Joseph B. Rosenfeld

Study on COgnition and Prognosis in the Elderly (SCOPE)

The Study on COgnition and Prognosis in the Elderly (SCOPE) is a multicentre, prospective, randomized, double-blind, parallel-group study designed to compare the effects of candesartan cilexetil and placebo in elderly patients with mild hypertension. The primary objective of the study is to assess the effect of candesartan cilexetil on major cardiovascular events. The secondary objectives of the study are to assess the effect of candesartan cilexetil on cognitive function and on total mortality, cardiovascular mortality, myocardial infarction, stroke, renal function, hospitalization, quality of life and health economics. Male and female patients aged between 70 and 89 years, with a sitting systolic blood pressure (SBP) of 160-179 mmHg and/or diastolic blood pressure (DBP) of 90-99 mmHg, and a Mini-Mental State Examination (MMSE) score of 24 or above, are eligible for the study. The overall target study population is 4000 patients, at least 1000 of whom are also to be assessed for quality of life and health economics data. After an open run-in period lasting 1-3 months, during which patients are assessed for eligibility and those who are already on antihypertensive therapy at enrolment are switched to hydrochlorothiazide 12.5 mg o.d., patients are randomized to receive either candesartan cilexetil 8 mg once daily (o.d.) or matching placebo o.d. At subsequent study visits, if SBP remains >160 mmHg, or has decreased by <10 mmHg since the randomization visit, or DBP is >85 mmHg, study treatment is doubled to candesartan cilexetil 16 mg o.d. or two placebo tablets o.d. Recruitment was completed in January 1999. At that time 4964 patients had been randomized. All randomized patients will be followed for an additional 2 years. If the event rate is lower than anticipated, the follow-up will be prolonged.

Syst-Eur. A multicentre trial on the treatment of isolated systolic hypertension in the elderly: Objectives, protocol, and organization

SummaryThe Syst-Eur Trial is a concerted action of the European Community’s Medical and Health Research Programme. The trial is carried out in consultation with the World Health Organization, the International Society of Hypertension, the European Society of Hypertension and the World Hypertension League. This article describes the objectives and the protocol of Syst-Eur, a multicentre trial designed by the European Working Party on High Blood. Pressure in the Elderly (EWPHE), to test the hypothesis that antihypertensive treatment of elderly patients with isolated systolic hypertension results in a significant change in stroke morbidity and mortality. Secondary endpoints include cardiovascular events, such as myocardial infarction and congestive heart failure.To be eligible patients must be at least 60 years old and have a systolic blood pressure averaging 160–219 mmHg with a diastolic pressure less than 95 mmHg. Patients must give their informed consent and be free of major cardiovascular and non-cardiovascular diseases at entry. The patients are randomized to active treatment or placebo. Active treatment consists of nitrendipine (10–40 mg/day), combined with enalapril (5–20 mg/day) and hydrochlorothiazide (12.5–25 mg/day), as necessary. The patients of the control group receive matching placebos. The drugs (or matching placebos) are stepwise titrated and combined in order to reduce systolic blood pressure by 20 mmHg at least to a level below 150 mmHg. Morbidity and mortality are monitored to enable an intention-to-treat and perprotocol comparison of the outcome in the 2 treatment groups.A one-year pilot trial (1989) showed that the protocol is practicable. The Ethics Committee therefore decided to start the definite study (1990), in which randomized patients will be followed for 5 years. Recruitment of new centres and of the required 3,000 patients will last 3 years (until 1993).

Ambulatory blood pressure monitoring in elderly patients with isolated systolic hypertension

Objectives: This study compared clinic and ambulatory blood pressure measurement and the reproducibility of these measurements in older patients with isolated systolic hypertension (ISH). Patients: Eighty-seven patients aged ≥60 years with ISH on clinic measurement were followed in the placebo run-in phase of the Syst-Eur trial. Methods: Clinic blood pressure was defined as the mean of two blood pressure readings on each of three clinic visits (six readings in total). Ambulatory blood pressure was measured over 24 h using non-invasive ambulatory blood pressure monitors. Results: Daytime ambulatory systolic pressure was, on average, 21 mmHg lower than the clinic blood pressure, whereas diastolic pressure was, on average, similar with both techniques of measurement. In the 42 patients who had repeat measurements, clinic blood pressure levels and the amplitude of the diurnal blood pressure profile (fitted by Fourier analysis) were equally reproducible. However, both were less reproducible than ambulatory blood pressure levels. The repeatability coefficients, expressed as per cent of near maximum variation (four times the standard deviation of a given measurement), were 52% and 45% for the clinic systolic and diastolic pressures, 56% and 42% for the amplitude of the diurnal profile, and 29% and 26% for mean 24-h pressures. Conclusions: In older patients with ISH, clinic and ambulatory systolic blood pressure measurements may differ largely: the prognostic significance of this difference remains to be elucidated. Furthermore, in these patients the level of pressure is more reproducible by daytime ambulatory blood pressure measurement than by clinic measurement.

Effect of aging on human plasma growth hormone response to clonidine.

The effect of the oral administration of 0.150 mg/m2 clonidine on the plasma level of human growth hormone (hGH) was studied in 53 adults (25 males and 28 females) aged from 28 to 68 years, of which 15 were healthy volunteers and 38 were hypertensive. Both the normal and hypertensive subjects of both sexes showed an age-related responsiveness of hGH to clonidine, with a normal or partial response in the younger subjects and blunting or lack of response in the more elderly subjects. In the females the blunting of the hGH response appeared at an earlier age than in the males. It is speculated that an alteration in the sensitivity of the central alpha-adrenergic receptors and a decrease in the sex steroid hormones may account for the progressive reduction in hGH secretion with advancing age.

Risk Factors for Development of Diabetic Nephropathy and Retinopathy in Jewish IDDM Patients

Risk factors associated with diabetic microvascular complications, with special reference to ethnic origin, were looked for in 231 young Jewish insulin-dependent diabetes mellitus (IDDM) patients with duration of diabetes ≥10 yr. Median age at diagnosis of diabetes was 9.2 yr (range 0.04–26.2 yr), and median duration of the disease was 15.3 yr (range 10.0–37.2 yr). Sixty-three percent of the patients were Ashkenazi Jews, and 37% were non-Ashkenazi Jews. HbA1 was evaluated every 3 mo in the last 10 yr of follow-up, and albumin excretion rate was tested in three 24-h urine collections. Direct and indirect ophthalmoscopy was performed every year since diagnosis of diabetes, and if retinal pathology was suspected, color photographs were taken. Microalbuminuria was detected in 31% and macroalbuminuria in 7% of the patients. Nonproliferative and proliferative retinopathy was found in 44 and 12% of the patients, respectively. On logistic regression analysis, two variables were significantly and independently associated with diabetic nephropathy—non-Ashkenazi origin and mean HbA1 values over the first 5 of 10 yr of follow-up. Variables significantly and independently related to diabetic retinopathy were non-Ashkenazi origin, mean HbA1 values over the last 10 yr of follow-up, and duration of diabetes. Because non-Ashkenazi Jews in Israel are of lower socioeconomic status than Ashkenazi Jews, we stratified our patients according to their socioeconomic parameters, median HbA1 values, and duration of diabetes. Non-Ashkenazi patients were at a higher risk to develop complications in all strata. We further stratified patients into four quartiles according to mean HbA1 values; there was a steep increase in the risk to develop macroalbuminuria in the 4th quartile of HbA1 (odds ratio [OR] 4.3 vs. 1.2 in the 3rd quartile) and proliferative retinopathy (OR 13.0 in the 4th quartile of HbA, vs. 2.8 in the 3rd quartile). We conclude that non-Ashkenazi Jewish IDDM patients are at significant risk to develop microvascular complications, independent of their glycemic control, duration of diabetes, and socioeconomic status. Careful follow-up and special efforts toward improving glycemic control should be focused on high-risk subgroups of patients.

Lymphoma presenting with adrenal insufficiency: Adrenal enlargement on computed tomographic scanning as a clue to diagnosis

A 73-year-old woman who presented with primary adrenal insufficiency and enlarged adrenal glands on computed tomographic scanning was ultimately found to have a large-cell lymphoma that had initially involved the adrenals and the stomach. A search of the English language medical literature revealed only seven other cases of lymphoma presenting with hypoadrenalism, none of which involved the stomach. As in this case, in most of those cases adrenal enlargement was documented on computed tomographic scanning. Despite its rare occurrence, lymphoma should be searched for in patients presenting with Addisons disease and enlarged adrenal glands.

Effect of Long-Term Allopurinol Administration on Serial GFR in Normotensive and Hypertensive Hyperuricemic Subjects

Acute experiments of uric acid infusion in animals and the clinical observation that in patients with gout there is an increased incidence of renal lesions, suggested that high levels of plasma uric acid may be detrimental to the kidney and cause a decrease in renal function. It is not known, however, whether hyperuricemia, not clinically associated with gout, causes kidney damage, nor is it known whether therapeutic reduction of serum uric acid levels slows the rate of the deterioration of renal function in such patients. To establish whether maintenance of normal plasma uric acid concentration in patients with hyperuricemia associated with various diseases has any effect on serial determination of GFR or slows the rate of kidney deterioration, this study was planned.

HYPERSENSITIVITY REACTION TO CHLORBUTOL-PRESERVED HEPARIN

Further blood cultures were taken. Gram-stained smears of the blood at 36 h showed scanty gram-negative (GN) rods, in four out of six bottles, which failed to grow on subculture. A generalised toxic erythematous rash compatible with penicillin hypersensitivity had also developed. Treatment was changed to cefuroxime I 5 g 8-hourly and amikacin 500 mg 8-hourly. Although the initial presumptive diagnosis was that this organism might be an aerobic opportunistic GN bacillus, the possibility that it could be an anaerobic GN rod was also considered, so GLC was done on 2 ml of blood from each of the blood culture bottles, from control uninoculated, and from inoculated blood culture bottles with no growth after 48 h using standard methods for the detection of short chain fatty acids.3 The chromatograms showed significant quantities of acetic, propionic, butyric, and succinic acids in the bottles in which GN rods had been seen, indicating the presence of anaerobic GN rods. The control bottles, apart from small amounts of acetic and lactic acid, were negative. IFA of smears from the positive blood culture bottles were tested with the pooled antisera of Bacteroides spp and anticapsular serum reported.2 There was positive fluorescence with both antisera identifying the organism as B. fragilis. Metronidazole was given intravenously (500 mg 8-hourly) for 24 h followed by metronidazole suppoositories 1 g twice daily which maintained serum levels of peak 26 4 and trough 24-3 3 mg/l. Amikacin was stopped. The dosages of cefuroxime and metronidazole were halved after 3 weeks. Therapy was continued for 6 weeks. The patient now made an uneventful recovery and was discharged after 7 weeks. In the rapid diagnosis of anaerobic infections, the use of GLC to detect short-chain fatty acids in specimens of pus is now well documented,l3-5 but its value in blood cultures is not yet well established,6,7 We previously reported the development and use of IFA in the rapid diagnosis of Bacteroicks infections,2 but IFA has not been applied to blood culture before. In this patient, using both techniques, the diagnosis was made within 2 h.

SEPTICÆMIA AND PULMONARY EMBOLISM COMPLICATING USE OF ARTERIOVENOUS FISTULA IN MAINTENANCE HÆMODIALYSIS

Abstract Seven cases of septicaemia in six patients with internal arteriovenous fistulae and undergoing maintenance haemodialysis are described. Two of these patients had pulmonary embolisms, the clinical picture being confirmed by serial chest X-rays. There was no connection between gross evidence of local infection and the development of septicaemia or pulmonary embolism. In contradistinction with the cases with external shunts, where septicaemia and pulmonary embolisms were treated by removal of the shunt, in cases with arteriovenous fistula, antibiotic treatment is usually sufficient, and only in one case was closure of the fistula required.

Angiotensin converting enzyme activity in the serum, lung and kidney of diabetic rats.

Abstract. Diabetes Mellitus in its early stages, is associated with kidney enlargement and increased glomerular filtration rate in humans and in rats. The present study was designed to clarify the direct effect of diabetes on serum and tissue angiotensin converting enzyme (ACE) activity in streptozotocin‐induced diabetic rats. Serum ACE activity, as determined using a radiometric assay, was significantly increased in the diabetic rats (n= 15) 14 days after induction of diabetes (670 ± 31 vs. 506±14 nmol ml‐1 min‐1). Lung ACE activity, but not renal, was significantly elevated at 7 and 14 days by 29 and 46%, respectively. Plasma renin activity in the diabetic rats was decreased at 7 and 14 days by 41 and 78%, respectively. Incubations of lung slices in the presence of glucose at different concentrations did not affect in‐vitro release of the enzyme. Administration of insulin (8 units kg‐1) to diabetic rats (n= 6) on the 4th day for 11 days reduced ACE activity to values below control. Thus, serum and lung ACE activity is increased in the diabetic rat and reduced upon insulin treatment.