Characterization and levels of the RNA polymerases during the embryogenesis of Artemia salina. Dormant embryos at the gastrula stage of Artemia salina contain three DNA-dependent RNA polymerases: I, II, and III. The enzymes are solubilized from whole embryos and they are separated by chromatography on DEAE Sephadex. The ratio of activities with native and denatured DNA at the optimal salt concentrations is 3.5 for RNA polymerase I, 0.1 for RNA polymerase II and 1.0 for RNA polymerase III.Mn(i2+) is more efficient than Mg(2+) for the three enzymes. RNA polymerase II is 50% inhibited by 5 ng/ml of alpha-amanitin while RNA polymerases I and III are 10% and 30% inhibited by 1 mg/ml. During the embryonic development there is am independent variation of the levels of the RNA polymerases. RNA polymerase I increases its specific activity 4-5-fold, RNA polymerase III increases 2-fold, and RNA polymerase II less than 2-fold. The increase in RNA polymerase activity may represent a mechanism to control the rate of synthesis of RNA during the embryogenesis of A. salina.


Identification of lead-binding components in rat liver: in vivo study. In vivo experiments using 203Pb and radioactively labelled precursors such as [14C] arginine and [3H] tryptophan were performed to identify lead binding components in rat liver. The distribution of lead in 9 tissues and the intracellular distribution in liver and kidney was also investigated. Male rats were injected intravenously with 18 mug of 203Pb/rat and the 203Pb radioactivity was measured in whole tissues as well as in nuclei, mitochondria, lysosomes, microsomes and soluble fractions obtained by centrifugation of liver and kidney homogenates. The subcellular fractions from liver were purified and fractionated into macromolecular components by ultracentrifugation, gel filtration, ion exchange chromatography and solvent extraction. Nuclei were fractionated into membranes, chromatin proteins (histone and residual non-histone proteins) and DNA. Most of the lead was detected in the nuclear membrane fraction bound exclusively to membrane proteins and absent in phospholipids. The intranuclear lead was associated with histone fractions and other basic or very weakly acid proteins as indicated by the incorporation of [14C] arginine and [3H] tryptophan. Lead was present in the chromatographically purified DNA fraction but whether lead was really bound to the nucleic acid was not determined. Mitochondria were fractionated into heavy, soluble and light subfractions representing the inner membranes, the intramitochondrial matrix and the outer membranes respectively. These subfractions contained appreciable quantities of lead. No appreciable lead was present in lipids of the mitochondrial membranes. Significant quantities of lead were associated with the endoplasmic reticulum. Fractionation of microsomes into rough and smooth membranes showed that lead was almost exclusively bound to membranes of rough-surfaced microsomes associated with the heavy rough membrane subfraction. No significant lead was present in the free polysome subfraction or in lipids from the endoplasmic reticulum. More than one lead binding site was identified in the soluble fraction, the high molecular weight components representing the most important lead binding site.


Relationship between induction of aryl hydrocarbon hydroxylase and de novo synthesis of cytochrome P-448 (P1-450) in mice. Phenobarbital, 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT), benzpyrene, 3-methylcholanthrene (3-MC) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were administered i.p. for 1 or 3 days to genetically "responsive" (C57BL/6J) and genetically "non-responsive" (DBA/2J) mice. 3-MC or benzpyrene stimulated aryl hydrocarbon hydroxylase (AHH) activity in C57BL/6J (B6) mice but not in DBA/2J (D2) mice. TCDD induced AHH activity in both B6 and D2 mice. Time-course studies showed that in the first 12 h after a single injection of 3-MC to B6 mice there was no shift in the reduced cytochrome P-450-CO complex absorption spectra from 450 to 448 nm, although AHH activity increased 4-5 times over (above) that of the control group. The relationship between induction of AHH activity by polycyclic hydrocarbons in B6 mice and the concomitant synthesis of cytochrome P-448 is discussed.


Mutation of human lymphoblasts by methylnitrosourea. The lag in phenotype expression of methylnitrosourea(MNU)-induced mutation to 6-thioguanine (6TG) resistance has been studied in a diploid human lymphoblastoid cell line. We find that a considerable period (8-12 days) elapses before new mutants appear in treated cultures; after 2 weeks, however, a stable maximum fraction is attained, as would be expected for a genetic mutation. We present preliminary data linking this phenotypic lag to the slow degradation rate of hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and to an apparent requirement for very low (less than 0.2% normal) cellular HGPRT content in order for cells to be resistant to 10 mug 6TG/ml. A series of reconstruction experiments are presented, the results of which support the conclusion that selective pressures in the assay procedure do not bias the quantitative estimates of induced mutant fraction.


Influence of dietary selenite on the binding characteristics of rat serum proteins to mercurial compounds. The effect of dietary selenite on the binding characteristics of serum proteins was investigated with rats. In the control serum, the maximal binding of phenylmercuric acetate (PMA) and methylmercuric chloride (MMC) to rat serum protein was approx. 18 and 9 nmoles per mg protein, respectively. The binding of Hg2+ was biphasic and it did not reach a maximum at the concentrations used. Selenite treatment caused a reduction in binding capacity of serum proteins to Hg2+ and PMA, and an increase in the binding affinities. However, there were no such changes for the binding of MMC. Selenite protection from mercury toxicity, therefore, acts not only via a change in tissue distribution and a change in the formation of seleno-proteins but, also, via a change in the binding characteristics to some mercury compounds. In the case of methylmercury, a different mechanism of protection must exist as the modification of tissue distribution, its binding to subcellular and soluble proteins and the binding characteristics remained equivocal.


Mouse liver and lung glutathione s-epoxide transferase: effects of phenobarbital and 3-methylcholanthrene administration. The effects of 3-methylcholanthrene (3MC) and phenobarbital (PB) administration on the levels of glutathione-S-epoxide transferase activity in supernatant preparations of liver and lung were studied in a number of different strains of mice, C57Bl/6, C3H, C3H-f, Balb/c-, A+ and DBA/2+. Three epoxide substrates, 3MC-11,12-oxide, styrene oxide (SO) and 3,3,3-trichloro-1,2-epoxypropane (TCPO), were employed in this investigation. PB administration (75 mg/kg body weight for 3 days) resulted in 13-57% increases in enzyme activity in the liver supernatant but was ineffective in inducing activity in lung. 3MC administration (40 mg/kg body weight for 2 days) on the other hand was without any effect on glutathione-S-epoxide transferase activity in both liver and lung.


Identification of the methyl phosphotriester of thymidylyl (3',5')thymidine as a product from reaction of DNA with the carcinogen N-methyl-N-nitrosourea. The methyl phosphotriester of thymidylyl(3'-5')thymidine, Tp(Me)T, was obtained as a product of enzymic digestion of N-[14C]methyl-N-nitrosourea-methylated DNA or of N-methyl-N-nitrosourea-methylated [14C]thymine-labelled DNA. The identity of the 14C-labelled Tp(Me)T products was shown by co-chromatography of the 14C-labelled enzymic digests with synthetic Tp(Me)T on Dowex 50 (NH4+ form, eluted at pH 8), and by co-chromatography, on silica gel in 3 solvent systems, of the Tp(Me)T-containing fractions from the Dowex 50 column. This identity was confirmed by showing that the 14C-labelled DNA-derived products hydrolysed in 0.1 M sodium hydroxide at 37 degrees C at a rate identical with that of synthetic Tp(Me)T, and gave the four expected UV-absorbing products (thymidine, thymidylyl(3'-5')thymidine, and the methyl esters of 3'- and 5'-TMP) in the same ratios as the authentic triester.


A comparison of the sulphite and thrombin methods for measuring fibrinogen concentration of plasma from patients undergoing thrombolytic therapy. A thrombin method for the determination of fibrinogen concentration has been compared with a non-enzymatic sulphite precipitation method on plasma from patients undergoing thrombolytic therapy with an intermittent plasminogen/streptokinase regime. There was very good agreement between the methods even when the determinations were made in the presence of high levels of fibrinogen degradation products (FDP), provided that the thrombin clottable fibrinogen was greater than 1 mg/ml. However, after extensive fibrinogen depletion, when the thrombin method underestimates fibrinogen concentration due to significant clot inhibition by FDP, an overestimate due to co-precipitation of fragments X and Y will be obtained by the sulphite method. This suggests that the simultaneous application of both techniques may provide a simple method of assessing the presence of high levels of anticoagulant FDP in various clinical disorders.


[Bisalbuminaemia in pancreatitis: structural modifications of human serum albumin by proteolytic enzymes of the pancreas (author's transl)]. Bisalbuminaemia in pancreatitis is a transient abnormality related to the presence, on electrophoresis of the serum, of a fast-moving albumin; this abnormal form is also found, in large amounts, in the ascitic or pleural effusions of the patients. Experiments reported here indicate clearly that the fast albumin can be produced by a degradation of normal serum albumin by the proteolytic enzymes of the pancreas (chymotrypsin or elastase in association with carboxypeptidases A and B). Stuctural analysis of the isolated fast albumin of the patients shows that the C-terminal end of the molecule is different from normal serum albumin, which can be understood by a limited enzymatic degradation by chymotrypsin or elastase followed by the action of carboxypeptidases. The discovery of bisalbuminaemia in a patient affected by pancreatitis is suspicious of the presence of an ascitic or pleural effusion and of a pancreatic pseudo-cyst with a fistula emerging in the effusion.


Automatic potentiometric titration and gas-liquid chromatography of underivatised free fatty acids. A rapid and precise method is described for the determination of total free fatty acids (FFA) in the serum followed by the separation of individual FFA by gas-liquid chromatography (GLC). After the extraction the FFA are directly injected into the gas-liquid chromatograph without esterification. DEGS-PS serves as stationary phase. The esterified fatty acids such as cholesterol esters, phospholipids or triglycerides do not interfere with the FFA determined by the GLC method. This method is compared to other commonly used titrimetric and gas-chromatographic procedures. The changes of the composition of individual FFA during and after ergometer work is reported.


Urinary albumin excretion in normal and diabetic subjects. Using an albumin radio-immuno-assay, urinary albumin concentration and excretion rate have been measured in diabetics and control subjects overnight, after several hours ordinary activity and during two successive one hour periods of recumbency. The urine albumin concentration was relatively constant throughout each of the four collection periods. Variations in albumin excretion rate were directly related to changes in urine flow. In assessing changes in urinary albumin, concentration and urine flow should be reported as well as the calculated albumin excretion rate. In the diabetics, selected for absence of clinical proteinuria, the mean concentration of albumin did not differ significantly from that of the controls. The overnight albumin excretion rate was higher in the diabetics, but this was due to the greater volume of urine.


Rapid determination of urine estriol by an on-column derivatization procedure. Estriol in pregnancy urine is determined by acid hydrolysis of steroid conjugates, followed by ether and aqueous sodium hydroxide extraction and gas chromatography. Derivatives are formed within the injection port of the gas chromatograph using tetramethylammonium hydroxide. Several samples may be processed simultaneously. Hydrolysis and extraction of a specimen are done in a single culture tube; for larger numbers of specimens, a Paton-Brown extractor may be used. With a two-column gas chromatograph, results on two specimens are available within one hour; twelve analyses may be completed within two hours.


Total and immunologically reacting muscle enolase in blood serum of Duchenne muscular dystrophy patients and carriers. All of 12 patients with Duchenne muscular dystrophy manifested raised activity of serum enolase but only 10 showed elevation of immunologically reacting muscle enolase (IRM-enolase). Total enolase was raised in 4 of 12 mothers and one of 8 sisters of the affected subjects but IRM-enolase was elevated in only one mother. These results are consistent with the view that enolase, unlike creatine phosphokinase which showed much more pronounced increase in the serum of patients and their female relatives, is associated with a structural component of the muscle cell distinct from the presumed site of molecular abnormality in this disease.


A single nonaqueous diazo reagent for the rapid determination of bilirubin in serum without lipemic interference. A nonaqueous reagent for directly determining serum bilirubin with 3,3'-dimethoxydiphenyl-4,4'-tetrazonium chloride in acidified dimethylsulfoxide is described. Conjugated or unconjugated bilirubin may be determined after extraction in acidified chloroform-ethyl acetate. The procedure is accurate (r2 0.97; recovery 100% for total, 98% for extracted bilirubin) and precise (C.V. 3.0% at 65 mg bilirubin per 1. The reagent develops endpoint color at 590 nm in less than 2 min, and the developed absorbance is stable for several hours. The method is intended for special applications where gross lipemia is encountered. Standardization with pure bilirubin in dimethylsulfoxide or chloroform is identical to standardization with aqueous bilirubin in protein standards.


Evaluation of the Vitatron "AKES" modification for optimal use in routine enzyme analysis. The Vitatron has been used as designed by the manufacturer under routine laboratory conditions (Broughton, P.M.G., Buttolph, M.A., Gowenlock, A.H., Neill, D.W. and Sleutelberg, R.G. (1969) J. Clin. Pathol. 22, 278). We assessed the possibilities of the AKES with regard to determination of the activities of three enzymes: alanine transaminase (AIT), aspartate transaminase (AsT) and lactate dehydrogenase (LDH) in serum. Precision, accuracy, carry over and sample-diluent contamination were evaluated. This resulted in recommendations for optimal use in terms of capacity and precision, which were supported by computations on a mathematical model for measuring results.


Studies on blood saccharoid fraction in normal and diabetic subjects. The exact nature of the saccharoid fraction (non-glucose reducing substances) in human blood is not known. The saccharoid fraction is increased in diabetic patients and a direct relationship exists to the height of the blood sugar. Some of the constituents of the saccharoid fraction, namely, glutathione, glucuronic acid and organic phosphate are significantly increased in diabetic patients. Fructose diphosphate and ATP are increased in the patients treated with oral hypoglycemic drugs. The known constituents of the saccharoid fraction which were determined accounted only for about 48% in normal and 36% in diabetic patients. The reduced contribution of these compounds to the saccharoid fraction in diabetic patients indicates that the nature of the saccharoid fraction may be different in diabetic patients.


Triglyceride lipases in acute hepatitis. Two triglyceride lipases in postheparin plasma, the lipoprotein lipase (LPL) and the hepatic triglyceride lipase (H-TGL) were separated by heparin-sepharose affinity chromatography and studied in controls and patients during the course of acute hepatitis. All three patients had increased content of triglycerides in the low density lipoproteins, and two of them had hypertriglyceridemia. Low activities of both lipases were found in the acute stage of the disease in all three patients. Concomitantly one of the patients had absolute low lecithin: cholesterol acyltransferase (LCAT) activity, and in the two other patients a relative LCAT deficiency was present. The increased content of triglycerides in LDL that may be found in liver disease, may not only be due to low H-TGL and LPL, but also LCAT deficiency.


[Adenosine deaminase activity in human erythrocytes and lymphocytes]. A radiochromatographic method is described for measuring enzymatic activity of adenosine deaminase in human erythrocytes and lymphocytes. [8-14C]-adenosine is converted into inosine and hypoxanthine; after chromatographic separation of the products, the radioactivity is determined. The kinetic properties of the enzyme have been studied. The Km values for the erythrocyte and lymphocyte enzymes are higher as compared with purified deaminase. Optimum conditions for substrate concentration for assay were established. The mean normal activity (+/- S.E. of mean) is: for erythrocytes, 494 +/- 61; nmol min-1 ml-1; for lymphocytes- 147 +/- 0.18 nmol min-1 10(6) cellules. The mean values are higher than that given by other methods working at a lower (non-staurating) substrate concentration.


Stability of testosterone and androstenedione in blood and plasma samples. In order to investigate the stability of testosterone (T) and androstenedione (Adione) in blood and plasma samples following study was undertaken. 1. Pooled blood samples were left unseparated at room temperature for varying time periods of up to 3 days before being centrifuged. Subsequent plasma T and Adione values measured by radioimmunoassay showed only small, insignificant variations. 2. Plasma, initially separated from the pooled blood sample, was left at room temperature for up to 24 h. There was no significant change in the levels of T and Adione measured over this period. There was also good correlation between steroid concentrations measured in blood and plasma. 3. T and Adione were measured in a pooled plasma sample after repeated freezing and thawing of the sample. All T values were well within the intraassay coefficient of variation; all Adione values were within the precision limits of the assay, although there was a considerable spread in individual values. It is concluded that the various handling procedures of blood or plasma have no significant effect on T and Adione levels.


Changes in serum and urinary myo-inositol levels in chronic glomerulonephritis. Serum and urinary myo-inositol and urinary glucose were estimated by means of gas-liquid chromatography in 54 patients with glomerulonephritis with and without renal failure. myo-Inositol clearance was calculated and an index was formulated which reflected changes in glomerular filtration, tubular reabsorption and catabolism of myo-inositol by the kidney. Serum and urinary myo-inositol levels were increased in glomerulonephritis with a close correlation to the degree of renal failure. In advanced forms of glomerulonephritis, glomerular filtration, tubular reabsorption and catabolism of myo-inositol were shown to be markedly deranged. Evidence obtained showed further that a derangement of tubular reabsorption and catabolism of myo-inositol also accompany milder forms of glomerulonephritis without decreased glomerular filtration. The myo-inositol index value, especially, was increased in patients with signs of disease activity as indicated by a histological examination of the kidney tissue. The index can also be regarded as a highly sensitive test of renal failure. Low grade glucosuria was shown to be frequently associated with glomerulonephritis with renal failure. Evidence was produced which suggested that the tubular reabsorption of myo-inositol was deranged earlier than glucose reabsorption in glomerulonephritis, although they may share a common step in the reabsorption process. The data suggest that the estimation of serum and urinary myo-inositol has advantages in the evaluation of kidney function.


D-Glyceric acidemia in a patient with chronic metabolic acidosis. A patient is described with glyceric acidemia and glyceric aciduria. The main clinical problems in infancy were severe metabolic acidosis and failure to thrive. The patient needs permanent treatment with bicarbonate. Hyperglycinemia, as described in the first case discovered elsewhere, was not present. The glyceric acid was found to have the D-configuration, as analyzed by capillary gas chromatography of its di-O-acetyl-l-menthyl ester. The abnormality may result from a defect in serine metabolism.


Photodynamic modification of proteins in human red blood cell membranes, induced by protoporphyrin. Illumination of erythrocytes or erythrocyte membranes with visible light in the presence of protoporphyrin causes photodynamic damage of the cell membrane. This process is reflected a.o. by a mutilated ultrastructure and changes of the physical properties of the membrane proteins. Illumination in the presence of protoporphyrin causes association of membrane proteins, leading to blurring of the protein bands in electropheretograms, disappearance of bands and the appearance of protein aggregates on top of the gels. The formation of large protein aggregates is also indicated by Sephadex gel filtration of the solubilized membrane proteins. In kinetic studies it appeared that spectrin and the bands 2.1, 2.2, 2.3 and 6 are most susceptible and that band 3 is least susceptible to this cross-linking reaction. Experimental results indicate that this cross-linking is caused by direct photooxidation of membrane proteins. Peroxidation of unsaturated fatty acids is not involved in the process. The significance of this process for studies on membrane structure and on photodynamic membrane damage is discussed.


The microdetermination of copper in plasma protein fractions. Electrophoresis on cellulose acetate membranes and electrothermal atomization for atomic absorption spectrophotometry have been combined to allow the determination of copper in protein fractions separated from only 2 mul volumes of serum. The sensitivity of the method is 5.2 X 10(-11) g of copper for 1% absorption at 324.7 nm, and the precision of replicate analyses at the 1.7-ng level is 0.086 (Relative Standard deviation). The mean recovery of copper from the alpha2-protein fraction of a serum sample was 94%. The method has been applied to a study of the changes in the copper content of the various protein fractions of sera from patients with Menkes' syndrome.


A new form of the solubility test for hemoglobin S; results from a survey of 3000 cases. A new form of the solubility test for the detection of Hemoglobin S is described. Glass ampoules containing one ml of the test solution ready for use are employed; they can be stored for more than one year at 4 degrees C. 3000 blood samples were analyzed by the solubility test and electrophoresis. The comparison between the two methods showed that the solubility test is highly satisfactory.


Hypothalamic-pituitary function following successful treatment of intracranial tumours. Hypothalamic-pituitary function was examined in seventeen patients treated in the past for extrasellar intracranial tumours. All patients had received a course of external cranial irradiation. Biochemical abnormalities of endocrine function were present in almost all of the patients. In particular, the growth hormone response to insulin induced hypoglycaemic stress was impaired in eleven out of fifteen patients. Preliminary data from a group of seven patients with intracranial tumours prior to radiotherapy are also presented. The possibility that cranial irradiation causes hypothalamic-pituitary dysfunction is discussed. The results suggest that endocrine assessment should be considered in patients who have been treated for intracranial tumours, even in the absence of direct pituitary involvement.


Cortisol binding capacity and oestrogen concentrations in maternal and cord plasma in pregnancies with normal and anencephalic fetuses. The cortisol binding capacity of maternal and cord plasma samples obtained at delivery from fifteen women and their normal infants and from seven women and their anencephalic infants was measured at 4 degrees C by a gel filtration technique. The concentration of oestrogen in these samples was measured by radioimmunoassay. There was no significant difference (t test) between the cortisol binding capacity of peripheral plasma from women with normal infants (1-55 +/- 0-24 mumol/1, mean +/- SD) and from those who delivered anencephalic infants (1-35 +/- 0-30 mumol/1), nor between the cortisol binding capacity of cord plasma from anencephalic infants (0-47 +/- 0-04 mumol/1) and that of normal infants (0-37 +/- 0-10 mumol/1). However, mean oestrogen concentrations in maternal and cord plasma from the pregnancies with an anencephalic fetus were significantly lower (P less than 0-01) than in the corresponding samples from normal pregnancy. It is concluded that oestrogen concentrations in maternal and cord plasma in normal pregnancy at delivery are much greater than those required to account for the increase in plasma cortisol binding capacity. Since plasma cortisol binding capacity in pregnancy with an anencephalic fetus is not diminished, the reduced excretion of corticosteroids relative to normal pregnancy in this condition is unlikely to be due to alterations in cortisol metabolism associated with a lower plasma cortisol binding capacity.


Changes in the pituitary-testicular system with age. In order to provide a comprehensive account of pituitary-testicular function in man, 466 subjects, ranging in age from 2 to 101 years, were studied to examine blood levels of the pituitary gonadotrophins (LH and FSH), the sex steroids testosterone and oestradiol, the binding capacity of the sex hormone binding globulin (SHBG), the free testosterone and oestradiol fractions, and the transfer constant for the peripheral conversion of testosterone to oestradiol. The results were compared with clinical indices of testicular size, sexual function and secondary sex hair distribution. Serum LH and FSH were low before puberty, increased in pubertal adolescents to levels somewhat above those of adults and subsequently increased progressively over the age of 40 years. Testosterone levels fell slowly after the age of 40, while there was a slight rise in plasma oestradiol with increasing age. FSH and testosterone showed small seasonal variations in young adult men, the lowest values being seen in winter. SHBG binding capacity was high in two prepubertal boys, fell in adult men, but increased in old age. Free testosterone and oestradiol levels fell in old age. The metabolic clearance rates (MCR) of testosterone and oestradiol also fell in old age, while the conversion of testosterone to oestradiol was increased. Many correlations were observed between various hormonal and clincial measurements. The evidence is consistent with a primary decrease in testicular function over the age of 40 years.


Hypothalamic hypopituitarism following external radiotherapy for tumours distant from the adenohypophysis. Three cases of panhypopituitarism and five of isolated growth hormone deficiency which occurred following previous external irradiation of tumours distant from the adenohypophysis are described. The hypothalamic pituitary region received between 2800 and 12 000 rads in each case, 1-9 years before endocrine deficiency was recognized. Evidence is presented that the site of damage is in the region of the hypothalamus rather than the pituitary gland itself. Individuals treated with X-ray therapy in whom the hypothalamic-pituitary region is exposed to irradiation would appear to be at risk of developing some degree of delayed hypothalamic-pituitary dysfunction.


A perspective on aldosterone abnormalities. Not all the varied clinical disorders in which aldosterone and the mineralocorticoid hormones are involved have been reviewed. Only those disorders in which the mineralocorticoid hormones and their regulatory factors are the principal cause of the biochemical and clinical abnormalities have been examined. These are many and varied. Appreciation of the extent and magnitude of their involvement in the regulation of blood pressure, body fluids, and electrolyte composition continues to grow. The major direct clinical impact of the mineralocorticoid hormones appears to be in two areas: hypertension and potassium homeostasis. Their part in the mosaic of hypertension is established in primary hyperaldosteronism, but they also appear to affect and modify the hypertensive process in primary or essential hypertension. The probe continues. Hypoaldosteronism is more than the rare occurrence associated with Addison's disease. It may be the clue to the presence of nonaldosterone mineralocorticoid excess syndromes, and is obviously of critical importance in an increasing number of patients with chronic renal failure of varied aetiologies.


Thyroid suppression tests during drug treatment of hyperthyroidism. In fifteen hyperthyroid patients treated for 5 or more consecutive years with propylthiouracil four or more yearly prognostic 'suppression' tests (Cassidy & VanderLaan, 1960) were done. In nine of the fifteen patients there was a progressive diminution over a period of 3-6 years in the values of these suppressed uptakes to 20% or below. Eight of these nine patients have remained euthyroid off therapy for 1-8 years (average 3-1 years). None have become hypothyroid. The data suggest a gradual continuing change in thyroid function over the course of years in some hyperthyroid patients on antithyroid therapy. This may be a long-term effect of the drug and may have prognostic significance.


Effect of dopamine infusion on plasma levels of growth hormone in normal subjects and in agromegalic patients. In ten normal subjects and in twenty acromegalic patients plasma levels of growth hormone were studied after administration of L-dopa and a dopamine infusion. In the ten normal subjects L-dopa, but not dopamine, increased plasma levels of GH. In the acromegalic patients both L-dopa and dopamine were followed by an inhibition of GH release. Since dopamine does not cross the blood-brain barrier, these results, although not excluding a site of action at median eminence level, support the thesis that the inhibitory effect of dopaminergic stimulation on GH release in acromegaly possibly involves receptors present on GH-secreting cells.


Effects of quinidine on blood flow rate and developed tension in blood-perfused canine papillary muscle. 1. The effects of quinidine on blood flow rate and developed tension were studied in isolated, blood-perfused papillary muscle preparations of the dog. Drugs were injected into the anterior septal artery. 2. Quinidine caused a dose-related increase in blood flow rate; the mean dose producing a 100% increase in blood flow rate was about 0-3 mg. 3. Quinidine in doses of 0-01-0-1 mg produced a positive inotropic response. With 0-3--1 mg of quinidine the positive inotropic response was preceded by a transient negative inotropic response. With 3 mg there was a monophasic negative inotropic response, the developed tension being reduced by about 40% of control. 4. Propranolol had no statistically significant effects on the responses of the blood flow rate and developed tension caused by quinidine. 5. These results indicate that quinidine has an action on coronary vessels in lower doses than on the myocardium, and that in low doses it has a positive inotropic action rather than the well-known negative inotrophic action exerted with higher doses.


The hepatic transport of taurocholic acid in the rat: development of a mathematical model. 1. The transport of taurocholic acid from portal blood to bile was studied in the anaesthetized rat by injecting a radiolabelled pulse of bile acid. 2. The transport process was very rapid, 50% of the dose being secreted within 5 min, and the total dose within 15 min. 3. The transport process had a large capacity. The secretory profile was little modified by a 500-fold increase in the injected dose. 4. The transport process was modelled with both analogue and digital computers. The simplest model which fitted the data comprised rapid uptake from portal blood, slow transport across the cell and rapid secretion into bile. The digital computer simulation suggested that this model is not unique, but will require further testing.


Release of renin from glomeruli isolated from rat kidney. 1. Glomeruli free from renal tubules and cell debris were isolated in large numbers from rat kidney cortex by a rapid, simple process of graded sieving on stainless steel meshes. 2. Glomeruli were viable, had fragments of the arterioles attached and contained renin. 3. Glomeruli, when incubated, released renin into the medium. Using a super-fusion technique this was shown to be time dependent until a basal secretion level was achieved. 4. Release of renin was directly proportional to the number of glomeruli and could be stimulated by isoprenaline, adrenaline and noradrenaline in order of the potency of their action on beta-adrenoreceptors. 5. Isolated glomeruli were therefore established as a useful model system for studying the release of renin by direct influences on the juxtaglomerular cells where haemodynamic, tubular and extrarenal influences are removed.


Effects of glucagon on pancreatic secretion in the dog. 1. The effects of glucagon on the secretion of pancreatic juice were investigated using blood-perfused canine pancreas preparations. 2. Intravenous administration of glucagon (3-30 mug/kg) to the donor dog elicited a dose-dependent increase in pancreatic secretion. Intra-arterial administration of glucagon (10-100 mug) into the perfused pancreas also elicited increased secretion. 3. There were slight increases in amylase concentration of the pancreatic juice with the largest doses of glucagon given by either route. 4. Glucagon-induced secretion was not modified by treatment with phentolamine, propranolol, atropine, guanethidine, tetradotoxin, haloperidol, prostaglandin F2alpha or calcitonin. 5. The results suggest that glucagon acts directly on the exocrine cells of the canine pancreas.


Comparison of the effects of (--)-isoprenaline, orciprenaline terbutaline, and Me506 on heart rate, soleus muscle contractility and pulmonary resistance of anaesthetized cats. 1. Three resorcinol derivatives with N-isopropyl (orciprenaline), N-t-butyl (terbutaline) and N-p-hydroxypheny-t-butyl (Me506) amine substituents have been compared with (--)-isoprenaline for their ability to produce beta-receptor mediated reductions in serotonin-induced increases in pulmonary resistance, decreases in soleus muscle contractility and increases in heart rate in anaesthetized cats. 2. For all parameters studied the four compounds produced similar maximal responses and dose-response curves were close to parallel. From the graphs doses of the compounds producing 50% of the maximal response (ED50) were interpolated, and from these dose-ratios with respect to (--)-isoprenaline [drug ED50:(--)-isoprenaline ED50] were calculated on a molar basis. 3. Increasing the size of the amine substituent from N-isopropyl to N-t-butyl led to an increase in beta-receptor stimulant activity in bronchial and skeletal muscle, but not in the heart. The change from N-t-butyl to N-p-hydroxyphenyl-t-butyl did not further affect stimulant activity in any of the parameters studied. 4. Calculation of selectivity ratios [molar dose-ratio (heart): molar dose-ratio (pulmonary resistance)] showed that orciprenaline was non-selective, and that terbutaline and Me506 showed a similar degree of selectivity for beta2- as opposed to beta1-receptor mediated actions.


Catechol-O-methyltransferase activity in erythrocytes of children with autism. 1. The activity of the enzyme catechol-O-methyltransferase (COMT) was determined in the erythrocytes of normal and autistic children. 2. There was no difference in enzyme activity between the two groups, although in both the normal and autistic females the erythrocyte COMT activity showed considerable within-group variation. 3. When the erythrocyte homogenates were divided into particulate and soluble fractions, some differences were observed. The COMT activity in the soluble fraction was less in erythrocytes from autistic males than in those from control males, whereas that in autistic females was higher than in those from control females.


Role of the renin-angiotensin system in hypertension produced by unilateral renal artery constriction in the rat. 1. Conscious rats which had undergone unilateral renal artery constriction were infused for 1 h with a specific antagonist of angiotensin II, 1-Sar-8-Ala-angiotensin II (P-113). 2. There was a highly significant correlation between the change in blood pressure induced by P-113 and the pre-infusion plasma renin concentration (PRC), regardless of initial blood pressure or the duration of stenosis. However, the blood pressure fall was not significantly greater in nineteen hypertensive rats than in eleven which remained normotensive. P-113 did not abolish the hypertension. 3. The extent to which angiotensin II supports blood pressure in rats with renal artery constriction is directly related to the PRC.


The fate of the orally administered bile acid sequestrant, polidexide, in humans. 1. The metabolic fate of the insoluble bile acid sequestrant polidexide, (poly-[2-(diethylamino)ethyl] polyglycerylenedextran hydrochloride), was studied in four adult humans following the oral administration of the 14C-labelled substance. 2. The mean cumulative recovery of 14C in faeces was 95-3% (s.e.m. = 1-1) of the administered dose, while mean cumulative recovery in urine was 0-37% (s.e.m. = 0-13) of the oral dose. 3. Only background levels of radioactivity were detectable in plasma samples taken 1-3 days after administration of tracer. 4. The findings suggested that polidexide was not absorbed from the gastrointestinal in man to any significant degree.


Gas exchange during exercise in healthy people. I. The physiological dead-space volume. 1. Physiological dead-space volume (V D) was measured in twenty-four healthy men and women aged from 20 to 71 years, at rest and at two rates of work on a treadmill, whilst breathing air and breathing oxygen. 2. The effect of correction of arterial carbon dioxide tension (Pa,CO2) to pulmonary capillary temperature on the resulting value for V D was investigated. We find that the effect is substantial and that a correction should be made. 3. Equations have been derived for the prediction of normal V D during exercise. The best prediction was given by a regression on height, age, carbon dioxide output, ventilation and respiratory frequency, with an upper 95% confidence limit of +81 ml.


Gas exchange during exercise in healthy people II. Venous admixture. 1. Venous admixture/cardiac output ratio (Qva/Qt) has been measured in twenty-four healthy volunteer subjects of both sexes aged 20-71 years, at rest and during the steady state of treadmill exercise at two rates of work, and breathing air and breathing oxygen. 2. With oxygen breathing, Qva/Qt was considerably less during exercise than during the time subjects were taking either normal or deep breaths of oxygen at rest, and did not significantly increase with the intensity of exercise. It is postulated that the increase in ventilation during exercise opens most or all of those alveoli which, during oxygen breathing at rest, close because of critically low ventilation/perfusion (V/Q) ratios. 3. With air breathing, Qva/Qt fell from rest to exercise (especially in older subjects), presumably due to improved ventilation of alveoli at the lung bases. With an increase in work rate Qva/Qt increased in all age groups. This increase was not due to increase in the shunt fraction (Qs/Qt), nor to limitation of diffusing capacity; it arose from an increase in V/Q variance. 4. Equations have been derived for the prediction of normal Qva/Qt during exercise, with or without correction for the effects of increasing pulmonary capillary temperature. These effects do not materially influence the accuracy of prediction, but may be relevant to some of the interpretations. In particular, they provide a further indication that Qs/Qt probably cannot be measured by breathing oxygen at rest, even in deep breathing.


Effects of parathyroid hormone on sodium and calcium transport in the dog nephron. 1. The effect of purified bovine parathyroid hormone on renal tubular reabsorption of sodium and calcium has been studied by micropuncture in intact and recently thyroparathyroidectomized dogs. 2. Parathyroid hormone increased the rejection of sodium and calcium proportionately at the late proximal tubule in both intact and operated dogs. 3. In both groups of dogs, there was increased delivery of sodium and calcium to the distal tubule after the hormone. However, the Ca/Na ratio decreased, suggesting some selective enhancement of calcium reabsorption before the superficial distal puncture site. 4. In the final urine, the Ca/Na ratio decreased highly significantly in both groups of dogs, indicating a further selective effect of parathyroid hormone on calcium reabsorption in or beyond the distal convoluted tubule.


Chloride depletion and hypochloraemia as a cause of renal sodium and water loss in the rat. 1. To study the effects of chloride depletion, without sodium depletion or change in plasma tonicity, on renal excretion of sodium and water, a single exchange peritoneal dialysis was performed in rats against a solution of glucose (15 g/1) containing either NaCl (150 mmol/l, control) or NaHCO3 (150 mmol/l, experimental); KHCO3 (4mmol/l)was added to both solutions. All rats were prepared before dialysis by a low NaCl diet for 10 days. 2. Peritoneal dialysis against NAHCO3 consistently produced a negative sodium and water balance compared with dialysis against NaCl. Despite this, subsequent electrolyte balance for 3 days showed that chloride-depleted rats excreted significantly more sodium and water and had a reduced urinary osmolality as compared with control animals. Increased sodium and water loss were unexplained by osmotic or bicarbonate diuresis. Kaliuresis was seen in the chloride-depleted rats but muscle potassium was not significantly depressed. 3. With sodium and water loss and continued renal chloride conservation, plasma chloride rose on the average from 88 mmol/l after dialysis against NaHCO3 to 100 mmol/l (control 104 mmol/l) at 72 h. Concomitant with this increase in plasma [C1-], on the third day after dialysis, during hydropenia, urinary osmolality and papillary [Na+] were not different from control cencentrations. 4. It is postulated that chloride depletion and/or hypochloraemia leads to diminished chloride transport in the loop of Henle and that this causes reduced sodium transport into the medulla, impaired concentration ability and inappropriate urinary sodium loss.


Urinary excretion of peptides and of hydroxyproline in Wilson's disease. 1. A study has been made of peptide excretion in twenty cases of Wilson's disease, ligand-exchange column chromatography being used to separate peptides from free amino acids. Previous reports of excess of peptide output in the disease were confirmed and the excess was shown to be highly significant statistically. 2. A considerable fraction of the excess of peptide output was shown to consist of hydroxyproline-containing peptides derived from collagen degradation. 3. The method of rank correlation showed that the difference both in free amino acid and peptide-bound amino acid output in cases of Wilson's disease and in control subjects was mainly quantitative; the pattern of amino acid excretion was qualitatively similar in both groups. 4. Evidence is presented that the increase copper output in the urine in the disease is not secondary to peptiduria.


A study in vivo of peritubular oncotic pressure and proximal tubular reabsorption in the rat. 1. Peritubular capillary microperfusion was used to examine the effects of protein-free and hyperoncotic homologous plasma on fluid reabsorption by proximal convoluted tubules in the hydropenic rat. 3H-labelled p-aminohippurate was added to perfusates for the purpose of estimating the extent to which tubules under study were bathed by the perfusates. [14C]Mannitol was added to perfusates in order to detect contamination of collected tubular fluid by perfusates. 2. Hydrostatic pressures were monitored in the peritubular microvasculature and adjacent proximal tubules during perfusion. Evidence for secretion of p-aminohippurate from perfusate into tubules under study was determined by collecting tubular fluid from both early and late puncture site. Fractional and absolute reabsorption were not affected by either the protein-free or the hyperoncotic plasma. 3. When acetazolamide was added to the perfusate both fractional and absolute reabsorptive rates decreased by an average of 36%, indicating that the techniques were capable of detecting a decrease in proximal tubular reabsorption. 4. It is concluded that under the conditions of this study changes in peritubular capillary protein concentrations have no detectable effect on the rate of proximal convoluted tubule fluid reabsorption.


Elimination of cholesterol in hyperlipoproteinaemia. 1. Cholesterol intake (about 0-25 mmol/day) and the faecal excretion of cholesterol, coprostanol and coprostanone were determined in normolipidaemic control subjects and hyperlipidaemic patients, whose bile acid kinetics had been previously studied. 2. The combined excretion of the neutral steroids (excluding plant sterol and plant sterol metabolites) averaged 1-07 +/- 0-13 (+/-SEM)mmol/day in the control subjects (n=14). The corresponding values in patients with hyperlipoproteinaemia type IIa (n=19), IIb (n=12) and IV (n=23) were 0-86 +/- 0-10, 0-93 +/- 0-11 and 1-48 +/- 0-17 mmol/day respectively. 3. The mean values for the net steroid "balance", defined as the combined amount of bile acid synthesized (determined by an isotope-dilution technique) and the faecal excretion of neutral steroids minus cholesterol intake, were 1-83 +/- 0-22 mmol/day in the control subjects and 1-60 +/- 0-15, 1-81 +/- 0-19 and 3-53 +/- 0-23 mmol/day in patients with type IIa, IIb and IV lipoprotein patterns respectively. 4. No significant correlations between net steroid "balance" and sex, age, serum lipid concentrations, body weight or body surface area were found in any of the groups of subjects. 5. It is concluded that patients with type II hyperlipoproteinaemia eliminate cholesterol as bile acids and neutral faecal steroids normally. The type IV lipoprotein pattern is associated with increased bile acid synthesis and/or elevated faecal excretion of neutral steroids, so that the net steroid "balance" is usually above the normal limit.


A study of changes in whole-body calcium, phosphorus, sodium and nitrogen by neutron activation analysis in vivo in rats on a calcium-deficient diet. 1. A method of measuring changes in the total body content of calcium, phosphorus, nitrogen and sodium in rats by activation analysis in vivo is described. 2. The change in the body content of the elements has been measured in rats on a calcium-deficient diet and in control animals, the body nitrogen being used to represent lean body mass for normalization. 3. There were siginificant differences in Ca/N and P/N but not in Ca/P ratios between the animals on a deficient diet and control animals at the end of the dietary period.


The effect of aluminium hydroxide orally on calcium, phosphorus and aluminium metabolism in normal subjects. 1. Five normal subjects were given 100 ml of aluminium hydroxide gel per day for 28 days. 2. The phosphorus balance became more positive in one subject, less negative in two and changed from negative to positive in the other two subjects. This was accompanied by a rise in the concentration of the fasting morning plasma phosphorus. Calcium balance did not change. 3. The normal subjects absorbed  0-3-3-6 mmol of aluminium/day, which is significantly less than that absorbed by five patients with chronic renal failure, three of whom were studied before, and two after, the observations on the normal subjects had been completed. 4. In a further five normal subjects on 100 ml of aluminium hydroxide gel/day the 08.00 hours concentration of plasma phosphorus did not fall, though there was a fall at 11.00, 14.00 and 17.00 hours.


The effect of cryogenic storage on human erythrocyte membrane proteins as determined by polyacrylamide-gel electrophoresis. A study was conducted to determine the effects of freezing on the major membrane proteins of isolated human erythrocyte membranes. Membranes in low or normal ionic strength medium were frozen at slow or fast freezing rates. The membrane protein composition and elution of proteins from the membranes were studied utilizing polyacrylamide-gel electrophoresis in a sodium dodecyl sulfate or an acetic acid-urea-phenol solvent system. Neither a change in the composition of the membrane proteins nor any elution of membrane protein during freezing and thawing was observed. The data indicate that any human erythrocyte membrane damage during freezing and thawing was not related to a change in major membrane protein composition. Human red cell membranes were stable at --80 or --196degreesC in the absence of a cryoprotective agent.


Survival of frozen-thawed human red cells as a function of cooling and warming velocities. Human red cells were equilibrated for 30 min at 20degreesC in buffered saline containing 2 M glycerol and then frozen to --196degreesC at 0.27, 1.7, 59, 180, 480, 600, and 1300degreesC/min and warmed at 0.47, 1, 26, 160, and 550degreesC/min. Cells frozen at 600 and 1300degreesC/min responded in the classical fashion for cells containing intracellular ice; i.e., survivals were low when warming was slow (less than 10%), but increased progressively with increasing warming rate. The sensitivity to slow warming presumably reflects the recrystallization of intracellular ice. Cells frozen at 59 and 180degreesC/min yielded high survivals at all warming rates. This response is also consistent with the findings for other cells cooled just slowly enough to preclude intracellular ice. Cells frozen very slowly at 0.27 and 1.7degreesC/min, however, responded differently; survivals were considerably higher when warming was slow (0.47 or 1degreesC/min) than when it was 26, 160, or 550degreesC/min. This response is analogous to that observed recently by others in mouse embryos and in higher plant tissue-culture cells and to that observed for many years in higher plants. It also confirms previous observations of Meryman in human red cells. It may reflect osmotic shock from rapid dilution but, if so, the basis of the osmotic shock is uncertain.


A membrane model describing the effect of temperature on the water conductivity of erythrocyte membranes at subzero temperatures. Thermodynamic models show that the loss of intracellular water from human erythrocytes during freezing depends heavily upon the water conductivity of the erythrocyte membrane. These calculations, which are based on the simple extrapolation of ambient conductivity data to subzero temperatures, show that more than 95% of cell water is transferable during freezing, whereas experiments show that at least 20% of cell water is retained. A study of the effects of different published values for the membrane water conductivity on cell water retained during freezing shows that this discrepancy may be a consequence of the simple extrapolation procedure. For a homogeneous membrane system, absolute reaction rate theory was used to develop a surface-limited permeation model that includes the resistance to the flow of water not only through the interior region of the membrane but also across possible rate-limiting barriers at the solution-membrane interfaces. The model shows that it is unlikely that a single rate-limiting process dominates water transport in the red cell as it is being cooled from ambient to subzero temperatures. The effective membrane conductivity at subzero temperatures could possible be much lower than a simple extrapolation of existing data would predict. With the aid of this model analytical predictions of intracellular water during freezing are more consistent with experimental observations.


The immunological capacity of peripheral lymphocytes in a blast-transformation system using frozen-stored cells. Suspensions of isolated peripheral lymphocytes were frozen to --95degreesC using a programmed freezing apparatus and dimethyl sulphoxide as a cryoprotective agent. In comparisons among fresh cells, frozen cells, and cells stored in storage medium, freezing was found to be the best method of storage with retention of almost the same immunocapacity as fresh cells and with the same coefficients of variation for results after stimulation with phytohemagglutinin, pokeweed mitogen, concanavalin A, purified protein derivative, and allogenic cells in mixed lymphocyte cultures as was obtained with fresh cells. Blast transformation was found to be dependent on the number of cells in the cultures, the amount of [14C]thymidine added, and the amount of phytohemagglutinin used by independent of the amounts of pokeweed mitogen and concanavalin A. The maximum responses for normal lymphocytes and lymphocytes from uremic patients after stimulation with phytohemagglutinin occurred simultaneously, but after stimulation with allogenic cells maximum response was obtained earlier for "uremic" than for normal lymphocytes. It was concluded that frozen-stored lymphocytes are suitable for in vitro quantitative measurements of the cellular immune response in an immunological sequential study provided that the above mentioned factors are well defined.


The influence of different freezing procedures and different cryoprotective agents on the immunological capacity of frozen-stored lymphocytes. The influence of a series of factors on the frozen storage of lymphocytes was investigated. The cells were frozen using different freezing programmes, using the cryoprotectants dimethyl sulphoxide and glycerol in different concentrations in the freezing medium, and with variations in the period of exposure of cells to cryoprotectants before freezing and after thawing. Cell viability was evaluated by quantitative measurements of the cell-mediated immune response after stimulation with phytohemagglutinin, pokeweed mitogen, concanavalin A, and allogenic cells in mixed lymphocyte cultures. The factors investigated were found to have an important effect on the immune response, so that careful investigation and exact specification of the freezing system are necessary before frozen cells are used in blast-transformation tests. The best freezing programme had a duration of approximately 40 min with a smooth progression through the temperature range where phase transition takes place. The optimum dimethyl sulphoxide concentration in this programme was 8--10%. Dimethyl sulphoxide had no toxic effect on the cells, and no equilibration period was necessary prior to freezing. An equilibration period of 15 min with 10% glycerol was even better than the optimum programme with dimethyl sulphoxide.


Survival of unprotected, mammalian plateau-phase cells following freezing in liquid nitrogen. Unprotected, mammalian cells in plateau phase are at least a factor of four times more sensitive to freeze-thaw damage than exponential-phase cells. The former suffer about 15-20% more sublethal damage after one freeze-thaw cycle than the latter and repair this damage more slowly. Exposure of plateau-phase cells to freeze-thaw damage lengthens the time required to traverse the cell cycle in the exposed generation. These cells may more closely represent the state in tissues than exponential-phase populations.


Ventilation-perfusion alterations induced by fiberoptic bronchoscopy. Pulmonary perfusion (Q) and ventilation (V) scintiphotography was performed in 16 patients undergoing diagnostic fiberoptic bronchoscopic examinations. Regional V/Q did not change in the majority of the patients who developed hypoxemia after bronchoscopic studies. An improvement in V/Q was detectable in the patients with a rise in arterial oxygen pressure (PaO2) after bronchoscopic examination, and this rise was associated in most with the removal of mucous plugs or extensive secretions. The data indicate that the behavior of PaO2 after bronchoscopic study is dependent upon both the extent of lavage and the yield of the procedure in terms of secretions and plugs. The results also indicate that the removal of secretions or plugs can be associated with rapid return of regional V and Q.


Pressure transducers as a source of bacteremia after open heart surgery. Report of an outbreak and guidelines for prevention. During four weeks in 1974, eight (26 percent) of 31 intensive care unit patients who had undergone open-heart surgery developed symptomatic Pseudomonas cepacia bacteremia in the intensive care unit one to three days after the open-heart surgery. An investigation demonstrated that operating room pressure transducers were being contaminated during cleaning with a detergent that contained P cepacia at the rate of 10(4) organisms per milliliter and that the organisms were transmitted to patients after open-heart surgery as a result of one to three days of contact with transducer-monitoring lines used in the operating room and brought to the intensive care unit with the patient. Pressure-transducer contamination, a frequently unappreciated but preventable cause of nosocomial bacteremia, can be minimized by sterilizing transducers between use on different patients by paying strict attention to aseptic technique when setting up, calibrating, and using monitoring systems; and by changing transducers, tubing, and monitoring fluid for each monitored patient at regular intervals.


Clinical and roentgenographic manifestations of acute and chronic blastomycosis. Roentgenograms and hospital records of 50 patients with blastomycosis proven by cultures were analyzed to determine possible differences between the acute and chronic forms of the illness. Six patients had acute blastomycosis with symptoms occurring three weeks or less prior to hospitalization. The remaining 44 patients had chronic illnesses with symptoms occurring up to six years (mean duration, ten months before hospitalization). The acute illness was characterized by toxic symptoms, chest pain without visible effusions, pneumonic-type consolidations on the chest films, and a relatively benign course. The chronic illness had less severe toxicity, but a high incidence of dissemination, with pleural reactions, hepatosplenomegaly, and cutaneous and osseous involvement. Sputum cultures were positive for Blastomyces dermatitidis in 36 of 46 patients; however, several specimens were frequently required for demonstration of the organism on wet preparations. Pleural fluid and material from skin lesions were also likely sources of the fungus. Skin tests and serologic studies were not helpful in most cases of either the acute or chronic form of the disease.


Surgery for congenital heart disease in the adult. A total of 205 adults with a variety of congenital heart lesions underwent operation for total correction of their defects. Operative and long-term mortality were 3 and 4 percent, respectively. There has been only one operative death in the past five years (85 patients). While most defects were repaired with good hemodynamic and symptomatic improvement, the three lesions associated with the worst results were cyanotic tetralogy of Fallot, severe pulmonic stenosis complicated by atrial septal defect, and ostium primum atrial septal defect. Myocardial failure due to end-stage myocardial fibrosis was the major cause of operative mortality. Myocardial fibrosis and irreversible pulmonary changes seemed to be the two factors limiting operative correctio


Transtracheal selective bronchial brushing for pulmonary infiltrates in patients with cancer. Patients with cancer frequently develop pneumonitis for which no cause is documented ante mortem. Noninvasive diagnostic techniques, such as sputum induction, are generally inadequate, especially in myelosuppressed patients. To avoid pulmonary contamination with organisms colonizing the oronasopharynx and to obtain uncontaminated speciemens, 38 patients underwent bronchial brushing utilizing a transtracheal approach after sputum induction and transtracheal aspiration failed to establish the etiology. Patients with thrombocytopenia were brushed after platelet transfusion. Eleven patients were not clinically considered to be infected; seven proved to have pulmonary metastases, of which one case was diagnosed by this technique; and four patients in whom no diagnosis was obtained by brushing subsequently proved to have interstitial fibrosis (three cases) or a collapsed lobe (one case). Twenty-seven patients were clinically presumed to be infected. Ultimately, 17 of these 27 patients were proven to have pulmonary infection, and 14 of these 17 were etiologically documented by brushing. In ten of the 27 patients presumed to be infected, no etiology could be established by any method. Seven of these ten patients were receiving broad-spectrum antibiotic therapy at the time. Significant but nonfatal complications, including hemoptysis, pneumothorax, and cervical cellulitis, occurred in seven patients; however, this procedure is a relatively safe and useful method to include in the orderly evaluation of myelosuppressed cancer patients with suspected pulmonary infections.


Severe airway disease due to inhalation of fumes from cleansing agents. A subject had severe airway obstruction and evidence of small-airway disease resulting from inhalation of "fumes" liberated during the course of mixing several drain-cleansing agents. The evidence in favor of the airways as the predominant site of damage was severe reduction of maximal expiratory flow in the presence of normal lung-recoil pressure in a nonsmoker who had no other known industrial exposures or predisposing respiratory conditions.


Esophageal perforation following use of esophageal airway. The esophageal airway has gained increasing acceptance in airway management during cardiopulmonary resuscitation, and its enthusiastic advocates are urging expansion of its use. A fatal case of esophageal perforation following the use of an esophageal airway is presented. Possible contributing factors are discussed. A modified esophageal airway which seems safer and more versatile, effective, and economic is described.


Chylopericardium with cardiac tamponade after cardiovascular surgery in two patients. Two patients developed postoperative chylopericardium leading to acute cardiac tamponade. Delayed diagnosis and urgent throacotomy did not prevent death in three-month-old patient after the Glenn anastomosis of the superior vena cava to the right pulmonary artery, whereas early recognition of chylopericardium following repair of an interrupted aortic arch in an 11-week-old patient was successfully treated by tube pericardiostomy. The literature is reviewed, and an anatomic predisposition for post-surgical chylopericardium is proposed.


Three unusual complications resulting from attempted repair of partial anomalous pulmonary venous drainage. The correction of shunts resulting from partial anomalous pulmonary venous drainage has become an accepted surgical procedure. Surgical complications, other than those that were purely postoperative, have been rare. The present report details the case histories of three patients with unusual complications resulting from this type of surgery. Unilateral pulmonary venous obstruction and repeated infections occurred in one patient. In another, obstruction of the superior vena cava resulted. In the third patient, an indaequate operation was performed when the site of partial anomalous pulmonary venous drainage into the coronary sinus was not recognized initially at the time of surgery.


Right and light ventricular dimensions as determinants of ventricular septal motion. Echocardiographic studies were performed in 86 patients with right ventricular volume overload. In 45 of these 86 patients, 58 echocardiograms were performed at different intervals in the postoperative period. For control purposes, 60 normal subjects and 18 patients with right ventricular pressure overload were also examined. The right ventricular end-diastolic dimension (RVED) and the left ventricular end-diastolic dimension (LVED) were measured on the echocardiograms. The RVED/LVED ratio was significantly elevated in patients with right ventricular volume overload. In all groups, a RVED/LVED ratio above 0.65 was usually associated with an abnormal motion of the septum; and on this basis the subjects with abnormal septal motion could clearly be separated from those with normal motion. After surgery, significant reductions of the RVED/LVED ratio were observed in patients whose septal motion reverted to normal. The RVED/LVED ratio remained significantly higher, usually above 0.65, in patients with persistent abnormal septal motion. These findings suggest that the relative sizes of the right and left ventricular cavities are probably major determinants of ventricular septal motion. Abnormal motion may result from a change in the end-diastolic shape of the septum.


Left anterior hemiblock of the 2:1 type in the presence of inferior wall myocardial infarction. A case of inferior wall myocardial infarction (IWMI) with left anterior hemiblock (LAH) is presented. The LAH became type 2:1 in the course of the disease. Electrocardiographic signs of LAH in the presence of IWMI are outlined, and the behavior and etiology of the T-wave changes are analyzed.


Intra-His bundle block complicating acute inferior myocardial infarction. The unexpected findings of atrioventricular block or delay in the His bundle and proximal branches are described in a 51-year-old man with acute inferior myocardial infarction with narrow QRS complexes. With the information from the His bundle electrogram, the site of atrioventricular block is precisely localized.


Cardiac motion in total electrical alternans. Gross pendular motion of the heart at half the heart rate was observed during cardiac catheterization and pericardiotomy in a patient with massive pericardial effusion and electrical alternans in the electrocardiogram. These observations support the hypothesis that total electrical alternans in pericardial effusion is a result of alternate change in cardiac position.


Clinical experience using a small-gauge needle for arterial puncture. The present study was undertaken to ascertain the feasibility of using a 25-gauge needle for arterial punctures. A total of 11,500 arterial punctures were performed over the past four years by this technique without any major complication. Repeated arterial punctures were well tolerated by all patients, and the necessity for indwelling arterial catheters was almost totally eliminated during this period of study.


Retrieval of embolized central venous catheters by a Dormia ureteral stone dislodger with straight filiform tip. Two cases are presented in which a Dormia ureteral stone dislodger with straight filiform tip was used to retrieve broken central venous pressure catheters from the right side of the heart and vena cavae. It should be emphasized that this particular model is more easily passed into the vascular system and more easily manipulated within the vascular system. The delicate filiform tip also contributes to greater safety. It should also be emphasized that entrapment of the proximal tip of a fractured central venous pressure catheter is most ideal prior to extraction.


Anomalous double blood supply to the lung. We report an unusual case in which an apparently normal upper lobe of the right lung was supplied by major systemic arterial and pulmonary arterial vessels. The anomalous artery arose from the descending aorta. Following interruption of this vessel, the machinery-like murmur previously present disappeared.


Rate-dependent premature beats in man.

Rate-dependent premature beats in man. Ventricular premature beats (VPBs) appeared in a patient after pacemaker insertion for complete heart block secondary to acute myocardial infarction. Contrary to expectations, the frequency of VPBs was directly related to the basic pacemaker rate. The VPBs are either reentrant beats or represent VPBs arising from pacemaker cells with "slow-response" characteristics, which have been shown to become more automatic with increasing rates of electrical stimulation. This case documents the phenomenon of rate dependency of VPBs in man and discusses its practical importance.


Role of computerized axial tomography in diagnosis and treatment of common neurosurgical problems of infancy and childhood. Computerized axial tomography (CAT) is a new, highly accurate technique for studying the skull and intracranial contents. It is rapid enough to be utilized in acute emergencies and safe enough to be utilized for routine serial followups and evaluation of outpatients with equivocal findings. Because CAT can delineate the ventricular system without need for contrast agent, can distinguish clearly between hematoma and edema and can differentiate cystic from solid tumors, it finds wide application in the evaluation of neurological disease.


Fetal Chiari's type III malformation.

Fetal Chiari's type III malformation. The morphological findings in a 4- to 5-month-old female fetus with Chiari's type III malformation are described. This observation strongly supports the view that a defective closure of the roof plate is the primary cause of this malformation, and relates it to the Arnold-Chiari and Dandy-Walker syndromes.


Ependymomas of childhood. I. Histological survey and clinicopathological correlation. We have conducted a correlative histological and clinical study on 34 cases of childhood ependymomas encountered at the Children's Memorial Hospital from 1953 to 1974. The cases were classified into grades A, B and C according to the extent of cytological differentiation and the correlation between the histological grades and the clinical outcome was obtained. It is concluded that the biological behavior of an ependymoma could be predicted to a large extent by the degree of cytological differentiation and by its anatomical location. A large share of the infratentorial ependymomas are well differentiated (grade A) and prognosis in this group is good when complete surgical removal could be accomplished. Most of the supratentorial ependymomas belong to the intermediate grade B and the malignant grade C; prognosis in these two grades is less predictable, approximately two thirds of these patients died within 3 years. The most malignant form is the ependymoblastoma. This is a highly primitive neoplasm histologically similar to medulloblastoma but shows evidence of ependymal differentiation. Most of the ependymoblastomas are located in the supratentorial region and the average length of survival is 20 months.


Cephalocranial disproportion. A complication of the treatment of hydrocephalus in children. Eight children with hydrocephalus showed signs of posterior fossa tonsillar impaction despite arrest of the hydrocephalus and patency of their CSF shunts. Contrast studies performed because of their clinical deterioration demonstrated cerebellar tonsillar herniation, and at posterior fossa decompression, this was confirmed in all cases. Improvement followed decompression. The pathogenesis of a state of cephalocranial disproportion following successful treatment of hydrocephalus resulting in symptomatic tonsillar herniation, is discussed.


Behavior modification in a residence and school for adolescent boys: a team approach. A behavior modification program emphasizing close communication and cooperation between educators and child care workers has proved effective in a school for adolescent boys with learning and behavior problems.


A truancy program: the child welfare agency and the school. A program devised to combine efforts of a child welfare agency and a public school system in combating truancy developed an effective working relationship.


Spinal cord seeding from cerebellar astrocytomas. Three juvenile patients with cerebellar astrocytomas which have seeded the spinal subarachnoid space are presented. Histologic verification of the similarity between the posterior fossa tumor and its spinal implant was obtained in two of the three patients. The cerebellar tumors in all cases have been benign (grade I),and the behavior, other than their seeding has also been indolent. Review of pertinent literature discloses no similar experience with cerebellar astrocytomas. Aggressive therapy is advocated for the rare patient with subarachnoid seeding from this benign lesion.


Headache in classical hemophilia. The risk of diagnostic procedures. Headache in a hemophiliac poses a major problem. The fact that at least half of hemophiliacs with proven intracranial hemorrhage present with a headache but no preexisting injury, requires an aggressive approach to the management of these patients. Recent articles point out successful instances of craniotomy in hemophilia, but relatively few hemophiliacs with headaches progress to that stage. We have reviewed the literature and added three cases in an attempt to establish the risk of spinal puncture and cerebral angiography in the evaluation of these patients. The data presented suggests that with replacement therapy and attention to angiographic technique, both procedures may be performed with minimal risk.


Subacute radiation myelopathy in a 12-year-old boy. Rapid onset over several days of a complete transverse myelopathy occurred 3 1/2 months after completion of mediastinal radiation for Hodgkin's disease in a 12-year-old boy. Postmortem examination revealed low cervical and high thoracic radiation myelopathy. The name "subacute radiation myelopathy" is proposed for this type of rapidly developing myelopathy.


Recognition of depressed affect in hospitalized psychiatric patients: staff and patient perceptions. A comparison of self-report vs. observer rating of depressed mood in a heterogenous inpatient population revealed wide variations in concordance among diagnostic groups. Patients diagnosed as having Affective Psychosis and ""Other'' illnesses showed the highest correlation between four self-report scales and an observer rating scale. Patients with a diagnosis of depressive Neurosis showed only modest correlation, while Schizophrenics revealed no significant correlation, on these instruments, suggesting inconsistent communication of affect from Schizophrenic patients to observers. In contrast, when self-report scales were intercorrelated, patients in all four diagnostic categories showed highly significant correlations, indicating that they were consistently reporting their affective state on these instruments. The implications of these findings for future research as well as for practical clinical management are discussed.


Group therapy for patients with hysteria (Briquet's disorder). It was found that group therapy helped patients with hysteria by (1) satisfying their need to talk (2) lessening their concern about their physical symptoms (3) giving them important knowledge of the illness (4) giving them new ways of handling the illness by themselves (5) giving them the support and the companionship of the other group members (6) reducing their need of medicines (7) reducing psychiatry visits (8) helping them to get along better with their families (9) increasing their self-confidence and (10) improving their mood.


Changes in serum dopamine beta hydroxylase activity related to coma. Dopamine Beta Hydroxylase (DBH) activity was determined in 24 deeply comatose patients enrolled in the Collaborative Study of Cerebral Survival. All patients had been without cerebral responsiveness or spontaneous respirations for at least 15 minutes. Patients were examined, EEGs performed and blood for DBH drawn within 24 hours of the cerebral insult. DBH activity was lower in the deeply comatose patients than in a group of 51 age matched normal individuals. It is postulated that destruction or inactivation of the central nervous system (CNS) and particularly of the cerebrum may result in lowered serum DBH activity through decreased activation of sympathetic nerve terminals.


Regression of bone metastases from renal cell carcinoma achieved by combined therapy. A case of renal cell carcinoma with successive multiple bone metastases which survived over a 36-month period is presented. A clinical and radiological regression of bone lesions was obtained by means of combined therapy (hormone therapy, radiotherapy, and immunotherapy), after the original tumor had been removed.


The prognosis of pelviureteric obstruction in childhood: a review of 190 cases. 190 children with pelviureteric obstruction are reviewed. Their symptoms are analysed and the pre- and post-operative radiographic appearances are assessed. The results are very encouraging with a clinical improvement in the majority of patients, free ureteric drainage in almost all and an improvement in the calyceal pattern in 65.9%.


The single ectopic ureter.

The single ectopic ureter. 32 cases of single ectopic ureter have been reviewed. The more remote the ectopic orifice opens from its normal position the more severe were the associated renal anomalies. In the great majority of cases, the corresponding kidney was dysplastic and radiographically functionless. An embryological explanation is proposed to account for the association of single ectopic ureter with a dysplastic kidney. Clinical symptomatology was dribbling incontinence in most female cases and various urogenital complaints in male. An accurate preoperative diagnosis is usually reached with a pyelogram and micturating cystogram. In some female cases a vaginogram or direct puncture and opacification of a vaginal cystic mass may be contributive. In the male, a radiological non-functioning kidney on one side of the urogram associated with a cystic mass palpated above the prostate is pathognomonic of an ectopic ureter opening in the seminal tract. Deferentography may confirm this diagnosis. Treatment of the condition is surgical. In the great majority of cases nephroureterectomy is required. In the male, the abnormal seminal tract involved in this complex malformation should also be removed.


Partial nephrectomy for renal tumour: 21 cases. Partial nephrectomy has been performed in 21 cases of kidney tumours. It can be used for well-limited parenchymatous tumours and obligatory in patients with a solitary kidney, but is not advisable for tumours originating in the urothelium. These results are compared with the parallel experience with radical surgery and followed during 46 years in the same centre, they give a greater value to this study and encourage the reasoned practice of partial nephrectomy for tumours especially in the solitary kidney.


Treatment of interstitial cystitis with immunosuppression and chloroquine derivatives. Azathioprine, an immunosuppressive agent, was given to 38 patients presenting with intestinal cystitis. Pain disappeared completely in 22 patients and pollakiuria did the same in 20 patients, including two very severe cases with very contracted bladder. Chloroquine or oxychloroquine, usually combined with salicylate, was given to 22 patients. Pain disappeared in 11 patients and pollakiuria in 4 patients. No effect was noted in 10 patients in the azathioprine group and in 8 patients in the chloroquine group. The remaining patients had partial alleviation. The results are analyzed separately for various grades of severity. Spontaneous cure can be expected only in 11% of cases of interstitial cystitis calculated from a large series. Immunosuppression or chloroquine derivates are indicated for patients who do not respond to other treatments.


Endocrine effects of oestrogen treatment in patients with prostatic cancer. In 36 men with prostatic cancer, the following findings were obtained: intravenous administration of 12.0 g diethylstilboestrol diphosphate (DSDP) induced a relatively slight decrease of the LH plasma level from 22.7 +/- 11.8 to 7.7 +/- 3.6 mIU/ml (34%), whereas the total testosterone plasma level decreased from 435.3 +/- 187.8 to 29.9 +/- 16.4 ng/100 ml (6.7%) suggesting a direct inhibitory effect of the oestrogen on testicular testosterone secretion. The apparently free, biologically active testosterone plasma level even decreased from 6.2 +/- 3.7 to 0.21 +/- 0.16 ng/100 ml (3.4%), due to the oestrogen-induced increase of the concentration of testosterone-binding beta-globulin (from 9.6 +/- 4.4 to 20.6 +/- 10.7-10(-8) M). 3--7 days after additional orchidectomy plus subcutaneous implantation of 100 mg dienoestrol diacetate a further decrease of the apparently free testosterone plasma level from 0.21 +/- 0.16 to 0.14 +/- 0.07 ng/100 ml was found. In contrast, 6 weeks after orchidectomy without oestrogen implantation a significant increase of th- apparently free testosterone plasma level -rom 0.21 %/- 0.16 to 0.34 +/- 0.15 ng/100 ml was observed (p less than 0.01). In view of these findings the biologically active free testosterone plasma level appears to be even more suppressed by intravenous administration of high DSDP than by orchidectomy. The most effective suppression of apparently free testosterone was achieved, however, by oestrogen treatment combined with orchidectomy.


Crystaloptical and spectroscopical findings with calcium oxalate crystals in the urine sediment: a contribution to the genesis of oxalate stones. Transmitted light microscope and scanning electron microscope investigations reveal various shapes of urine calcium oxalate crystals. In addition to tetragonal bipyramids, weddellite forms further crystal shapes that have been heretofore interpreted exclusively as whewellite crystals. Weddellite is stabilized by urine foreign ions. In vivo formation of whewellite crystals occurs with massive crystallization only.


Chemical sympathectomy with phenol for chronic prostatic pain. A case of chronic prostatitis where conventional chemotherapy and repeated transurethral resections failed to relieve pain is described. A cutaneous uretero-entero anastomosis was performed for troublesome pain and incontinence and only a permanent sympathetic block with phenol at the level of L4 achieved complete pain relief.


Nephroureterectomy in urinary tuberculosis. 130 total nephroureterectomies were performed for advanced renal tuberculosis with multiple ureteric stenoses. The important part played by ureteric lesions in maintaining vesical foci after simple nephrectomy is emphasised. The operation performed through the lumbar and intraperitoneal route does not carry any risk.


Evaluation of histological malignant stages of epithelial bladder tumours: a simplified classification. A simplified practical histological classification of four stages of bladder epithelial tumours is proposed in accordance with the terminology adopted by WHO. The structural characters of neoplastic elements are considered with respect to their relations with the basal membrane delimiting the epithelia. This criterion gives valid information regarding real malignancy of the tumour and may be applied to biopsies obtained endoscopically. This is very important not only with regard to prognosis but also to therapeutic indications.


Normal urographic findings in Nigerians. A review of excretory urographic studies in Nigerians at the Lagos University Teaching Hospital shows that the average renal lengths in adult patients is 12.2 cm. Male patients had slightly longer kidneys than females while the left kidney was longer and higher than the right in most cases and in both sexes. There was symmetry in the pelvicaliceal architecture of both kidneys of the same patient in 85% of cases while disparity in renal length for the same patient was less than 1.5 cm in 89% of cases. Pelviureteric duplication was seen in 4.4% of patients with a male to female ratio of 2:1. The results obtained for the Nigerian patients are not significantly different from those obtained by other authors on caucasians.


Ureteric obstruction associated with uterine prolapse. 14 cases of ureteric obstruction in patients with uterine prolapse are presented. The clinical, radiological, endoscopic and surgical observations are considered and discussed. Ureteric dilatation develops in two successive stages each of which has a different mechanism. In the first stage, stretching of the terminal ureter leads to a fusiform and gradual dilatation. In the second more advanced stage, caudal and posterior displacement of the trigone and bladder base leads to a rotation of the intramural ureter forming a sharp angle with the juxtavesical ureter, causing further ureteric obstruction. These observations emphasize the importance of urographical evaluation in patients with uterine prolapse.


The physiology and pathophysiology of the ureter. A review is given of the theories concerning the transport of urine from the calyces to the bladder. The application of hydrodynamic laws on the propulsion of urine, the visco-elastic characteristics of the ureter wall, the myogenic versus the neurogenic origin of spontaneous activity of the ureter and the presence of pacemaker areas, are discussed. The changes of peristaltic activity and intraluminal pressure during obstruction, infection and reflux are summarized.


Metabolism of digitoxin in man and its modification by spironolactone. The effect of spironolactone on the metabolism of intravenously administered 3H-digitoxin (80 muCi) was investigated in eight patients. In three of them the labelled glycoside was given on a second occasion after spironolactone treatment had been discontinued for at least 65 days. Of total urinary radioactivity 79% was unaltered drug and 12% consisted of water soluble compounds. No digitoxigenin or digoxigenin and only trace amounts (less than 2 %) of digoxin and the bis- and monoglycosides of digoxigenin were found. After spironolactone total urinary radioactivity was unchanged but the fraction eliminated as unchanged digitoxin fell from 79 to 66 % and the water soluble compounds increased from 12 to 26 % (p less than 0.05). In addition spironolactone caused a 20 ( reduction in the half-life of serum radioactivity (p less than 0.01) and a  16 % reduction in the volume of distribution (p less than 0.05). Induction of hepatic enzymes by spironolactone is proposed to explain the alteration in the metabolism of digitoxin in man. Both the altered metabolic pattern and the reduction in the volume of distribution appear to contribute to the reduction in half-life.


Mechanism of the interaction of propranolol and a potent vasodilator antihypertensive agent - minoxidil. A study, using non-invasive techniques, was carried out in ten patients with essential hypertension to examine the mechanism of the hypotensive effect of propranolol when used in combination with a potent vasodilator antihypertensive - minoxidil. The hypotensive effect of minoxidil, a mean (+/- SEM) decrease of 42.4 +/- 4.3 mm Hg, was accompanied by a marked increase in heart rate, cardiac index and plasma renin activity and a significant decrease in total peripheral resistance, limb vascular resistance and pre-ejection period. Addition of propranolol further reduced mean arterial pressure by an average of 12.9 +/- 2.0 mm Hg. Propranolol returned cardiac index to control values and total peripheral resistance index rose but not to control levels. Plasma renin activity was significantly reduced by propranolol. By multiple regression analysis no correlation was found between propranolol-induced decrease in mean arterial pressure and changes in cardiac index, total peripheral resistance index or plasma renin activity. Quantitatively, the reduction in cardiac index observed probably accounted for the hypotensive effect of propranolol. The role of plasma renin activity reduction in the hypotensive effect of propranolol in this situation remains to be clarified. The findings in the present study were consonant with the known actions of vasodilator antihypertensive agents and propranolol and indicate the applicability of non-invasive methodology to the investigation of cardiovascular drugs in man.


Observations on the efficacy and pharmacokinetics of sotalol after oral administration. The effects of sotalol after oral administration were measured on the tachycardia induced by strenuous exercise in normal subjects. Plasma sotalol levels were also determined. The oral administration of sotalol (50, 100, 200 and 400 mg) to 6 subjects produced a progressive reduction in the tachycardia induced by severe exercise. This was similar to the effects of 25, 50, 100, 200, 400 and 800 mg given to different subjects. Each increase in sotalol dose produced a successively greater reduction in exercise tachycardia. This did not appear to be maximum even with 800 mg. Oral sotalol was rapidly absorbed and produced peak blood levels in 2 - 3 hours. The plasma levels of sotalol measured 2 hours after the oral administration of 25 to 800 mg showed never more than a six-fold variation between different subject. The half-life of sotalol in plasma was 12.7 +/- SE 1.6 hours. There was a significant correlation between the logarithm of the plasma sotalol concentration and the percentage reduction of exercise heart rate. It is concluded that the oral administration of sotalol either once or twice daily (depending on dose level) will provide satisfactory 24-hour blockade of beta-adrenoceptors.


Bioavailability and pharmacokinetics of beta-methyldigoxin after multiple oral and intravenous doses. To obtain true half lives, glycoside elimination from six healthy subjects was studied for 14 days after multiple intravenous doses or oral administration of a daily maintenance dose of beta-methyldigoxin 0.3 mg. After oral or intravenous administration of beta-methyldigoxin ceased, the plasma concentrations declined from the 14th to the 16th days with a half life of 1.7 days. From the 16th to the 20th day a change from a shorter to a longer half life of 2.8 and 2.9 days was observed. Similar half lives were found in urine: after the last dose the initial slope from the 14th to the 16th day had a half life of 1.8 days, and the terminal slope had one of 3.2 days. The results indicate release of the glycoside from slowly equilibrating tissues.


Comparative clinical pharmacology of intravenous cefoxitin and cephalothin. Intravenous doses of 0.5, 1, and 2 g cephalothin and cefoxitin, a semi-synthetic cephamycin antibiotic highly resistant to bacterial cephalosporinase, were infused over a period of 3 minutes into 18 normal adult males by a randomized, crossover design. Serum and urine data on cefoxitin best fit a two-compartment open model. Serum concentrations following cefoxitin were higher and more prolonged and urine recoveries higher than those following equal doses of cephalothin. The terminal serum half-life of cefoxitin was longer at all dose levels. Renal clearance of cephalothin-like activity exceeded that of cefoxitin, which may possess dose-dependent kinetics. Whereas cephalothin has been reported to metabolize by greater than 35% to the less active desacetyl form, cefoxitin was metabolized by 0.1 to 6% to the descarbamyl form in individual subjects.


Plasma levels of carbamazepine and carbamazepine-10,11-epoxide during treatment of epilepsy. Carbamazepine and its epoxide in plasma were measured by liquid chromatography in 25 patients treated with a mean dose of carbamazepine of 12.5 +/- 3.3 mg/kg body weight. The mean concentrations of parent drug and metabolite were 5.4 +/- 2.5 mug/ml and 1.10 +/- 0.42 mug/ml, respectively. A singificant correlation was found between the plasma concentrations of the two compounds (r = 0.64; p less than 0.001), but marked interindividual variation existed in the ratio of carbamazepine to carbamazepine to epoxide. Based on simultaneous measurements in plasma and cerebrospinal fluid, the unbound fraction of carbamazepine in plasma was of the order of 20% as compared to 45% for the epoxide. Thirteen ambulant patients suffering from partial epilepsy with complex symptomatology, who were already being treated with phenytoin in optimal doses (plasma level 14-20 mug/ml) were also given carbamazepine. At plasma levels of the latter of about 5 mug/ml there was no further reduction in the frequency of partial or generalized epileptic seizures. In five patients the dose was increased to produce plasma concentrations of 7 - 8 mug/ml. There was still no improvement and side-effects were seen in three patients.


Some aspects of the intestinal absorption of zinc in man. Serum zinc concentrations in peripheral venous blood were determined in 8 healthy volunteers at various times after oral administration of 50 mg Zn++. The same dose was given to 6 patients surgically treated for obesity by jejuno-ileostomy. In the healthy volunteers the mean serum zinc concentration before dosing was 0.89 mug/ml and a mean peak concentration of 2.39 mug/ml was found after 3 h. In the patients the starting level was lower, 0.67 mug/ml, and a mean peak concentration of 1.31 mug/ml was found 90 min after treatment. In the patients the areas under the serum concentration-time curve was approximately 1/3 of that in the healthy subjects. Zn++ 50 mg was also given to 3 patients undergoing transumbilical catheterization of the portal vein for diagnostic purposes and serum zinc concentrations were measured in portal and peripheral venous blood sampled simultaneously. No significant differences were found between the concentration of zinc in portal and peripheral venous blood during absorption, which suggests slow passage of zinc across the intestinal wall.


Decreased drug binding in serum from patients with chronic hepatic disease. The binding of 3 drugs to serum proteins of patients with chronic hepatic disease has been studied by an ultrafilitration technique, and compared to that of normal subjects. The binding of phenylbutazone was reduced in all patients, salicylate in patients with inactive liver disease and sulphadiazine in patients whose disease was active. Analysis of binding data showed a real reduction in the capacity of albumin to bind the drugs in the majority of patients. Addition of bilirubin to normal plasma caused a reduction in sulphadiazine binding, but had no effect on the binding of salicylate or phenylbutazone. The possible causes of this reduction in binding are discussed.


Comparison of the acetylation of procainamide and sulfadimidine in man. The acetylation of procainamide and sulfadimidine has been measured simultaneously in plasma and urine in 20 healthy human volunteers by a specific G.L.C. method, after single and multiple oral dral doses of procainamide retard tablets. A distinct bimodality (9 rapid and 11 slow acetylators) was apparent from the concentrations of procainamide and N-acetylprocainamide both in urine and plasma, which was in complete agreement with data about sulfadimidine acetylation. The influence of acetylator phenotype on the relative concentrations of procainamide and N-acetylprocainamide in plasma as cn 5 additional healthy subjects after a single oral dose of procainamide. The present results show that acetylator phenotype can now be determined using procainamide as the test substance, and for this purpose multiple doses offer hardly any advantage over a single dose of the drug. However, because the separation between rapid and slow acetylators is less pronounced for procainamide than for sulfadimidine, precise criteria must be established for the conditions of the test, and the influence of diseases, such as renal insufficiency, should be taken into consideration.


The influence of disulfiram on the half life and metabolic clearance rate of diphenylhydantoin and tolbtamide in man. Diphenylhydantoin (DPH) and tolbutamide serum levels were studied in ten volunteers before and after 4 days of disulfiram treatment. The mean DPH half life increased significantly from 11.0 +/- a.2 h to 19.0 +/- 3.3 h, and the mean DPH metabolic clearance rate decreased significantly from 51.2 +/- 17.2 ml/min to 33.9 +/- 12.0 ml/min during medication. No significant changes in the half life or metabolic clearance rate of tolbutamide was observed.


Measurement of plasma levels of tricylic psychoactive drugs and their metabolites by UV reflectance photometry of thin layer chromatograms. A method has been developed for the determination of perazine, clozapine, imipramine and amitriptyline and their demethylated metabolites in plasma. Other metabolites measured were perazine sulfoxide and the N-oxides of clozapine and perazine, the latter two following their reduction to the parent drugs with ascorbic acid. 10-Hydroxynortriptyline was identified as an amitriptyline metabolite in plasma. The general procedure included extraction of alkalinized plasma samples (3 - 6 g) with benzene or toluene and thin layer chromatography of the extracts, followed by reflectance photometry of the plates at appropriate wave lengths in ultraviolet light. Spots of questionable identity were further characterized by two-dimensional chromatography and by colour reactions. Therecoveries of compounds added in therapeutic concentrations were between 70 and 98 %. The limits of detectability were 5 - 10 ng/g plasma.