Modification of cerebrovascular CO2 reactivity by inhibition of dopamine beta-hydroxylase. The influence of sympathetic nervous activity on cerebral circulation and cerebrovascular CO2 reactivity was investigated through inhibition of dopamine beta-hydroxylase (DBH). A PO2 electrode, a PCO2 electrode and a plate-type thermocouple-flowmeter were placed on the pial surface of the cat brain. Cerebrocortical PO2, PCO2, cerebrocortical blood flow and arterial blood pressure were continuously recorded before, during and after intracarotid infusion of 10 mg/kg of fusaric acid, a potent DBH inhibitor. The effects of 5% CO2 inhalation and hyperventilation were measured before and after the inhibition of DBH. Following the intracarotid infusion of fusaric acid, cerebrocortical PO2 and cerebrocortical blood flow increased significantly. After the inhibition of DBH, the degree of the increase in cerebrocortical PO2 during 5% CO2 inhalation was enhanced while the degree of the decrease in cerebrocortical PO2 during hyperventilation did not show any significant change. The cerebral vasodilatation caused by fusaric acid suggests that the sympathetic nervous system takes part in the resting tone of cerebral blood vessels. The increase in the cerebrovascular CO2 reactivity produced by the inhibition of DBH suggests that the sympathetic nervous system modifies cerebrovascular CO2 reactivity.


Tonate and Guama-group viruses isolated from mosquitoes in both a savannah and coastal area in Surinam. Isolation of arboviruses was attempted from October 1972 till the end of 1973 from mosquitoes caught in both a savannah forest near Powaka and a coastal area near "Fernandesweg" in Surinam. Two types of arbovirus were isolated: eleven strains of Tonate and ten strains of Guama-group. In the savannah area ten strains of Tonate and five of Guama-group were isolated, whereas in the coastal area the numbers were one and five, respectively. All strains in the savannah area were isolated from pools of Culex portesi. In the coastal area the strains were obtained as follows: one Tonate strain from a pool of Culex taeniopus, four Guama-group strains from pools of Coquillettidia venezuelensis, and one from a pool of Culex spp.


Body fluid oxygen tension and prognosis in patients with ruptured aneurysm. Body fluid gas pressure and electrolytes of patients with ruptured aneurysm were continuously analyzed. Intracranial pressure (ICP) was regulated at the level of 120-100 mm H2O by cerebral ventricular drainage. There was no significant change in the pH, PCO2, HCO3-, Na+, K+, Ca++ in the cerebrospinal fluid (CSF) of patients with slight or moderate disturbance of consciousness (lethargic-drowsy state). The PcsfO2 of the patients with marked disturbances of consciousness (semicoma-coma) was significantly low. PcsfO2 of the patients with cerebral vasospasm was significantly lower than for those without vasospasms. PcsfO2/PaO2 was 0.27 +/- 0.01 in the patients with vasospasm and 0.50 +/- 0.01 in those with vasospasm. PcsfO2 tended to decrease in patients with markedly bloody CSF. When the bloody CSF was cleared by ventricular drainage, PcsfO2 increased. PcsfO2 did not return to a normal value in the patients with marked disturbances of consciousness despite sufficient arterial oxygen tension. This suggests that PcsfO2 and PcsfO2/PaO2 should provide a convenient index for the prognosis of patients with ruptured aneurysm.


pH dependence of blood-brain barrier permeability to lactate and nicotine. Brain uptake of radiolabeled D and L-lactate, D-glucose and nicotine, as measured by the intra-carotid bolus method, was examined over a range of pH of the injected solution. The uptake of L-lactate was highest at pH 6.1, and lowered significantly at pH 7.2, 7.5 and 8.4. In contrast, the uptake of the D-enantiomer was not as dramatically affected. Glucose uptake was not affected by alterations in pH. Nicotine uptake decreased with pH reduction through a range of 8.3-4.2. These data suggest that it is the uncharged molecule which penetrates the blood-brain barrier by both carrier and lipid mediation. A mechanism relating to these observations is postulated and possible relevance to lactate washout from ischemic brain discussed.


Arterial air embolism in the cat brain.

Arterial air embolism in the cat brain. In cats air embolism of the brain was produced by injecting 0.6 ml blood foam into the innominate artery proximal to the origin of both common carotid arteries. Air embolism caused transient ischemia of the brain, reaching a maximum within 1 min after injection. Resolution of the air embolism began a few minutes later and was completed within 15 min in the center and within 30 min in the border zone of the main supplying arteries. During this phase tissue perfusion was inhomogenous with reduced flow rates in some areas and reactive hyperemia up to 300% in others. This resulted in venous hyperoxia and a decrease of arteriovenous oxygen difference to as low as 2 ml/100 ml blood. Reactive hyperemia was accompanied by brain swelling and an increase in intracranial pressure from 3.6 +/- 1.2 to 12.3 +/- 2.0 mm Hg. The reason for hyperemia was a decrease of cortical pH which fell from 7.33 +/- 0.03 to 7.03 +/- 0.05, and which caused a dilation of pial arteries up to 260%. Immediately after embolism, the EEG flattened and oxygen consumption decreased. After normalization of flow, oxygen consumption returned to normal, but EEG only partially recovered. Air embolism had little effect on the water and electrolyte content of the brain, and produced very little damage to the blood-brain barrier.


CO2-induced kidney calcification.

CO2-induced kidney calcification. Light microscopic examination of kidney tissue of guinea pigs exposed to 1.5% CO2, 21% O2, and balance N2 for periods as long as 42 days and of rats exposed to the same CO2 concentrations for up to 91 days showed that the incidence of focal kidney calcification increased with length of exposure. Calcification occurred primarily in the tubules of the renal cortex. Another group of guinea pigs were exposed to 1% CO2, 21% O2, and the balance N2 for periods up to six weeks and were later killed at regular intervals, together with control animals of the same litter. In the exposed animals, arterial PCO2 was elevated by 3-4 mmHg and hydrogen ions by about 4 nmol/liter. The standard bicarbonate level was lowered by 1-1.5 mmol, indicating a lack of renal reabsorption of bicarbonate (HCO3), which in turn placed greater stress on the bone buffer system and apparently caused bone calcium and phosphorus mobilization. Bone calcium and phosphorus levels exhibited a cyclic decrease, which resulted in cyclic hypercalcemia and hyperphosphatemia, after one week and six weeks of exposure to 1% CO2. Kidney calcium content increased significantly after two weeks of exposure (27%) and remained at this elevated level during subsequent exposures between the third and sixth weeks. These findings indicate that once the kidney calcification process has started, kidney mineralization is independent of fluctuations in the blood calcium level. A rise in plasma phosphate level that occurred after one day of exposure could have been a precipitating factor in the calcification process. The small but consistent increases in ionized calcium during a 4-week exposure to 1% CO2 may have stimulated the parathyroid, causing an increased blood calcium level that was independent of the two calcium tides in the blood associated with marked bone calcium loss.


Carbon dioxide and vitamin D effects on calcium metabolism in nuclear submariners: a review. Studies in nuclear submariners show that calcium excretion falls rapidly to 50% of pre-patrol levels during long patrols and remains low for many weeks after return to fresh air. This has previously been attributed to a specific effect of continuous exposure to the inevitably raised ambient CO2 levels, but other environmental factors cannot be ignored, in particular isolation from sunlight, which leads to reduced skin synthesis of vitamin D. The role of vitamin D is examined with reference to measured mean circulating blood levels of 25-hydroxyvitamin D at the beginning and end of a submarine patrol and in human exposure chamber investigations. It is concluded that although CO2 exposure has specific effects on calcium metabolism, causing a considerable reduction in urinary calcium excretion, a state of hypovitaminosis C occurs in long submarine patrols that has effects outweighing those of CO2 toward the end of patrols and afterward. The significance of this effect to submariners' health is discussed.


[Cause of failure in the surgery of renovascular hypertension]. The experience of 193 operations on 172 patients with affected renal arteries is described. The causes of failure in the surgery are analyzed. Organ-preserving operations with reconstruction of 189 renal arteries were performed on 136 patients. Primary nephrectomies were performed on 36 patients. During recent 3 years nephrectomies were made in 8% of 70 operations. Postoperative mortality was about 7%, mainly due to atherosclerotic patients. The main causes of uneffective operations are as follows: technical errors in revascularization of the kidney, pyelonephritis and neuroangiosclerosis non-diagnosed preoperatively, progressing lesions of the vessels in atherosclerosis and panarteritis.


The pathophysiological basis of fluid therapy in small animals. The principles underlying fluid therapy and their application to some medical problems in small animals are presented. The renal mechanisms which normally regulate the volume, electrolyte concentration and pH of extracellular fluid are reviewed. The major clinical disturbances are considered together with the specific means of correcting them by fluid therapy.


[Isolation of anti-foot and mouth IgG by means of affinity chromatography]. The coupling of the F. M. D. antigen with unsoluble CNBr-activated sepharose (2B or 4B) induced the production of an active agent with which the specific F. M. D. antibody of the investigated solution may covalently couple. Coupling procedures prove most effective with the use of buffer solutions of high ion strength that is necessary for the reduction of a protein-protein adsorption initiated by the polyoelectrolite nature of proteins. The produced complexes of the type CNBr activated sepharose--12C antigen--antibody after elimination of the unspecific serum proteins are dissociated up to the release of a specific IgG antibody.


[Dynamics of multiplication of BHK21C13 cells in a suspension]. In order to master a new method for the production of a F. M. D. vaccine the authors have studied the reproduction dynamics of BHK21C13 cells in the conditions of a suspension culture. The culturing of the cells has been carried out under laboratory conditions, investigating also the concurrent changes in the pH value along with the cell dynamics. The nutrient medium used and the conditions of cultivation has made it possible to study the properties and obtain a qualitative cell suspension. The cells obtained have shown equally good growth in a monolayer medium and in a suspension, and are appropriate for the reproduction of the F. M. D. virus.


[Breakdown of luliberin, somatostatin and substance P as an effect of hypothalamic endopeptidases]. Acid and neutral proteinases were isolated with the purpose of investigating their participation in the breakdown of hypothalamic peptides and proteins. The acid proteinase was purified about 1000-fold from hypothalamus by precipitation with acetone, chromatography on SP-Sephadex G-50, gel filtration through column of G-100 and chromatography on DEAE-Sephadex A-50. The molecular weight of the enzyme was approximately 50.000. Maximal activity against hemoglobin was obtained at pH 3,2--3,5: serum albumin was split much more slowly. Hypothalamus acid proteinase was partially inhibited by beta-phenyl pyruvate, benzothonium cloride, and was completely inhibited by low concentrations of pepstatin. This proteinase splits somatostatin, Substance P and some C-fragments of Substance P. The probable sites of enzyme action on these peptides were determined by the end group dansyl technique. Neutral proteinase was isolated from the supernatant fraction(100.000 g) of a 0,3 M sucrose homogenate of bovine hypothalamus by chromatography on DEAE Sephadex A-50, gel filtration through Sephadex G-100 and rechromatography on DEAE sephadex A-50 using luliberin as substrate. The rates of breakdown of luliberin and denaturated hemoglobin were measured by fluorometric estimation of acid-soluble peptides wieht o-phthaldialdehyde. The purifed enzyme preparations have a pH optimum of activity at 7--7,5. The enzymes molecular weight was approximatelyy 30--40.000. Enzyme activity was inhibited by L-1-tosylamide-2-phenylethylchloromethyl ketone, p-chloromercuribenzoate and divalent ions Co2+, Zn2+ and was significantly enhanced by dithiothreitol. The Km values for the reaction of hydrolysis of luliberin and hemoglobin were 1,33.10(-5) and 5,2.10(-5) M respectively. The neutral proteinase from the hypothalamus cleaves luliberin, somatostatin and Substance P. Sites of action of the enzyme upon those peptides were determined by means of the dansyl technique. The acid proteinase, most likely cathepsin D, and neutral proteinase from hypothalamus, may play an important role in the formation and breakdown of peptide hormones in the hypothalamus.


[Heterogeneity and regulation of glutamate dehydrogenase activity in mammalian brain and liver]. The present report concerns the study of the catalytic properties and the coenzyme affinity of glutamate dehydrogenase (GDH) and its isoenzymes in various preparations of the brain and liver as well as the different regulatory mechanisms controlling the ratio of the rates of biogenesis and breakdown of glutamate (Glu). The investigations carried out showed that GDH activity of various preparations of brain and liver (crystalline enzymes, cellular extracts and mitochondria) are markedly different from each other by their catalytic and regulatory properties as well as by their coenzyme activity. The data obtained make us conclude that nicotinamide-hypoxanthine-nucleotide (deaminoNAD) is a more effective coenzyme in the oxidative deamination of Glu, than other piridine nucleotides (NAD, NADP, deamino-NADP). It is supposed that in the formation of ammonia and amino acids in brain and especially liver, together with other known mechanisms an important role may be ascribed to the process of transdeamination. In this aspect, as a co-factor of oxidative deamination of Glu deamino-NAD (D-NAD) is thought to be of significant importance.


[Red cell metabolism and function in shock (author's transl)]. In patients with shock the metabolism and O2-function of the erythrocytes were studied following separation according to cell-age by density layer centrifugation using a new supporting medium. Metabolic acidosis in patients with postoperative shock (n=8) and in patients with shock due to severe congestive heart failure (n=12) provoked decreased levels of 2,3-diphosphoglycerate, ADP, ATP and reduced glutathione. Raised lactate/pyruvate ratios were observed also in both groups, whereas the O2-function of the erythrocytes was markedly disturbed in all patients. Patients of both groups received glucocorticoid-infusions resulting in a significant improvement of the extent and pattern of the red cell metabolic disorder.


[Radial hemolysis reaction with arboviruses]. A modification of the radial hemolysis test with arboviruses of the antigenic groups A and B was developed with Sindbis, Chikungunya, Venezuelan equine encephalomyelitis, West Nile, dengue 1 and 2 viruses. Goose erythrocytes were sensitized with hemagglutinating sucrose-acetone antigens of these viruses from mouse brains at pH optimal for each virus.


Multiple forms of soluble monophenol, dihydroxyphenylalanine: oxygen oxidoreductase (EC 1.14.18.1) from potato tubers (Solanum tuberosum). III. Influence of pH on the molecular weight distribution of enzyme activity in potato juice. Gel chromatography on Sepharose and on Sephadex was used to separate the soluble phenol oxidase in various potato juices into multiple molecular forms ranging from 36,000 to 800,000 daltons. Adjustment of potato juice from physiological pH (ca. 6) to pH 4.5 or to pH 7.8 resulted in the predominance of low-mol.-wt. (less than 150,000 daltons) or high-mol.-wt. (greater than 150,000 daltons) enzyme forms, respectively. This suggests association phenomena of subunits. In potato juice of physiological pH and in potato juice adjusted to pH 4.5, all enzyme forms exhibited both monophenol and o-diphenol oxidase activities (assayed at pH 6.0). In potato juice adjusted to pH 7.8 considerable loss of monophenol oxidase activity (assayed at pH 6.0) occurred. This suggests that o-diphenol oxidase is more alkali-stable than monophenol oxidase. The significance of these findings for enzyme purifications and for the in vivo action of the enzyme is discussed.


[Analysis of citric acid and citrates. Citric acid and urolithiasis]. In the first part the physico-chemical, analytic chemical and physiologic biochemical properties of the citric acid are discussed. In the second part the author enters the role of the citric acid in the formation of uric calculi. In the third part is reported on the individual methods of the determination of citric acid and the method practised in the author's laboratory is described.


[Analysis of oxalic acid and oxalates].

[Analysis of oxalic acid and oxalates]. It is reported on individual methods for the estimation of the oxalic acid in body fluids, particularly in the urine. The case in question is a survey of the oxalate estimation methods, which, however, has no pretensions to completeness. The at present most actualestimation methods are brought somewhat more in detail. The data are not sufficient for the laboratorytechnical performance of the individual methods, this would transgress the possibilities of the work. However, the original papers are cited which contain all the necessary details. Some technical difficulties and disturbances in the individual estimation methods are also entered. Despite excellent work of several teams the problems of standardization, of the absolutely reliable reference methoda as well as of an objective consideration of advantages and disadvantages of individual, often subjectively judged methods is not yet solved. Comparing these methods, one gets the impression that several reliable methods of the same value are established. It seems that this estimation method brings the greatest progress which will reliably establish so small quantities of oxalate as they are in the blood or in the liquor. By this also the oxalate clearance and the renal oxalate treatment becomes more exactly establishable than up to now.


[Culture and morphological characteristics of Haemophilus influenzae and pneumococcus in bronchial infection]. In the cultures obtained by inoculating sputum samples faken from patients with bronchial infection into solid agar medium prepared on Hottinger's hydrolysate with fresh rabbit blood added Haemophilus influenzae produced colonies varying in their from (dome-shaped, conical, trapeziform), as well as in the morphology of the organisms. Pneumococci produced mainly flat colonies surrounded by the zone of alpha hemolysis. Along-side with isolated H. influenzae and pneumococcal colonies, symbiotic colonies could be observed. In these colonies pneumococci were diffused among H. influenzae.


The presence of deoxyribonucleolytic activity in cytoplasmic ribosomes of rye (Secale cereale L) germs. Deoxyribonucleolytic activity was found to be associated with cytoplasmic ribosomes and ribosomal subunits of rye germs. The activity has the pH optimum at 5.0. Treatment of ribosomes and 60S subunits with 0.5 M-ammonium chloride released a considerable part of deoxyribonucleolytic and ribonucleolytic activity; treatment of 40S subunits resulted in a complete release of deoxyribonucleolytic activity and partial release of ribonucleolytic activity. This suggests the presence in ribosomes of rye germs of two types of nucleolytic enzymes: an enzyme of the nuclease I type with deoxyribonuclease and ribonuclease activities, and typical ribonucleases hydrolysing RNA only.


[Use of the serum enzymes gamma-glutamyl transpeptidase and pseudocholinesterase in hepatic pathology]. Serum gammaglutamyl transpeptidase (gammaGT) and seudocholinesterase (CHE) were studied in 20 patients with acute viral hepatitis and 36 with alcoholic cirrhosis. All had from moderate to severe clinical evolution. gammaGT is an enzyme useful to determine, as to follow clinical-biochemical evolution of viral hepatitis specially in the colestatic form. CHE can be used as an evolution pointer of liver insufficiency specially in cirrhosis.


Regional changes in monoamine synthesis in the developing rat brain during hypoxia. 4, 14 and 28 days old rats were exposed to hypoxic environment of 6% O2-94% N2 for 30 min. Tyrosine hydroxylase and tryptophan hydroxylase activity was studied in different brain regions (hemispheres, striatum, midbrain and brainstem in vivo by measuring the accumulation of dihydroxyphenylalanine (Dopa) and 5-hydroxytryptophan (5-HTP) respectively, after inhibition of aromatic L-amino acid decarobyxlase with NSD 1015. Tyrosine and tryptophan levels in the different brain regions were measured simultaneously. The tyrosine and tryptophan levels in the various brain parts were generally not influenced during exposure to hypoxia. Tyrosine hydroxylase activity decreased in most areas in the 4 and 14 days old rats, and all brain areas studied in the 28 days old rats. Tryptophan hydroxylase activity decreased markedly in all brain areas at all ages studied. It is concluded that the enzymes tyrosine hydroxylase as well as tryptophan hydroxylase seem to be equally affected during hypoxia in the different brain regions studied.


Effects of X-rays or aseptic inflammatory reaction on the circadian rhythm of tyrosine aminotransferase in mouse liver (TAT activity of mouse liver). Effects of x-rays or aseptic inflammatory reaction on the circadian rhythm of tyrosine aminotransferase in mouse liver (TAT activity of mouse liver). Acta physiol. pol., 1979, 30 (4): 479--487. The circadian rhythm of tyrosine aminotransferase (TAT) was investigated during 48 hours in the liver of mice subjected to: -- subcutaneous inflammatory reaction -- ionizing radiation. The cyclic changes in the circadian enzyme activity were described with a harmonic function. In relation to the control mice in the experimental mice statistically significant changes were demonstrated in the activity of tyrosine aminotransferase associated with desynchronization of the circadian TAT rhythm, particularly evident in the first hours of the first day of the experiment. The functions of enzyme activity changed in the second 24-hour period showed, both qualitatively and quantitatively, a tendency for a gradual return of normal TAT activity in the 24-hour periods.


Renal proximal tubular acidification. Role of brush-border and cytoplasmic carbonic anhydrase. Carbonic anhydrase is found in the cytoplasm and brush border membranes of renal proximal tubular cells. Both the soluble and the membrane-bound enzyme have been assigned roles for the secretion of hydrogen ions into the tubular fluid and hence also for the reabsorption of bicarbonate. Attempts were made to differentiate between the roles of these enzymes for the rate of proximal tubular acidification. Proximal tubules of rats were instilled and perfused with bicarbonate solutions containing carbonic anhydrase inhibitors, especially designed to be impermeable to cell membranes. The acidification rate was measured with an antimony micro-electrode system--the only instantly responding micro-pH electrode. The membrane impermeable inhibitors had no effect on this rate in contrast to acetazolamide, which markedly inhibited the acidification rate when administered intraluminally. It is therefore concluded that the cytoplasmic carbonic anhydrase is the important enzyme for the proximal tubular acidification rate, and hence the rate of bicarbonate reabsorption. The function of the brush border enzyme remains an outstanding problem.


Rumen motility in experimental acidosis of the rumen in sheep. In rumen acidosis, induced by infusion of saccharose solution and solutions of different volatile fatty acids and lactic acid into the rumen, and during induced disturbances of acid-base equilibrium in the arterial blood the motility of the dorsal sac of the rumen, the pH of rumen content and the indices of acid-base equilibrium in the arterial blood were investigated. The pH and the indices were determined by the micromethod of Astrup with an Acid-Base-Cart ABC-1 unit. During saccharose-induced acidosis of the rumen the pH of its content was decreased and its motility was strongly inhibited. Acidification of rumen content corresponded to the dissociation constant of a given acid. The motility of the rumen was inhibited most strongly by butyric acid, followed with regard of this effect by acetic acid, propionic acid and lactic acid. It was found that hydrogen ions as well as anions and non-dissociated forms of acids produced in the rumen were responsible for inhibition of this motility and that the rise in the concentration of hydrogen ions in the blood had no inhibitory effect on the motility of the rumen.


Renal function in hypercalcemic dogs during hydropenia and during saline infusion. The effects of calcium-gluconate infusions on renal function were studied in unanesthetised dogs. Each dog was studied during hydropenia and saline infusion. Hypercalcemia, mean serum calcium 3.85 mmol/l (hydropenia) and 3.62 mmol/l (saline infusion), increased fractional excretion of sodium (CNa/CIn), calcium (CCa/CIn), and magnesium (CMg/CIn). The increase was significantly higher in saline-expanded dogs than in hydropenic dogs. Fractional excretion of potassium (CK/CIn) was increased in hydropenia but remained unchanged in saline-expanded animals. Fractional excretion of phosphate (Cp/CIn) was not consistently changed by hypercalcemia. Fractional excretion of chloride (CCl/CIn) was markedly increased in saline-expanded dogs but was not changed in hydropenia. Urine osmolality was reduced in hydropenic dogs but unchanged in saline-expanded dogs. In hydropenic as well as in saline-expanded dogs tubular reabsorption of solute-free water (TcH2O/CIn) increased during the first hour of hypercalcemia. In hydropenic dogs hypercalcemia caused a slight but significant decrease in blood pH, standard bicarbonate, and base excess. In hydropenic as well as in saline-expanded dogs glomerular filtration rate (CIn), renal plasma flow (CPAH), and filtration fraction were unaffected.


Adaptive changes in cerebral blood flow and oxygen consumption during ethanol intoxication in the rat.. Cerebral blood flow (CBF) and oxygen consumption (CMRO2) were measured during acute and long-term ethanol intoxication in the rat. The purpose was to investigate whether the adaptive changes (development of tolerance) occurring in the CNS during ethanol intoxication were associated with changes in CBF and/or CMRO2. Consistent with other studies we found that acute severe ethanol intoxication (median blood alcohol concentration (BAC = 5.4 mg/ml)) caused a significant decrease in CBF and CMRO2. After 3-4 days of severe intoxication (BAC of 6.6 mg/ml) these physiological variables were less affected indicating that functional tolerance had developed: CMRO2 and CBF during acute ethanol intoxication were 9.3 ml/100 g/min and 60 ml/100 g/min respectively; after the long term intoxication period these variables reached 11.2 ml/100 g/min and 78 ml/100 g/min respectively, i.e. values not significantly lower than those of the control group. After induction of hypercapnia (PaCO2 about 80 mmHg) CBF increased by 360% in the control group; in the acutely intoxicated group CBF increased by only 127% and in the long term intoxicated group by 203% indicating that the cerebrovascular CO2-reactivity had also adapted to the ethanol intoxication. It is concluded that adaptive changes of the CNS to chronic ethanol intoxication comprise alterations in CMRO2, CBF and cerebrovascular reactivity.


Blood acid-base equilibrium in experimental acidosis of the rumen in sheep. Blood acid-base equilibrium in experimental acidosis of the rumen in sheep. Acta Physiol. Pol., 1979, 30 (4): 543--551. Experimental acidosis of the rumen was induced in sheep infusing into it through a fistula a solution of saccharose and solutions of different volatile fatty acids and lactic acid. Arterial-blood acid-base equilibrium indices were determined by the Astrup micromethod with an Acid-Base-Cart ABC-1 unit. It was found that during saccharose-acidosis partly compensated metabolic acidosis develops and that acid-base equilibrium disturbances are caused by all volatile fatty acids and lactic acid. When they are infused in equimolar amounts into the rumen the strongest and earliest disturbances in that equilibrium are caused by acetic acid, followed by butyric, lactic and propionic acids.


Effect of substance P on CCK- or VIP-induced choleresis in anesthetized dogs. 10 anesthetized dogs were provided with acute common bile duct fistulas and the gallbladder was excluded. Hepatic bile output and biliary content of sodium, potassium and amylase were studied. 6 caval infusions were administered of CCK, 0.3 Ivy U.kg-1.min-1, with a superimposed infusion of SP, 20 ng.kg-1.min-1. 7 caval infusions were given of VIP, 50 ng.kg-1.min-1, with a superimposed infusion of SP, 20 ng. kg-1.min-1. CCK increased bile output and biliary content of sodium, potassium and amylase by 78-110%. The corresponding increase induced by VIP was 55-85%. Biliary pH was not influenced. SP abolished the effects of both CCK and VIP. It is suggested that all peptides studied influenced canalicular bile secretion by changing the electrolyte excretion.


Retinal and choroidal contribution to retinal metabolism in vivo. A study in pigs. The glucose metabolism of the retina was studied in vivo, by determining glucose, oxygen and lactate a-v differences for choroidal and retinal blood in pigs at different levels of intraocular pressure. At normal intraocular pressure the choroidal a-v differences were 0.07 and 0.11 mmol/l for glucose and oxygen respectively. The corresponding figures for the retina were 0.44 and 2.15. At increased levels of intraocular pressure the choroidal and retinal glucose and choroidal oxygen a-v differences increased, thus at least partly compensating for reduced blood flow. A major part of the oxygen and glucose consumed by the retina was delivered by the choroid. The total amount of oxygen extracted from choroidal and retinal blood could only account for complete oxidation of 37% of the extracted glucose. The results obtained in determinations of lactate a-v differences indicate that part of the remaining glucose is used for anaerobic glycolysis.


Lithium effects: relation to lithium dose and to plasma peak levels. In a 24-hour study, plasma peak lithium was determined in manic-melancholic patients who routinely had their entire lithium dose at night. A correlation analysis was undertaken of the relation of plasma peak level and the dose of lithium to a number of lithium induced changes: Increase in urine volume, weight gain, decrease in plasm phosphate, increase in plasma magnesium, decrease in plasma urea, increase in plasma alkaline phosphatase, increase in urinary pH. Only the changes in plasma phosphate and in urine pH were significantly correlated to the peak value of plasma lithium. The increase in urine volume was significantly correlated to the dose of lithium.


Neuroleptic-potentiating effect of alpha-methyl-p-tyrosine compared with haloperidol and placebo in a double-blind cross-over trial. The hypothesis that schizophrenia results from overactive dopaminergic influences suggests that reducing dopamine synthesis may increase the clinical effects of dopamine receptor blocking neuroleptic drugs. The neuroleptic potentiating role of alpha-methyl-paratyrosine (AMPT), a tyrosine hydroxylase inhibitor, was compared with haloperidol and placebo in a double-blind cross-over trial. Both AMPT and haloperidol increased the anti-schizophrenic effect of neuroleptic treatment in reduced dose compared with placebo (P less than 0.05), though two patients relapsed during the AMPT period. Both drugs slightly increased extrapyramidal symptoms, but the effect was greater with haloperidol. The limited antipsychotic effect and the potential for aggravating neurological symptoms suggest that the combination of AMPT and neuroleptics does not offer a superior advantage to treating schizophrenia. AMPT, however, may still be used as a research tool in elucidating pathogenetic mechanisms.


In vivo and in vitro effect of cyclophosphamide on Borrelia duttoni. Sera taken from mice given cyclophosphamide 75 min previously fails to substantially inhibit borrelial multiplication in vitro. Mice given cyclophosphamide were infected with Borrelia duttoni. Inability to demonstrate specific antibody in these mice did not prevent recovery from infection, resolution of the bacteraemia or appearance of an antigenic variant. Cyclophosphamide may delete suppressor lymphocytes allowing enhanced production of antibodies which may not only protect, but induce antigenic variation. Alternatively, recovery from infection may be unrelated to the immune response.


Ticks and spirochetes.

Ticks and spirochetes. The concept is expressed that Borrelia developed as symbionts of ticks (especially Argasidae) but act as parasites in mammals and birds ... borrelial reservoirs and amplifiers following bites by infected ticks. Certain tick borreliae may multiply in lice but one Borrelia has evolved into a n independent species (B. recurrentis) associated only with lice and humans. Seventeen argasid tick species are known as vectors of Borrelia species and 4 ixodid tick species are known as vectors of B. theileri.


A method for macroscopic assessment of countries' receptivity to cholera. It was shown possible to assess macroscopically countries' receptivity to cholera through the use of two commonly available socio-economic indicators. The indicators used were per capita GNP and population density per km2 of inhabitable area. These are related respectively to two major determinants of cholera receptivity: standard of living and population congestion. The global assessment of cholera receptivity indicated the seriousness of cholera as a public health problem in Africa and Asia. It also showed that cholera epidemics are a potential danger to a majority of the population of Latin America.


The effect of oral pancreatic extract on jejunal bactericidal activity in protein-deficient vervet monkeys challenged with Vibrio cholerae. Eleven vervet monkeys (Cercopithecus aethiops) were fed with an "O" protein diet. After the serum albumin level fell below 2.5 g/100 ml the animals and 4 controls, which received regular monkey chow, were orally infected with a monkey-adapted strain of Vibrio cholerae. The total bactericidal activity of the jejunal fluid decreased during feeding with "O" protein diet, but increased after challenge with V. cholerae in all groups. The non-immunoglobulin-bound bactericidal activity, which also decreased during protein depletion, remained less in those animals receiving placebo instead of pancreatic extract after challenge.


Antigenicity testing of plain and aluminium hydroxide-adsorbed whole-cell cholera vaccines. The antigenicity of a plain and of an aluminium hydroxide-adsorbed whole-cell cholera vaccine was investigated by the active mouse protection test and the vibriocidal antibody production assay in mice. In the active mouse protection test, between the antigenicity of the Inaba and Ogawa component of the two vaccines was no significant difference. The antibody production test, however, revealed that the adsorbed vaccine elicited higher and longer lasting immune response than the plain one. The antibody response to a two-dose immunization schedule was substantially superior to that after a one-dose schedule.


Effect of intra-arterial injection of crude cholera enterotoxin on canine small bowel. Injection of a crude preparation of cholera enterotoxin into the superior mesenteric artery caused isotonic fluid secretion by the canine small bowel. In dogs previously exposed to cellular antigens of Vibrio cholerae, the time course of the intestinal response to intra-arterial injection of crude enterotoxin was similar to that observed after intraluminal exterotoxin challenge.


Resistance of gram-negative bacteria to antibiotics in large calf agglomerations. The antibiotic resistance of E. coli, Citrobacter, Enterobacter-Klebsiella and Pseudomonas aeruginosa strains isolated from calves was tested. A high proportion of multiresistance was found even in E. coli strains isolated from newborn calves. Gram-negative bacteria isolated from animals in three large calfhouses were almost 100% resistant to ampicillin, tetracyclines and sulphonamides. Multiresistance was general and varied from 5 to 12 antibiotics among different strains. Initial high sensitivity to antibiotics which had never been used before was observed. Antibiotic resistance rapidly increased after use started. The usefulness of antibiotics in E. coli induced diarrhea is questioned and oral rehydration is appraised.


Regulation of Leishmania populations within the host. IV. Parasite and host cell kinetics studied by radioisotope labelling. Tritiated thymidine pulse labelling followed by autoradiography has been used to analyse the kinetics of Leishmania donovani infections within the mouse host. Resistant strains of mice show much lower parasite proliferation rates than do susceptible strains. In chronic infections the rate is also reduced. Parasitised mononuclear phagocytes may undergo mitosis. No evidence for selective destruction of parasitised cells in chronic infections was found by labelling methods. It is possible to get parasite labelling in vitro immediately after biopsy to levels comparable to those seen in vivo.


[New aspects of the part of the vector played by Ixodes ricinus L. in Switzerland. Preliminary note (author's transl)]. The authors, after having recalled their recent work on Ixodes ricinus ecology, give the new results about the part played by this species in the transmission of different infectious agents in Switzerland. I. ricinus was already known to be the most important vector of the tick borne encephalitis virus, and of protozoans of the Babesia genus. In this article, we describe the existence in the hemolymphe of different I. ricinus populations, of a rickettsia species related to the RMST group (Rocky-Mountain Spotted Fever), of a trypanosome, which is close to T. theileri, and of an infectious larval form (L3) of Dipetalonema rugosicauda. An outline is suggested with the object of illustrating the functioning of a natural foci of tick encephalitis. The biological significance of the unusual presence of trypanosomes and of larval filariae in ticks is also discussed. The authors underline the fact that rickettsia, trypanosomes and filarial forms are observed for the first time in Swiss I. ricinus.


Comparative study on the anticellular and antiviral effects of interferon and the haemopoietic stem cell inhibition factor. Pretreatment with crude interferon preparations obtained from suspension cultures of bone marrow, spleen and thymus cells or from mouse L-cell cultures or with mouse serum interferon preparations did not change the colony-forming activity of bone marrow cells on syngeneic transplantation to lethally irradiated mice. Preparations of L-cell culture interferon, dialysed and purified by carboxymethyl-Sephadex (G-25) column chromatography, showed an inhibitory effect on exogenous colony formation by bone marrow cells. The results suggested the presence in crude interferon preparations of a substance either inhibiting the anticellular effect of interferon or stimulating colony formation. The factor produced by thymus cells following their treatment with antilymphocyte serum inhibited colony formation by bone marrow cells and, unlike interferon, possessed no antiviral activity when tested in cell cultures.


Dissociation of tick-borne encephalitis virus by Triton X-100 and cetyltrimethylammonium bromide. The uses of the nonionic detergent Triton X-100 (TX-100) and the cationic cetyltrimethylammonium bromide (CTAB) for the production of tick-borne encephalitis (TBE) virus subunits were compared. TX-100 splitted the virus into haemagglutinating envelope components which contain the virion proteins V3 and V1 and into a lipid-free nucleoprotein composed of RNA and V2. The lipid content of the released envelope fragments decreased with increasing detergent concentration. By the use of CTAB, the viral glycoprotein V3 could be prepared in electrophoretically pure and active, i.e. haemagglutinating form.


Electron microscopy of Akabane virus.

Electron microscopy of Akabane virus. Electron microscopy of negatively stained purified virus and of thin sections of infected cells and tissues showed Akabane virus being similar in morphology and morphogenesis to members of the family Bunyaviridae.


Antiviral activity of benzothiazole and benzothiazolinethione derivatives in cell cultures. The virus inhibitory activity of benzothiazole, benzothiazolinethione and naphthothiazole derivatives was tested with vaccinia virus, Newcastle disease virus (NDV) and western equine encephalomyelitis (WEE) virus in the agar-diffusion plaque-inhibition test. Among 58 compounds examined, 5 showed medium activity and selectivity with vaccinia virus. The highest selective effect was found with 3-(2-ethylthio-6-benzothiazolylaminomethyl)-2-benzothiazolinethione. A much lower inhibitory effect was observed with several derivatives against WEE virus. One derivative (2-mercaptobenzothiazole) showed a low inhibitory effect against NDV.


Inhibition of vesicular stomatitis virus multiplication in Vero cells by 2-deoxy-D-glucose. 2-Deoxy-D-glucose (DOG) effectively inhibited vesicular stomatitis virus (VSV) multiplication in Vero cells when pyruvate-containing medium was used as an energy source. The effectiveness of the antimetabolite was markedly reduced by substituting glucose for pyruvate in the maintenance medium. Addition of DOG at intervals during the viral growth cycle caused a notable decrease in viral yields. This inhibiting effect was reversed by mannose and to a lesser extent by glucose. VSV-RNA synthesis was greatly reduced, thereby eventually resulting in decreased levels of virus proteins. Polyacrylamide gel electrophoresis of purified VSV grown in medium containing pyruvate and DOG revealed the presence of two peaks in the region of the virus G protein. Possibly, DOG induces the synthesis of aberrant viral proteins which become incorporated into the viral membrane, resulting in noninfectious particles.


Sendai virus multiplication in the presence of ceruloplasmin and homologous virus envelopes. Preincubation of Sendai virus with ceruloplasmin induced in chorioallantoic membrane (CAM) fragments the synthesis of a population with decreased infectivity and high haemagglutinating (HA) and neuraminidase (NA) activities, whereas preincubation with solubilized virus envelopes led to the production of a viral population with the same infectivity as the control, but with lower HA and NA activities. Preincubation of the virus with a mixture of ceruloplasmin and solubilized envelopes depressed the overall virus synthesis; the resulting population had a low infectivity and high HA and NA activities. The variation in the HA/NA ratio indicates a modification in the envelope structure.


Analysis of herpes simplex virus isolated from patients with recurrent herpes keratitis exhibiting "treatment-resistance" to 5-iodo-2'-deoxyuridine. Four strains of herpes simplex virus (HSV) were isolated from two patients with recurrent herpes keratitis who failed to respond to 5'-iodo-2'-deoxyuridine (IDU) treatment. Two of the four isolates were highly resistant to IDU in cell culture and the other two isolates were more susceptible to IDU than an HSV-1 laboratory strain. From each patient, an IDU-resistant and an IDU-susceptible virus was isolated. All 4 isolates possessed the ability to induce the thymidine kinase (TK) activity in cell lines lacking that activity. All the isolates were type 1 HSV, since the filamentous structures, recognized as a biological marker of type 2 HSV, were not observed in infected cells.


Latent herpesvirus hominis 1 in the central nervous system of psychotic patients. Cerebrospinal fluids (CSF) from 35 patients with senile or presenile dementia and from 13 patients with schizophrenia and related syndromes were examined in cell cultures with the aim to isolate Herpesvirus hominis 1 (HVH 1) or other viruses. Serum and CSF antibodies to HVH 1 and/or interferon in the patients indicated a recent HVH 1 antigenic or viral activity. In the CSF of two senile demented patients and of one patient with schizoaffective psychosis, agents of low virulence, causing a cytopathic effect in 3 or 4, but not more, subsequent passages were detected and identified as HVH 1 by immunofluorescence. A focus of cells containing HVH 1 antigen at the cell membrane and in cytoplasm was visualized by immunofluorescence in an explant from nucleus amygdalae from 1 of 6 patients with schizophrenia and related syndromes examined. In the original biopsy materials, various virus-like structures were found in nuclei and cytoplasm of astrocytes and neurocytes and in axons in the neuropil.


Annual examination of influenza virus infection among pigs in Miyagi prefecture, Japan: the appearance of Hsw1N1 virus. Annual dissemination of swine and Hong Kong influenza viruses among hogs in Miyagi prefecture, Japan, was examined by virus recovery and serological tests. The serological examination revealed that two distinct influenza A viruses, H3N2 and Hsw1N1, had caused dual epidemic in pigs since mid-1977. Some individual sera contained antibodies against both strains. Although positive sera against Hong Kong or swine influenza viruses appeared in the serosurvey throughout the year, the positive ratios indicated a peak in the early spring of 1978. During this high prevalence period, positive sera against the H3N2 strain were found throughout the prefecture, but high incidences of Hsw1N1 virus were found only in limited areas to the north-east of Sendai City. Four strains of influenza A virus were isolated from bronchial swabs collected from hogs in April, 1978. These strains were identified as Hsw1N1 viruses and were closely related to the A/New Jersey/8/76 strain.


Heat-selected mutants of pigeon pox virus. Two mutants of pigeon pox virus were derived from virus isolated from naturally infected pigeons. One (S 39) was obtained by cultivation of the original virus in chick embryo chorioallantoic membranes at 39 degrees C, and the second (S m) by heating the original virus at 56 degrees C for 30 min. The mutants were less pathogenic to pigeons than the original virus. The original virus and the mutant S 39, but not the mutant S m produced plaques in primary chick embryo cell cultures. Pigeons inoculated with the mutants were resistant to challenge with the field virus.


Clearance of antibody and complement in serum after challenge of mice previously vaccinated or infected with influenza virus. Mice previously vaccinated or convalescent after infection with mouse-adapted influenza virus were challenged by various routes with live or inactivated virus. The levels of haemagglutination inhibiting and complement-fixing antibodies and complement in serum were found to decrease distinctly within several hours after challenge: the reconstitution to initial levels occurred within three days.


Viraemia in Clethrionomys glareolus -- a new ecological marker of tick-borne encephalitis virus. Viraemia was studied in adult Clethrionomys glareolus subcutaneously infected with 12 strains of tick-borne encephalitis (TBE) virus isolated in western and eastern foci of TBE. Nine strains caused viraemia regularly or irregularly, reaching titres higher than the threshold level of TBE virus infectivity for its vectors, ixodid ticks (2.5 -- 4.5 log LD50/0,03 ml) and three strains caused lower levels of hiraemia (0.4 -- 1.5 log LD50/0.03 ml). The ability or inability of various TBE virus strains to cause viraemia in adult C. glareolus in titres higher than the threshold level of infectivity for tick vectors was considered as an ecological marker of TBE virus. This marker was designated Cg: Cg+ and Cg- for TBE virus strains inducing respectively higher and lower levels of viraemia than the threshold of infectivity.


Jos virus infection in domestic animals and primates. Pathogenicity and immunological studies. Three species of domestic animals (rabbits, sheep and goats) and two species of primates Erythrocebus patas monkeys and baboon (Papio anubis) were infected with Jos virus. None of the infected animals developed viraemia or overt clinical disease. Complement-fixing and neutralising antibodies were demonstrated in sera of infected animals.


Heterotypic interference between influenza viruses A/Aichi/2/68 and B/Massachusetts/1/71. Virus particles produced by MDCK cells mixedly infected with 3 PFU/cell each of A/Aichi/2/68 (H3N2) (Aichi) and B/Massachusetts/1/71 (Mass) influenza viruses exclusively possessed haemagglutinin (HA) of Mass, although approximately one-fifth of the mixed yield had coding potential for Aichi serotype. Synthesis of major viral proteins of Aichi was markedly suppressed by co-infecting Mass. By increasing the multiplicity of co-infecting Aichi to 30 PFU/cell, interference became reciprocal. Aichi interfered with replication of Mass more severely than Mass did with replication of Aichi. All the major viral proteins of both Aichi and Mass were expressed within the infected cells.


Inhibition by Coxiella burnetii of ascites tumour formation in mice. Mice injected intraperitoneally (i.p.) with killed purified Coxiella burnetii organisms were protected from ascites development and death caused by i.p. inoculation of sarcoma-180 cells. The extent of protection was a function of the relative dose of C. burnetii and tumour cells, and of the time of injection of C. burnetii. Phase II C. burnetii organisms exerted an antitumour protection at least as high as phase I C. burnetii organisms.


Inefficacy of digitalis in the control of heart rate in patients with chronic atrial fibrillation: beneficial effect of an added beta adrenergic blocking agent. The role of digoxin and the new beta adrenergic blocking agent, timolol, in controlling heart rate at rest and during exercise was investigated in 28 patients with chronic atrial fibrillation. Digoxin failed to prevent excessively rapid heart rates during mild to moderate exercise. Increasing digoxin blood levels from a mean of 0.6 to 1.8 ng/ml had no effect on heart rate either at rest or during exercise. The addition of timolol, 20 to 30 mg/day, resulted in a satisfactory and significant attenuation of the rapid heart rates both at rest and during exercise. Heart rates at rest were 91 and 98 beats/min in the patients with low and high digoxin dosage and rose to 135 and 139 beats/min, respectively, during exercise. Timolol reduced the heart rate to 67 at rest and to 92 beats/min during exercise. The effect of beta adrenergic blockade at rest was less pronounced in patients whose initial heart rates were below 90 beats/min. Digoxin alone may not suffice to control excessive heart rate in patients with chronic atrial fibrillation. The additional beta adrenergic blockade actually normalizes the heart rate response in these patients.


Arysulfatase A modulation with pH in multiple sulfatase deficiency disorder fibroblasts. It has been observed that multiple sulfatase deficiency disorder (MSDD) fibroblasts contained from profoundly deficient to near normal amounts of arylsulfatase (ARS) A depending on the medium in which they were cultured. Our present findings show that the major factor determining the enzyme level is the pH of the medium during growth. In media which became acidic or was maintained at low pH (less than 7), the cells expressed the enzymopathy, while in high pH media (7.4), the cells produced enzyme. The high and low enzyme states were reversible. The ARS A deficiency in MSDD must, therefore, be a secondary manifestation of a mutation in another system.


Preparation of cardioplegic solutions.

Preparation of cardioplegic solutions. The manufacturing methods and quality control procedures for two cardioplegic solutions are described. Procedures for preparing individual bottles or batches of two cardioplegic solutions (one with and one without albumin) and a carbonate-bicarbonate buffer solution are described. Final buffered cardioplegic solutions with albumin are stable for seven days. Cardioplegic solutions without albumin and buffer are stable for 30 days. The chemical and physiological factors affecting the content and preparation of cardioplegic solutions used during intracardiac surgery are reviewed. Because consistency is attained more readily, and because control procedures, including quarantining, are applied more readily to batch production of cardioplegic solutions, it is advised that this method be used.


Selective IgA deficiency and circulating immune complexes containing bovine proteins in a child with chronic graft versus host disease. We have previously shown that a selective absence of serum and secretory immunoglobulin A (IgA) may lead to the development of circulating immune complexes which appear to contain bovine milk antigens. We report here that high levels of circulating immune complexes were found in the serum of a child who was treated for severe combined immunodeficiency by bone marrow transplantation but in whom the IgA-producing cells subsequently failed. As increasing amounts of complexes appeared over a two year period, the child had a parallel progression of an apparent chronic graft versus host disease including a Sjögrens syndrome and scleroderma. Very large amounts of complexes were eventually formed but the level fell 77 per cent after milk was excluded from the diet. Chemical studies on the complexes showed that the majority of complexes did contain bovine milk proteins, and fluorescence antibody staining of skin biopsy samples showed the presence of dense deposits of bovine casein in the dermis. The relationship between bovine protein-antigen antibody complexes and the chronic graft reaction remains uncertain.


Choline chloride in schizophrenia.

Choline chloride in schizophrenia. The authors investigated the possibility that choline chloride might reduce schizophrenic symptoms by increasing central cholinergic activity. In a single blind crossover study, up to 20 g/day of choline chloride had no significant effect on clinical ratings of nine schizophrenic patients. However, there was some evidence that choline significantly increased symptoms of depression.


A method for the isolation and identification of dengue viruses, using mosquito cell cultures. An improved method for the isolation and identification of dengue viruses is described. Viruses were isolated in mosquito cell cultures (C6/36 or AP-61), identified by indirect fluorescent antibody technique, and typed by complement-fixation test, using the cell culture fluid as antigen. The sensitivity of this method was compared with mosquito inoculation in comparative titrations of 16 low passage dengue virus strains. Although lower virus titers were obtained by the mosquito cell culture technique, its decreased sensitivity was compensated for by the much larger volume (588X) which could be assayed. By incubating the mosquito cells at 32 degrees C, dengue viruses can be identified and typed within 6 days after inoculation.


Patterns of postcibal gastroesophageal reflux in symptomatic infants. Symptomatic infants displayed three patterns of gastroesophageal reflux after drinking apple juice (20 ml/kg or 300 ml/m2 of body surface area). The type I pattern occurred in patients who had continuous postcibal gastroesophageal reflux, large hiatal hernias and frequently required an antireflux operation. A functional motility disorder suggesting delayed gastric emptying appeared to be important in infants with discontinuous reflux (type II pattern). These infants had frequent gastroesophageal reflux for only 2 3/4 hours postcibally, antral-pylorospasm, increased low esophageal sphincter pressures, and a high incidence of pulmonary symptoms and non-specific watery diarrhea. The mixed (type III) pattern of gastroesophageal reflux occurred in a small number of infants and exhibited features of both type I and II patterns.


The fat embolism syndrome treated with oxygen, diuretics, sodium restriction and spontaneous ventilation. The fat embolism syndrome is a self limiting disease with its mortality related to the degree of respiratory failure. Treatment therefore is directed at maintaining satisfactory pulmonary gas exchange throughout the course of the disease. In 28 consecutive patients diagnosed with fat embolism syndrome and severe respiratory failure, therapy consisted of oxygen, diuretics, sodium restriction and a trial of spontaneous ventilation. There was no mortality.


Blood and ruminal fluid profiles in carbohydrate-foundered cattle. The relationships of acetylhistamine and histamine to the clinical signs of carbohydrate-induced acidosis were investigated in beef steers. Blood pH and plasma L-lactic acid decreased and serum sodium, serum potassium, ruminal fluid L-lactic acid, ruminal fluid histamine, and ruminal fluid and blood acetylhistamine increased in carbohydrate-engorged steers as compared with the changes in the steers while feeding on pasture (forage-fed steers). Twelve to 14 hours after the steers had become engorged, clinical signs of laminitis ("feedlot founder") were observed in three of six steers. These signs appeared 4 to 6 hours after blood acetylhistamine attained maximal concentration (2.9997 +/- 1.7054 microgram of histamine base/ml of blood) and blood pH decreased to 7.260 +/- 0.026 at 8 hours after engorgement. Blood histamine value reached 0.1298 +/- 0.1095 microgram of histamine base/ml 4 hours after engorgement (8 to 10 hours before the appearance of clinical illness), but had reached maximal concentration 32 hours after engorgement (0.3300 +/- 0.028 microgram of histamine base/ml of blood).


Comparison of capillary ear blood and arterial blood to validate capillary sampling as an accurate assay of blood gas in swine. Capillary sampling in swine can be performed as an accurate assay of arterial blood gases. Studies with swine provided results similar to, or slightly more favorable than, those reported for human beings, depending upon which cutaneous technique was used on human beings. On the basis of free flow or arterilization of the cutaneous sample and of the correlation between capillary and arterial pH, CO2 partial pressure (PCO2), and O2 partial pressure (PO2) values, the capillary sampling technique of complete incisement of a 2-mm section from the tip of the warmed porcine ear could be a substitution technique for arterial blood sampling. Free flow with this technique was maximized and high correlation coefficients (r) for pH (r = 0.96), PCO2 (r = 0.82), and PO2 (r = 0.90) capillary-arterial values (n = 37) were obtained.


The effects of unanesthetized arterial puncture on PCO2 and pH. Painful unanesthetized arterial puncture may produce transient hyperventilation, and this hyperventilation might alter resting values of arterial pH and PCO2. We investigated this possibility by comparing pH and PCO2 values of blood samples obtained by arterial puncture with values of arterialized venous blood obtained by a painless method. In 19 consecutive subjects, virtually no difference in pH or PCO2 resulted from an arterial puncture that could not be attributed to the inherent precision of the measuring instrument. Mean +/- SEM pH was identical (7.45 +/- 0.05) both before and during an arterial puncture, as was PCO2 (34.4 +/- 1.2 mm Hg). The variation (SD) in PCO2 within an individual subject was +/- 1.7 mm Hg, which was almost identical to the inherent precision of the Radiometer ABL-2 acid base laboratory (SD, +/- 1.32). We conclude that an unanesthetized arterial puncture provides an accurate measurement of resting pH and PCO2.


Ionized calcium levels in critically ill surgical patients. Ionized calcium levels measured in 74 critically ill surgical patients averaged 1.97 +/- 0.25 mEq/l, significantly lower than the average (2.26 +/- 0.14) in 34 healthy individuals. The mortality rate increased as ionized calcium levels decreased. Of four patients with ionized calcium levels lower than 1.40 mEq/l, none survived. The average total calcium (4.0u mEq/l) in the critically ill patient was also significantly lower than in controls (4.55 +/- 0.40 mEq/l). The albumin levels were severely reduced (2.80 +/- 0.59 mg/dl) in the patients and significantly lower than in controls (5.31 +/- 0.53 g/dl). There was, however, no correlation between ionized calcium and albumin. Although measured ionized calcium levels correlated with the total calcium level (r = 0.56) and with estimated ionized calcium levels (r = 0.53), it must be emphasized that severe ionic hypocalcemia may occur despite normal total or calculated ionized calcium levels. Consequently, it is hoped that all hospitals with critically ill patients will soon have this analysis available.


[Kawasaki's disease. a case presentation]. A case of Kawasaki's disease in a girl of 2 10/12 years of age is presented. She had a typical clinical picture, without cardiovascular afectation, and with good final results. Apparently this is the third case reported in the Spanish medical literature. Attention is called to the low incidence of MLNS in the western countries--only 50 cases reported--as compared with the great number reported from Japan. The problems of diagnosis and pathogeny are discussed, particularly their intimate relation to infantile polyarteritis nodosa, because of the similarities in the cardiovascular alterations in both processes, above all in mortal cases.


Labetalol as a hypotensive agent in otological operations. The usefulness of labetalol, a new combined alpha and beta adrenoceptor antagonist as a hypotensive agent in otological operations was studied in 18 otherwise healthy patients. After a single 1.0 mg/kg i.v. dose the maximum decrease in systolic (18%) and diastolic (8%) blood pressure occured between 5 to 15 minutes (mean 11 min), and the pretreatment blood pressure values were reached in 15 to 55 min (mean 26 min). Similarly, after a single 2.0 mg/kg i.v. dose the maximum blood pressure decrease (32%/20%) was observed in 5 to 40 minutes (mean 23.5 min) lasting 30 to 95 minutes (mean 60.1 min). Generally, a moderate decrease in blood pressure without a concomitant increase in heart rate or excessive hypotension was found.


[Penicillin biosynthesis and amino acid metabolism in Penicillium chrysogenum in experiments with washed mycelium]. The study of the amino acid metabolism in Penicillium chrysogenum with the use of washed mycelium showed that the amount of the free intracellular amino acids significantly decreased during the process of penicillin production. Still, such a decrease did not cover the nitrogen requirements of the culture for the antibiotic synthesis and mobilization of the protein nitrogen took place. By the end of the process the amount of the protein nitrogen markedly decreased. At the same time alpha-amino nitrogen was absent in the fermentation broth filtrate. About 14 amino acids (including cysteine and valine) which participate in constriuction of the penicillin molecule nucleus were found in the amino acid poll. However, the amounts of cysteine and valine were not high and probably other free intracellular amino acids participated in their synthesis. It was shown that one of the limiting factors in the process of penicillin biosynthesis was synthesis of cysteine, a sulphur-containing amino acid which is one of the precursors of the antibiotic molecule nucleus.


[Effect of amino acids on the growth of a B. polymyza 1538 culture and the biosynthesis of polymyxin B]. The effect of a number of the most important amino acids on the growth of B. polymyxa 1538 and polymyxin B biosynthesis was studied. It was found that all of the amino acids tested except D-L-threonin and L-alpha-gamma-DABA inhibited the initial growth of the organism. D-L-threonine and L-alpha-gamma-DABA had some stimulating effect on the culture growth without affecting the final accumulation of the biomass. The antibiotic synthesis proceeded more vigorously when the medium contained D-L-threonine, L-alpha-gamma-DABA, L-asparagine, L-proline, L-glutamine, D-L-asparaginic acid and L-glutamic acid in the concentrations tested. Neither of the tested amino acids used alone or in combination provided the levels of polymyxin B biosynthesis observed on the media containing rich sources of organic nitrogen.


Comparison of cefamandole nafate to cefamandole by microbiological assay. Before microbiological assay, cefamandole nafate should be hydrolyzed for 1 h at 37 degrees C in pH 8 buffer (0.1 M) or for 30 min at room temperature in aqueous solutions containing 1.25 molar equivalents of sodium carbonate.


Dissolution of bilateral staghorn cystine renal calculi. Bilateral staghorn renal calculi in a 7-year-old girl with cystinuria were dissolved over a period of 6 months, using a high fluid intake, urinary alkalinisation, and D-penicillamine. Even in children with extensive cystine urolithiasis, medical management may avert the need for surgery.


Takayasu's arteritis as a differential diagnosis of systemic juvenile chronic arthritis. After a series of throat infections an 8-year-old girl presented with fever and limb pain, initially diagnosed as juvenile chronic arthritis. Persistent symptoms led to further investigations when she was shown to have an arteritis affecting her aorta.


Effects of clonidine, guanfacine and three imidazolidine derivatives related to clonidine on blood pressure, heart rate and gastric acid secretion in the anaesthetized rat. The effects of histamine, guanfacine, clonidine (2,6-dichlorophenylimino-2-imidazolidine) and the 2,6-dibromo, 2,3- and 2,5-dichloroanalogues of clonidine were assessed on blood pressure, heart rate and gastric acid secretion in the anaesthetized rat, with lumen-perfused stomach. Histamine (100 microgram/kg to 1 mg/kg) and clonidine (250 microgram/kg to 1 mg/kg) each caused acute increases in acid secretion, the magnitude and duration of which were dose-dependent: the secretory effect of clonidine was blocked by cimetidine (2 mg/kg). Histamine produced a short-lasting hypotension with no effect on heart rate, whereas clonidine produced an initial transient rise followed by a prolonged fall in blood pressure accompanied by a marked bradycardia. Guanfacine and the three clonidine analogues all produced cardiovascular effects similar to those of clonidine; however, only the 2,6-dibromo analogue increased gastric acid secretion. These results confirm previous findings using guinea-pig atria that only imidazolidine derivatives with 2,6-substitution in the phenyl ring activate histamine H2-receptors mediating gastric acid secretion in the rat; this is not so for the hypotensive and bradycardic effects of the compounds.


The pharmacological profile of a potential hypnotic compound RU 31158. RU 31158, 6-(orthochlorophenyl)-1, 2-dihydro-2 (N-methylpiperazine-1-yl) methylene-8-nitro-IH, 4H-imidazo [1,2-a] [1,4] benzodiazepin-1-one methanesulphonate, demonstrated potent hypnotic activity compared to diazepam when examined in the mouse and rat. RU 31158 potentiated minimal hypnosis in mice induced by both hexobarbital and chlorprothixene with ED50 values of 2.15 (1.53-3.01) and 0.69 (0.46-1.02) mg/kg p.o. respectively; these compared to values for diazepam of 17.00 (11.25-25.67) and 3.60 (2.25-5.76) mg/kg p.o. RU 31158 also potentiated hexobarbital in the rat with an ED50 value of 1.2 (0.7-2.0) mg/kg p.o. as compared to 32.0 (27.5-38.5) mg/kg p.o. for diazepam. Sleep studies in the rat confirmed the hypnotic properties of RU 31158, and also showed that the duration of action at 8.0 and 16.0 mg/kg p.o. was not longer than 9 hours. RU 31158 also showed potent minor tranquilizer, anxiolytic, and anti-convulsant properties in a series of pharmacological tests.


Hypotensive action of OPC-1427, a new beta-adrenergic blocking agent in rats. 8-Acetonyloxy-5-[3-(2-(3,4-dimethoxyphenyl)-ethylamino)-2-hydroxypropoxyl]-3,4-dihydrocarbostyril (OPC-1427), is a newly synthesized cardioselective beta-adrenoceptor blocking agent and we examined the effects of this compound given intraperitoneally to consious Kyoto Wistar normotensive (WKR), spontaneous hypertensive (SHR) and DOCA-NCl hypertensive (DOCA rat) rats. The results were compared to findings with propranolol and practolol. OPC-1427 produced a significant hypotensive action in SHR and DOCA rats and this effect was less in WKR. With propranolol and practolol effective hypotensive effects were seen in WKR and DOCA rats but not in the SHR. The efficacy of the hypotensive action of these agents was propranolol greater than OPC-1427 = practolol in WKR, OPC-1427 greater than practolol in SHR, and OPC-1427 greater than practolol = propranolol in DOCA rats. Thus OPC-1427 appears to be a promising beta-adrenoceptor blocking agent which exerts a hypotensive state, as demonstrated in hypertensive rats.


[Biological determination of the beta blocking activity of human serum]. A method of biological assessment of the Beta blocking activity of human serum is reported. It is based on the catecholamine response of rat myocardial cells in culture, incubated in the serum to be tested. Its advantage is that it takes into account all block-blocking substances present in the serum, not only the drug itself but also its possible active metabolites. The results obtained by this method in 10 healthy subjects after 60 mg penbutolol were compared with those given by chemical dosage and ergometry. The ergometric and biological changes were parallel from the 2nd and the 8th hour while the serum levels of the drug rapidly. This discordance could be due to the presence of an active metabolite, 4-hydroxy-penbutolol.


[Unstable angina with threatening coronary lesions turned down for surgery. Outcome and prognostic factors]. The aim of this study based on a series of 200 patients, was to define the outcome and the prognostic factors of patients presenting with unstable angina, according to Bertolazi's criteria [3] and at least one stenosis greater than 80% on a proximal segment of a main coronary trunc, and to determine which factors should eventually be taken into consideration in the discussion of surgical indications. 70 out of 200 patients (35%) were turned down for direct revascularisation surgery because of an ejection fraction less than 0,35 and/or a poor arterial run off. Coronary arteriography showed 30% patients with a menacing stenosis (greater than 80%) on all three vessels, 36% on two vessels and 22% on a single vessel. The distribution and the extent of the lesions was about the same as in the operated patients. 20% patients had an ejection fraction less than 0,35, 24% between 0,34 and 0,50, and 56% greater than 0,50. At patient, the follow up period ranges from 22 to 66 months (average 32 months). In this group, the hospital mortality was 2,9%, the secondary cardiac deaths 16% and the global mortality 19% compared to 12,6% for the operated patients in the same period. The incidence of secondary non-fatal infarction was low (9%). 52% of survivors have persistent angina, 39% severe (Class II or III). Two prognostic factors were detected from this study: the type of angina: the intermediary syndrome had a bad prognosis, 38,5% mortality compared to 13% for aggravated chronic angina; and the ventriculography: patients with ejection fractions less than 0,35 had 64% mortality compared to 7,3% for those with ejection fractions greater than 0,40. The number of menacing lesions, the extent of the lesions of the artery involved did not affect the prognosis when severe abnormalities of left ventricular function were absent.


[The activity and properties of fructose-1,6-diphosphatase in various tissues (Liver, Kidneys, skeletal muscle, small intestine mucosa) in swine]. The following parameters are recommended for activity determination of FDPase by release of inorganic phosphate at 37 degrees C of enzyme from liver and kidneys of swine: pH 7.5, 2 mMol concentration of fructose-1,6-diphosphate, 5 mMol concentration of Mg ions, and ten minutes of incubation. When the activity of FDPase was analysed with temperatures of 22 degrees C, and 45 degrees C, rises were recorded up to the highest temperature. ADTA was strongly activating along with 2 mMol of Mg ions in a test arrangement of 5 mMol concentration. Manganese, zinc, and cobalt ions are strong activators even in low concentrations (0.2 or 1.0 mMol), whereas copper, cadmium, and mercury ions are strong inhibitors of the enzyme. Average activities of FDPase were analysed by means of the optical test in the liver and kidneys of fetuses aged 98 days. They were 1.79 or 0.38 units in one gram of tissue. In pigs for slaughter they had been 2.06 or 3.58 units in one gram of tissue.


Activation of rotavirus RNA polymerase by calcium chelation. Two types of particles were isolated during purification of rotavirus. Dense (D) particles have a density of 1.38 in CsCl and exhibit spontaneously a fully active endogenous transcriptase. Light (L) particles (density of 1.36 in CsCl) need to be treated with chelating agents to show a polymerase activity. The activation process of L particles was studied under strictly controlled monovalent, divalent, and hydrogen ion concentrations. These experiments demonstrate that i) activation is not affected by the ionic strength ii) activation occurs only at a pH higher than 7.1 iii) a low concentration of chelating agent (40 muM EDTA) is sufficient to activate the enzyme. Treatment of particles with EGTA, which chelates selectively Ca2+, leads to unmasking even in the presence of magnesium, indicating that the concentration of free calcium ions plays a major role in the activation process. Various glycosidases, detergents, and chelating agents were tested in respect to unmasking properties. Of these compound only chelating agents turned out to be efficient. Following activation, two glycopeptides were solubilized. These glycopeptides have an apparent molecular weight of 34,000 and 31,000 daltons and react with concanavalin A. The role of Ca2+ upon the stability of virus particles, and the activation of the endogenous transcriptase in vitro and in the infected cells is discussed.


Isolation of the structural proteins of western equine encephalitis virus by isoelectric focusing. Western equine encephalitis virus was disrupted with Triton X-100 and subjected to isoelectric focusing in a sucrose or urea gradient. The two envelope proteins, E1 and E2 were not well separated in a sucrose gradient, while the E1 and E2 proteins were distinguished as two major peaks which focused in a urea gradient at about pH 7.5 and 10, respectively. Isolated E1 protein refocused at pH 6.5 in a sucrose gradient isoelectric focusing column. When Western equine encephalitis virus was treated with Triton X-100 in 0.01 M phosphate buffer (pH6), hemagglutinating E1 protein was solubilized, which isoelectrofocused at pH 6.5. Purified nucleocapsids focused at pH 4 in a sucrose gradient on an isoelectric focusing column. After ribonuclease treatment of the purified nucleocapsid more than 95 per cent of the viral RNA was acid-soluble, and hte nucleocapsid protein isoelectrofocused at about pH 4.


Terminal transferase-like activity in human melanoma cells. An enzyme activity, capable of attaching deoxynucleotides to single-stranded oligonucleotide primers, has been detected in extracts from cultured melanoma cells. The substrate preferences of this activity show it to be distinct from the calf thymus terminal transferase (EC 2.7.7.31).


Oral pindolol in acute evolving myocardial infarction. Pindolol was administered orally (5 mg 8th-hourly) to 30 patients 5--19 (mean = 9.0 hrs) hours after onset of acute myocardial infarction. There were no serious side effects during the acute phase of infarction, only one hospital death and two late deaths at follow-up 2--82 (mean = 37 wks) weeks after hospital discharge. In contrast to healthy volunteers, patients with acute infarction had unpredictable absorption of pindolol from the gastrointestinal tract; this was attributable in part to concurrent administration of narcotic analgesics.


Review: the significance and management of raised blood pressure in pregnancy. Recent advances in the diagnosis, management and prognosis of hypertension in pregnancy are discussed, with emphasis on antihypertensive drug treatment. The use of diuretics, alpha-methyldopa, clonidine, hydrallazine, beta-adrenergic blockers, diazoxide, chlormethiazole, diazepam and heparin is given special attention.


Transport of glutamine by rat kidney brush-border membrane vesicles. Transport of glutamine by brush-border vesicles prepared from the renal cortex was studied. The transport system had both Na+-dependent and Na+-independent components. The presence of Na+ in the incubation resulted in an 'overshoot' at 30s at which time the rates of transport were approx. 8 times the values obtained in the absence of Na+. Variation of the glutamine concentration showed that the system obeyed Michaelis-Menten kinetics with Km and Vmax. values for the Na+-dependent system of 0.86 mM and 9.6 nmol/min per mg of protein respectively. Vesicles obtained from chronically acidotic rats showed similar kinetic characteristics. The Km and Vmax. values for the Na+-dependent system were 0.76 mM and 9.6 nmol/min per mg of protein respectively. There was increased uptake of glutamine by vesicles from acidotic rats and this increase was associated with increased activity of gamma-glutamyltransferase in these preparations. Vesicles from acidotic rats, however, showed no increase in glucose transport and no increase in the activity of maltase, another brush-border enzyme.


Intracellular localization of long-chain acyl-coenzyme A hydrolase and acyl-L-carnitine hydrolase in brown adipose tissue from guinea pigs. The activities of long-chain acyl-CoA hydrolase (palmitoyl-CoA hydrolase, EC 3.1.2.2) and long-chain acyl-L-carnitine hydrolase, EC 3.1.1.28) in brown adipose tissue from cold-exposed and control guinea pigs were studied. Mitochondria from cold-exposed animals hydrolysed 21 nmol of palmitoyl-CoA/min per mg of protein and 1.3 nmol of palmitoyl-L-carnitine/min per mg of protein, and the specific activities were respectively 2 and 5 times as high in cold-exposed as in control animals. The subcellular-localization studies showed that both the long-chain acyl-CoA hydrolase and long-chain acyl-L-carnitine hydrolase were localized in the mitochondria. A location also in the soluble fraction cannot be excluded. The long-chain acyl-CoA hydrolase activity was doubled when the mitochondria were disrupted; this indicates that the enzyme is localized in the matrix compartment.


Adenylate metabolism in the heart. Regulatory properties of rabbit cardiac adenylate deaminase. The kinetic properties of a 300-fold purified cardiac AMP deaminase were studied and compared with those of the corresponding enzyme from skeletal muscle. The heart enzyme is activated by ATP and less efficiently by ADP, and is inhibited by Pi, phosphocreatine and GTP. ATP, even at micromolar concentrations, is able to abolish the effects of the inhibitors. The affinity of the enzyme for AMP is low in the absence of activators (Km 3.1 mM), but, in the presence of ATP, becomes as high as that of skeletal-muscle AMP deaminase (Km 0.4 mM). The maximal activation by ATP is observed at alkaline pH (pH 7.5-8.0). Under the same conditions ATP is maximally inhibitory for skeletal-muscle enzyme. These results suggest that AMP deaminase in the heart is always in the activated state, whereas in skeletal muscle the enzyme is active only during exhaustive contractions.


Stimulation of mitochondrial calcium ion efflux by thiol-specific reagents and by thyroxine. The relationship to adenosine diphosphate retention and to mitochondrial permeability. Respiring rat heart mitochondria were loaded with Ca2+ and then treated with Ruthenium Red. The factors affecting the subsequent Ca2+-efflux were studied. Addition of rotenone or antimycin led to a decline of efflux except at pH values above 7.2, provided the load was less than about 80 nmol per mg of protein. Oligomycin reversed the effect of the respiratory inhibitors. Independently of respiration, efflux was stimulated by the uncoupler trifluoromethyltetrachlorbenzimadazole, by mersalyl and by thyroid hormones. The stimulated efflux could be diminished by ADP, with Mg2+ as cofactor if efflux was rapid. With respiration in progress, efflux could be stimulated by N-ethylmaleimide and 5,5'-dithiobis-(2-nitrobenzoate). The effects of mersalyl and of thyroid hormones could be diminished with dithiothreitol. In the absence of stimulating agents, the Ca2+ efflux was proportional to the load up to some critical amount, this critical amount was decreased by the agents. Thyroxine and mersalyl caused not only loss of Ca2+, but also simultaneous, but not necessarily proportional, loss of internal adenine nucleotides. Both efflux rates were kept at a low value by bongkrekic acid added before the stimulating agent. It is concluded that Ca2+ efflux is a measure of a permeability controlled by the binding of ADP (an Mg2+) to the inner membrane, and that this in turn depends on the maintenance of certain thiol gropus in a reduced form by a reaction that uses NADH and ATP and the energy-linked transhydrogenase.


Uptake of L-tri-iodothyronine by isolated rat liver cells. A process partially inhibited by metabolic inhibitors; attempts to distinguish between uptake and binding to intracellular proteins. 1. Rat liver cells obtained by dispersion with collagenase were used to investigate the mode of entry of L-tri-iodothyronine into the cell. 2. The hormone was taken up very rapidly at 23 degrees C; the linear phase of uptake lasted for up to approx. 20 s. 3. A plot of the initial rates of uptake against different concentrations of L-tri-iodothyronine yielded a sigmoidal curve. The Eadie--Hofstee plot (v/[S]2 versus v) yielded two straight lines. The uptake component with an apparent Kt value of 86 +/- 15 pM was designated as system I, and the second uptake component with an apparent Kt of 726 +/- 11 pM as system II. The Hill plot for system I was not linear; the apparent Hill coefficient for system II was calculated to be 2.1.4. Uptake of L-tri-iodothyronine by system I was higher at pH 6.4 than at pH 7.4; system II was relatively insensitive to changes in the pH of the external medium. 5. Both systems exhibited a transition temperature at about 16 degrees C in the Arrhenius plot. The activation energies of the two systems below and above 16 degrees C were 72.8 and 47.7 and 54.4 and 33.1 J/mol respectively. 6. Inhibitors of cellular energy reduced the uptake by system I to a larger extent than that by system II. 7. Replacement of Na+ in the external medium by either K+ or choline led to uptake that followed normal Michaelis--Menten kinetics. 8. Thiol-group-blocking agents reduced the uptake of the hormone by both systems. 9. Treatment of liver cells with beta-glucosidase, Pronase and neuraminidase led to a decrease in the uptake of L-tri-iodothyronine by system I, whereas uptake by system II was decreased after treatment with phospholipase A2, beta-galactosidase. Pronase and neuraminidase. 10. The stereoisomer D-tri-iodothyronine (100--3000 pM) did not affect system I, but uptake by system II decreased with increasing concentration of D-tri-iodothyronine. Reverse L-tri-iodothyronine (2--100 pM) and L-thyroxine (100--3000 pM) did not influence uptake by either system. 11. Under identical conditions of incubation, the uptake of L-tri-iodothyronine was 3.7 times higher than binding to cytosol proteins. The binding was insensitive to metabolic inhibitors. The results suggest that cytosol proteins are not directly involved in the uptake of L-tri-iodothyronine. 12. Plasma-membrane vesicles also take up the hormone rapidly at 23 degrees C. Increasing the osmolarity of the external medium led to a decrease in the uptake of L-tri-iodothyronine by vesicles. 13. Uptake as a function of L-tri-iodothyronine concentration exhibited a sigmoidal curve. The Eadie--Hofstee plot showed two uptake components with apparent Kt values of 96.8 and 1581 pM. 14. The results of our study are consistent with a carrier-mediated translocation of the hormone into the cell.


Comparison of superoxide with other reducing agents in the biological production of hydroxyl radicals. Iron--EDTA was shown to catalyse OH. production from H2O2 and ascorbate by a mechanism largely independent of superoxide. When ascorbate and superoxide were both present, the ascorbate mechanism was more important than superoxide as a source of OH., and would appear to be more significantly biologically.


[5'-methylthioadenosine phosphorylase from Caldariella acidophila. 1. Purification and partial characterization]. 5'-Methylthioadenosine phosphorylase has been isolated from C.acidophila, a thermophilic bacterium living in acid hot springs at temperatures ranging from 63 to 89 degrees C. The enzyme has been purified to homogeneity in 32% yield. The enzyme shows a high degree of thermophilicity, its temperature optimum being 93 degrees C in the in vitro assay. The enzyme is exceptionally stable; no loss of activity was observable after exposure for 1 h at 100 degrees C. The optimum pH is about 7,2, with one-half of the maximal activity occurring at pH 6 and 9. The apparent Km for the substrates are: 8,3 x 10(-5) M for MTA and 4,3 x 10(-4) M for phosphate ions.


[Enzymologic characterization of adenosine nucleosidase of medicinal plants (Medicago sativa)]. Adenosine nucleosidase (adenosine ribohydrolase, E C 3.2.2.7) was purified from alfalfa leaf juice. The final preparation shows a single band on polyacrylamide gel electrophoresis; the enzyme activity is stable for 12 hrs between pH 5.5 and pH 8.5, but is completely lost on heating at 55 degrees C for 10 min. Optimal pH for the hydrolysis of adenosine is between pH 5 and pH 6. Among nine purine nucleosides tested, only adenosine, 2'-deoxyadenosine and purine riboside were hydrolyzed by the enzyme preparation. A Km value of 7 x 10(-6) M was found with adenosine as substrate at pH 7.4. Of the two reaction products, adenine exerted a weak inhibitory effect, while D-ribose was without effect on the initial rate of adenosine hydrolysis. The data reported are compared with those obtained on the enzymes from other plant sources.


[Role of NADPH-dependent lipid peroxidation in the oxidase inactivation in mixed hepatic microsomal function]. When mouse liver microsomes were preincubated at 37 degrees with buffer, the monooxygenase activity was nearly constant and lipid peroxidation very low over 15 min. When preincubated with NADPH, there was an increase in lipid peroxidation accompanied by loss in enzyme activity (about 40%). The addition of EDTA 5 or 40 mM depressed lipid peroxidation and protected the monooxygenase activity with a rate increasing with concentration. The addition of FeSO4 0.5 mM had only little effect one enzyme activity whereas stimulated the response of the 2-thiobarbituric acid test.


Mechanisms of prolongation of pre-ejection period in patients with left ventricular disease. In order to determine the mechanism underlying prolongation of the pre-ejection period in patients with left ventricular disease, 11 patients with congestive cardiomyopathy and 29 with coronary artery disease, 10 of whom were taking beta-adrenergic blocking drugs, were studied non-invasively. Recordings of carotid pulse, and apex, phono-, and echocardiogram were obtained. In the absence of treatment with beta-blocking drugs, prolongation of pre-ejection period correlated closely with incoordinate left ventricular wall movement during isovolumic contraction assessed from simultaneous apex and echocardiograms. There was no correlation between pre-ejection period index (PEPI) and end-diastolic dimension and PEPI correlated poorly with fractional shortening and peak Vcf. A PEPI of greater than 140 ms was associated with incoordinate contraction in all but one case, and of less than 140 ms with normal contraction in all. Therapeutic doses of beta-blocking drugs caused prolongation of PEPI to a greater extent than would have been predicted from wall movement during isovolumic contraction. Incoordinate left ventricular contraction and a negative inotropic effect both therefore prolong PEPI, but by different mechanisms, whose effects can be separated in individual patients using non-invasive methods based on echocardiography.


Pharmacokinetics of closely related benzodiazepines. 1 It is commonplace for drugs to vary by only minor chemical differences. This is particularly so for those seven benzodiazepines discussed in this paper which are related both as precursors and as metabolites. However, minor chemical differences may cause major differences in physicochemical and pharmacodynamic properties. 2 Although the physicochemical differences are difficult to relate to effect, the influence of structure on absorption, distribution and elimination is of considerable importance in governing duration of effect, as shown by studies in monkeys and in man. This in turn dictates the suitability of a particular drug as a day or night sedative, as an anticonvulsant, or as an anxiolytic. 3 Structure affects the relative potency of the compounds as anticonvulsants, anxiolytics or sedatives so that judicious choice of a particular compound for a particular patient and condition will lead to improved therapy. It is fallacious to consider all benzodiazepines as similar.


Pharmacokinetics and metabolism of temazepam in man and several animal species. 1 Absorption, excretion and detoxification of temazepam were investigated in man, mouse, rat and dog. Considerable interspecies variation was apparent with respect to excretion and metabolite patterns in blood and urine. Animal species were exposed to equal or greater concentrations of all the metabolites occurring in man. 2 Pharmacokinetics of temazepam in man were investigated in a single dose study at two dose levels, and in a multiple dose study. The results of both studies were analyzed and interpreted with the help of compartmental models. Values were obtained for excretion pattern (0-infinity), half lives (1.95, 0.5, 10.0 and 1.9 h), amounts in all compartments, and for steady-state conditions. 3 The bioavailability of the hard gelatin capsule dosage form was compared with that of a suspension serving as the ideal dosage form, and found to be acceptable.


Bioavailability of temazepam in soft gelatin capsules. 1 Healthy volunteers received single doses of temazepam 30 mg in conventional gelatin capsules, suppositories or in solution. They experienced marked sedation and sleepiness. The onset of sleepiness was prompt after the administration of the solution; this latter showed the fastest absorption and gave the highest peak plasma levels. This observation led to the development of the soft gelatin capsule. 2 To assess bioavailability of the formulation, plasma levels of temazepam were determined in healthy volunteers after single oral administration of soft and hard capsules, and after seven consecutive night-time doses of the soft capsule. Absorption from the soft gelatin capsule was faster and produced earlier and higher peak plasma levels. There were no differences in relative availability. 3 The apparent half-life of temazepam after night-time administration was shorter than after morning administration, but no change was observed between the first and seventh night-time doses.


Effects of temazepam, flurazepam and quinalbarbitone on sleep: psychomotor and cognitive function. 1 The effect of temazepam 15 and 30 mg, flurazepam 15 and 30 mg, quinalbarbitone 100 and 200 mg and placebo were studied in 14 healthy male volunteers according to a Latin-square design. At 14-d intervals subjects received capsules 30 min before bedtime on 2 consecutive nights and were evaluated for objective sleep characteristics, for morning estimates of sleep characteristics, and for cognitive and psychomotive performance and subjective state at 3.5, 10.0 and 22.5 h after ingestion. 2 Changes in sleep induction and sleep maintenance were observed with temazepam 30 mg and flurazepam 30 mg had the greater effect on cognitive performance, whereas quinalbarbitone 20 mg had the greater effect on psychomotive performance. Subjective assessments of alertness were most affected by flurazepam, and by quinalbarbitone 200 mg. 4 The results suggest that temazepam produces less residual effects and is shorter acting than quinalbarbitone and flurazepam.


Hypnotic efficacy of temazepam: a long-term sleep laboratory evaluation. 1 Temazepam was evaluated in a strictly defined insomniac patient population under sleep laboratory conditions. Two protocols were used: a short-term (26-night) and a long-term (54-night) protocol evaluated the efficacy of the drug administered at night at 15 mg (short-term study) and 30 mg (long-term study), respectively. 2 Temazepam seemed to be both safe and effective at doses of 15 and 30 mg with up to 5 weeks of ingestion. 3 Suppression of slow wave sleep was observed at the high dose, but no suppression of REM sleep, found in studies with other benzodiazepines, was noted. 4 No evidence was found for development of tolerance or rebound effects.


Double-blind evaluation of the safety and hypnotic efficacy of temazepam in insomniac outpatients. 1 Efficacy of temazepam 30 mg at night as an hypnotic was compared with placebo in 55 out-patients with insomnia. The study was double blind, with two comparable groups of patients established by random allocation. Placebo and medication were taken for 4 consecutive nights and sleep questionnaires were completed the next day. 2 Patients reported that temazepam was more effective than placebo in reducing the difficulty of falling asleep and improving sleep maintenance. They also indicated that they awoke less and were less disturbed by early morning awakenings reported as a group that the average duration of sleep was increased by 1 hour. 3 The patients receiving temazepam reported being more alert in the morning and for the entire day than with placebo.


Pharmacokinetics and metabolism of various benzodiazepines used as hypnotics. 1 In the management of insomnia with drugs, any action should be restricted to the duration of the night and residual effects should be absent during the day-time. The intermittent type of drug action desired is fundamentally different from drug treatment where a constant effect is sought. 2 Duration of drug action is dependent on the kinetics of distribution and elimination of the parent drug and its effective metabolites. In addition biopharmaceutical factors, such as those which promote a rapid rate of absorption, are important. 3 These considerations serve as a guide for a review of the kinetics and metabolism of various benzodiazepines.


Double-blind evaluation of the efficacy and safety of temazepam in outpatients with insomnia. 1 The efficacy and safety of temazepam 30 mg, compared with glutethimide 500 mg and placebo, were evaluated in double-blind conditions in a 4-day study in 75 outpatients with a history of insomnia. 2 Temazepam and glutethimide were rated by the patients as effective and significantly superior to placebo for general quality of sleep, time required to fall asleep, frequency of nocturnal and early morning awakenings, and duration of sleep. 3 Residual effects reported for temazepam and glutethimide immediately after awakening and during the day were similar to or less than those reported for placebo.


The effects of repeated nocturnal doses of clobazam, dipotassium chlorazepate and placebo on subjective ratings of sleep and early morning behaviour and objective measures of arousal, psychomotor performance and anxiety. 1. Repeated nocturnal doses of 30 mg clobazam and dipotassium chlorazepate 15 mg showed no significant effects compared to matching placebo on tests of psychomotor performance and serial subtraction of numbers given in the morning and afternoon of the day following treatment. 2. Both active preparations improved the perceived quality of sleep compared to placebo. 3. A reduction in rated anxiety scores was found with clobazam on the afternoon of the day following treatment together with an elevation of critical flicker fusion thresholds. 4. Dipotassium chlorazepate was found to impair performance of a low level conceptual task but not to influence performance at a more difficult level.


The effect of spontaneous changes in urinary pH on mexiletine plasma concentrations and excretion during chronic administration to healthy volunteers. 1. The effect of spontaneous changes in urinary pH on renal excretion and plasma concentration of mexiletine has been examined during chronic administration of subtherapeutic doses of the drug to healthy volunteers. 2. Significant correlations were found between urinary pH and the plasma concentration and renal excretion of mexiletine. 3. Prediction of plasma mexiletine concentrations from our data suggests that the amount of mexiletine in plasma would increase by more than 50% following a rise in urinary pH similar to that which occurred spontaneously in our subjects. 4. Factors which influence urinary pH should be considered when the dosage of mexiletine is chosen. Extremes of urinary pH may account for some cases of inefficacy of the drug, and for the occurrence of unwanted effects at conventional doses.