The biosynthesis of 1a, 1b-dihomo-PGF2 and 1a,1b-dihomo-PGF2 alpha from 7, 10, 13, 16-docosatetraenoic acid by an acetone-pentane powder of sheep vesicular gland microsomes.

Thin-layer chromatographic (t.l.c.) analysis of the products formed from the incubation of an acetone-pentane powder of sheep vesicular gland microsomes with 7,10,13,16-docosatetraenoic acid (adrenic acid) revealed the presence of two products having Rf values identical to PGE2 and PGF2alpha. These products were purified by t.l.c., derivatized by treatment with methoxyamine, diazomethane, and N,O-bis-(trimethylsily1)-trifluoroacetamide, and these derivatives used for gas chromatography and gas chromatography-mass spectrometry. The results were consistent with 1a, 1b-dihomo-PGF2 and 1a, 1b-dihomo-PGF2alpha proposed structures. Formation of 1a, 1b-dihomo-PGF2 alpha could be increased, at the expense of 1a, 1b-dihomo-PGE2 by the addition of copper and reduced glutathione to the incubation mixture. Reduction of 1a, 1b-dihomo-PGE2 with NaBH4 in methanol resulted in total conversion to two products having chemical and physical properties consistent with 1a, 1b-dihomo-PGF2alpha and 1a, 1b-dihomo-PGF2beta proposed structures. The initial rate of adrenic acid-dependent oxygen uptake was determined to be 25% of that of arachidonic acid. The prostaglandin synthetase inhibitors, naproxen and 5,8,11,14-eicosatetraynoic acid (Ro 3-1428) inhibited adrenic acid-dependent oxygen uptake; Ro 3-1428 was shown to be a time-dependent inhibitor.


Stimulation by prostaglandin E2 of glucagon and insulin release from isolated rat pancreas.

To ascertain whether prostaglandins (PG) may play a role in the secretion of glucagon and in an attempt to elucidate the conflicting observations on the effects of PG on insulin release, the isolated intact rat pancreas was perfused with solutions containing 1.1 x 10(-9) to 1.8 x 10(-5)m PGE2. In the presence of 5.6 mM glucose significant increments in portal venous effluent levels of glucagon and insulin were observed in response to minimal concentrations of 2.8 X 10(-8) and 1.4 X 10(-7) PGE2, respectively; a dose-response relationship was evident for both hormones at higher concentrations of PGE2. When administered over 60 seconds, 1.4 X 10(-6)M PGE2 resulted in a significant increase in glucagon levels within 24 seconds and in insulin within 48 seconds. Ten-minute perfusions of 1.4 X 10(-6)M PGE2 elicited biphasic release of both islet hormones; Phase I glucagon release preceded that of insulin. Both phases of the biphasic glucagon and insulin release which occurred in response to 15-minute perfusions of 10 mM arginine were augmented by PGE2. These observations indicate that PGE2 can evoke glucagon and insulin release at concentrations close to those observed by others in the extracts of rat pancreas. We conclude that PG may be involved in the regulation of secretion of glucagon and insulin and may mediate and/or modify the pancreatic islet hormone response to other secretagogues.


The measurement of E and 19-hydroxy E prostaglandins in human seminal plasma.

A method is described which measures the four main prostaglandins of human semen (PGE1, E2, 19-hydroxy PGE1, and 19-hydroxy PGE2). For routine measurements E1 and E2 are measured together as are 19-OH E1 and 19-OH E2. These are measured by forming oximes in aqueous solution extraction, methylation and trimethyl silylation followed by gas chromatography. The method has sufficient sensitivity to measure the levels found in the majority of semen samples. The normal range in men with proven fertility was 90 to 260 mug/ml of 19-hydroxy Es and 30-200 mug/ml of Es.


Premature labor and indomethacin.

Women in the 29th - 32nd week of gestation were admitted to hospital following the onset of premature labor contractions. After treatment with bed rest and beta-stimulating drugs, those patients with persistent uterine contractions were treated with oral indomethacin (25 mg every 6 hours for 5 days). The effect of indomethacin therapy was monitored by serial external tocometry recordings. This treatment schedule with indomethacin was repeated on several occasions at intervals of 5 to 10 days. Using a standardized technique, uterine contractility was monitored every second or third day throughout the entire treatment period. In this way, the frequency of contractions was evaluated in the presence or absence of indomethacin therapy. Following indomethacin treatment, there was a significant decrease in the frequency of contractions in all cases and a complete arrest of contractions occurred in some women. An increased frequency of contractions was observed during those times that the patient did not receive indomethacin. The plasms concentration of 15-keto-13, 14-dihydro-PGF2alpha, the major serum metabolite of PGF2alpha, was determined by the gas chromatography - mass spectrometry method before and after indomethacin in a limited number of cases. At the doses given for the duration of therapy used, no untoward effects could be detected in either the mother or the infant. These results indicate that indomethacin is a potent and useful drug in the treatment of premature labor.


Influence of dietary vitamin E on prostaglandin biosynthesis in rat blood.

A vitamin E (alpha-tocopherol) deficient diet stimulated prostaglandin biosynthesis in coagulating rat blood. Prostaglandins were extracted from serum, purified and bioassayed. The identity of prostaglandin E2 was confirmed by gas chromatography-mass spectrometry. Withholding vitamin E from the diet caused a marked increase in PGE2 and a lesser increase in PGF2alpha production in serum. In rats maintained on diets containing different concentrations of vitamin E, serum concentrations of PGE2 and PGF2alpha were inversely related to serum concentrations of alpha-tocopherol. These data suggest that in vitro alpha-tocopherol inhibits the endogenous conversion of arachidonic acid into PGE2 and PGF2alpha. The possibility that alpha-tocopherol may inhibit the formation of endoperoxide intermediates of PGE2 and PGF2alpha biosynthesis and subsequent induction of platelet aggregation is discussed.


Effect of prostaglandins on protein, RNA, DNA and collagen synthesis in experimental wounds.

The effect of exogenous prostaglandins E1, E2 and F2alpha (PGE1, PGE2 and PGF2alpha) on 3H-leucine, 3H-uridine, 3H-thymidine and 3H-proline incorporation in experimental cutaneous wounds has been studied in rats. Prostaglandins E1 and E2 markedly stimulate the incorporation of these tritiated precursors, into protein, RNA, DNA and collagen synthesis, whereas F2 inhibits it. All tested prostaglandins exhibit their maximum effect within the first hours following administration. Most active is PGE1. These observations indicate that application of prostaglandins significantly stimulate incorporation with protein, RNA, DNA and collagen synthesis in the skin of wounded rats and thus, may play a role in epidermal cell growth and division as well as in scar-forming tissue.


The effects of some natural prostaglandins on isolated human circular bronchial muscle.

PGE1 relaxed isolated human circular bronchial muscle over a wide concentration range as did isoprenaline. Surprisingly isoprenaline was more potent than PGE1. PGF2alpha weakly contracted this muscle preparation whereas histamine was more potent. PGE2, however, produced paradoxical results, relaxing some tissues and contracting others, always in a concentration-related manner irrespective of tissue tone. In preparations that contracted to PGE2, tachyphylaxis induced to PGF2alpha also applied to PGE2, but did not affect PGE1 relaxations of histamine contractions. These findings suggest that pge2 can stimulate either PGF2alpha or PGE1 receptors of isolated human bronchial muscle.


Prostaglandin E1 inhibits the pulmonary vascular pressor response to hypoxia and prostaglandin F2alpha.

In the anesthetised dog an infusion of exogenous prostaglandin E1 (100muG/min) inhibits the pulmonary vascular pressor response to hypoxia. Both 25 and 100muG/min PGE1 can reduce the transient pulmonary hypertension caused by a bolus of prostaglandin F2alpha. This suggests that hypoxia and PGF2alpha may share a final common pathway in producing pulmonary vasoconstriction. These results may help to explain the mechanism by which endotoxin inhibits the pulmonary vascular response to hypoxia. This effect is probably achieved by stimulating the production of an endogenous dilator prostaglandin. Exogenous PGE1 can mimic this effect.


Prostaglandin F2alpha (PGF2alpha) and prolactin secretion in rats.

Plasma prolactin and F-prostaglandins (PGF) were measured anesthetized male Sprague-Dawley rats before and at 15, 30, 45 and 60 minutes following i.v. injection of either PGF2alpha (4 mg/kg), chlorpromazine, 1 mg/kg or chlorpormazine (1 mg/kg) after pretreatment with i.p. indomethacin (2 mg/kg). Following PGF2alpha administration, plasma prolactin levels increased significantly only at 15 and 30 minutes in spite of extremely high PGF levels throughout 60 minutes. Besides the expected rise in plasma prolactin, chlorpromazine caused a transient but statistically significant increase in PGF. Indomethacin blocked the chlorpormazine-induced PGF rise but not prolactin increase. Animals stressed with ether anesthesia showed elevation of plasma prolactin, which was not blocked by indomethacin although PGF concentration fell. Theese results indicate that PGF2alpha can stimulate prolactin release. This effect does not appear to be physiologic since very high PGF levels are required. Furthermore, blockade of prostaglandin synthesis by indomethacin does not prevent the release of prolactin in response to chlorpormazine or stress. Our findings do not support a possible role of PGFs as intermediaries in prolactin release. However, it is possible that PGFs may work through other mechanisms not investigated in our study.


The effect of the prostaglandin F2alpha analogue ICI 81008 on uterine small arteries and on blood pressure.

The effects of PGF2alpha and its analogue ICI 81008 have been compared on the small arteries of the omentum uteri on the rat. The vessels measured 20-80 mum in diameter and were examined by intra-vital-microscopy. While the maximum responses of PGF2alpha and ICI 81008 were similar, the duration of the effect of ICI 81008 was significantly longer (P is less than 0.001). At 15 minutes after the administration of the drugs the effect of ICI 81008 was still almost maximal, while the PGF2alpha response disappeared.


Neonatal serum bilirubin levels following the use of prostaglandin E2 in labour.

A prospective study of 447 labours and the resulting neonates failed to reveal a significant difference between the mean serum bilirubin concentrations on the third and sixth day following spontaneous, accelerated or induced labour. A similar incidence of neonatal jaundice (bilirubin concentrations of 10 mg/100 or more) was found in the studied groups. However, there was a tendency for neonates born after accelerated or induced labour to have slightly higher bilirubin levels than those born after spontaneous labour. No strong dose dependent effect on the level of bilirubin concentration following Prostaglandin E2 induced labour was demonstrated.


Progesterone withdrawal induced by ICI 81008 in pregnant rats.

Of a total of 343 pregnant rats treated with the prostaglandin F2alpha analogue ICI 81008, 137 aborted, while 83 had reduced and 123 intact litter. These biological variations depended primarily on the gestational timing of treatment and on the dose and route of administration of this synthetic PG. In comparison with the 107 controls, all experimental rats which aborted had a drastic reduction in plasma progesterone levels which was highly significant (P is less than 0.001) until day 18. In contrast, those animals which escaped suboptimal ICI 81001 treatment with a partly resorbed litter, only had a moderate reduction in progesterone which was statistically significant (P is less than 0.01) until day 16 when levels of this steroid normally begin to decrease. Ineffective treatment did not affect progesterone levels and intact pregnancy. In contrast to progesterone, there was no correlation between plasma estradiol-17beta levels and the consequences of ICI 81008 treatment.


[Chlorophyll mutations induced by gamma radiation in Phaseolus vulgaris L].

In a study of chlorophyll mutants of Phaseolus vulgaris L. through Co60 gamma radiation, five types of mutants, classified as albino, cream, yellow, yellow-green and light green were obtained; all were lethal; their segregation was always proportionally lower than the Mendelian. Gamma radiation-induced mutations in black beans do not depart significantly from those obtained elsewhere in barley and wheat.


[Spasmolytic effect of histamine in the isolated intestine of the hamster (Cricetus auratus)].

A comparative study of the effects produced by histamine on 15 different sections of the small intestine of hamsters (Cricetus auratus) from the stomach to the ileocecal valve was performed to find a substitute for that of guinea pigs and to ascertain which of the sections was the most sensitive. Changes in tone, amplitude and frequency of contractions with respect to control (spontaneous motility, were significant (P less than 0.01); the variance analysis showed no significant variations in the sensitivity or the motility of the different sections.


[Various aspects of comparative leaf anatomy of 2 Bromeliaceae (Aechema mexicana Baker and Hechtia glomerata Zucc)].

The leaf anatomy of two Bromeliaceae, Hechtia glomerata Zucc., a terrestrial xerophyte of arid zones, and Acehmea mexicana Baker, a tropical moist forest epiphyte, is compared; these species show adaptations to different extremes of adverse environmental conditions as to water uptake. The leaves of A. mexicana have more water storage tissue than those of H. glomerata; on the other hand, H. glomerata is capable of root absorption. In A. mexicana, modified nonfunctional stomata increase transpiration resistance. Also, this species shows more specialized foliar trichomes which permit the uptake of water and possibly of nutrients. The balance between transpiration and absorption rates is regulated in both species by the combined presence of peltate scales and stomata. The degree of adaptation to drought presented by epiphytic species is more complicated than that shown by terrestrial species. Epiphytic plants like A. mexicana may be derived from xerophytic species that have undergone readaptation to a humid climate. The conspicuous negative geotropism in the leaves of A. mexicana causes the formation of basal deposits of water, which play an important functional role in survival.


Restriction of isoproterenol-induced myocardial Ca uptake and necrotization in rats by a new Ca-antagonistic compound (ethyl-4-(3,4,5-trimethoxycinnamoyl) piperazinyl acetate (Vascordil)).

As shown in previous investigations overdoses of isoproterenol produce an abundant myocardial Ca uptake, followed by high energy phosphate breakdown, mitochondrial damage and, eventually, cardiac fibre necrotization. Conversely Ca antagonistic compounds such as verapamil, D 600 or prenylamine which reduce the transmembrane Ca influx into the heart muscle cells, can prevent high energy phosphate deficiency and cardiac lesions. Ethyl-4-(3,4,5-trimethoxycinnamoyl) poperazinyl acetate (Vascoril) is another compound which, according to our tracer studies, interferes with transmembrane Ca uptake into the myocardium. As expected the rat hearts were also protected by Vascoril against isoproterenol-induced metabolic disorders and structural alterations. Equiprotective subcutaneous doses, as studied on the right ventricular myocardium of rats, were 600 mg/kg Vascoril, 250 mg/kg prenylamine, 17 mg/kg verapamil or 10 mg/kg D 600.


Inhibition by cinnarizine of heart ionic changes induced by isoprenaline.

Cinnarizine, a specific blocker of Ca entry in depolarized smooth muscles, exerts a protection upon cardiac lesions induced by isoprenaline. Its action has been studied on ionic changes induced in hearts of rats injected with 30 mg/kg isoprenaline subcutaneously. Cinnarizine (20 mg/kg) was administered intraperitoneally 2 hours before isoprenaline. Ionic contents (Na,K,C,Mg) were measured over an observation period of 3 days following drug treatment. Isoprenaline induced changes in the content of the various ions studied. Changes occurring in the atria were reversible. The following observations were made in the apex: Mg, transient increase in the first hour followed by a long-lasting decrease; Ca, progressive increase up to 6 hours followed by a progressive restoration; Na, increase up to 24 hours followed by restoration. These ionic changes were significantly reduced by cinnarizine.


Transmural metabolic gradients of the canine left ventricle in coronary constriction, systemic hypoxia, hemorrhagic shock, and isoproterenol infusion.

In the left ventricle of the dog, a transmural difference is present in the normal state for various metabolites and persists in the experimental conditions studied. ATP stores are maintained both in the endo-as well as epicardium at the expense of PC. This is true for systemic hypoxia, hemorrhagic shock, and isoproterenol infusion. In severe ischemia, however, endocardial ATP is lower, while the transmural gradient for PC is increased due to a marked decrease in endocardial PC content. Our studies underline the importance of nonhomogeneity of the left ventricular wall and demonstrate that the subendocardium is more subject to anaerobic metabolism, especially when coronary perfusion pressure is decreased.


Myocardial metabolism at different environmental temperatures in experimental myocardial necrosis.

Although the effect of cold and heat stress on myocardial metabolisms has been widely studied, this parameter has not been investigated over a wide range of environmental temperatures after myocardial infarction. Since high as well as low temperatures are known to adversely affect the myocardium, changes in enviromental temperature are likely to be of great importance to patients suffering from acute coronary insult. Therefore, the myocardial metabolism was studied at different environmental temperatures in albino rats with isoproterenol-induced infarct-like myocardial necrosis. Male albino rats weighing 100 to 150 g were selected for the study. The investigations included ECG (lead II), histology, serum free fatty acids (FFA), serum triglycerides (TGS), cardiac noradrenaline, cardiac glycogen, and adrenal ascorbic acid, after the induction of myocardial necrosis. The biochemical changes were minimum between 10 and 15 degrees C while, at 4 degrees C, marked changes were observed. No significant change was seen in the serum triglycerides.


Membrane phospholipid metabolism in the isoproterenol-induced cardiomyopathy of the rat.

Within 60 minutes after treatment with low doses of IPR (5 mg/kg), relative specific activity of cardiolipin and sphingomyelin significantly increased in the heart. Other phospholipids of the heart were not significantly changed. Relative specific activity of cardiolipin increased much later in liver and salivary gland. Activity of CTP:PA cytidyl transferase increases 40% at 1 hour following treatment with IPR. No significant change was observed in the respiratory control ratio of heart mitochondria for 2 hours following injection with IPR; however, a significant decrease was observed 24 hours after IPR.


Role of free fatty acids in catecholamine-induced cardiac necrosis.

Previous studies have demonstrated that catecholamines produce massiive disseminated cardiac necrosis closely resembling experimental myocardial infarction. Since catecholamine-induced lipolysis increases myocardial oxygen demand and increased levels of FFA are associated with a depression of myocardial function during myocardial hypoxia, the effect of inhibition of lipolysis on myocardial necrosis induced by isoproterenol was studied. Measurements of creatine phosphokinase (CPK) activity in extracts of whole heart homogenates provide a sensitive and relatively specific index of cellular necrosis. Accordingly, CPK activity was measured in rat hearts 48 hours after the animals had received either isoproterenol, given s.c., 3 times at hourly intervals, or isoproterenol after prior administration of nicotinic acid. Control animals were given saline. With increasing doses of isoproterenol, CPK activity in whole heart homogenates was depressed from 21.7 +/- 0.40 in untreated animals (N = 36) to 14.9 +/- 0.46 in animals given the highest dose of isoproterenol (N = 47). In animals in which isoproterenol-induced lipolysis was inhibited by nicotinic acid, CPK was less depressed (16.3 +/- 0.36, N = 47) than with isoproterenol alone (p less 0.02). Nicotinic acid given alone did not interfere with CPK activity. This study suggests that part of the necrosis induced by isoproterenol is due to increased release and oxidation of FFA in the rat heart.


Changes in fatty acid composition of cardiac lipids accompanying myocardial necrosis.

Administration of isoproterenol induces changes in phospholipids of heart muscle membranes. Longer and more unsaturated fatty acids replace shorter and less unsaturated fatty acids. Dietary polyunsaturated fatty acids, i.e., C22:6, replace C18:2 and C20:4 in phospholipids of heart muscle. Increased sensitivity to isoproterenol and increased myocardial cell damage is accompanied by a relative increase in long chain polyunsaturated fatty acids in phospholipids of heart muscle. Development of myocardial necrosis increases with a progressive replacement of C18:2 and C20:4 by C22:6. Alterations in fatty acid composition of membrane phospholipids and consequent changes in membrane properties may play an important role in myocardial cell damage. Myocardial damage following administration of isoproterenol is increased when there is enhanced intramyocardial lipolysis and an increased amount of polyunsaturated fatty acids in membrane phospholipids. Mocardial damage is decreased when there is reduced intramyocardial lipolysis and the membrane response makes the membranes less permeable and more stable.


Disturbed myocardial calcium metabolism: a possible pathogenetic factor in the hereditary cardiomyopathy of the Syrian hamster.

In the BIO 8262 inbred strain of cardiomyopathic Syrian hamsters, a latent disturbance of their myocardial calcium metabolism could be evidenced. Whereas the myocardial calcium content of untreated young cardiomyopathic hamsters with prenecrotic hearts did not differ from that of healthy control animals, it was distinctly elevated 6 hours after injection of isoproterenol (1 mg/kg body weight s.c.) in cardiomyopathic animals remaining unchanged in healthy controls. However, the same dose of isoproterenol induced elevated myocardial 45Ca uptake in both strains, although that of the cardiomyopathic hearts was distinctly greater. Later, during the stage of spontaneous progressive necrotization of the hearts, a spontaneously increased myocardial uptake of 45Ca and calcium content became manifest. By combined treatment with isoproterenol and verapamil, a substance which is known to decrease the calcium conductivity of myocardial cell membranes without blocking beta-adrenergic receptors, the isoproterenol-stimulated 45Ca uptake by prenecrotic cardiomyopathic hearts as well as the increase of their calcium content could be inhibited. Long-term treatment with verapamil alone beginning during the prenecrotic phase of the cardiac condition, was fully effective in preventing myocardial overload as well as necrotization. These findings demonstrate that overload with calcium of cardiomyopathic cells of the hamsters can be influenced beneficially. Therefore, the disturbed myocardial calcium metabolism in the hereditary cardiomyopathy of the Syrian hamster is considered a decisive pathogenetic factor.


Key role of Ca in the production of noncoronarogenic myocardial necroses.

Skeletal and heart muscle fibers undergo severe functional and structural alterations, resulting in necrotization as soon as extracellular Ca ions penetrate excessively into the sarcoplasm, so that the capacities of the Ca binding or extrusion processes become insufficient. In mechanically injured skeletal muscle fibers, this necrotization process begins in the neighborhood of the membrane lesion where a large Ca inward transport takes place. Accordingly, elimination of Ca from the Ringer solution or an outward electric current which blocks the influx of extracellular Ca prevents the onset of necrotization, whereas additional Ca or an inward electric current which augments the influx of Ca potentiates the course of degradation. The crucial reaction in the production of necroses in skeletal and heart muscle fibers is a high energy phosphate deficiency which results (a) from excessive activation of Ca-dependent intracellular ATPases, and (b) from Ca-induced mitochondrial destruction. This applies especially to myocardial fiber damage caused by large doses of beta-adrenergic catecholamines such as isoproterenol. The number and size of the isoproterenol-induced cardiac lesions are obviously determined by the extent and, particularly, by the duration of the Ca-mediated high energy phosphate penury. Substances which sensitize the myocardium to catecholamine-induced necrotization (9-alpha-fluorocortisol, dihydrotachysterol, NaH2PO4) act by potentiating intracellular Ca overload and high energy phosphate breakdown. Conversely, verapamil D 600, and other Ca-antagonistic compounds protect the structural integrity of the heart muscle fibers by restricting transmembrane Ca influx and, consequently, ATP and creatine phosphate exhaustion.


Prevention of myocardial generation in hamsters with hereditary cardiomyopathy.

A number of drugs have been tested for their ability to prevent or change the course of skeletal and heart lesions occurring with a 100% incidence in cardiomyopathic hamsters (UM-X7.1). These drugs were selected because they act either on the metabolism or turnover of Ca or on adrenergic receptors. Verapamil (Isoptin), a potent inhibitor of myocardial transmembrane Ca conductivity, was found to completely prevent the myocardial lesions in myopathic hamsters. The hamsters were 28 to 30 days of age at the beginning of the experiment and were injected subcutaneously twice daily during 30 consecutive days in doses of 0.5 mg during the first week and 0.75 mg during the subsequent weeks. The protection afforded by Verapamil was no longer evident 30 days after interruption of the treatment. The severity of both cardiac and skeletal muscle lesions was found significantly lowered in hamsters receiving Dibenamine. It is assumed that Verapamil acts mainly by preventing excessive calcium influx in cardiomyocytes, whereas Dibenamine improves the microcirculation, which is deficient during the necrotizing phase of the polymyopathy. The latter assumption rests on the fact that, in myopathic hamsters, the reactivity pattern of alkaline phosphatase is altered at the level of the capillaries of cardiac and skeletal muscles.


Metabolic changes in the myocardium of hamsters with hereditary muscular dystrophy.

Depressed fatty acid (FA) oxidation found previously in various types of cardiomyopathies has been attributed to the lack of carnitine in heart muscle. This is not the case in the cardiac lesion of hamsters, strain BIO 14.6, between the ages of 3 and 6 months. We observed depressed CO2 production by heart homogenates of diseased animals from labeled acetate (1/20), butyrate (1/15), octanoate (1/3, and palmitate (1/4) in the presence of carnitine. The activity of carnitine palmitoyltransferase (forward reaction) and FA activating enzymes was unchanged. The oxidation of 1,4-labeled succinate as well as acetyl CoA was depressed to approximately 40% of the control, whereas [2-14C]pyruvate and [U-14C]oxoglutarate were oxidized at 60 to 70% of the control level. The CO2 production from [1-14C]pyruvate and [1-14C]oxoglutarate showed no reduction. No significant difference was found in myocardial triglyceride content and palmitate esterification into neutral lipids. The possible cause of different magnitudes of depressed oxidation of these substrates is unknown. It may be that the acetyl-CoA derived from FAs and that derived from pyruvate are metabolized by the TCA cycle to different extents, or that the endogenous metabolism participates to different degrees in the presence of different substrates.


Morphological and biochemical studies on the heart of the cardiomyopathic Syrian hamster.

Histological and ultrastructural observations of embryonic hearts and cultured cells from hamsters with inherited cardiomyopathy (BIO 14.6 line) showed a significant delay in maturation of the sarcomeric units in comparison with those of unrelated healthy control hamsters. Phase-contrast microscopic observation of the cultured cardiomyocytes revealed more rapid diminution of beating frequencies in the diseased hamsters than in the controls. Negatively stained ultrastructure and yield of the actomyosin extracted both from the cardiomyopathic and the control hamsters showed no fundamental differences. Disc electrophoresis of the erythrocyte ghosts revealed, at least, a quantitative difference in one of the composing proteins between these two groups.


Left ventricular function in Syrian hamsters of different ages with hereditary cardiomyopathy.

Hemodynamic data of cardiomyopathic hamsters of the strain BIO 8262 aged 70 days and more than 200 days were compared with those of control groups. Left ventricular systolic pressures and heart rate revealed no great differences between the groups. Left ventricular diastolic pressure was lower in both older groups than in both younger groups. Contractility, as measured by dp/dt max as well as VCE and Vmax, showed considerably lower values in the myopathic groups. Although congestive heart failure connot be observed in the BIO 8262 strain, a decrease in cardiac performance can be postulated particularly in the 70-day age group in the stage of acute necrosis. The hypothesis is supported that circulatory congestion seen in the BIO 14.6 hamster is a separate entity, not necessarily connected to the myocardial lesions.


Cardiovascular effects of dopamine in the normal and failing heart of experimental animals.

Dopamine exerts marked positive inotropic effects in the dog with no effect on heart rate. This effect is abolished by propranolol, reduced by reserpine, and unaffected by atropine. Dopamine exhibits similar inotropic activity in the normal guinea pig and in guinea pigs with experimentally induced heart failure. In the isolated perfused hamster heart, dopamine caused marked increases in left ventricular pressure with slight increases in heart rate. However, in the failing heart of the myopathic Syrian hamster, dopamine caused moderate increases in left ventricular pressure with much greater increases in heart rate. The total heart work of the failing heart under the influence of dopamine is significantly higher than that of the normal heart. The energy utilization under this condition is equal in both hearts. Therefore, the calculated efficiency of the failing heart treated with dopamine is much higher than that of the normal heart treated similarly.


Scanning electron microscopy of the heart.

Dog hearts were studied with the scanning electron microscope. This technique provides a better perspective of the relationships between organelles than can be obtained with other methods. Extensive communications between mitochondria, sarcoplasmic retiuclum, and nuclear envelop were demonstrated; this suggests the presence of a direct pathway between mitochondria and nuclei for the transport of ATP and perhaps other substances.


Nuclear deoxyribonucleic acid content in congenital cardiac malformations.

Cytophotometric measurements of the DNA content of human heart muscle nuclei were performed on normal and congenitally malformed hearts of children. Congenital malformations of the heart lead to an early increase of the ploidy pattern as a sign of myocardial overload. This increase is significant. It starts, at the earliest, after the 3rd week of life. The degree of polyploidization of the muscle nuclei in malformed hearts is dependent on the type of overload. Pressure load produces a stronger shift to higher ploidy values than does volume load. The polyploidization is not dependent on either the heart weight at autopsy or the age of the child. It may be concluded that increasing functional requirement is the main cause of physiological and pathological polyploidization in hearts of children.


Ultrastructure of human myocardium after total cardiopulmonary bypass during open-heart surgery.

During cardiopulmonary bypass surgery without coronary perfusion, most myocardial cells show ischemic lesions of the mitochondria but all other cell organelles remain unchanged. Ischemic damage to the myocardial cells caused by cardiopulmonary bypass surgery for a period of 47 minutes is reversible, since, after 20 minutes of reperfusion of the heart, the first signs of mitochondrial recovery can be observed. Bypass times exceeding 50 minutes cause severe irreversible damage to many myocardial cells.


Myofibrillar alterations in ischemic myocardium after glucose-insulin-potassium infusion.

GIK infusion after experimental coronary artery ligation in dogs appears to reduce the size of the infarct and influence the ultrastructure of some of the cells bordering the infarct. These cells contain fine filamentous material thought to be actin, which appears to originate near the intercalated disc and is thought to represent a reparative process in reversibly injured cells and a hypertrophic response in normal cells adjacent to the infarct.


Myocardial ultrastructure and contraction during short periods of experimental ischemia.

The relationship of structure and function of the intact myocardium during the early minutes of experimental ischemia was studied in the anesthetized, open-chest pig. Regional contraction of ischemic and normal myocardium was measured, using isometric strain gauges on the anterior and lateral left ventricle. Biopsies for electron microscopy were taken consecutively 5, 10, 15, and 20 minutes after anterior descending artery occlusion-each followed by 10 minutes of reperfusion. Contraction of the ischemic area fell significantly within 15 to 30 seconds following occlusion, returning to 68, 50, 40, and 28%, respectively, after 5, 10, 15, and 20 minutes fo ischemia. In contrast, slight morphological changes were detected only after 5 and 10 minutes of ischemia, becoming more clear after 15 minutes, and unequivocal after 20 minutes-when return of contraction was minimal. The morphologic alterations in the ischemic area as seen by electron microscopy were: reduction of glycogen granules and specific changes in the mitochondria. The latter, consisting of swelling, disruption of cristae, and reduction of matrix, began to appear at 5 minutes and were more evident after 10 minutes of ischemia. These changes, although present, were not always proportional to sequential ischemic periods. This apparent lack of correlation between contraction and morphology could be due to sampling problems or to the focal nature of the ischemic process. However, it could imply that the changes seen by electron microscopy are a "late" phenomenon as compared to the loss of function. Morphologic corroboration of the immediate decrease of contraction of ischemic myocardium still escapes the perception of current morphological techniques. It is hoped that more refined stereological measurements will help bridge the present gap between function and morphology in early myocardial ischemia.


Electrolyte changes in myocardial injury.

The shifts in the myocardial electrolyte metabolism during secondary or primary cardiopathies in dogs and rats, respectively, are described. Major attention is paid to the changes of Ca in the myocardial tissue. The increase in the Ca level after ligation of ramus circumflex of the left coronary artery, or after F-COL + Na2HPO4, and vitamin D2 administration, is regarded as a triggering process for more profound successive changes in the metabolism of the myocardial cell, which eventually lead to depletion of the high energy phosphate reserves. In the dogs with experimental coronary occlusion, the normalization of the myocardial ionogram, i.e., the ratio of K, Na, Ca, and Mg, was achieved by means of the mechanical heart assist, using the original design of the blood pump, where bypass and counterpulsation principles work simultaneously. The normalization of the Ca level in this case was achieved on the basis of a marked reduction of the volume work of the left ventricle, which is secured by the bypass component; on the other hand, the counterpulsation component of the combined pump secures the reduction of pressure work placed upon the left ventricle (represented by the decrease fo the end-diastolic pressure) and helps in the opening of the collaterals in the infarcted area during early diastole. Thus, the oxygen supply to the ischemic zone is improved. On the basis of our experiments with the combined blood pump, the failing heart is supported, not only hemodynamically, but also from the metabolic point of view. A similar effect is achieved by the administration of K-Mg-aspartate, and K-L- or K-DL-aspartate in dogs with experimental infarction. In primary electrolyte steroid cardiopathies characterized by necrosis, K-Mg-aspartate or K-aspartate only prevents the Ca increase in the myocardial tissue, whereas Mg-L- or Mg-DL-aspartate remains without andy effect. The necrotic changes observed after vitamin D2 administration are always accompanied by extremely high Ca levels in the myocardium. It shown in our experiments that administration of K-Mg-aspartate or Fe-dextran decreases the Ca level and reduces the necrotic and myolytic changes in the cardiac tissue. The authors recommend as an effective means in the therapy of acute heart failure the combination of mechanical heart support with the causative pharmacological therapy.


Membrane permeability alterations as manifestation of early cardiac muscle cell injury.

Studies with extracellular fine structural diffusion protein tracers, horseradish peroxidase and ferritin, were carried out on catecholamine-induced cardiac muscle cell injury. Epinephrine, norepinephrine, and isoproterenol were administered in a dose of 4- 6 mug/100g body weight by continuous intravenous infusion. For follow-up studies, isoproterenol was also given subcutaneously in a dose of 8.5 mg/100 g body weight as a single injection. In contrast to saline-infused controls and following epinephrine infusion, where these tracers always remained extracellular, norepinephrine- and isoproterenol-infused animals exhibited alteration of sarcoplasmic membrane permeability to macromolecules in the early stage of evolution preceding fine structural changes of cardiac muscle cells. This was reflected by the intrasarcoplasmic presence of peroxidase in some cardiac muscle cells which otherwise showed no ultrastructural alteration. Deposition upon and selective binding of the extracellular protein tracer, peroxidase, to intact myofilament was also a characteristic early change that may affect the contraction-relaxation mechanism of the myofilaments and may contribute to the evolution of necrobiotic alteration. In structurally altered cells, peroxidase showed similar affinity to contraction bands and fragmented myofilaments. Furthermore, these studies disclosed different sensitivities of various membrane components of the cardiac muscle cell. While in the early pahse of cell damage no peroxidase could be detected in various intrasarcoplasmic compartments, with increasing severity of the lesion the external and internal mitochondrial membranes as well as the sarcoplasmic reticulum were also affected. When the large molecular tracer, ferritin, was used, the sequence of events in altered cardiac muscle cells followed that outlined for peroxidase. However, free ferritin molecules could not be demonstrated in the sarcoplasm of cardiac muscle cells which exhibited normal ultrastructure.


Isoproterenol-induced necrotic lesions of embryonic heart tissue.

Chick embryos were used for analyzing the effect of isoproterenol on the embryonic heart. Isoproterenol (2 x 80 mg/kg in 48 hrs) was injected into the amniotic sac from the 5th embryonic day to the time of hatching. From the 5th to the 7th embryonic day (ed), transposition of great vessels occurs. From the 7th to the 14th ed, blockade of development of coronary vascularization was regularly observed, particularly in the ventral wall of the right ventricle. This effect is always associated with persistence of intertrabecular spaces in the nonvascularized area and with a higher water content in the heart. From the 10th to the 12th ed, degenerative changes of the cardiac musculature can be observed. Lesions were characterized by typical myolysis; capillaries in the affected area were dilated and blocked with packed erythrocytes. Necrotic changes were localized only in those parts of the ventricular walls where the vascular bed and myoarchitecture were normally developed. In comparison with similar changes in adult specimens, inflammatory cellularization is lacking.


Histochemical and electron microscopic studies of acute cardiomyopathy induced by restraint stress in pigs.

In 23 healthy crossbred pigs of Yorkshire and Swedish Landrace (body weight 85 to 90 kg), stress was produced by pharmacological restraint. Cardiac lesions were observed in all the experimental animals, but no alterations were seen in the 9 controls. The lesions consisted of focal myocardial necrosis with infiltration of mononuclear inflammatory cells. Histochemical stains for two dehydrogenases, cytochrome oxidase and unspecific esterase, were applied to fresh-frozen sections of heart muscle. The damaged muscle fibers exhibited initially an increase in formazan deposits, and then a decrease and total loss of enzymatic activity. A reduction or total loss of glycogen and accumulation of lipids were demonstrated in the damaged myocardium ultrastructurally. The mitochondria were swollen with focal loss of the cristae. They often exhibited electron-dense of diverse appearance. In degenerating cells, the myofilaments usually lacked the normal cross-striations whereas, in necrotic foci, the changes ranged from clumping to complete lysis of the myofilaments. The sarcoplasmic reticulum and the T system contained numerous dilated vesicles in cells with mitochondrial and myofibrillar damage. It was concluded that the myocardial alterations, following restraint stress, were caused by a reflex liberation of cardiotoxic catecholamines.


Myocardial lesions induced by rapeseed oil-rich diet in the rat: ultrastructural aspects.

Rats were fed a diet containing 15 g% of rapeseed oil rich in erucic acid (55%). At different stages of the experiment, the hearts were examined in the electron microscope and planimetric studies were performed, with special attention to lipid accumulation and mitochondrial mass. The already known data concerning the early appearance and reversibility of the intracellular lipidosis, the delay (2 to 3 months) in the occurrence of the cellular lesions, and the lack of correlation between the degree of lipidosis and degenerative changes were confirmed...


Myocardial injury produced by antineoplastic drugs.

Histologic and ultrastructural studies were performed on the heart of 16 patients with fatal leukemias or solid tumors. Multifocal myocardial degenerative lesions, characterized by alterations in contractile elements, mitochondria, and nuclei, were found in 12 patients treated with high total doses of anthracyclines, but not in 3 patients who did receive such therapy. One patient who received a high dose of cyclophosphamide as well as a high total dose of daunorubicin exhibited extensive hemorrhagic myocardial necrosis and multifocal degenerative lesions. This study documents the cardiotoxic effects of anthracyclines and cyclophosphamide.


Depressed myocardial function in subacute experimental viral myocarditis.

A model of experimental Coxsackie virus B3 myocarditis has been developed in the weaning Syrian golden hamster. The acute infection is characterized by extensive viral replication in the myocardium, associated with transient myocytolysis and leukocytic infiltration. At 2 weeks after inoculation, there is survival without evidence of cardiac hypertrophy or failure, and minimal residual light microscopic changes. In order to evaluate myocardial function during convalescence form this form of myocarditis, muscle mechanics were studied in left ventricular trabeculae careae in 10 infected and 7 control animals, 18 days after inoculation. Maximum developed tension of the infected animals was depressed by 25%, and there was a significant decrease in the time to peak tension. Furthermore, the infected muscles required less stretch to reach that length at which maximal developed tension was produced. These data indicate that myocardial function remains depressed during early convalescence from acute Coxsackie virus B3 myocarditis and suggest that this state is associated with decreased compliance. Studies of myocardial morphology and function at longer intervals after acute experimental viral myocarditis are indicated, to further test the hypothesis that viral myocarditis might be a precursor chronic isiopathic cardiomyopathy.


Morphological changes after combined administration of isoproterenol and K+,Mg2+-aspartate as a physiological Ca2+ antagonist.

The possibility of prevention of isoproterenol (ISO)-induced morphological changes by Ca2+ antagonists was investigated in the heart muscle of dogs. ISO in a dose of 7 mg/kg caused marked histochemical and electron microscopical necrotic changes. K+, Mg2+ aspartate (K,Mg-ASP) administered alone in a dose of 100 mg/kg changed slightly almost all cell components. K,Mg-ASP treatment applied prior to administration of ISO after 24 hours resulted in an improvement of the ultrastructure, which generally exhibited marked restoration resembling metabolic regeneration and/or enhanced metabolic activity.


Pathological accumulation of calcium by mitochondria: modulation by magnesium.

Magnesium causes a marked decrease in the initial rates of respiration-supported calcium uptake by isolated heart mitochondria. Differential responses of mitochondrial respiration and cytochrome b redox states in the presence and absence of magnesium indicate that with magnesium present, heart mitochondria retain the ability to phosphorylate ADP after calcium uptake. Electron microscopy of the isolated mitochondria after calcium accumulation revealed markedly different crystal structures within the matrix space depending on the presence or absence of magnesium. The results suggest a "protective" effect of magnesium on the phosphorylating mechanism of mitochondria during active calcium uptake. Further, magnesium appears to determine the type of crystal structure formation within the intramitochondrial compartment.


Possible role of magnesium loss in the pathogenesis of myocardial fiber necrosis.

Cellular loss of Mg is associated with uncoupling of oxydative phosphorylation and disruption of Mg-dependent intra-mitochondrial enzyme systems. The link of Mg loss and its association with intracellular Ca accumulation in the pathogenesis of myocardial fiber necrosis (MFN) has been clearly established in dietary Mg deficiency. Rapid loss of myocardial Mg has been demonstrated also in acute hypoxic states and in patients succumbing to myocardial infarction. Evidence from this laboratory indicates that loss of myocardial Mg may be a basic biochemical denominator in the development of MFN of diverse etiology, initiating a stereotyped ionic disequilibrium which encompasses loss of inorg. P and K accumulation of Na and Ca. This applies to MFN elicited by NaH2PO4 loading of parathyroidectomized rats, by injection of cardiotoxic dosages of adrenergic amines or by ligation of coronary vessels. Prevention of myocardial Ca accumulation by prior parathyroidectomy, did not interefere with emergence of MFN nor did it obviate the Mg loss and the remaining electrolyte disturbances. These parallel findings with three unrelated models of MFN do not support the view of a determinant role of CA overload. Administration of Mg salts, on the other hand, provided substantial protection against MFN induced by NaH2PO4 loading of PTX rats or by isoproterenol. The protective effect was reflected in a highly significant shift of the deranged myocardial electrolyte pattern towards normal. In rats pretreated for 3 weeks with DCA-saline, isoproterenol induced myocardial electrolyte changes including Mg depletion were associated with an enormous potentiation of the arrhythmogenic propensity of this catecholamine, resulting in almost 20,000-fold increase in its acute toxicity. Pretreatment with Mg salts or Mg-sparing drugs offered clear-out protection against arrhythmias as well as against catecholamine-induced MFN.


Effect of ethanol on diazepam distribution in rat.

The effect of an acute oral dose of ethanol (3 g/kg), administered 30 min prior to oral administration of 14C-diazepam (5 mg/kg), on the fate of radioactivity in rats was examined. Ethanol pretreated rats possessed higher tissue levels at 60, 90 and 120 min than control animals. Blood, liver, kidney and plasma tissues showed 1.5 fold differences, adipose tissue exhibited a 2.4 to 3.6-fold increase, with brain showing 3.9, 4.5 and 5.4 fold higher levels of 14C at 60, 90 and 120 min respectively. Octanol extraction of plasma and ethyl acetate extraction of brain tissues indicated ethanol pretreated animals possessed a higher percentage of extractable radioactivity than controls. Thin-layer chromatography of the extracts suggested that biotransformation of 14C-diazepam was inhibited by ethanol, causing brain levels of 14C-diazepam at 60 min to be 6.4 fold higher than that observed in controls.


Substituted cycloalkanol ethers of psychostimulant activity: studies on quantitative structure-activity relationships.

Quantitative relationships between chemical structures and locomotor activities of 20 substituted cycloalcanol basic ethers have been investigated using Hansch- and Free-Wilson methods. The Hansch-type regression analysis performed on 10 compounds having different cycloalkyl-rings revealed the highly significant role of the hydrophobic characteristics on the activity tested. The QSAR-study of 20 cycloalcanol-ethers according to Free and Wilson gave a significant equation with good statistical indices. On the basis of the results the compounds under study appear not to exert their activity through interaction with receptor raising strict sterical and electrical requirements.


The selective effects of alpha-methyl aromatic amino acids on brain monoamine metabolites and behavior in cats.

Alpha-methyldopa or alpha-methylmetatyrosine (100 mg/kg) were administered orally to cats and the EEG recorded for 9 hours. Through the first 6 hours after each administration, the concentration of cisternal cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) selectively decreased from control (hour 0) while homovanillic acid (HVA) levels showed only small changes. On observation, the animals were quiet but awake. At 9 hours after alpha-methyldopa administration, the percentage decrease of 5-HIAA was significantly greater from the percentage decrease of HVA. The EEG record from 6-9 hours following either drug showed fewer intervals of EEG synchronization in both duration and frequency. These results indicate that behavior and EEG can be related to changes in brain monoamine metabolism determined in CSF. After either drug administration, dopamine turnover (as indicated by HVA) was higher than that of serotonin (as indicated by 5-HIAA) which corresponded to EEG desynchronization and other behavioral indicators of wakefulness.


The influence of delta9-tetrahydrocannabinol, cannabinol and cannabidiol on tissue oxygen consumption.

The mechanism of the hypothermia produced in mice by the naturally occurring cannabinoids, delta9-tetrahydrocannabinol, cannabinol, and cannabidiol, was investigated by evaluating the direct effect of these drugs on the oxygen consumption of tissue homogenates and isolated mitochondria. The tissues studied were brain, liver, skeletal muscle, and heart; the mitochondrial preparations were limited to brain and skeletal muscle. The in-vitro studies included a description of the influence of various cannabinoid vehicles containing Tween 80, ethanol, Pluronic F68, and albumin on the oxygen consumption of tissue preparations. Of these vehicles, only albumin was without effect on all tissues. The other vehicles produced diverse responses, including some that were qualitatively different; the data illustrate that the influence of each vehicle on oxygen consumption must be defined for each tissue employed. In spite of the different vehicle effects, delta9-tetrahydrocannabinol generally reduced oxygen consumption of all tissue preparations; however, the vehicles were capable of modifying the dose-effect relationship. The results of all three drugs prepared in Pluronic F68 on brain and skeletal muscle indicated that the cannabinoids generally cause a dose-related depression of oxygen consumption. The findings demonstrate that the cannabinoids can directly decrease oxidative metabolism of tissue and isolated mitochondria and that a marked response occurs in the concentration range of 1 X 10(-5) to 1 X 10(-4) M. Because these concentrations can exist in tissues following the in-vivo administration of delta9-tetrahydrocannabinol, the results suggest that the depressant effect of the cannabinoids on metabolic rate may contribute to the mechanism of the hypothermia produced by the drugs.


Effect of selenium on methylmercury binding to subcellular and soluble proteins in rat tissues.

The possible mechanism involved in the protection of Se against the toxicity of methylmercury was investigated with rats. Pretreatment with Se increased the Hg content slightly in the blood (30%), moderately in the testes (doubled), and markedly in the brain (5 times), while decreasing that in the kidneys by half. The Hg content in the liver, spleen, heart and plasma was not significantly affected. Of the subcellular fractions, most (40-50%) of the tissue Hg was found in the soluble fraction (cytosol) of the liver, kidneys and spleen, but not the brain which had 65% of its Hg located in the crude nuclear fraction and only 24% in the soluble fraction. Se did not significantly affect the subcellular Hg distribution other than that which could be accounted for by its effect on the whole tissue uptake. In the soluble fraction, most of the Hg was associated with hemoglobin-containing and low molecular weight (MW less than 5,000) fractions, which is in contrast to reported data for inorganic Hg which binds to metallothionein (MW = 10,000). The distribution pattern of methylmercury between different molecular weight proteins within the soluble fraction was not significantly affected by Se which is also in contrast to reported work on inorganic Hg. Thus, Se pretreatment may protect the kidneys by reducing their methylmercury uptake, but apparently protects other organs by a different mechanism. The possible mechanism of protection by Se against inorganic Hg in which this element is diverted to presumably less critical proteins in the soluble fraction is apparently not operating in the case of methylmercury.


Barbital-induced cross-tolerance to barbiturates by the intracisternal route of administration.

Male rats receiving 2.4 mg of barbital-sodium intracisternally every 3 hours for 4 injections exhibited a significant decrease in sleeping time over that of control animals when challenged with pentobarbital 17 hours after the last pretreatment. These tolerant animals did not show a significant increase in either (14C)-leucine incorporating activity or hepatic aminopyrine demethylase activity. This intracisternal induced cross tolerance to pentobarbital is apparently not due to hepatic enzyme induction, but may be related to an altered sensitivity of the central nervous system to these agents.


Reserpine and calcium: interaction at the injection site.

The subcutaneous administration of calcium prior to reserpine prevented the development of the well-known reserpine effects. Pretreatment with other bivalent cations induced a similar effect. The inhibitory effect of reserpine on the in vitro uptake of labelled catecholamines in brain homogenates was also prevented in rats pretreated with bivalent cations. On the other hand when calcium was injected at a site other than that of reserpine, there was no antagonistic effect. The latter results suggest an interaction between bivalent cations and reserpine at the injection site that prevents the systemic absorption of reserpine.


Regional formation of 6-methoxy-1,2,3,4-tetrahydro-beta-carboline in rat brain extract.

In the presence of 5-methoxytryptamine (5-MeOT), 5-methyltetrahydrofolic acid (5-MTHF) yields 6-methoxy-1,2,3,4-tetrahydro-beta-carboline (6-MeOTHbetaC) in rat brain extracts, possibly via formaldehyde formation catalyzed by methylenetetrahydrofolate reductase. The formation of 6-MeOTHbetaC in selected brain regions, ranging from 452 +/- 40 pmol formed per mg protein per hour in corpus striatum to 119 +/- 17 pmol in cingulate cortex, is significantly correlated with the regional distribution of 1,2,3,4-tetrahydro-beta-carboline (THbetaC) formed from 5-MTHF and tryptamine (r = 0.76, p less than 0.01) as well as that of methylene-beta-phenylethylimine (MbetaphiEI) from 5-MTHF and beta-phenylethylamine (betaphiEA; r = 0.90, p less than 0.01). FAD enhances the activity, lowering both Vmax and Km values with respect to 5-MeOT and Vmax, but not Km, with respect to 5-MTHF.


Effect of pretreatment with prednisolone on enzyme efflux from isolated skeletal and heart muscle.

In a previous study, the efflux of creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) which takes place from isolated mouse skeletal muscle was shown to be significantly reduced by pretreatment of the intact animal with diethylstilbestrol (DES). This compound is known to reduce the high serum enzymes present in patients with Duchenne's muscular dystrophy (DMD). Glucocorticoids also reduce the serum enzymes in DMD. The purpose of this study was to determine if pretreatment with the glucocorticoid, prednisolone, also lowered the efflux from isolated mouse skeletal and cardiac muscle. The results of these studies show that prednisolone pretreatment lowers the enzyme efflux from isolated skeletal muscle, but not from heart. There is an optimal dose which produces this reduction, which if exceeded, augments the efflux. Thus two agents are now known which lower the efflux of CPK and LDH from isolated skeletal muscle. These same two agents lower the high serum enzymes in DMD. This suggests, but does not prove, that the mechanism by which these agents lower the serum enzymes in DMD is by reducing enzyme efflux from skeletal muscle.


Absorption of sulfate ions in the rat lung.

To investigate the absorption of 35S-sulfate ions from the rat lung in the presence of sodium, ammonium, and chloride ions, 0.1 ml of isotonic sucrose solution containing the salts was instilled via a tracheal cannula into anesthetized animals. After various times the lungs were removed and assayed for 35S-radioactivity. Sulfate ion absorption was found to be nonsaturable and proportional to the concentration of sulfate ion, with a t 1/2 =34.5 minutes. Ammonium ions enhanced the absorption of sulfate ions by 10.8 +/- 3.1% and chloride ions decreased the absorption of sulfate ions by 6.6 +/- 3.0%.


Effect of plasma protein binding on the anticoagulant action of warfarin in rats.

The relationships between the anticoagulant effect and the concentrations of free and total (sum of free and protein-bound) warfarin in plasma were determined in rats following intravenous administration of single doses of racemic warfarin or S(-)-warfarin. The concentration of total warfarin required to elicit a defined anticoagulant effect varied widely between animals while the concentration of free warfarin showed much less variation. This indicates that the anticoagulant effect of warfarin is a function of its free concentration in plasma.


Saturable binding of morphine to rat brain-stem slices and the effect of chronic morphine treatment.

The binding of morphine to brainstem slices was studied with nanomolar concentrations of (3H)-morphine. Rat brainstem slices were incubated at 35 degrees C and immediately homogenized. Bound morphine was estimated using Millipore filters to separate unbound morphine. Binding of labelled morphine was markedly inhibited by either non-labelled morphine or naloxone, indicating that a substantial portion of the binding is saturable. The saturable morphine binding to slices was significantly greater than that to brainstem tissue homogenized prior to incubation with morphine, whereas non-saturable binding was the same in both preparations. Saturable binding of morphine to brainstem slices was lower in rats rendered tolerant to morphine (using pellet implantation) than in non-tolerant controls. It appears that chronic morphine treatment decreases the affinity of the opiate receptor for morphine. It is concluded that the slice is the preferable preparation for the in vitro estimation of opiate receptor binding and that chronic morphine treatment alters the binding of morphine to brainstem.


Stabilization of brain free polysomes by morphine.

The effect of morphine on brain free polysomes prepared from mouse brain was studied. It was found that morphine binds to polysomes and protects them from disaggregation. The significance of this effect with respect to brain protein is discussed.


Acetylcholine storage and its stabilization by morphine.

Acetylcholine binds to adenosine-triphosphate in vitro by ionic bonds between the ammonium ion and the phosphate, as shown by nuclear magnetic resonance data. This binding is further increased by morphine, which also binds to adenosine-triphosphate, but not to acetylcholine. The opiate antagonists naloxone and naltrexone show similar effects. This may offer a molecular explanation of acetylcholine release impairment in nerve endings by narcotic analgestic drugs.


Noradrenergic involvement in the acute effects of ethanol.

These studies were designed to determine several, possibly related, physiological correlates of an acute dose of ethanol. Male rats were injected with 0.5, 1.0, or 2.5 g/kg of ethanol intraperitoneally, and the accumulation of newly synthesized labeled norepinephrine (from 3H-tyrosine) and of labeled norepinephrine metabolites was examined in several brain regions. Ethanol treatment increased labeled norepinephrine and decreased norepinephrine metabolities in the hypothalamus, brain stem plus midbrain, and telencephalon, without altering endogenous norepinephrine levels. A time course, selected on the basis of previous behavioral studies (Jaffe and Pohorecky, submitted manuscript) on the effects of ethanol on central noradrenergic neurons, disclosed that the accumulation of labeled norepinephrine metabolites was higher than that in saline-injected controls from 30-60 minutes after ethanol injection in the brainstem plus midbrain area, while between 5 and 35 minutes levels were lower than those in control animals. Plasma corticosterone levels were highest 30 minutes after saline injection, while in the ethanol group (1 g/kg) steroids were highest 60 minutes after the injection. Body temperature was significantly decreased only by the 2.5 g/kg dose of ethanol; the hypothermia became evident 50 minutes after an injection of this dosage. We conclude that the brief hypermotile stage produced by a 1 g/kg dose of ethanol (Jaffe and Pohorecky, submitted manuscript) is possibly related to the increased synthesis and release of norepinephrine from central noradrenergic neurons.


Thermal alterations in onset and offset rate constants for chlorpheniramine.

The onset and offset rate constants for chlorpheniramine were obtained using the longitudinal muscle of guinea pig ileum. Between 21 degrees C and 37 degrees C these values follwed linear Arrhenius plots with activation energies similar to other biological systems. Below 18 degrees C the nature of the antagonism changed prohibiting estimation of the rate constants. It is concluded that at higher temperatures the histamine receptor behaves in a uniform manner, but below 20 degrees C a change in properties occurs.


Avoidance and poke behavior in rats after gonadectomy and hormanal treatment.

The effects of gonadectomy and hormonal treatment upon such emotional behavior as discriminated lever-press avoidance and poke activity were examined in the rat. Gonadectomy at 2 mo of age significantly increased the avoidance of female animals but did not affect those of males or the poke performance of either sex. High, multiple, subcutaneous injections of estradiol benzoate (125 mug/kg), progesterone (80 mg/kg) or their combination led to significant declines in avoidance behavior among females spayed at 2 mo of age. Other significant findings included a sex difference in poke performance where intact females, compared to intact males, executed more responses. Significant decrements in poke behavior were also observed for all subjects, regardless of sex, during testing and from one session to the next.


The role of the adrenal medulla in the contol of gluconeogenesis in the rat.

The role of adrenal catecholamines in the control of gluconeogenesis was determined in adrenal-demedullated (AD) and sham-operated (SO) rats. In animals which were fasted, plasma levels of glucose, lactic acid, glycerol, alanine as well as liver or skeletal muscle glycogen, and incorporation of lactic acid-14C into glucose were not significantly different between AD and SO rats. During exercise (forced running), SO rats were found to have significantly higher plasma glucose levels, lower skeletal muscle glycogen levels, and greater incorporation of lactic acid-14C into glucose that AD rats. No significant differences in plasma levels of lactic acid, glycerol, alanine, or liver glycogen were detected in the animals which were exercised. During a combined regimen of fasting and exercise, SO rats exhibited higher plasms glucose levels and significantly greater incorporation of lactic acid-14C into glucose than did AD rats. Epinephrine administration produce quantitatively similar effects on blood glucose levels and on incorporation of lactic acid-14C into glucose in fasted, exercised AD and SO rats. Glucose utilization, as measured by the disapperance of glucose-14C from the plasma of fasted, exercised rats, was not altered by adrenal demedullation. It is concluded that, under certain conditions, adrenal medullary catecholamines play a significant role in the control of gluconeogenesis in the rat, probably through an effect on the glucose synthesizing enzyme systems of the liver.


Incidence and range of microscopic hematuria in patients with indwelling urinary catheters.

The presence and number of red blood cells (RBCs) in the urine after catheterization were ascertained in 40 patients without urinary tract pathology or other cause for hematuria. Before catheterization, 90% of the patients had less than or equal to 1 RBC/high power field (HPF), a figure similar to that for normal volunteers. Two days after catheterization, however, 61,5% of the patients had 2 RBC/HPF with a range between zero and "too numerous to count." The incidence of "hematuria" (greater than or equal to 2 RBC/HPF) declined with time. Neither urinary specific gravity nor urinary tract infection could be correlated with hematuria. At any time after catheterization, 90% of the patients had greater than or equal to 50 RBC/HPF. These data may be helpful in differentiating hematuria caused by the catheter from that due to drug reactions or disease states.


Bioenergetics in clinical medicine. III. Inhibition of coenzyme Q10-enzymes by clinically used anti-hypertensive drugs.

Background data revealed that some American and Japanese patients with essential hypertension, including many who were not being treated with any anti-hypertensive drug, had a deficiency of coenzyme Q10. Eight clinically used anti-hypertensive drugs have now been tested for inhibition of two mitochondrial coenzyme Q10-enzymes of heart tissue, succinoxidase and NADH-oxidase. Diazoxide and propranolol significantly inhibited the CoQ10-succinoxidase and CoQ10-NADH-oxidase, respectively. Metoprolol did not inhibit succinoxidase, and was one-fourth as active as propranolol for inhibition of NADH-oxidase. Hydrochlorothiazide, hydralazine, ans clonidine also inhibited CoQ10-NADH-oxidase. Reserpine did not inhibit either CoQ10-enzyme, and methyldopa was a very eak inhibitor of succinoxidase. The internationally recognized clinical side-effects of propranolol may be due, in part, to inhibition of CoQ10-enzymes which are indispensable in the bioenergetics of cardiac function. A pre-existing deficiency of coenzyme Q10 in the myocardium of hypertensive patients could be augmented by subsequent treatment with propranolol, possibly to the "life-threatening" state described by others.


Reduction of enzyme efflux from isolated skeletal muscle and heart by diethylstilbestrol.

It was previously shown that the efflux of creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) from isolated mouse gastrocnemius was reduced 20% by a daily dose of 10 mug of diethylstilbestrol (DES) given for 14 or 21 days. The present study was designed to ascertain to what degree increasing doses of DES could suppress the CPK and LDH efflux from isolated skeletal muscle, and if DES affected heart in a similar manner. A total of 36 mice were injected with saline or 20, 100, 250 and 500 mug DES in saline daily for 14 days. The spontaneous efflux of CPK and LDH from the isolated gastrocnemius and heart was then compared in control and treated mice. The reduction in efflux was partially dose-dependent: increasing doses up to 100 mug DES per day, progressively reduced skeletal muscle efflux of CPK to 50% and LDH to 30%; higher doses had no additional effect. LDH efflux from heart was similarly reduced by DES, but over a narrower dosage range. This is the first agent shown to lower the spontaneous enzyme efflux from these two organs. These studies confirm that DES lowers the enzyme efflux from skeletal muscle; and though this effect is dose-related, the efflux could not be completely suppressed. The mechanism responsible for this reduction remains to be determined.


Human deficiencies of vitamin B6. I. Studies on parameters of the assay of the glutamic oxaloacetic transaminase by the CAS principle.

Human deficiencies of vitamin B6 may be detected and accurately measured by a dual enzymic assay which is based on the CAS principle, i.e., the unsaturation and saturation of the coenzyme (pyridoxal 5'-phosphate) of a Coenzyme - Apoenzyme System. Glutamic oxaloacetic transaminase (GOT) is excellent for this assay. Two control groups (24 athletes and 25 students) showed deficiencies of GOT activity of 11+/-6% and 12+/-7%, respectively, which are negligible and which may be compared with analogous data from disease states. Contrary to a previous report, GOT activities must be determined within one day of preparation of the enzyme for meaningful assays. Frozen storage of erythrocyte hemolysates up to 21 days showed increasing apparent dissociation of pyridoxal 5'-phosphate from the coenzyme - apoenzyme system corresponding to increasing false deficiency levels. Dilution of the hemolysates and frozen storage augmented the apparent dissociation and false levels. This dual GOT assay is effective to detect and measure human deficiencies of vitamin B6.


Identification and quantification of drugs in human amniotic fluid.

Since drugs administered to gravid females are rapidly transferred to the fetus, transplacentally acquired drugs and drug metabolities should be excreted by the fetus into amniotic fluid. Analyses have been carried out on amniotic fluid obtained at the time of delivery using a gas chromatograph-mass spectrometer-computer system. The drugs that have been identified are caffeine, secobarbital and phenobarbital. Theobromine (3,7-dimethylxanthine) and smaller amounts of 1,7- and 1,3-dimethylxanthine, three metabolites of caffeine, were also found in amniotic fluid, but metabolites of secobarbital and phenobarbital were not detected. It is known that human fetal tissues have active enzyme systems for metabolizing drugs, but these results suggest that this may be a selective rather than general occurence.


Decreased drug tolerance following endocrinological manipulation in the rat.

Nine groups of rats of rats were either hypophysectomized, adrenalectomized or left unoperated. These groups were then subjected to daily increasing injections of either morphine HCL, sodium pentobarbital, chloridiazepoxide or saline. Hypophysectomy seemed to lower the lethal dose of the three drugs tested. Adrenalectomy seemed to have only a minimal effect on the lethal dose of morphine HCL or sodium pentobarbital.


Drug induced biogenesis of nitrosamines.

It has been demonstrated that potentially corcinogenic nitroso compounds are readily formed when certain widely used drugs with secondary alkylaminostructures (e.g. nortriptyline and fenfluramine) or drug metabolities with such structures (e.g. norpropoxyphene) are reacted with nitrite in dilute acid aqueous medium or in human gastric juice under simulated gastric conditions. The reactions occur so readily in vitro that new quantitative procedures for the determination of these drugs have been developed and based on these principles. The potential hazards associated with the long term clinical use of such drugs are discussed.


Effect of various pharmacological agents on prostaglandin induced increases in microvascular permeability.

The anti-histamines, pyrilamine and chlorpheniramine, the serotonin antagonist, methysergide, the beta-adrenolytic, phenoxybenzamine and the anti-cholinergic, atropine, antagonized the prostaglandin E1 induced increases in vascular permeability. None of the non-steroidal anti-inflammatory agents acted as antagonists at these doses.


Free amino acids in plasma and erythrocytes during and after cardiopulmonary by-pass in open-heart surgery.

The concentrations in plasma and erythrocytes of free amino acids before, during and after cardiopulmonary by-pass have been determined. During by-pass and the early postoperative period the total alpha-amino nitrogen decreased, mainly because of changes in glucogenic amino acids; ketogenic amino acids, on the other hand, increased. The phenylalanine/tyrosine ratio was markedly increased in all cases.


Restoration of nucleic acid biosynthesis after clinical death and factors stimulating the process in vivo.

The biosynthesis of RNA and DNA falls almost to zero in 60 min after the death of rabbits from anoxia, in all the organs of the body. Rapid artificial cooling of the rabbits to 20 degrees C undertaken within 10 min after death preserved nucleic acid biosynthesis and permitted restoration of life 3-4 h after death, with recovery beginning in 60 min. During the reanimation the addition of ATP to the blood stimulated the restoration of RNA biosynthesis in the spinal cord to a considerable extent; the addition of cocarboxylase to the blood promoted cardiac RNA biosynthesis as well as cardiac and pancreatic DNA biosynthesis during recovery.


Concentrations of free amino acids in plasma, erythrocytes and cerebrospinal fluid in coma.

The concentrations of free amino acids were measured in plasma and erythrocytes in 15 patients, and in cerebrospinal fluid in eight patients, who were in coma. Although there was a variety of causes of coma, there seemed to be a characteristic pattern of the concentrations of amino acids for coma, and the plasma/cerebrospinal fluid ratios also showed constant patterns.


The use of cholinesterase in severe head injury.

White rats were subjected experimentally to head injury, and also observations were made on them and on 12 patients with head injuries. It was found that injection of cholinesterase brought back to normal function the endogenous cholinesterase system, the adrenal cortex and the properdine--albumin complex system. Stabilization of these indices of homeostatic activity improved the chances of survival of the animals and patients. It was concluded that it would be desirable to administer cholinesterase more frequently in the treatment of head injury.


Aspects of anaesthetic management of heterologous extracorporeal hepatic support in patients with acute liver failure.

Some anaesthetic aspects of heterologous extracorporeal hepatic support for patients with acute liver failure have been investigated in animals and men. Two types of anaesthesia during hepatectomy in pigs were performed in 20 experiments divided into two groups. A convenient anaesthetic technique was found to be the combined use of neuroleptanalgesics, gamma-OH, small doses of thiopental sodium and nitrous oxide--oxygen mixture. The necessity for care in the procedure of temporary liver support for 'poor-risk' patients is outlined. A minimal use of drugs which are metabolized by the liver, and avoidance of potent analgesics, narcotics, hypotension and hypoxia are the main principles for safe extracorporeal hepatic assistance to critically ill patients.


Localization of irritant receptors in the airways of the dog.

In dogs the authors have recorded from single fibres of the vagus nerve the action potentials originating from rapidly adapting receptors (irritant receptors) of the tracheo-bronchial tree activated both by inflation and deflation and by i.v. injection of histamine. A gross localization between extrapulmonary airways was established for 196 such receptors by probing the structures containing them. For 82 receptors a precise localization was determined within the extrapulmonary airways and for 51 receptors, localized in the lung parenchyma, a further precise localization was established along the intrapulmonary airways be dissecting the lung tissue. 66.9% of these receptors were found to be in the intrapulmonary airways and 33.1% in the extrapulmonary airways. Their distribution along the tracheo-bronchial tree resulted as follows: 4.75% in the higher 2/3 of the trachea, 9.25% in the lower 1/3 of the trachea and the carina, 19.0% in the main bronchus, 25.0% in the lobar bronchi, 36.8% in bronchi having a diameter larger than 1 mm and 5.2% in bronchi having a diameter smaller than 1 mm. Therefore the concentration of irritant receptors increases going from the upper trachea to the lobar bronchi and then sharply decreases reaching the smaller airways.


Kinetics of inert gas equilibration in an exclusively skin-breathing salamander, Desmognathus fuscus.

Characteristics of cutaneous gas exchange in amphibians were studied by analysis of the equilibration kinetics of an inert test gas in salamanders which have neither lungs nor gills. Specimens of the common dusky salamander (Desmognathus fuscus, Plethodontidae, Urodela), average body mass 6.1 g were equilibrated with 20% chlorodifluoromethane (Freon 22) in oxygen. The time course of subsequent elimination of Freon 22 into atmospheric air was more rapid in living than in dead animals. This difference was attributed to convective transport by blood flow. Several alternative models were proposed, providing a basis for quantitative analysis of the data. All models yielded similar values for convective conductance due to blood flow. In order to calculate blood flow therefrom, a simplified circulation model based on anatomical evidence was used: the cardiac output is in part directed to the skin, subserving gas exchange with the environment, and in part to the internal organs; the blood returning from both skin and internal organs is mixed before reaching the heart. Depending on assumptions regarding the model and the partitioning of blood flow to the skin and to internal organs, the following range of values was calculated from the experimental data: cardiac output, 85-195 mul/(min-g body mass); cutaneous blood flow, 27-63 mul/(min-g body mass). Due to inherent assumptions these values must be considered minimum estimates.


Action of intercostal muscle afferents on the respiratory rhythm of anesthetized cats.

Experiments designed to reveal an action of intercostal afferent stimulation on the rhythm of breathing were carried out on barbiturate-anesthetized, paralyzed cats, ventilated by a positive pressure respirator. Tetanic stimuli were applied to midthoracic, external intercostal nerves of intact animals and of animals displaying an apneustic pattern consequent to vagotomy and pontine lesions. In intact animals, the respiratory rhythm, as indicated by phrenic efferent activity, could be paced by intercostal nerve stimuli when they were timed to occur in a particular relationship to the lung volume cycle. Apparently, the action of the stimuli supplemented the phasic, volume-related afferent input. The response required considerable spatial summation and resulted from the action of intercostal afferents to either shorten inspiration or prolong expiration. These reflex effects could be attributed to activation of group II afferents. Although the actions of these afferents were relatively weak in the intact preparation, they proved potent in terminating an apneustic breath; brief stimuli, if they activated group II afferents, cut short phrenic discharge and initiated an expiratory phase, thereby restoring a reasonably normal respiratory rhythm.


Krogh constants for diffusion of nitrogen and carbon monoxide in bladder tissue.

We have measured diffusion of N2 and CO through the walls of urinary bladders of cats. The excised bladders were inflated with various gas mixtures and suspended in air. Values of the Krogh diffusion constants at 37 degrees C are 1.14 X 10(-5) for N2, and 1.79 X 10(-5) for CO (units are cm2-min-1-atm-1 and standard errors are less than 10% of the values).


Medullary relay neurons in the carotid-body chemoreceptor pathway of cats.

Central terminations of the carotid body chemoreceptor afferents were localized by recording field potentials and unit activity evoked by electrical stimulation of the carotid sinus nerve, and unit activity during chemical stimulation of the chemoreceptors. Areas where evoked responses with short latency could be recorded and which contained neurons that responded to carotid body excitation were located in two regions of the medulla, about the level of the obex: a dorsal region which included the nucleus tractus solitarius and the reticular formation just below this nucleus; and a ventrolateral region which included the nucleus ambiguus and the ventrolateral reticular formation around that nucleus. The evoked field responses in the two regions were similar. In these two regions, the only neurons which increased their firing both to NaCN and a decreased PIO2 had a respiratory, bursting activity which was phase locked with phrenic nerve firing. The authors' findings suggest that there is a direct synaptic input from carotid body chemoreceptor afferents onto medullary respiratory neurons.


Role of histamine in the hypoxic vascular response of the lung.

The lung vasculature responds to alveolar hypoxia by constriction and when the hypoxia is localized to one region of the lung, vasoconstriction is also localized to that region. Histamine has been alleged to have a role in the vasoconstrictor response with generalized alveolar and thus systemic hypoxia, but the role for histamine is not clear in localized alveolar hypoxia. Studies were, therefore, undertaken to determine the contribution of histamine to the localized pulmonary vasoconstrictor response to hypoxia. A divided tracheal cannula was used in anesthetized dogs which allowed for ventilation of one lung with oxygen to maintain normal systemic oxygenation (mean PaO2 =73 mm Hg) while the other lung was ventilated with nitrogen as an alveolar hypoxic stimulus. Perfusion to each lung was determined with the 133Xe technique utilizing external counters over the chest. Perfusion (Q) was decreased by 32% (P = 0.002) to the hypoxic lung after 10 minutes of unilateral nitrogen breathing. After intravenous infusion of 20 mg of chlorpheniramine maleate, a potent antihistamine, the decrease in Q to the hypoxic lung was unchanged at 30%. After 40-100 mg chlorpheniramine the decrease in perfusion was again unchanged at 34%. Therefore a significant role was not demonstrated for histamine in the regional pulmonary vasoconstrictor response to alveolar hypoxia in the absence of systemic hypoxemia.


The CO2 conductivity electrode, a fast-responding CO2 microelectrode.

A fast-responding CO2 microelectrode system is presented; it consists of a double-lumen polyethylene catheter provided with a stainless steel catheter tip covered by a CO2-permeable membrane, and connected with each lumen separately to a conductivity cell. The catheter is flushed with bidistilled water at constant flow rate and conductivity of inflowing and outflowing water is measured. The change of conductivity in the water leaving the catheter after exposure of the electrode to a medium containing CO2 is related to the PCO2 of the medium. High sensitivity and fast response, both depending on the flow rate of the carrier water, are shown to oppose each other. When cells are placed at a distance of 45 cm from the membrane, response time for 90% deflection is about 10 sec (at flow rates of 5 ml/min), but when located inside the electrode tip at a distance of within 10 mm from the membrane response time is reduced to about 4 sec. Hydrodynamical aspects concerning dispersion of CO2 in the carrier water and reaction kinetics of CO2 hydration are discussed.


[Carotid auscultation. Correlation in 200 patients with 332 angiograms].

1. Results of auscultation of carotid arteries have been reviewed in 200 adults patients with 332 carotid angiograms. Cases with abnormal cardiac bruits of supraclavicular buits were excluded. There was no case with stenosis of the external artery or significant anemia. 2. The present series of patients comprises : 100 with internal carotid artery (ICA) stenosis, 50 with ICA occlusion and normal contralateral ICA, 50 with cerebral space-occupying lesions. 3. A bruit was present in 80/132 ICA stenosis (60 per cent), 60/84 ICA stenoses reducing the lumen by more than 75 per cent (71 per cent), 20/48 ICA stenoses reducing the lumen by less than 75 per cent (41 per cent). It appeared likely that the presence of an ICA stenosis plays a role in the presence of a contralateral bruit where a contralateral stenosis or occlusion are present. 4. An ipsilateral bruit was present in 50/50 ICA occlusions. A contralateral bruit was present in 7 patients the ICA angiogram being normal. A bruit was present on both sides in 4 patients and it may be that some patients are somewhat apt to have bruits. 5. There was no bruit in 49 patients with normal carotid angiograms and a cerebral space-occupying lesion. Data from the present series suggest that where both ICA's are normal auscultation is falsely positive in less than 10 per cent of patients.


[Amyotrophy and neuronal depopulation of cerebral origin].

Amyotrophy of cerebral origin was analyzed in 12 hemiplegics by means of comparative histological, histoenzymological, histographic and biochemical analysis of biopsies carried out in symmetrical zones. In the 6 cases in which atrophy predominated on the paralyzed side, it occurred early, the deficiency affecting the upper limb in particular and the sensory disturbance being irregular. Attempted numeration of the motor units remaining, according to the "incremential" method of stimulation, suggests a numerical reduction on the hemipelgic side. Despite reservations and general criticisms of this method, its comparative value, although approximate, must be acknowledged. However, although amyotrophy presumes a transsynaptic change in trophic function to have taken place in the peripheral neurone, neuronal depopulation--if one accepts it--cannot be other than functional.


[Resistance in cerebrospinal fluid flow in normal pressure hydrocephalus].

C.S.F. resistance to flow (Rf) was measured in 24 patients by the mean of a constant infusion manometric test, and the results were compared with those of pneumo-encephalography and isotope cisternography. It is concluded that Rf is constantly elevated in patients with normal pressure hydrocephalus, is at least as reliable as the two other tests and therefore provides a really valuable aid to the identification of the patients to be shunted.


[Methyl bromide poisoning. 3 cases, 1 fatal. Neruopathological study of one case of coma with myoclonus followed for 5 years].

Three new cases of methyl bromide poisoning (leakage from a fire extinguisher) are reported. Two of these were characterized, after an initial period of coma and myoclonic status, by an action myoclonus. Electrical data are presented. A follow up of 4 and 8 years allowed to study the effect of drugs, two of which (clonazepam and baclofene) being pecularly contributive. The third patient outlived for 5 years in a stuporous state with myoclonus. The anatomical findings consisted mainly of a necrosis of both inferior colliculi with gliosis in the upper brain stem reticular formation and moderate changes in the dentate and pontine nuclei. Their significance is discussed in view of physiological and experimental knowledge.


[Pure (dynamic ?) agraphia of frontal origin. Apropos of one case].

A case of pure graphic disorder without any disorder of speech, reading or praxis is described. The conditions under which it occurred after surgery for frontal oligodendroglioma would seem to confirm that a single frontal lesion is involve affecting in particular the foot of F2. This case is compared with similar ones which have appeared in the literature and are classified within the wider category of kinesthetic disorders caused by frontal lobe lesion.


Vertebral trephine biopsy.

Vertebral trephine biopsy is a safe and swift method of diagnosis of vertebral abnormality. The procedure is no more disturbing for the patient than lumbar puncture, and saves the patient, radiologist and clinician, considerable time and effort.


Nerve entrapment at the elbow in rheumatoid arthritis.

Although there was some delay in the posterior interosseous branch of the radial nerve conduction time in six of the 152 rheumatoid elbows, in no case were there clinical signs attributable to entrapment of this nerve. Some delay in ulnar nerve conduction was recorded in 27 of the 152 elbows; this was marked in 12. These patients tended to be older and to have more severe disease of the elbow.


Occupation in relation to the carpal tunnel syndrome.

A survey was made of the work and hobbies of 658 patients with the carpal tunnel syndrome. Seventy-nine per cent of the patients were employed in work requiring light, highly repetitive movements of the wrists and fingers. Fifty-one per cent of the unemployed housewives knitted. It is suggested that this type of manual activity can be a causal factor in the development of the, so-called, 'spontaneous' carpal tunnel syndrome.


The use of beta-N-acetylglucosaminidase excretion to investigate renal disease in rheumatoid arthritis.

Urine levels of the lysosomal enzyme beta-N-acetylglucosaminidase have been measured in patients with arthritic disorders; significantly higher levels were found in patients with rheumatoid arthritis (mean: 332.9 nmol/h/mg creat.) than in those with degenerative joint disease (mean: 86.31 nmol/h/mg creat.; P less than 0.001). Analysis of the results shows that salicylates were responsible for some of this difference, but suggests that rheumatoid disease itself may cause renal damage.


Polymyalgia rheumatica and giant cell arteritis: a seven-year survey.

The seven-year results of all cases (84) diagnosed as polymyalgia rheumatica or giant cell arteritis are reported. The diagnosis proved to be incorrect in seven, of which six had a polyarthritis. Most cases were treated with prednisolone, starting with 20 mg daily for those with evidence of cranial arteritis, and 10 mg for those without. Fourteen patients were withdrawn from treatment (after three months to 31/2 years--mean 21 months), but three relapsed and treatment has been restarted. There was no correlation between the presence or absence of arteritis, the starting dose of prednisolone and the subsequent duration of treatment. A small group (7) received higher doses without obvious advantage. Twenty-two started on 5-9 mg daily, but the dose had to be increased in 13 because of inadequate control of symptoms. Objective physical abnormality, particularly painful limitation of shoulder movement, was present in most cases. No patient developed a serious complication of the disease after treatment had been started. Complications of treatment were infrequent. Spinal osteoporosis occurred in seven, but did not cause long-term disability.


Synovitis in polymyalgia rheumatica.

Synovitis was observed in 13 out of 88 consecutive patients with polymyalgia rheumatica. It is described in detail in five patients, on the basis of clinical radiological observations, joint aspiration, arthroscopy and biopsy. The synovitis of polymyalgia rheumatica cannot be distinguished histologically or at arthroscopy from the appearance seen in mild rheumatoid arthritis. Clinically, however, the synovitis of polymyalgia rheumatica is mild, transient and confined to one or two joints or tendon sheaths. It is not followed by joint deformity or by radiological erosive changes in the bone ends. It may occur at any stage of the disease but particularly at its onset, or when the dose of corticosteroid treatment is reduced.


Scleritis associated with hyperuricaemia.

A patient with scleritis associated with hyperuricaemia successfully treated with colchicine is described. The relationship between scleritis and hyperuricaemia is discussed.


[Chronic traumatic arteriovenous fistulae (author's transl)].

In two patients with femoral arterio-venous fistulae angiography could show arterial and venous collaterals with differing circulation phases. When angiography shows retrograde flow in the artery distal to the fistula, the volume of arterial collateral circulation is unrelated to the peripheral blood-supply. Venous collateral circulation has to be included in the fistular circulation. Angiography permits distinguishing a venous by-pass circulation for the return of blood from the periphery. In one patient a large aneurysm of the iliac vein was found. Special features of angiography, particularly after surgical closure of the fistula, are mentioned.


[Isomorphism of primary and secondary tumors of bone in radiographs (author's transl)]Radiologic findings of spread of malignant lymphoreticular processes in the lungs and their response to cytostatic therapy (author's transl)].

Retrospective evaluation of follow-up series of chestfilms of 30 patients suffering from malignant lympho-reticular processes of the lungs and treated with cytostatic drugs. Among 130 changes of form there were foci of infiltration which could be recognized as due to malignant lymphoreticular deposits. They were large zones of shrinking, stripey scars, perivascular densities with vague contrours, an accent on reticular basic pulmonary structure, widening of interlobar septa and stripey shadows in the shape of plate atelectases. During the changes developing in time, the tumor adhered to a certain degree to its primary pattern of spread. Combinations of different types of foci appear to be signs of the severity of the disease.


[Tomometry, a novel radiological procedure (author's transl)].

The physical and technical principles of this revolutionary method of investigation are described. They explain the advantages over usual radiological techniques, i.e. mainly the possibility of showing far smaller density steps of intracranial structures, as well as some drawbacks. Finally, indications, limits and sources of possible errors are outlined.


[The diagnosis of occult mammarian carcinoma (author's transl)].

The proceeding of dedection of ocult mammarian carcinomas by an effective coordination of mammography and thermography is described. The frequency was 7%o of 2000 examinations and with that higher than given in the literature. The importance of post-operative controls is emphasized.


The clinical significance of biphasic venous emptying curves from the lower limb in venous occlusion plethysmography.

The utilization of venous occlusion plethysmography in the routine diagnosis of acute venous thrombosis in the leg has disclosed a previously unreported type of biphasic venous emptying curve that has proved to be of special diagnostic significance. The examinations were undertaken with a Dohn plethysmograph for segmental application of the calf. The emptying curves in question had an initial phase at the ordinary rapid rate, changing distinctly within 1.5 sec into a definitely slower phase of venous emptying. Biphasic emptying curves were found to be characteristic of patients with isolated, high venous obstruction, mostly acute thromboses, but more or less intact veins in peripheral parts of the leg. The same type of pathological emptying curves could be provoked by external compression of the femoral vein or Valsalva's manoeuvre, providing experimental evidence of the underlying mechanism. The venous emptying course might be similarly influenced also by varicose veins, pregnancy, and right heart failure. The diagnostic experience of biphasic emptying curves in clinical practice indicates, that this particular way of interpreting venous occlusion plethysmography is a valuable complement to phlebography in the detection of proximal venous obstructions in the lower limb, whether due to iliac thrombosis or elusive intrapelvic tumours.


Bone mineral content and estimated total body calcium in normal children and adolescents.

Bone mineral content in the distal part of the forearm was measured in 301 normal children and adolescents aged from 7-20 years to estimate total body calcium in these age groups. From year 7 to 9 and from year 15 to 20 the mean values in boys were significantly higher than those in girls. In the lower age groups there was a slow increase in estimated total body calcium with age, followed by a sharp increase at the age of puberty.