystic ovary syndrome from control subjects. The mild insulin resistance of polycystic ovary syndrome is related only to obesity and is therefore unlikely to play an important role in the hyperandrogenism associated with the syndrome.     

Enhanced insulin response to oral glucose load in patients with angina pectoris associated with ST segment elevation in the absence of epicardial coronary arterial obstruction

The authors treated 10 patients with microvascular angina (MVA) manifesting angina pectoris, ST segment elevation suggestive of transmural myocardial ischemia, and no epicardial arterial obstruction. Since such patients frequently showed abnormal responses to oral glucose loading, the authors investigated the glucose and insulin responses to glucose loading in 10 MVA patients, 25 patients with vasospastic angina (VAP), 25 patients with effort angina (EAP), and 25 control subjects. Insulinogenic index, peripheral insulin activity [= 10(4)/(peak glucose x insulin at glucose peak)], glucose area, and insulin area were calculated. The MVA group included two patients with impaired glucose tolerance and two newly diagnosed diabetic patients. These proportions were similar to those in the VAP and EAP groups. Glucose levels at 30 to 180 min and insulin levels at 90 to 120 min in the MVA group were higher than in the control group. Peak glucose, glucose area, peak insulin, and insulin area were higher in the MVA group than in the control group (p<0.01). Those in the VAP and EAP groups were also higher. Insulin/glucose ratio at 120 min was higher, peripheral insulin activity, lower, in the disease groups than in the control group (p<0.05). The MVA patients showed a hyperglycemic and hyperinsulinemic response to oral glucose loading, as did the patients with EAP and VAP. Enhanced insulin response to oral glucose loading may also contribute to the pathogenesis of MVA.     

Physician-guided treatment compared with a heparin protocol for deep vein thrombosis

BACKGROUND: Effective heparin therapy, defined by therapeutic prolongation of the activated partial thromboplastin time (APTT), decreases the risk of recurrent venous thromboembolism. Achieving therapeutic prolongation of the APTT within 24 hours of the start of heparin therapy has proved difficult. We hypothesized that a protocol that delivered high initial heparin infusions to patients without identifiable risk for bleeding complications would decrease the time to achieve a therapeutic anticoagulant effect without increasing the incidence of major bleeding complications. METHODS: To test this hypothesis, we studied concurrent patient cohorts. We defined a therapeutic anticoagulant effect (APTT > 55 seconds) to be an APTT more than 1.5 times the upper limit of normal. Twenty patients with acute symptomatic deep vein thrombosis received a 5000-U heparin bolus, followed by 1680 U/h (low risk to bleed) or 1240 U/h (high risk to bleed), adjusted by protocol-directed response to APTT results. Forty-eight patients with deep vein thrombosis were treated by their physicians. The Kaplan-Meier method was used to examine the proportion of patients who achieved an APTT greater than 55 seconds as a function of time. RESULTS: The two study cohorts did not differ with respect to age, weight, or risk factors for venous thromboembolism. Analysis of Kaplan-Meier curves showed that the heparin protocol decreased the time to achieve a therapeutic anticoagulant effect (P = .025). Ten (91%) of 11 patients (95% confidence interval, 59% to 100%) without risks to bleed who were treated by the heparin protocol and 29 (60%) of 48 patients (95% confidence interval, 45% to 74%) not treated by the protocol had an initial therapeutic APTT (P = .006). CONCLUSION: A protocol that delivers higher initial heparin infusions to patients without identifiable risks for bleeding decreases the time needed to achieve therapeutic prolongation of APTT, when compared with nonprotocol physician management.     

Effectiveness of three different doses of carvedilol for exertional angina. Carvedilol-Angina Study Group

Carvedilol is a nonselective beta-receptor antagonist with vasodilating properties primarily due to selective alpha-1 antagonism. This 4-treatment, 5-period, double-blind, crossover study evaluated the efficacy and safety of 3 doses of carvedilol (12.5, 25, and 50 mg given twice daily) versus placebo in 122 patients with chronic stable angina. Carvedilol in doses of 25 mg twice daily and 50 mg twice daily was statistically superior to placebo with respect to time to angina (placebo: 316 seconds; 25 mg carvedilol: 337 seconds, p = 0.0039; 50 mg: 345 seconds, p <0.0001) and time to 1-mm ST-segment depression (placebo: 301 seconds; 25 mg: 313 seconds; 50 mg: 323 seconds; p <0.0001). The percentage of patients reporting any adverse experience was slightly less in those receiving placebo (placebo: 28.4%; 12.5 mg: 33.1%; 25 mg: 34.5%; 50 mg: 31.9%). Carvedilol is effective and safe in treating patients with chronic stable angina.     

Magnetic stimulation of the brain in generalized epilepsy: reversal of cortical hyperexcitability by anticonvulsants

Observations on experimental models suggest that diffuse cortical hyperexcitability is an important abnormality in the generalized epilepsies. We used the threshold for transcranial magnetic stimulation as an index of motor cortical excitability in 89 neurologically normal control subjects and 56 patients with idiopathic generalized epilepsy (20 untreated and 36 chronically treated with anticonvulsants). Magnetic stimulation was repeated in 10 patients after valproate monotherapy had been commenced and in 23 control subjects. The threshold intensity was significantly lower in the untreated patients (46 +/- 5% [mean +/- 95% confidence interval]) than in the control subjects (56 +/- 2%). Treated patients had significantly higher thresholds (64 +/- 4%) than did untreated patients and control subjects. A significant increase in threshold intensity (8 +/- 2%) occurred in patients retested after starting valproate; there was no significant change in retested control subjects (-1 +/- 2%). Threshold intensity was positively correlated with plasma valproate levels (rs = 0.37). The findings suggest that cortical excitability is increased in idiopathic generalized epilepsy and is reduced following anticonvulsant treatment. Transcranial magnetic stimulation is of use in examining the pathophysiology of generalized epilepsy. Furthermore, changes in threshold intensity in response to anticonvulsant treatment may prove useful in guiding therapy.     

Clinical significance of CD45RO expression on peripheral blood mononuclear cells in HTLV-I-infected individuals

The phenotype of peripheral blood mononuclear cells (PBMC) was examined in 13 healthy volunteers, 26 HTLV-I carriers, and 58 ATL patients (22 smouldering, five chronic, 24 acute, and seven lymphoma type). The percentage of CD4+, CD25+, CD28+ and CD45RO+ cells in the PBMC of the chronic and acute type patients was significantly higher than that of the volunteers, whereas the percentage of CD8+ and CD45RA+ cells in these patients was significantly low. The histogram for CD45RO fluorescence intensity (FI) revealed two patterns: pattern A consisted of CD45RO+ cells with high FI (CD45ROhigh) and intermediate FI (CD45ROint). Pattern B consisted exclusively of CD45ROhigh. Pattern A was evident in all volunteers. The percentage of subjects showing pattern B was increased in an order that reflected disease progression. In the patients with pattern A, the CD45ROint cells were CD4+ and CD8-, and the FI of CD2, CD3, and Fas within the CD45ROint cells appeared to be lower than that within the CD45ROhigh cells. The acute type patients with pattern A had a significantly longer survival curve than that of these patients with pattern B. These results suggest that the presence of CD45ROint cells may be related to protection against disease progression in HTLV-I-infected individuals.