Clinical Evaluation of Practolol,a New Cardioselective Beta-blocking Agent in Angina Pectoris

In a controlled double-blind study practolol, a new cardioselective beta-blocking drug, was given to 15 patients with angina pectoris, and compared with propranolol 80 mg. q.d.s. The dose of practolol ranged from 200 to 600 mg.b.d. and was decided by initial open titration in individual patients. Though practolol did not influence the incidence of angina or glyceryl trinitrate consumption, it increased the duration of exercise possible in exercise tests and reduced the amount of ischaemic S—T depression in the radiocardiogram during exercise. Propranolol reduced the incidence of angina and, in the exercise tests, increased the amount and duration of exercise but did not affect the degree of S—T depression. Unlike propranolol, practolol did not produce any adverse effects on bronchial smooth muscle. Hence it is concluded that practolol is an effective drug in treating angina, and in the dosage used is of potential value in patients with asthmatic bronchitis and angina. It should, however, be used cautiously in anginal patients with heart failure.     

Regulation of RNA metabolism in relation to insulin production and oxidative metabolism in mouse pancreatic islets in vitro

This study was undertaken to investigate the long-term effects of different substrates, in particular glucose, on the regulation of islet RNA metabolism and the relationship of this regulation to the metabolism and insulin production of the islet B-cell. For this purpose collagenase-isolated mouse islets were used either in the fresh state or after culture for 2 or 5 days in RPMI 1640 plus 10% calf serum supplemented with various test compounds. Islets cultured with 16.7 mM glucose contained more RNA than those cultured with 3.3 mM glucose. Culture of islets in glucose at low concentrations inhibited glucose-stimulated RNA synthesis and this inhibitory effect was reversed by prolonged exposure to high glucose concentrations. Culture with 10 mM leucine and 3.3 mM glucose or with 10 mM 2-ketoisocaproate and 3.3 mM glucose increased the total RNA content of islets as compared to that of islets cultured with 3.3 mM glucose alone. Islets cultured with 5 mM theophylline maintained a high RNA content in the presence of 3.3 mM glucose. Theophylline also increased the islet RNA content when added together with 16.7 mM glucose, as compared to 16.7 mM glucose alone. Theophylline probably exerted this effect by decreasing the rate of RNA degradation. Changes in islet RNA metabolism showed a close correlation to changes in islet total protein biosynthesis, whereas islet (pro)insulin biosynthesis and insulin release exhibited different glucose-dependency patterns. The response of islet oxygen uptake to glucose was similar to that of islet RNA and protein biosynthesis. It is concluded that the RNA content of the pancreatic islets is controlled at the levels of both synthesis and degradation. Glucose stimulates the RNA synthesis and inhibits its degradation. Moreover, the results suggest that regulation of RNA synthesis may be mediated through islet metabolic fluxes and the cAMP system.     

A host of hypercholesterolaemic homozygotes in South Africa.

From 1972 to 1979 34 patients with homozygous familial hypercholesterolaemia were seen in one clinic in Johannesburg. All were Afrikaners and most lived in Transvaal Province. Their epidemiological, genetic, clinical, and biochemical characteristics were studied. The course of the disease varied considerably among the 34 patients, with no fewer than six surviving into their fourth or fifth decades. In some patients arterial atheroma was severe while cutaneotendinous xanthomas were slight and vice versa. Coronary heart disease was common but peripheral and cerebral arterial disease was rare. Another prominent finding was high concentrations of low-density lipoprotein cholesterol coupled with low high-density lipoprotein cholesterol values. The prevalences of homozygotes and heterozygotes with familial hypercholesterolaemia in Transvaal Afrikaners, calculated from this group of patients, were 1 in 30,000 and 1 in 100 respectively. These figures are the highest ever reported and may help to explain why South African whites have the highest death rate from coronary heart disease in the Western world.     

De novo inv del(4) in an infant with the Wolf-Hirschhorn syndrome

An infant was found to have a de novo complex rearrangement of one chromosome 4. Her karyotype was interpreted as 46,XX,inv del(4)(pter::p16.3::q31.2----p15.2::q31.2----qter). Clinically she showed the features of the Wolf-Hirschhorn syndrome.     

Isatin (indole-2,3-dione) in urine and tissues: Detection and determination by gas chromatography—mass spectrometry

A simple procedure based upon capillary column gas chromatography-mass spectrometry (GC—MS) is described for the detection and determination of isatin (indole-2,3-dione) in body fluids and tissues. After addition of 5-methylisatin as internal standard to urine or tissue homogenates, organic extracts are dried and derivatized successively with hydroxylamine hydrochloride and the reagent N-tert.-butyldimethylsilyl-N-methyltrifluoroacetamide (MTBSTFA). The tert.-butyldimethylsilyl derivatives obtained show good GC—MS properties and allow quantification by selected-ion monitoring of m/z 333 (isatin) and m/z 347 (internal standard). Adult and newborn human urine output values lie in the ranges 0.4–3.2 mg/mmol of creatinine (5–30 mg per 24 h) and 0.002–0.518 mg/mmol of creatinine, respectively. There is a discontinuous regional distribution in rat tissues. The GC—MS properties of a number of derivatives formed by successive reaction of isatin with hydroxylamine hydrochloride (or methoxyaminehydrochloride or ethoxyamine hydrochloride) and MTBSTFA, bis(trimethylsilyl)trifluoroacetamide, pentafluoropropionic anhydride or pentafluorobenzyl bromide are also described.     

Do emergency tests help in the management of acute medical admissions?

A two year combined retrospective and prospective study of 555 acute medical admissions to a district general hospital was carried out to assess the value of emergency biochemical, haematological, radiological, and electrocardiographic tests in diagnosis and treatment. For the study the tests were considered helpful only if they disclosed an abnormality and resulted in a definite diagnosis or change of treatment which would not have been possible from the history and examination alone. A total of 2372 emergency tests were carried out in the 555 patients who presented with 579 acute medical problems. Only 403 (17%) of the test results were abnormal and, of these, only one third helped in treatment and less than one third helped in diagnosis. The most useful diagnostic tests were serum amylase activity in abdominal pain, the electrocardiogram in chest pain, the chest radiograph in respiratory problems, and cerebrospinal fluid analysis in suspected meningitis or subarachnoid haemorrhage. The most useful tests in treatment were blood sugar value in diabetes, PCO2 in obstructive airways disease, and haemoglobin concentration in gastrointestinal haemorrhage. Of the tests requested by far the most often--blood urea and serum electrolyte concentrations--only 7% gave abnormal results and were rarely of any help in either diagnosis or treatment. Analysis of the reasons for the uncritical use of emergency tests by house officers suggested that better undergraduate training, regular audit by senior members of medical units, abolition of routine investigational procedures, and more selective laboratory reports would help to build up the house officer''s confidence in his own skills of history taking and physical examination without recourse to indiscriminate use of laboratory and other investigations.     

Telomere lengthening early in development

Stem cells and cancer cells maintain telomere length mostly through telomerase. Telomerase activity is high in male germ line and stem cells, but is low or absent in mature oocytes and cleavage stage embryos, and then high again in blastocysts. How early embryos reset telomere length remains poorly understood. Here, we show that oocytes actually have shorter telomeres than somatic cells, but their telomeres lengthen remarkably during early cleavage development. Moreover, parthenogenetically activated oocytes also lengthen their telomeres, thus the capacity to elongate telomeres must reside within oocytes themselves. Notably, telomeres also elongate in the early cleavage embryos of telomerase-null mice, demonstrating that telomerase is unlikely to be responsible for the abrupt lengthening of telomeres in these cells. Coincident with telomere lengthening, extensive telomere sister-chromatid exchange (T-SCE) and colocalization of the DNA recombination proteins Rad50 and TRF1 were observed in early cleavage embryos. Both T-SCE and DNA recombination proteins decrease in blastocyst stage embryos, whereas telomerase activity increases and telomeres elongate only slowly. We suggest that telomeres lengthen during the early cleavage cycles following fertilization through a recombination-based mechanism, and that from the blastocyst stage onwards, telomerase only maintains the telomere length established by this alternative mechanism.