[Course of experimental cardiac insufficiency under conditions of high altitude depending on the periods of adaptation].

The data characterizing the compensatory hyperfunction of the circulation and respiration with dosaged insufficiency of the mitral valve in animals, depending on the periods of adaptation to high-altitude are presented. Unadapted animals with insufficiency of the mitral valve had more serious disorders of hemodynamic and gaseous exchange accompanied by stasis in the lesser and greater circulation. 52.9% of the animals died during the first days after the formation of the mitral defect. In animals adapted to the high altitude hypoxia the process coursed with less pronounced disturbances of circulation and respiration; 28.6% of the animals died.


[Allogeneic hepatic cell suspension in the treatment of liver insufficiency].

A study was made of a possibility of using isolated hepatocytes for the treatment of diseases of the liver in animals. The optimal dose of the cell suspension in intravascular, intraperitoneal, intrapleural and subcutaneous administration was determined; a reaction of the experimental animals to this biological substrate was studied. The efficacy of the isolated hepatocytes in the treatment of hepatic insufficiency is demonstrated; also a comparative assessment of the mentioned methods of the cell suspension administration is given.


[Changes in the composition of fatty acids in blood plasma lipids and in various organs in traumatic shock].

The composition of fatty acids of the total lipids of the myocardium, lungs, liver, intestine, adipose tissue, and blood plasma was studied during traumatic shock reproduced in dogs by crush of soft tissues of the hip. The formation of the shock process was accompanied by a rise in the percentage content of linoleic and arachidonic acids in the blood plasma and some organs; a close correlation existed between the linoleic acid content in the adipose tissue and the blood. Oleic acid deficiency was revealed in the lipids of the organs under study.


[Serotonin metabolism in the duodenal tissue of intact rabbits].

Serotonin, 5-oxyindolacetic acid content, and monoaminooxidase activity proved to exceed such in the kidney of rabbit. This pointed to the high capacity of the intestine in respect to the accumulation of serotonin and the processes of its catabolism. The reverse regularity was noted for 5-oxytryptophanedecarboxylase, the activity of which was about 12 times greater in the kidney than in the intestine, this apparently characterizing a low capacity of this tissue in the course of decarboxylation of 5-oxytryptophane.


[Changes of various indicators of brain metabolism in excessive stimulation of the body and the effect of etimizol on these changes].

In case of an excessive irritation (a 3-hour electrical stimulation) of the organism there were observed marked changes in the brain metabolism in rats. These changes were expressed in the exhaustion of noradrenaline stores and disturbances of energy metabolism, leading to reduction of the creatinphosphate level. Preliminary (before the electrical stimulation) administration of ethimizol prevented deficiency of noradrenaline and creatinphosphate in the brain tissue of the animals subjected to the excessive irritation.


[Neurotropic activity of phenylpyrrolidones-2].

Experiments were conducted on mice and rats; a study was made of the pharmacological activity of three isomers of phenyl derivatives of pyrrolidone-2 (P-2). The latter represented a cylic form of gamma-aminobutyric acid (GABA). All the three preparations suppressed the motor activity, decreased the muscle tone and the body temperature, potentiated the action of hexenal, possessed the antispasmodic and hypnotic activity. 4-phenyl-pyrrolidone-2 (phepyron) proved to be most active. In comparing the pharmacological activity of phenyl P-2 derivatives and analogous GABA derivatives the latter were found to possess no antispasmodic or hypnotic activity, and were less toxic. It is supposed that no transformation of phenyl P-2 derivatives into analogous GABA derivatives occurred in the organism.


[Effect of tyramine on the cerebrovascular resistance and arterial pressure during the action of prostaglandins E].

A resistographic study of the cerebrovascular resistance (CVR) and of the arterial blood pressure showed prostaglandins (PG), type E, to inhibit the pressor action of tyramine on the cerebral vessels and the blood pressure. Indomethacin--an inhibitor of PG biosynthesis, retarded the tyramine tachyphylaxis and restored its pressor effect. Ipraside, the monoaminooxidase inhibitor, failed to influence the speed of tyramine tachyphylaxis development under conditions of indomethacin infusion, but increased the pressor effect of tyramine. It is supposed that inomethacin influence was based on the hypersensitivity of the vascular adrenoreceptors.


[Production of interferon and virus-neutralizing antibodies in adult mice infected with enteroviruses during the neonatal period].

Newborn albino mice were inoculated with enteroviruses and in 6 weeks reinfected with homologous or heterologous strains. Strains moderately pathogenic for newborn mice led to formation of specific immunologic memory. Mice infected after birth with highly pathogenic strains produced specific antibodies for a long time and lacked secondary response. Production of interferon was not associated either with the strain pathogenicity for newborn mice or with the presence of antibodies.


[Analysis of the changes in duration of the action potentials of the myocardial cells of guinea pigs in local anaphylactic reaction and the effect of histamine].

The relationship between the frequency of the spontaneous activity and the action potential duration (APD) has been studied on the right cardiac auricular appendage of guinea pigs during cardiac anaphylaxis (ovalbumine was used as an antigen, 2.10(-4)--2.10(-5 g/ml) and histamine action (1.10(-4)--1.10(-5) g/ml) under the following experimental conditions: a) in normal Tyrode solution; b) under the block of Ca-channels by verapramil (2-4 mg/1) or D-600 (0.2-1 mg/1): c) under the block of K-channels by tetraethylammonium (10-20 mM). Analysis of diagrams interspike interval--APD revealed that the antigen and histamine induced the directi prolongation of the APD usually masked by the positive chronotropic action of these agents. The relative prolongation of APD took place at the whole range of spontaneous frequency. These data supported the hypothesis advanced earlier on the principal role of slow Na-Ca-channels activation in the mechanism of cardiac anaphylaxis and histamine action on the myocardium.


[Effect of the rhythm of administration of 1,2-dimethylhydrazine on its carcinogenic action].

The regimen of DMH treatment with the same total dose influenced the realization of its carcinogenic effect. The most extensive intestinal tumours were observed when DMH was administered once a week in a dose of 21 mg/kg of body weight. Daily treatment in a dose of 3 mg per kg results in development of a less marked malignant tumour process restricted to the colon alone. However, under such conditions the liver displayed marked dystrophic and necrobiotic lesions and occasionally tumours as well. Frequent entry of the carcinogen in small doses into the organism led to a significant decrease of cytochrome P450 content in the liver microsomes. This apparently slowed down the DMH metabolism, its conversion into the proximal metabolite and the binding of the latter to the macromolecules of enterocytes.


[Artificial ossification of muscular flap after plastic surgery of the bone cavity under the effect of electric current].

Experiments in rabbits revealed that transplantation of a muscular flap on the central feeding pedicle in the tibis medullary canal and its electro-stimulation with direct microelectric current of 18-20 muA with the alternating polarity speeded up the process of reorganization of the muscular flap in the depth of which new osseous tissue was forming. Electrostimulation of osteogenesis in case of the muscular plastic transplantation promotes restoration of the anatomic integrity of the bone.


[Biological activity of follicle-stimulating hormone in the pituitary gland of human fetuses].

Biological methods were used to study the changes in the folliculo-stimulating hormone (FSH) level in the hypophysis of human fetuses. FSH was found to be present in the hypophysis of fetuses during the whole period of investigation: from the 8th to the 34th week. Marked sex differences both in the total and in the relative FSH content were revealed in the adenohypophysis from the 17th to the 34th weeks of gestation.


[Study of autonomy of action of white gene in allophenic mice].

An allophenic mouse and three allophenic embryos were obtained by aggregating 8-cell-embryos of Miwh/Miwh and +/+ genotypes. The coat colour and pigment epithelium of the eyes indicated chimerism. Melanoblasts of genotype Miwh/Miwh were lost during the embryonic development. Variations of coat colour in a chimeric mouse were due to the interaction of normal melanocytes with the surrounding dermal cells which consisted of clones of Miwh/Miwh or +/+ genotypes and a mixture of both. Certain differences between the right (chimeric) and left (normal) eye development and a greater rate of normal clones growth were observed in the allophenic mouse. Pigmentation of the eyes of two allophenic embryos was less than normal. This indicated the autonomy of gene white action in mice.


[Microtubules and their relationship with the subsynaptic structures and the nuclear membrane in human neuroblasts].

The appearance of microtubules and the development of their interrelations with the synaptic area and the nuclear envelope in differentiating neuroblasts from the anterior horn of the spinal cord in the first half of human antenatal ontogenesis was traced by methods of electron microscopy. A hypothesis was put forward on the functional purpose of the above interrelations between the microtubules with the subsynaptic area of the neuroblast and its nucleus.


[Effect of vagotomy on the morphological and functional state of the rat adrenal medulla].

After bilateral subphrenic vagotomy in male rats (in 7 and 45 days) there was revealed a sharp dilatation of the venous sinusoids, diminution of the chromaffin tissues area, and a more intensive chromaffin reaction in the adrenal medulla. Vagotomy resulted in a marked alteration of the ultrastructural organization of the secretory cells and the endothelium. Glucose administration to vagotomized animals caused only insignificant variations in adrenaline content in the chromaffin cells. Thus, vagotomy resulted in reduction of the functional activity of the adrenal medulla secretory cells.


[Comparative analysis of the regenerative activity o the muscular and neural tissues after trauma and after transplantation of minced muscle].

Regenerative processes in the body muscle of fish Variocorhinus capoeta sevangi were studied both after the excision of a portion of three muscle segments and following autografting minced muscle into the defect formed. Muscle trauma resulted in a damage field, including the defect and the adjacent degeneration zone. The inflammation, necrotic mass resolution and regeneration of the nerve and muscle tissues were lengthy. Formation of myogenic elements started during the 3rd week only. Individual regenerating nerve fibers in the damage zone appeared 2 months later. Filling the defect with minced muscle accelerated the regeneration. The grafted muscle fiber fragments were not only involved in the regenerative process, but also stimulated the plastic activity of the muscle and nerve tissues of the grafted bed.


[Use of the light-dispersion spectroscopy for detection of the precipitation reaction].

The light beating spectroscopy technique was used to detect the precipitation test. The system consisting of human serum globulin--rabbit antiserum against human globulins was studied. A possibility of detecting the precipitation test for much more diluted systems of the antigen and antibody by means of the light beating technique than by the routine visual method was demonstrated.


[Dental receptor projections to the sensomotor zone of the rabbit cerebral cortex].

Topic organization of the dental representation was studied in experiments on rabbits by the method of induced potentials. Every tooth proved to be locally represented in the sensory-motor zone of the brain cortex. These zones do not overlap in the case of stimulation of the threshold strength. Topic dental projection region occupies a territory including fields Par I, Praecag, Preacgr, and PC.


[Heparin clearance during activation of the anticoagulation system in animals].

Retarded heparin-35S clearance from the blood stream during activation of the blood anticoagulation system was observed. Under these conditions the half-life of heparin-35S increased from 1.6 h in control animals to 2.35 h in the animals after intravenous injection of a threshold dose of thrombin causing activation of the anticoagulation system. Retarded heparin-35S clearance from the blood stream during activation of the blood anticoagulation system is accompanied by increase of its absorption in the liver and in the auricular atrii.


[Electrical activity of the cortex and subcortical structures during the development of hypoxia due to blood loss].

Previous experiments on dogs showed that in several cases, along with the development of hypoxia, polymorphous delta-waves changed into synchronous oscillations, also of delta range, the so-called standard slow complexes (SSC). The new experimental data showed discharges of neuronal pool during SSC to be present in the caudate nucleus, lateral and medial thalamus, hypothalamus, hypocampus, n. amygdale, and mesencephalic reticular formation. The most frequent neuronal pulse activity was connected with the second half of the SSC negative phase (P is less than 0.01). Discharge flashes of the neuronal pool during the SSC indicated that SSC reflected the physiological processes occurring in these structures.


[Effect of electrostimulation of the supraoptic region of the hypothalamus on lipid metabolism and the development of atherosclerosis].

A three-week electrical stimulation of the hypothalamic supraoptic zone in rabbits which were on atherogenic diet for 3 to 8 weeks accelerated and intensified the development of hypercholesterolemia and lipidosis of the coronary arteries, as well as the metabolic changes in the myocardial tissue. The latter changes were expressed in the reduction of the tissue noradrenaline level, diminution of the creatine phosphate content, and an increase of inorganic phosphorus and lactic acid.


[Changes in the fast uterine muscle biopotentials in rabbits with chronic hypoxia].

Changes of the high-frequency electrical activity in the myometrium after a separate and simultaneous ligation the uterine and ovarian vessels were studied in chronic experiments (137 experiments on 18 non-pregnant rabbits which had already had pregnancies in the past). The highest and most prolonged (up to 45 days) inhibition of the amplitude and frequency of rapid (peak) potentials of the myometrium follows a simultaneous ligation of the uterine and ovarian arteries and veins. The amplitude and frequency of biopotentials is gradually restored with the compensation of blood circulation by the collateral blood channels.


[Reaction of vessels of the microcirculatory bed of subcutaneous tissue to exposure to an argon laser beam].

The effect of argon laser irradiation on the microvessels of the subcutaneous fat tissue of rabbit's ear placed into Clark's transparent chamber was studied. Capillaries and venules were found to be sensitive to argon laser irradiation; functional disturbances of microcirculation were most distinct. Following laser irradiation an active reconstruction of the microcirculatory bed with the redistribution of the blood stream took place along with destruction of the vascular wall and perivascular inflammation.


[Protein-containing liposomes and their organ distribution following intravenous administration].

Comparative characteristics of the distribution of phophokinase-125I was studied in rats after the intravenous injection in free or liposome-entrapped state. Significant increase of protein entrapment by the organs and prolonged tissue retention (up to 6 days) were found after the liposomes administration as compared to injection of free material (no label was found after 24 hrs). Intracellular localisation of the label in the liver was revealed autoradiographically 24 hrs after the liposome injection; it was absent after its injection in free state. Enzyme assay in liver homogenates revealed intact specific activity after liposome administration, and confirmed the quantitative data obtained with radiolabeled protein.


[Taurocholic acid synthesis in dogs maintained on a high cholesterol diet].

Labeled 35S-taurocholic acid synthesis was studied in dogs with gall bladder fistulae, fed high cholesterol diet. During the first period (1--2 months) dietary cholesterol caused a significant increase in the 35S-taurocholic acid synthesis. In 5--6 months, at the period of development of the pathological process in the liver, there was a decrease of synthesis and secretion of bile acids, and of cholesterol sediment in the bile. The level of plasma cholesterol in these dogs increased only slightly.


[Participation of the H-2 system in regulating the sensitivity of mice to morphine].

The pain susceptibility of congenic-resistant mouse strains A/Sn, C3H/Sn and C57BL/10 Sn after the injection of morphine was studied. Strains sensitive and resistant to this narcotic were distinguished among congenic-resistant A/Sn and C3H/Sn mice. The morphine sensitivity inheritance is characterized by dominance. The possibility of the major histocompatibility mouse system (H-2) participation in the genetic control of mouse susceptibility to morphine is discussed.


[Growth of cultured blood cells in the presence of the cryoprotector polyethylene oxide 400].

The effect of polyethylene oxide 400 (PEO-400) cryoprotector on the mitotic activity of human peripheral blood leukocytes stimulated with PHA was studied in a culture. The cytologic peculiarities of the blood cell growth on addition of PEO-400 prior to cultivation are manifested in the preservation of the transformation capacity and mitosis despite a significant reduction of the mitotic activity in comparison with control cultures.


[Mechanism of action of granulocyte breakdown products on granulocytopoiesis].

Blood serum leukopoietic activity after the injection to intact Wistar rats of products of 12 and 60 million homologous granulocytes lysis per 100 g of animal body weight, and the character of the serum action on the proliferation and differentiation of stem hematopoietic cells in the spleen of lethally irradiated mice were studied. Accumulation in the blood of granulocytopoietins resulting from the action of the products of granulocytes lysis was noted. Granulocytopoietins stimulated the proliferating activity of stem cells and their differentiation into granulocytes in the spleen of the lethally irradiated mice. A conclusion was drawn on the stimulating action of granulocyte lysis products on the hemopoiesis through the granulocytopoietins.


[Reaction of cells in the anterior lobe of the rat pituitary after acute cooling].

The anterior hypophysis (AH) of rat exposed to total cooling at --10 degrees C for 6 min was studied histologically and autoradiographically. 3, 6, 12, 18, and 24 hours after the exposure the diurnal cycle of modifications of the functional state of the AH secretory cells, the number of mitoses and of the labeled DNA-synthesizing cells was traced. In 12 hours a considerable activation of the thyrotrops and a doubling of mitoses occurred; there was no change of the labeled cells index for twenty four hours. The data obtained showed that stress reaction to cold was characterized by the intensification of the thyrotropic function and an acceleration of mitotic process in the AH cells.


[Effect of deoxycytidine on the frequency of sister chromatid exchanges in human lymphocytes detected by using 5-bromdeoxyuridine].

The frequency of sister chromatid exchanges (SCE) was studied in cultivated blood lymphocytes of three normal individuals under elimination of DNA synthesis inhibiting action of 5-bromodeoxyuridine (BrdUrd 0.05 mM) with deoxycytidine (Cdr 0.1 and 0.01 mM). The frequency of SCE was significantly increased in the presence of 0.1 mM Cdr. In parallel with SCE frequency, Cdr elevated the percentage of metaphases of the second division. The increase of SCE in the presence of Cdr may be connected with normalization of the DNA replication under its action.


[Photooptical and ultrastructural changes in the microcirculatory bed of the kidney after functional vasoconstriction].

In experiments on rats it was found that at the early stages (5 to 15 minutes) after vasoconstriction of the kidney caused by adrenaline solution there occurred sharp narrowing of the intraorganic arterial bed lumen, particularly that of the afferent arterioles. Ultrastructural changes in the glomerular renal capillary components observed were morphological expression of the effect of angiospasm and circulatory hypoxia. Residual phenomena of constriction of the renal microcirculatory bed still persisted at later stages--in 3, 7 days. These changes characterized the stage of peculiar mobility and contractile properties of their endothelial cells, caused by spasmogenic disturbances of microcirculation.


[Amyloid transfer from a syngenous transplant of amyloid spleen in intact and amyloid mice].

Investigations were carried out on male CBA mice with casein-induced amyloidosis. Fragments of spleens from the amyloid and intact donors were transplanted simultaneously to the opposite kidney poles, subcapsularly, to the intact and amyloid recipients. Amyloid deposits were found in 40 per cent of intact recipients both in their own spleens and in the grafts from intact donors. In amyloid recipients amyloid deposits developed in the grafts from intact donors only in 5 per cent of the animals (observation periods from 5 days to 6 months after the transplantation). It is amyloidogenic cells migration and the depression of this mechanism in amyloid mice.


[Morphofunctional stateof the cholinergic nervous apparatus of the normal duodenum and the duodenum after subdiaphragmatic vagotomy].

Histochemical study of the intramural nervous apparatus of the duodenum was carried out under normal conditions and following bilateral subphrenic vagotomy. Morphometric and microspectrofluorimetric methods gave informations on the reduction of the number of the cholinergic nervous fibers and of the acetylcholinesterase activity in them after a brief increase of these indices during the first 24 hours after vagotomy, with their subsequent return to the initial values.


[Ultrastructure of the adrenal medulla and blood catecholamine levels after exposure to thermal injury].

A task was set to carry out electron microscope analysis of the adrenal gland medullary component and to compare with the biochemical data determinations of blood catecholamines during the burn shock. It was found that the response of the sympatho-adrenal system was phasic in character. During the erectile state of burn shock the elimination of adrenaline and noradrenaline took place, while during the torpid one further release of the granule content occurred exclusively on account of adrenaline. The distinctive moment of this period is intensification of the synthetic processes. It should be emphasized that the holocrine type of secretion prevailed after the burn, and just the latter led to the exhaustion of the adrenal medulla. Burn disease is characterized by processes coursing in the direction of restoration; however, catecholamine synthesis and secretion were less intensive than in healthy animals.


[Selective secretion of rat salivary glands after anion administration and the effect of barbiturate on it].

A study was made of the secretion of labeled anions and their metabolites in the salivary composition of 96 adult Wistar rats. Salivary glands were characterized by a high selectivity in the secretion of substances. After the subcutaneous injection of 14C-acetate, 32P-orthophosphate, 35S-thiocyanate, 131I-iodide to control animals in the physiological state 14C concentrated 2.5--6 times more in the mixed saliva than in the blood, but the 32P level was 5 to 20 times less in the saliva than in the blood; 313I and 35S occupied an intermediate position between 14C and 32P. Penetration of labeled anions and their metabolites into the mixed saliva from the blood of rats given barbital Na (medinal) changes significantly: the relative activity of 14C, 35S, 131I saliva/blood was less than in control animals, but the relative activity of 32P saliva/blood proved to be higher in comparison with control rats.


Monocyte-mediated inhibition of lymphocyte blastogenesis in Hodgkin disease.

Mononuclear leukocytes isloated from the blood of previously treated patients with advanced active Hodgkin disease contained high concentrations of monocytes and showed poor lymphocyte blastogenesis to mitogens. In five of eight patients with disseminated disease, blastogenesis became normal or improved markedly when the leukocyte suspensions were depleted of monocytes before culture. Addition of autologous macrophages to the monocyte-depleted lymphocytes resulted in a reappearance of the inhibition of blastogenesis. Monocyte inhibition was associated with the presence of active disease, lymphocytopenia, and low lymphocyte/monocyte ratios in the peripheral blood. The role of previous treatment is uncertain, since inhibition tended to disappear when the patients were retreated. Inhibitory monocyte-lymphocyte interactions may be one of the causes of impaired cell-mediated immunity in Hodgkin disease.


Effects of temperature on granulocyte preservation.

With the increasing use of granulocyte transfusion it is becoming important to determine if granulocytes can be preserved for a few days. If so, the optimum storage conditions must be identified. We studied the function in vitro of granulocytes collected as they would be for transfusion by continuous-flow centrifuge leukapheresis (CFCL) and filtration leukapheresis (FL). Granulocytes collected by CFCL maintained normal ability to phagocytose and kill bacteria after 48 hr and normal chemotaxis after 24 hr of storage at 20 degrees--24 degrees C. Neither 1 degrees--6 degrees C nor 37 degrees C were as effective in preserving chemotactic response. Agitation of the granulocyte suspension during storage caused reduced bacterial killing and chemotaxis. Granulocytes collected by FL functioned very poorly after 24 hr storage at all temperatures studied. These studies suggest that it may be possible to store CFCL granulocytes at 20 degrees--24 degrees C for 24 hr. FL granulocytes should not be stored at all.


Hereditary abnormality of platelet aggregation attributable to nucleotide storage pool deficiency.

An abnormality of platelet aggregation has been detected in six family members with mild bleeding tendencies. In citrated platelet-rich plasma, primary aggregation induced by ADP or epinephrine and agglutination in response to ristocetin were present but second wave aggregation and aggregation in response to collagen suspension were absent or greatly reduced. Sodium arachidonate-induced aggregation was normal although aggregation in response to prostaglandin G2 was reduced and depended entirely on the presence of plasma or ADP. Further tests indicated that the platelets produced prostaglandins but did not release ATP in response to thrombin or sodium arachidonate. Platelets from the patients were found to contain reduced amounts of ADP and 5-hydroxytryptamine and to be unable to retain radioactivity during prolonged incubation at 37 degree C with radiolabeled 5-hydroxytryptamine. Although electron microscopy revealed an absence of very dense bodies, the platelets appeared otherwise normal. The findings are discussed in relation to previous studies of nucleotide storage pool deficiency and the light they shed on platelet physiology in general.


Beta O-thalassemia intermedia.

Three patients with a relatively mild form of beta O-thalassemia who did not require regular blood transfusions are described. Globin synthesis was studied by gel filtration and urea-carboxymethylcellulose chromatography of stroma-free hemolysates prepared from peripheral blood and bone marrow cells labeled in vitro with 14C-leucine. gamma/alpha Synthetic ratios in peripheral blood were in the same range as in patients with the severe clinical form of beta O-thalassemia, while gamma/alpha synthetic ratios in bone marrow cells were higher than in that group of patients. The size of the free alpha-chain pool measured in one case was smaller than in other patients with "classical" Cooley anemia. It is concluded that the severity of the clinical course in beta O-thalassemia does not correlate with the imbalance in alpha verus gamma chain synthesis in peripheral blood and is determined by the synthetic ratio in bone marrow cells, where the bulk of hemoglobin synthesis takes place.


32P and acute leukemia: development of leukemia in a patient with hemoglobin Yakima.

In 1954 a then 31-yr-old male was found to have erythrocytosis. Over the ensuing decade he received 72 mCi32P. In 1964 his daughters were found to have erythrocytosis. Further investigation led to the discovery of hemoglobin Yakima, a variant with high oxygen affinity. He received no further therapy and was well until 1975, when he developed the preleukemic syndrome. Within 12 mo. he developed acute nonlymphocytic leukemia accompanied by fetal erythropoiesis. Because the inital discovery of this type of hemoglobinopathy came 27 yr after the introduction of 32P for use in the treatment of polycythemia vera, and because there are now known to be more than 39 different high-oxygen-affinity hemoglobins, we anticipate that more patients such as ours have been exposed to 32P. The exposed population should be cosely followed, since this will likely permit assessment of the risk of 32P-induced leukemia in a nonneoplastic condition.


Expression of the major sialoglycoprotein (glycophorin) on erythroid cells in human bone marrow.

The major sialoglycoprotein of human erythrocyte membranes (glycophorin) is one of the most-studied membrane proteins. Although the structure is relatively well known, almost nothing is known about its expression in erythroid cells. To study this we raised an antiserum that reacted specifically with this protein. This was accomplished by immunization of rabbits with a preparation of glycophorin followed by absorption with En(a-) erythrocyte membranes, which lack glycophorin. By use of this antiserum and a staphylococcus protein A technique we could establish that only bone marrow cells of erythrocyte lineage express glycophorin at the cell surface. This occurs in basophilic normoblasts and later stages of erythrocyte differentiation, whereas pronormoblasts do not seem to contain glycophorin.


Pyruvate kinase-catalyzed ATP-formation in human red blood cell membranes.

Previous studies on the linkage between enzymatically catalyzed ATP-generating reactions in the red blood cell membrane and the sodium and potassium transport in the control of overall glycolysis of human erythrocytes were controversial. In this study a significant amount of pyruvate kinase activity is shown to be localized within the membrane. Membrane fragments produce 20.5 mumol of ATP per 10(10) membranes per hour from phosphoenolpyruvate and ADP. The kinetics of the membrane-localized pyruvate kinase do not differ from those of the enzyme from hemolysates. The results clearly document the presence of the second ATP-generating enzyme of glycolysis, pyruvate kinase, in human red blood cell membranes. The main fraction of the enzyme is deeply hidden in the lipid layers of the membrane. It can be demasked by mechanical desintegration of membranes at high levels of activity. It is suggested that the amount of the membrane-localized fraction of pyruvate kinase is related to the clinical severity of the hemolytic process in pyruvate kinase deficiency.


Oxymetholone treatment in myelofibrosis.

In order to study the effect of oxymetholone therapy in advanced myelofibrosis, 11 patients (4 females, 7 males) were given, 3--5 mg per kg body weight, long-term oxymetholone treatment in a prospective multicenter study. Five cases had previously had a diagnosis of polycythemia vera. All patients had anemia initially, 4 leukocytopenia and 10 thrombocytopenia in addition. Hepato-splenomegaly was present in all cases but in varying degree. Five patients required regular blood transfusions before treatment. In 9 of the 15 courses given, there was normalization of the peripheral blood or substantial improvement (better than 3 g hemoglobin/dl or 50 X 10(9) platelets/1) after androgens. Significant effects were noted both on hemoglobin values and platelet counts. The need for blood transfusions ceased completely in all 5 cases. When oxymetholone treatment was reduced or interrupted 4 patients relapsed; 2 of them responded to a renewed course. The red cell counts returned to previous polycythemic values in one patient and another died from acute leukemia. The results of this study suggest that androgens might be of value in advanced cases of myelofibrosis with transfusion-requiring anemia or severe thrombocytopenia.


Antithrombogenicity of immobilized urokinase and its clinical significance.

Urokinase (UK), a plasminogen activator was immobilized on nylon surface by application of a newly devised technique. When applied clinically, this new preparation proved to have excellent thromboresistance.


Problems in the detection of carriers of hemophilia A: the influence of stress and thrombin.

After exposure to stress, factor VIII coagulant activity and factor VIII antigen were determined in healthy volunteers for about 3 days. Three out of four volunteers at different time showed results resembling a carrier state. In vitro incubation of plasma with thrombin in decreasing concentrations showed increased factor VIII coagulant activity, although no fibrin clot or fibrin monomers were formed. The concentration of factor VIII antigen remained constant. The action of thrombin can explain the misclassification of known carriers.


[Nutrition, alcohol and oesophageal cancer (author's transl)].

Nutritional factors are suspected to cause oesophageal cancer as well as other cancers of the digestive tract. Sideropenia, lack of molybdenum, tannins have been reported to be associated with the disease. Polycyclic hydrocarbons and nitrosamines have been found in alcoholic beverages from high incidence regions; the significance of the small amounts detected remains to be assessed. A recent survey in Iran points out the role of poor and monotonous diet. In Brittany, no major deficiencies were found, neither in quantity or quality, in the diet of 200 male cases of oesophageal cancer when compared with a population control group. Differences in consumption were detected for a few items; the most obvious discrepancies concerned the various alcoholic beverages for which the proportion of heavy consumers was systematically greater among cases. Alcohol and tobacco are both independently associated with the disease; there is a dose-response relationship for both and their effects are multiplicative. The mechanism of the action of alcohol in oesophageal cancer is briefly discussed.


[Rubidazone (22 050 RP): clinical study. Phase II trial in solid tumors and lymphomas (author's transl)].

Rubidazone is a semisynthetic antibiomitotic close to daunorubicin and doxorubicin. Fifty two patients with various advanced cancers received rubidazone intravenously at the initial unitary dose of 200 mg/m2 in a single injection at three week intervals; this base line dosage had been adapted in function of leuko-platelet variations observed between the injections. An objective improvement was noted in 18 patients out of 51 evaluable patients (34% of the cases), 6 times the regression of tumoral volume was greater than 50 per cent but not complete (3 breast adenocarcinomas and 3 lymphomas). Manifestations of intolerance-toxicity were minor on the haematologic side (32%); however, they were relatively frequent from the digestive (63%) and general (82%) point of view; symptoms of cardiac disturbances (21%), responsible for the discontinuation of the chemotherapy, necessitate careful attention in the management of the treatment. The comparison of the results of this trial with those obtained by trials using other drugs belonging to the same chemical family don't show, for solid tumors, any difference in efficacy between rubidazone, daunorubicin or duborimycin; however, the difference is very striking with doxorubicin which showed more efficacy (6.5% as 29% of regression greater than 50%). Owing to the conditions of admission and the very strict criteria of analysis in this study, it would seem useful to go into details regarding the interest of rubidazone in lymphomas (only one failure has been recorded out of 6 treated cases).


[Nutrition and carcinoma of the breast: presentation of a french investigation (author's transl)].

The existence of dietary risk factors in breast cancer of post-menopausal women is a recent, and yet unproven hypothesis. A French survey made possible by the cooperation of general surgeons and radiotherapists practising in private clinics is currently in progress in a number of metropolitan departments. A preliminary evaluation of the first 654 questionnaires has proved entirely negative. There was no difference between women with breast cancer and a population of age-matched controls with regard to weight, height or the various traditionnal indices of obesity. However, the number of patients studied is too small to allow this hypothesis to be still rejected.


[Genetics and human cancers: methods of study (author's transl)].

The role of hereditary factors in the etiology of cancer is difficult to prove. However, one may precise a hereditary relationship in those cancers which are either transmitted as a monofactorial trait, or secondary to a hereditary disease, or linked to a genetic marker. Most often, it is necessary to fall back on familial investigations, which may sometimes indicate an excess of familial cases. However, a familial concentration of certain cancers may also be due to hereditary factors, as well as to a common environment.


[HLA system and malignant diseases (author's transl)].

Since ten years, there is an extensive search for association between antigens of the major histocompatibility system HLA and malignant diseases. Data show only weak associations with Hodgkin disease and acute lymphocyte leukemia. For studies of a variety of solid tumours the difference between patients and controls do not attain statistical significance, except for nasopharyngeal carcinoma. According to the gene frequency variations in populations and the ethnic differences in some cancers, inter-population studies are possible. Significant geographic associations between some cancers and HLA antigens have been found. They give evidence for a genetic background of susceptibility or resistance to cancer.


[Familial leukemia (author's transl)].

Among 2966 acute leukemia, 26 familial cases were reported. Leukemia occured mainly in the first relative individuals and particularly in the sibship. The relative risk for a sib of leukemic patient is four time more than for random people. Leukemia was often similar among patients of the same family and the onsets of the disease occured approximatly at the same age whatever the time between the dates of diagnosis. Twins with leukemia were often monozygotous. Relative risk of leukemia among twins, decreases according to the age: the probability of leukemia for a twin is: (a) 100 p. cent if the other twin is leukemic before 1 year old; (b) 15 p. cent between 1 to 4 years old and (c) similar to other sib after 4 years old. Among chronic leukemias, only chronic lymphocytic leukemia seems to have a genetic background for susceptibility. Some familial diseases (congenital aplastic anemia, Bloom's disease, Ataxia telangiectasia) or congenital diseases (Down's syndrome) increase the risk of leukemia.


[Primary immunodeficiencies and malignant proliferations (author's transl)].

The occurrence of malignant proliferative diseases in patients with primary immune deficiencies is far more frequent than in normal individuals. These malignant proliferations may supervent in all types of immune deficiencies but are more frequent in the Wiskott-Aldrich syndrom, ataxia telangiectasia and variable immunodeficiencies. The incidence of malignant lymphomas is striking since they account for two thirds of the malignancies. This fact does not support the hypothesis of a faulty immunological surveillance and would be in accordance with the hypothesis of a direct role of antigenic stimulations occurring on an immune system devoid of regulatory mechanisms.


[Incidence of new cases of cancer in 1975 in the Department of Bas-Rhin].

The recording of new cases of cancer in the Bas-Rhin department interest about 883 000 persons in 1975. 3 073 cancer cases have been registered. The data show an incidence of 424 per 100 000 for male population and 309 per 100 000 among female population. Among male population: lung cancer is the most frequent, it represents 17.1 per cent of male cancers with an incidence of 72.5. In second position cancer of the rectum and recto-sigmoid which represents 7.9 per cent of cancers; it has an incidence of 33.4 per cent. Then followed in this order: prostate cancer with an incidence of 32.3, colon cancer with an incidence of 30.1, cancer of the stomach, and bladder. Among female population: breast cancer is by far the most frequent, it represents 27.5 per cent of all cancers, the incidence is 88.4; next corpus uteri cancer with an incidence of 29.5; colon cancer with an incidence of 25.4, followed by cervix uteri cancer with an incidence of 22.1. The genital localizations, on the whole represent 23.2 per cent of cancers with an incidence of 75.3. It is too early to interprete the recorded disparities among the different districts, nevertheless, one can think that the low rates reported in some districts is due to an under-recording.


Residual piperonyl butoxide in agricultural products.

The residual levels of piperolyn butoxide (PB) in agricultural products were investigated for 531 samples of 10 species. For the determination of PB a high speed liquid chromatograph equipped with a fluorometric detector was used. The detection limit of PB was 0.1 ppm. PB was detected from 3 barleys and 3 wheats harvested in U.S.A. ans Australia. It was not detected from the others. The residual range was from 0.2 to 1.4 ppm.


Alternations in the activity of some digestive enzymes of Channa punctatus, exposed to lead nitrate.

The effect of exposure of Channa punctatus to a sub-lethal concentration of lead nitrate on the activities of alkaline phosphatase, acid phosphatase amylase, maltase, lactase, trypsin and pepsin has been investigated. A decrease in the activity of alkaline phosphatase has been recorded after 15 days of exposure but there was no significant change after 30 days. Acid phosphatase showed an elevation in activity of both stages. All the three carbohydrases shows elevation after 15 days, followed by an inhibition after 30 days of treatment. The activity of pepsin and trypsin remained above the normal level throughout the tensure of the experiment reveal that the pattern of alteration in enzyme activities is different in liver and digestive system.


The maternal distribution and placental transfer of cadmium in zinc deficient rats.

Although a transitory maternal zinc deficiency has been shown to result in an increased cadmium-induced fetotoxicity, the results of the present investigation indicated that a maternal zinc deficiency apparently did not affect the placental transfer of cadmium. However, a zinc deficiency did alter the maternal distribution of cadmium. The increased cadmium fetotoxicity associated with a maternal zinc deficiency may be caused by a maternal alteration rather than a direct effect on the fetus. Further study is necessary prior to any definitive statement concerning the effects of a maternal zinc deficiency on cadmium fetotoxicity.


Metal toxicity to embryos and larvae of eight species of freshwater fish-II: copper.

Fish larvae and early juveniles of all species tested (brook trout, rainbow trout, brown trout, lake trout, northern pike, white sucker, herring, and smallmouth bass) were more sensitive to copper than the embryos. Embryo survival was affected only at the higher concentrations tested, for all species except the rainbow trout. The concentrations of copper that caused significant effects on the larval standing crop were similar for all species (31.7-43.5 microgram Cu/1) except the northern pike, which seemed to be considerably more resistant (104.1 microgram Cu/1). Copper concentrations shown to have no significant effects on the early developmental stages of these species are considered close estimates of the copper concentrations that would have no measurable adverse effects during a complete life cycle toxicity test under similar test conditions.


The effects of petroleum of different stages of incubation in bird eggs.

Artificially incubated mallard eggs were treated externally with 5 microliter of No. 2 fuel oil or 5 microliter of Southern Louisiana crude oil at various times during the incubation period. Embryos were most sensitive to petroleum during the first 10 days of incubation. Southern Louisiana crude oil was more toxic to mallard embryos than No. 2 fuel oil. Hatching weights of ducklings from treated eggs were usually not different from hatching weights of control ducklings. Petroleum may cause bill abnormalities among embryos exposed to a lethal amount of oil early in incubation, but few external malformations of any kind were observed among survivors of the oil exposure. The breeding effort of colonial aquatic birds would be in the greatest danger from oil contamination when a large portion of the birds are in the early stages of incubation.


A simple portable voiced, unvoiced and "s" indicator.

This unit is called a V.S.F. indicator, the initials V.S.F. denoting Voiced "s" and Fricative indicator. It has been developed by the R.N.I.D. as an economical and portable speech training aid. A microphone is plugged into the device which classifies speech sounds on 3 lamps arranged vertically. The upper red lamp denotes voiced sounds. An amber light, centre, deonotes fricative sounds except "s" sounds which are indicated on the lower greeen lamp. The operation of the green light depends on the low frequency energy, while the amber and green lights are controlled by the rate of zero crossings. Informal trials in a variety of different types of special clinics have indicated that the most useful areas seem to be with profoundly deaf children and adults, although speech therapists have also reported promising reactions from children with a variety of communication disorders.


Acoustic trauma effects from doubling the exposure time.

Guinea pigs were used to test acoustic trauma effects from doubling the exposure time. Previously, two frequencies (20 kHz and 4 kHz) were used in conjunction with each other (ie double exposure) to see whether a prior exposure of the cochlea to one frequency would alter the extent of damage caused by a secondary frequency, when compared with damage caused by either frequency alone. A reduced area of damage was attained after double exposures. To complete the series, the same two frequencies were used separately, but the exposure time was doubled. The results from the 20 kHz series surprisingly indicated that a reduced area of damage was obtained after doubling the exposure time. No significant differences were found in the 4 kHz series.


Air as the caloric stimulus.

The use of air as the caloric medium was investigated and compared to that of water. The ability of air and water to generate surface temperatures close to the fluid outlet temperature was studied by irrigation onto a thermocouple. Results of caloric tests performed with air and water are compared by calculating the average nystagmus response for the hot and cold stimuli for two groups of sixty patients. Also, the number of canal paresis, directional preponderance, mixed, bi-lateral canal paresis and normal responses are compared for each group. Finally, the effect of performing a bi-thermal air caloric on a patient having a unilateral drum perforation is discussed.


Ear dominance effects in loudness following auditory adaptation.

In recent years there has been much attention to the study of ear differences in the response to auditory stimuli. However, the possibly of ear differences in auditory adaptation effects has apparently not been investigated. The present authors used a monaural heterophonic balance to investigate the adaptation of a 500 Hz adapting tone. Ten subjects were tested in the left ear, ten in the right. Left ear adaptation was 4.20 dB, while right ear adaptation was 12.88 dB (p is less than or equal to .001). Previous differences in binaural adaptation studies could conceivably have been partially influenced by the ear adapted. It is suggested that the possibility of ear differences in loudness adaptation be taken into account in future studies.


Integrated leprosy control in Guyana.

Guyana instituted a "find and treat" leprosy program in 1971 that made use of existing out-patient facilities and staff. The program, based on an integrated domiciliary approach to diagnosis, treatment, and examination of contacts, has proved successful. This article describes development of the program and discusses the prospects for control and eventual eradication of leprosy in Guyana.


Improving education and research through the Pan American Health and Education Foundation (PAHEF).

A highly productive method for aiding medical education in the Americas has been developed that involves using a revolving fund to buy large quantities of essential textbooks at low cost. The procedure, which utilizes medical schools as intermediaries, has made it feasible to sell books directly to medical students. Establishment of the revolving fund was made possible by a loan of US$2 million from the Inter-American Development Bank. To facilitate the operation an independent nonprofit corporation, the Pan American Health and Education Foundation (PAHEF), was created to receive and administer the funds. The foundation works closely with PAHO. In the first six years since its establishment the PAHEF program has grown rapidly, involving a total of 146 medical schools in the PAHEF-sponsored distribution of 335,000 texts. The program has also been extended successfully to nursing schools, and plans are now underway to extend it still further to a wide variety of other health workers.


Venoms of coral snakes (Micrurus spp.): report on a multivalent antivenin for the Americas.

A multivalent coral snake antivenin was prepared in horses immunized with a mixture of venoms from the species Micrurus nigrocinctus, M. mipartitus, and M. frontalis, following immunization procedures previously reported (2). Plasma from the horses was fractionated with ammonium sulfate. The antivenin produced was then tested against venoms from ten species. The neutralization titers obtained indicate it would be useful in treating bites received from most of the important coral snake species in North and South America, namely: M. fulvius, M. alleni, M. carinicaudus dumerilii, M. corallinus, M. frontalis, M. lemniscatus, M. mipartitus, M. nigrocinctus, and M. spixii. The authors note that appropriate cooperation by scientists in various countries would make production of this antivenin an easy matter, and that the product could conveniently be distributed via PAHO or other international agencies. They also note that the antivenin showed no significant neutralizing effect against M. surinamensis venom. This situation would appear to justify preparing a monovalent antivenin against M. surinamensis, or else including M. surinamensis venom in an immunization formula for a multivalent antidote.


Sanitation norms in rural areas: a cross-cultural comparison.

Mortality rates have sharply decreased throughout the world in the twentieth century. While the communicable diseases that had been the principal killers of mankind have been largely brought under control, the enteric and other diseases, which are directly related to sanitation practices, have not been affected. Improvement in health status in the developing nations, especially in isolated rural areas, will hinge on changes in sanitation norms. Modification of these norms must be based on an awareness of what they are and of the values that are associated with them. Sanitation norms in rural areas of three countries--in the southeastern United States, Puerto Rico, and the Dominican Republic--are reviewed on the basis of a study in which essentially the same survey instrument was used in the three samples. Sanitation norms relating to the source of water and storage for household use are compared, as are personal hygiene practices and patterns for the disposal of liquid wastes, garbage, and other solid wastes. Selected attitudinal values are also examined.


Salmonella infection in market swine, Trinidad and Tobago.

Salmonella organisms were isolated from samples of mesenteric lymph nodes taken from healthy market swine at an abattoir in Port-of-Spain, Trinidad and Tobago, on 36 different visits over a 12-month period. Of the 869 samples examined, 160, or 18,4%, were positive for Salmonella. A total of 19 serotypes were isolated of which S. agona was the most prevalent. The findings are compared with observations by other workers.


Intermediate objectives for the monitoring of family planning services.

Since progress during the early stages of a program cannot easily be measured in terms of the ultimate objectives, there is need to develop a set of intermediate indicators for purposes of necessary evaluation and monitoring. Family planning programs suggest a series of useful intermediate objectives that have a clear cause-and-effect relationship with regard to their ultimate goals. It is important that they be expressed as specific targets. They should provide for a numerical definition of the target population; a given time frame; a service design which takes into account patient load, personnel performance, and service capacities; and a record system that can readily retrieve information about service utilization and also identify each patient individually. At the same time, allowance should be made for periodic review and adjustments in light of modifications that are bound to occur in the composition of the target population as well as possible changes of a sociopolitical nature that might affect the program's scope.


Ecology and health.

Health is commonly conceived as having fixed and universal aims, while conditions interposed by environmental and cultural conditions are often ignored or at least shunted to one side. Rejecting this point of view, the author asserts that health in any society should be defined in terms of ecological reality--that is, in terms of the cultural and environmental variables affecting the population. He also notes that acceptance of this concept does not imply perpetuation of a natural but static situation. Rather, it implies searching for ways to improve the situation without necessarily striving for international goals that may be unsuitable or impossible to achieve. The concept also implies that we should ask how to define a satisfactory health level for a given set of conditions--and then consider how to achieve that level. The search for answers to these questions and subsequent programs based on the results will require a multidisciplinary approach. Within this context two PAHO facilities, the Pan American Center for Human Ecology and Health (ECO) and the Pan American Center and Engineering and Environmental Sciences (CEPIS), can provide strong support for activities in the Americas. Specifically, ECO is in a good position to collaborate on ecological planning, model-building, and research evaluation, while CEPIS is geared to provide advice and assistance in the key field of environmental sanitation.


[In vitro somatostatin secretion from the median eminence and the neurohypophysis].

The mechanisms of somatostatin secretion from nerve endings were investigated using the rat median eminence and neurohypophysis in vitro. Determination of total immunoreactive somatostatin content yielded: 36 +/- 2,7 ng per median eminence and 0,74 +/- 0,09 ng per neural lobe. Upon increasing the external potassium concentration a significant rise in somatostatin release from both tissues was observed. (Neural lobe: from 0,86% to 7,4%, median eminence: from 0,09% to 0,47% of total content per 30 minutes). A significant increase in hormone output was also observed following electrical stimulation. The secretory response was abolished whenever external calcium was omitted or replaced by manganese. It is concluded that somatostatin secretion from median eminence and neural lobe in vitro shows two characteristics typical of a neurosecretory process: release upon membrane depolarization and dependence of this process on external calcium.


[Biosynthesis of beta-endorphin].

We have demonstrated that beta-lipotropin is a precursor molecule and that during its maturation, it gives rise to beta-endorphin. This model is similar to proinsulin, proparathyroid hormone and proglucagon models. Since beta-endorphin is also found in the hypothalamus, one can foresee that its biosynthesis will be similar if not identical. It is then conceivable to believe that the other hypothalamic factors are issued from larger precursor molecules. When this will be shown, and well established, studies on their control mechanism will be much easier.


The pathogenesis of myasthenia gravis.

The identification and purification of the acetylcholine receptor molecule has permitted a major advance in understanding the pathogenesis of Myasthenia gravis. The author explains the central role of the receptor and its connections with the main features of the disease. He gives a description of the pathogenic mechanisms involved.


Clinical assessment of skeletal muscle function.

A systematic clinical analysis of skeletal muscle function is presented. Tests range from assessment of muscle weakness with a new hand-held dynamometer (the "Hammersmith Myometer") to studies of the contractile properties of the quadriceps and adductor pollicis muscles described in terms of the force generated at different frequencies of stimulation of the motor nerve, the force-sustaining capability and the time course of relaxation following a brief tetanus. A new measure of the energy-exchanging capacity of muscle is given by the Myothermogram (MTG - so named by analogy with the Electromyogram - EMG). The technique measures metabolic heat production in muscles when maximally activated by voluntary effort or electrical stimulation and the heat changes during sustained contractions. The MTG offers a practical means for assessing in normal and diseased human muscle the metabolic capacity, economy of force maintenance and fatigue mechanisms. Needle biopsy provides safe, rapid and repeatable access to muscle for diagnosis, studies of chemical energy exchange and the correlation of function and metabolism with constituent muscle fibre types. This approach provides a possible basis for recognising the functional disorder and for evaluating the effects of physiotherapy and drug treatments in patients with neuromuscular disorders.


Digoxin toxicity compared with myocardial digoxin and potassium concentration.

1 Twenty-nine dogs were given digoxin (0.25 mg) by mouth twice daily for eight days. Some of them (group 1) also received diuretics and others (group 2) a mineralocorticoid. The dogs were then given an intravenous bolus injection of digoxin and plasma and cardiac muscle were analysed for digoxin and potassium. 2 In the digitalized dogs, myocardial potassium concentration decreased following the intravenous injection of either 0.05 or 0.15 mg/kg digoxin; in contrast, in those dogs given diuretics or mineralocorticoid the potassium concentration increased. 3 Ventricular arrhythmias occurred after digoxin injection (0.05 mg/kg) in the hypokalemic dogs, in those given a mineralocortocoid and in those dogs which received a toxic digoxin dose (0.15 mg/kg). No arrhythmias where seen in the control (digitalized) group. 4 Myocardial digoxin concentrations were similar in the control digitalized group and in the mineralocorticoid-treated dogs after the intravenous administration of the lower digoxin dose (0.05 mg/kg). The myocardial digoxin concentration was significantly higher in the hypokalemic group and in the group receiving the higher digoxin dose (0.15 mg/kg). 5 There was no obvious relationship between the occurrence of arrhythmias and the myocardial concentration of digoxin or potassium.


On the conductance pathway traversed by strontium in mediating the asynchronous release of acetylcholine by motor nerve impulses.

A study was made to determine whether the Sr2+ dependent asynchronous release of acetylcholine by nerve impulses is mediated by the conventional Ca2+ conductance channel or, as has been suggested recently, through an alternative ion pathway. Experiments were performed on the frog neuromuscular junction by the use of standard electrophysiological techniques. Repetitive nerve stimulation in Sr2+-Ringer solutions caused a marked increase in miniature end-plate potential (m.e.p.p.) frequency which was dependent on Sr2+ concentration and inhibited in a competitive fashion by the known Ca2+ antagonists, Co2+ and Mg2+. The equilibrium dissociation constants (KdS) determined for both Co2+ (0.09 +/- 0.01 mM, mean +/- s.e. mean, n = 5) and Mg2+ (3.7 +/- 0.3 mM, mean +/- s.e. mean, n = 4) were essentially the same as the reported values for these antagonists in blocking Ca2+ -mediated transmitter release by nerve impulses. These results suggest that Sr2+ mediates asynchronous evoked transmitter release through the conventional calcium conductance channel.


Effects of droperidol on activity of carotid body chemoreceptors in cat.

1 The effect of droperidol on the spontaneous activity of carotid body chemoreceptors and on their response to various stimuli was studied in 21 anaesthetized, paralyzed and artificially ventilated cats. Carotid body blood flow was controlled with a perfusion pump, and drugs were injected into the perfusion circuit. 2 In low doses, droperidol transiently increased the rate of spontaneous chemoreceptor activity, but in higher doses it depressed chemoreceptor activity after an initial stimulation. 3 Droperidol reduced or abolished the normal increase in chemoreceptor activity produced by stagnant asphyxia. This effect did not depend solely on the ability of droperidol to suppress spontaneously occurring impulses. Chemoreceptor responses to sodium cyanide, and to dopamine were also inhibited. 4 Dopamine antagonists other than droperidol were also studied for their effect on chemocreceptor activity. Chlorpromazine depressed spontaneous chemoreceptor activity and also reduced the chemoreceptor responses to sodium cyanide and dopamine, as did pimozide. The effects of these dopamine antagonists were much briefer and less marked than those of droperiodol. 5 Although the influence that we have shown droperidol to have on peripheral chemoreceptor activity has an uncertain basis, it may have important implications in human and veterinary medicine.


Models for investigating the aetiology of cerebral arterial spasm: comparative responses of the human basilar artery with rat colon, anococcygeus, stomach fundus, and aorta and guinea-pig ileum and colon.

1 The pharmacological similarity between human basilar artery and a number of isolated tissues (rat colon, anococcygeus, stomach fundus and aorta and guinea-pig ileum and colon) has been assessed during investigations of the aetiology of cerebral arterial spasm. 2 The responses of each of the six tissues to human normal and abnormal cerebrospinal fluid (CSF) and to human serum were compared with those of the human isolated basilar artery. 3 These studies revealed the presence of a vasodilator factor in CSF from subarachnoid haemorrhage patients and several tissues may be of use for further work in identifying the vasoactive substances in CSF. 4 No tissue displayed exactly the same spectrum of biological reactivity as the human basilar artery. The rat stomach fundus showed the closest similarity and was further studied for similarities in drug-induced responses. 5 The rat stomach fundus, like the human basilar artery, was contracted by 5-hydroxytryptamine, prostaglandin F2alpha and histamine and relaxed by dopamine. However, noradrenaline relaxed the fundus but contracted the basilar artery.


Antagonism of the effects on thermoregulation of delta9-tetrahydrocannabinol by clomipramine in the rat.

1 The effect of pretreatment with clomipramine hydrochloride (15 mg/kg, i.p.) on the (--)-trans-delta9-tetrahydrocannabinol (delta9-THC)-induced changes in body temperature and brain amines of the rat was investigated. 2 A dose of 0.05 mg/kg of delta9-THC produced hyperthermia and a decrease in whole brain concentration of 5-hydroxyindoleacetic acid (5-HIAA). Doses of 2 and 5 mg/kg produced hypothermia and increases in brain 5-HIAA whereas 0.5 mg/kg did not affect either parameter. delta9-THC, at any of the doses, did not affect the whole brain concentrations of dopamine, noradrenaline or 5-hydroxytryptamine. 3 Clomipramine modified these responses of delta9-THC in that the dose-response curves appeared to be shifted to the right. 4 It is concluded that clomipramine acts as an antagonist to these actions of delta9-THC by interfering with entry of delta9-THC into tryptaminergic neurones.


The effects of methotrexate and melphalan in sheep.

1 Sheep were injected with either methotrexate or melphalan in an attempt to lower the numbers of neutrophil granulocytes in peripheral blood. 2 Methotrexate, 5.0 mg/kg intravenously, on three consecutive days, produced no noticeable clinical or haematological changes. 3 A single dose of melphalan, 1.0 mg/kg intravenously, depleted lymphocytes and granulocytes, but the numbers of the latter then rose to values exceeding the levels before melphalan treatment. Doubling the dose of melphalan proved fatal. 4 The failure of methotrexate to produce changes can be explained in terms of ruminant metabolism.


Acetylcholine and somatically evoked inhibition on perigeniculate neurones in the cat.

1 Perigeniculate neurones in cats were found to be inhibited by iontophoretically applied acetylcholine (ACh) and some of them by somatic sensory stimulation under certain experimental conditions. 2 Under chloralose anaesthesia, perigeniculate neurones could be divided into two groups with regard to their spontaneous activity, sensitivity to glutamate and reaction to sensory inputs. Somatic sensory stimulation clearly inhibited the glutamate discharges of those perigeniculate neurones which were characterized by a high sensitivity to glutamate and the absence of spontaneous activity. ACh had no clear inhibitory effect. 3 Under fluothane and urethane anaesthesia, no somatic sensory influence was noticed but ACh depressed almost all perigeniculate neurones. 4 In an unanaesthetized midpontine pretrigeminal preparation, the inhibitory effect of ACh was confirmed. 5 No conditions were found which the inhibitory influences of ACh and those of somatic sensory stimulation could be observed simultaneously on the same neurone. Therefore, it could not be established whether ACh mediates the somatic sensory influences on perigeniculate cells.


Anatagonism of the inhibitory effects of adenosine 5'-triphosphate on the isolated taenia of the guinea-pig caecum: structure-activity relationships within a series of isatogen derivatives.

1 A series of eight isatogen derivatives was studied on isolated tissues taken from guinea-pigs. The ability of the compounds to relax the taenia, to inhibit adenosine 5'-diphosphate (ADP)-stimulated respiration in mitochondria and to antagonize the inhibitory effects of adenosine 5'-triphosphate (ATP) on smooth muscle was measured. 2 All the derivatives inhibited ADP-stimulated respiration in mitochondria and relaxed the smooth muscle. These two effects were found to be significantly correlated. 3 Only half the compounds blocked the inhibitory effects of ATP, and all of these had a chemically reactive group (nitro, methoxy or pyridyl) in the 2'2-position. 2-2'-Pyridylisatogen was the most effective blocking agent. 4 The blockade of the inhibitory effects of ATP is not related to the other actions of the derivatives.


The effect of amitriptyline on presynaptic mechanisms in noradrenergic nerves.

1 Electrically evoked and resting overflow of tritium was measured from mouse vas deferens previously incubated with [3H]-(--)-noradrenaline. 2 At low concentrations (1.6 X 10(-7) to 4 X 10(-6)M) amitriptyline increased only the evoked tritium overfow while higher concentrations increased both evoked and resting overflow. 3 In the presence of atropine (1 X 10(-6 M) amitriptyline still produced an increase in evoked tritium overflow. 4 In the presence of a concentration of cocaine (1.1 X 10(-5) M) which produced a maximal blockade of the uptake of exogenous noradrenaline the application of amitriptyline still produced an increase in evoked tritium overflow. 5 In the presence of a concentration of phentolamine (1 X 10(-5) M) that produced complete blockade of the presynaptic alpha-adrenoceptors, amitriptyline still produced an increase in evoked tritium overflow. 6 In the presence of cocaine and phentolamine together the effect of amitriptyline on evoked overflow was abolished. 7 It is concluded that amitriptyline may raise synaptic levels of noradrenaline by blocking presynaptic alpha-adrenoceptors controlling noradrenaline release and by blocking its uptake into sympathetic neurones.


Potentiation by substance P of contractions of the isolated vas deferens of the mouse elicited by electric field stimulation and by drugs.

1 Isolated vasa deferentia from the mouse were opened longitudinally and suspended in Krebs solution at 37 degrees C in an organ bath. Contractions of the muscle were elicited by electric field stimulation, noradrenaline (10(-6) M) and acetylcholine (10(-6) M). Continued transmural stimulation evoked a biphasic response comprising a rapid twitch followed about 10 s later by a smaller, sustained rise in muscle tone.2 The amplitudes of nerve-mediated and drug-induced responses were considerably potentiated by substance P (SP) in the dose range 10(-12) to 10(-7) M. Higher concentrations of SP were directly spasmogenic. The sensitizing property of SP was dose-dependent and was usually well maintained, but always disappeared quickly on washing the preparation. In some experiments SP facilitated the twitch, but not the subsequent phase of the electrically-induced contraction or the response to externally applied noradrenaline.3 Phentolamine (10(-6) M) failed to block this effect of SP, but itself potentiated the nerve-mediated twitch, and completely abolished the sustained secondary contraction.4 Desmethylimipramine (10(-6) M) enhanced the delayed contraction but not the immediate contraction.5 The uptake of tritiated noradrenaline (3 x 10(-7) M) by vasa was inhibited by desmethylimipramine (10(-6) M) and increased by nialamide (3 x 10(-5) M), but was not modified by SP (10(-6) M).6 Nerve-mediated release of accumulated radioactivity was accelerated by phentolamine, but not by SP or desmethylimipramine.7 These findings suggest that SP sensitizes the muscle cells to depolarizing stimuli but that it has no facilitatory effect on sympathetic neural elements.


Acute myocardial ischaemia in anaesthetized cats: effects of papaverine.

1 The effects of papaverine on coronary blood flow, myocardial oxygen consumption, myocardial oxygen tension and the ischaemic ECG pattern were studied in anaesthetized open-chest cats representing three models of acute coronary insufficiency: ligation, spasm, and perfusion of the coronary artery at a stabilized insufficient level. 2 Despite the increase in myocardial oxygen consumption reflecting elevation of oxygen demand, papaverine improved the signs of myocardial ischaemia (the myocardial oxygen tension and ECG pattern), as long as there was a possibility of an increase in blood supply to the affected zone. Where this was exluded, the symptoms were actually aggravated. 3 The results suggest that there is no basis for dividing coronary dilators into 'benign' and 'malignant' according to their ability to increase myocardial oxygen requirements. A coronary dilator enhancing oxygen demand may prove beneficial even following complete coronary artery occlusion.


Effects of monocrotaline pretreatment of rats on removal of 5-hydroxytryptamine and noradrenaline by perfused lung.

1 The alkaloid, monocrotaline, causes significant pulmonary damage in many species, including the rat. We, therefore, determined whether the inactivation of biogenic amines by perfused lungs of rats was modified by prior treatment of the animals with monocrotaline.2 Young rats (45 to 50 g) treated for 21 days with monocrotaline (22 mug/ml) in their drinking water developed right ventricular hypertrophy. Treated animals gained weight more slowly and consumed less food and water than control rats that drank tap water. Lungs from monocrotaline-treated animals were heavier and had a higher protein content than control lungs.3 Isolated lungs from treated animals removed and metabolized 50% less perfused 5-hydroxytryptamine than did controls.4 The diminished 5-hydroxytryptamine metabolism was probably due to impaired delivery of substrate to intrapulmonary monoamine oxidase (MAO) since MAO activity in 600 g supernatant fractions of homogenates of lungs from monocrotaline-treated rats was not different from control values.5 Pulmonary removal of perfused noradrenaline was decreased about 60% by the 21-day treatment, suggesting that the effects of monocrotaline were somewhat nonspecific.6 These effects were not caused by monocrotaline directly, since perfusion of lungs from untreated animals with this drug did not alter removal of co-perfused 5-hydroxytryptamine.7 Reduced pulmonary removal of circulating biogenic amines following pretreatment with monocrotaline may reflect damage to capillary endothelium, which could also affect other metabolic functions of lung.


Catecholamine uptake by isolated coronary arteries and atria of the kitten.

Kitten coronary arteries and atria incubated with [3H]-(-)-noradrenaline or [3H]-(+/-)-isoprenaline showed concentration- and temperature-dependent accumulation of amines (unchanged and/or as metabolites). In addition, coronary arteries incubated with [3H]-(+/-)-isoprenaline showed temperature-insensitive amine accumulation due to binding to connective tissue fibres. 2 With low concentrations of [3H]-(-)-noradrenaline (20 ng/ml) accumulation of radioactivity in both tissues was neuronal since it was reduced by desipramine, metaraminol or cocaine but not by the extraneuronal inhibitor, cortisol. 3 In coronary arteries incubated with [3H]-(+/-)-isoprenaline (5 microgram/ml) for 1 or 10 min, uptake was extraneuronal since it was inhibited by cortisol, 17beta-oestradiol or phenoxybenzamine. 4 Atria incubated with (+/-)-isoprenaline (5 to 1000 microgram/ml) showed non-neuronal, biphasic accumulation of amine. There was a high capacity, low affinity initial uptake process (apparent Km 136 micron) which was resistant to steroidal extraneuronal uptake inhibitors but which could be abolished by phenoxybenzamine. A slower uptake occurred after 2 min which was sensitive to steroidal and other extraneuronal uptake inhibitors. 5 Inhibition of uptake processes did not alter sensitivity of coronary arteries to dilator effects of catecholamines. However, experiments with extraneuronal uptake inhibitors were limited by the relaxant effects of cortisol and 17beta-oestradiol themselves. 6 In atria inhibition of neuronal uptake by desipramine or cocaine led to supersensitivity to (-)-noradrenaline but not to (-)-adrenaline or (+/-)-isoprenaline. Chronotropic responses to (-)-noradrenaline were increased five fold and inotropic responses three fold.


The development of tachyphylaxis to electrical stimulation in guinea-pig ileal longitudinal muscles and the possible participation of adenosine and adenine nucleotides.

1 Electrically (30 Hz) induced contractions of guinea-pig isolated ileal longitudinal muscles were reduced by tetrodotoxin (1 micron), adenosine (30 micron) and morphine (10 micron). 2 When stimulated with 10 or 30 Hz for 10 s at 1 min intervals, a progressive decline of amplitude of the contraction was seen (development of tachyphylaxis). At this time, the contractile response to 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) (10 micron) was also greatly reduced. 3 The smaller responses to electrical stimulation and DMPP during tachyphylaxis were restored to their initial amplitude by the addition of theophylline (10 micron). The appearance of tachyphylaxis was prevented by pretreatment with theophylline (1 to 10 micron) and was greatly accelerated by pretreatment with dipyridamole (0.1 1 micron). 4 In [14C]-choline or [3H]-adenosine preloaded muscle strips, electrical stimulation (30 Hz) increased the 14C- or 3H-output, the effect being sensitive to tetrodotoxin blockade. The tachyphylaxis to electrical stimulation was accompanied by a considerable and sustained increase in 3H-output, an effect that was accelerated by dipyridamole (1 micron). The 14C-output initially increased but fell off gradually with the development of tachyphylaxis at which time theophylline (30 micron) reversed the fall. 5 There was a marked increase in the proportion of released [3H]-adenosine to its derivatives during the development of tachyphylaxis. Approximately 60% of the released total radioactivity after tachyphylaxis was found to be [3H]-adenosine. 6 These results suggest that the development of tachyphylaxis may be closely associated with the release of endogenous adenosine derivatives (mostly adenosine) which have presynaptic inhibitory actions on the cholinergic elements in guinea-pig ileum.


Effects of drugs on the accumulation and spontaneous release of noradrenaline in the rat anococcygeus muscle.

1 The ability of drugs to inhibit noradrenaline accumulation and to release noradrenaline was studied in the isolated anococcygeus muscle of the rat. 2 Noradrenaline, tyramine, 2-amino,6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN), 2-amino,6,7-dimethoxy-1,2,3,4-tetrahydronaphthalene (dimethyl ADTN), and 5-hydroxytryptamine were all potent inhibitors of noradrenaline accumulation and potent releasers of noradrenaline. ADTN was accumulated by the rat isolated anococcygeus muscle. 3 Amphetamine and desipramine were potent inhibitors of noradrenaline accumulation but poor releasers of noradrenaline. 4 Methoxamine, oxymetazoline, acetylcholine, and angiotensin were poor inhibitors of noradrenaline accumulation and did not release noradrenaline. 5 The mechanism of action of these drugs is discussed.


Effect of labetalol on the uptake of [3H]-(-)-noradrenaline into the isolated vas deferens of the rat.

1 The effects of the combined alpha- and beta-adrenoceptor blocking drug, labetalol, on the uptake of [3H]-(-)-noradrenaline into the isolated vas deferens of the rat have been determined and compared with those of some other alpha-adrenoceptor blocking drugs and cocaine. 2 Labetalol, like cocaine, produced a simple competitive inhibition of [3H]-(-)-noradrenaline uptake and was about 4 times less potent than cocaine. It is concluded that labetalol is a potent inhibitor of uptake1. Phentolamine and thymoxamine also inhibited [3H]-(-)-noradrenaline uptake, and were respectively 8 and 14 times less potent than cocaine. Tolazoline, piperoxan and yohimbine were inactive in concentrations up to 30 microgram/ml. 3 The uptake1 blocking action of labetalol could explain, at least in part, the previously reported difference in its ability to block noradrenaline and phenylephrine vasopressor responses in the anaesthetized dog. 4 The possibility that uptake1 inhibitory concentrations of labetalol could be present in the blood of subjects receiving normal antihypertensive doses of the drug is discussed.


Hypotension produced by intravenous apomorphine in the anaesthetized dog is not centrally mediated.

1 Intravenous administration of apomorphine (1.25 to 20 microgram/kg) in the anaesthetized dog produced a dose-dependent decrease in blood pressure which was antagonized by haloperidol but not influenced by propranolol or atropine. 2 Intracarotid administration of apomorphine produced a systemic hypotension which was significantly smaller than that seen with intravenous injection. 3 Doses of apomorphine that caused a decrease in blood pressure on intravenous injection, had no effect on blood pressure or caused retching accompanied by an increase in blood pressure on intravertebral or intracisternal administration. The animals showed a marked hypotension on intravertebral or intracisternal injection of clonidine. 4 From these results it is concluded that the hypotension seen with intravenous apomorphine cannot be explained by a central site of action.


Presynaptic actions of gamma-aminobutyric acid and some antagonists in a slice preparation of cuneate nucleus.

1 A slice preparation of the rat cuneate nucleus is described which is suitable for electrophysiological studies on the presynaptic action of drugs. 2. Superfusion of a slice with gamma-aminobutyric acid (GABA) depolarized the afferent nerves in a concentration-related manner. The responses were Cl-dependent. Depolarizations to high concentrations of GABA often faded. Glycine and L-glutamate had little effect. 3 (+)-Bicuculline antagonized GABA in an apparently competitive manner (pA2 = 5.35) at low response levels. Strychnine was 10 times less potent. Responses to high concentrations of GABA were sometimes potentiated by (+)-bicuculline and strychnine. 4 Bemegride and leptazol both antagonized GABA, but with low potency and in a manner which was clearly not competitive.


Effects of gamma-aminobutyric acid on nerve terminal excitability in a slice preparation of cuneate nucleus.

1 Superfusion of a slice preparation of the rat cuneate nucleus with gamma-aminobutyric acid (GABA) depolarized the afferent nerve fibres and increased their excitability. However, before the depolarization had reached its peak the increased excitability reversed to a decreased excitability, an effect which outlasted the depolarization. 2 Both components of the GABA excitability response were dose-related Cl--dependent and antagonized by bicuculline. 3 Possible mechanisms underlying the sequence of excitability changes are discussed.


Plasma clearance of neostigmine and pyridostigmine in the dog.

1 The pharmacokinetics of neostigmine and pyridostigmine was studied in conscious dogs by the use of a cross-over design. 2 Both neostigmine and pyridostigmine were cleared from plasma in a biexponential manner. 3 The apparent volume of distribution of pyridostigmine was invariably greater than that of neostigmine, and its fast disposition half-life was approximately three times longer. 4 The whole body clearance and the urinary elimination of pyridostigmine was approximately twice that of neostigmine. 5 The slow disposition half-life of pyridostigmine was approximately three times longer than that of neostigmine, suggesting that the longer duration of action of pyridostigmine is related to the differential clearance of the two quarternary amines from plasma.


Mechanical responses of the isolated cervix and uterine horn of pregnant rats near term to drugs.

1 The responses of circularly cut strips of cervix and uterine horn from rats on days 20 and 22 of pregnancy to drugs were compared in vitro. 2 The cervix exhibited similar responses and sensitivities to acetylcholine, bradykinin, prostaglandin (PG) F2alpha (day 20) and isoprenaline (day 20) as did the uterine horn but was less sensitive or responded less consistently to isoprenaline (day 22), oxytocin and PG1. PGE2 was more potent on the cervix (day 20). 3 Before term the relatively inextensible connective tissue of the cervix plus contractions of the smooth muscle would help to prevent foetal expulsion. At term the cervical smooth muscle is sufficiently unresponsive to allow cervical dilatation.


Brain tryptophan metabolism on the 5-hydroxytryptamine and kynurenine pathways in a strain of rats with a deficiency in platelet 5-HT.

1 Brain 5-hydroxytryptamine (5-HT) metabolism has been compared in albino (Sprague-Dawley; SD) and in Fawn-Hooded (FH) rats, which have an inherited platelet 5-HT deficiency. 2 It was confirmed that blood 5-HT levels in the FH rats were about one quarter of those in the SD rats. 3 Brain 5-HT and 5-HIAA were however higher in FH rats on a per gram basis; there was no difference between the strains on a per brain basis, because of the smaller brain weights of the FH rats. 4 Brain and plasma tryptophan were not significantly different in the two strains. Plasma kynurenine was higher in the FH rats, and brain kynurenine was also higher either on a per gram or on a per brain basis. 5 The reserpine-releasable brain 5-HT was the same proportion of total brain 5-HT in the two strains. 6 Experiments with pargyline suggested that the turnover of 5-HT was somewhat higher in the FH rats on a per gram basis, but not significantly so on a per brain basis. 7 It is concluded that although brain tryptophan metabolism may be somewhat accelerated along both the 5-HT and kynurenine pathways in the FH rats there is no gross deficiency in the binding of 5-HT in their brains analogous to that found in their platelets.


The effect of ergotamine on tissue blood flow and the arteriovenous shunting of radioactive microspheres in the head.

1 The radioactive microsphere method was used to study the effects of ergotamine (5, 10 and 20 mug/kg, i.v.) on systemic and regional haemodynamic variables in chloralose-urethane anaesthetized cats. The influence of the drug was also studied on the number of 15 mum microspheres escaping entrapment in the head to emerge in the left external jugular vein.2 Ergotamine decreased the heart rate and cardiac output. Since arterial blood pressure remained unchanged, calculated total peripheral resistance increased.3 The regional distribution of cardiac output obtained with 15 mum microspheres agreed well with previous studies in cats where 25 mum spheres were used. The most pronounced difference was that in the present investigation more microspheres, apparently escaping through arteriovenous anastomoses (AVAs), were detected in the lungs than when larger spheres had been used.4 Coronary blood flow decreased, while uterine blood flow was increased by the drug. The microsphere content of the lungs, which receive the spheres not only via bronchial arteries but also via AVAs, was greatly reduced by all doses of ergotamine. Ergotamine did not influence tissue blood flow to other major organs such as the brain, kidneys, skin, liver, skeletal muscle or the gastrointestinal tract.5 In the 16 experiments, 0.46 +/- 0.05 (s.e. mean)% of the total microspheres injected (equivalent to 11.7 +/- 1.4% of microspheres detected in the left-side of the head) appeared within 2 min of microsphere injection into the left external jugular vein. The highest dose of ergotamine significantly reduced the shunting of the microspheres in the head.6 Since 15 mum microspheres are only likely to reach the lungs by passing into the venous circulation through large glomus-type AVAs, we conclude that ergotamine reduces the fraction of microspheres appearing in the lungs by causing strong vasoconstriction in the AVAs in the head.7 In conformity with the closure of head AVAs is the finding that ergotamine reduced the jugular venous Po(2) and O(2) saturation thereby increasing the A-V O(2) saturation difference.8 It is quite possible that decreased A-V shunting may be the prominent mechanism of the antimigraine action of the drug, since sudden opening of AVA's has been implicated in the pathophysiology of migraine-syndrome.


The binding of haloperidol to human blood platelets and interactions with 5-hydroxytryptamine and dopamine.

1 The binding of [3H]-5-hydroxytryptamine ([3H]-5-HT), [3H]-haloperidol and [3H]-dopamine to human blood platelets was investigated and the effects of unlabelled haloperidol on [3H]-5-HT binding and (+)- and (-)-butaclamol on [3H]-haloperidol were studied. 2 Scatchard analysis did not show any specific binding of [3H]-haloperidol or [3H]-dopamine to platelets, but two binding sites were identified for binding of [3H]-5-HT. 3 Unlabelled haloperidol reduced the binding of 5-HT in concentrations comparable to those inhibigint 5-HT-induced platelet aggregation; (+)- and (-)-butaclamol did not affect the binding of [3H]-haloperidol. 4 It is concluded that haloperidol binding represents saturation of the platelet membrane, and that the platelet is not a suitable model for investigation of dopamine-drug interactions.


Effect of crotamine, a toxin of South American rattlesnake venom, on the sodium channel of murine skeletal muscle.

1 Crotamine (0.5 mug/ml) augmented the single twitch response of the rat and mouse isolated diaphragm to direct stimulation and prolonged the time course of contraction. At higher doses (10 to 50 mug/ml), contracture was observed with spontaneous fibrillation.2 The resting membrane potential of diaphragm was rapidly depolarized to about -50 mV within 5 minutes. No increase of depolarization occurred on prolongation of the incubation time or increase of crotamine concentration from 0.5 mug/ml to 50 mug/ml. The effect was not reversed by washing.3 Tetrodotoxin, low Na(+) (12 mM), Ca(2+) (10 mM) and procaine (1 mM) prevented the crotamine-depolarization. However, depolarization resumed when crotamine and the antagonists were removed.4 Low Cl(-) (8.5 mM) and pretreatment with ouabain enhanced depolarization by crotamine.5 High K(+) (25 to 50 mM) prevented the further depolarization by crotamine and the membrane potential was restored to normal on washout of crotamine with normal Tyrode solution.6 Effective membrane resistance was decreased by about 50% by crotamine.7(24)Na-influx of the rat diaphragm was increased by crotamine. (42)K-influx was slightly increased if tetrodotoxin was also present but was decreased in the absence of tetrodotoxin.8 No effect on the miniature and evoked endplate potential of the rat diaphragm was observed. Skeletal muscles from frog and chick were not affected.9 It is inferred that crotamine acts on a molecule regulating the Na(+) - permeability of the Na(+) channel of murine muscles. It is proposed that extracellular K(+) depresses the permeability of the Na(+) channel by acting on the same regulator molecule.


Vasodilatation by prostaglandin F2alpha in the canine tongue through a parasympathetic mechanism.

1 The vascular bed of the tongue in situ was perfused with blood through the lingual arteries at a constant pressure in anaesthetized dogs. All drugs except for SQ 14,225 were administered intra-arterially.2 Prostaglandin F(2alpha) (PGF(2alpha)) produced a dose-dependent increase in blood flow through the lingual arteries (vasodilatation).3 Marked desensitization was observed on the vasodilator responses to repeated administration of PGF(2alpha).4 The vasodilator response to PGF(2alpha) was abolished by tetrodotoxin in doses that abolished the vasodilator response to electrical stimulation of the lingual nerve.5 The vasodilator response to PGF(2alpha) was not affected by hexamethonium in doses that almost abolished the vasodilator response to lingual nerve stimulation.6 The vasodilator responses to PGF(2alpha) and to lingual nerve stimulation were scarcely modified by (-)-hyoscyamine in doses that fully antagonized the vasodilator response to acetylcholine.7 Electrical stimulation of the vago-sympathetic trunk and noradrenaline produced a decrease in blood flow through the lingual arteries.8 These results indicate that the vasodilator response of the tongue to PGF(2alpha) is due exclusively to excitation of parasympathetic postganglionic neurones and that neuronal receptors involved are quite distinct from nicotinic receptors.9 Intravenous administration of SQ 14,225, an inhibitor of angiotensin I converting enzyme or kininase II, augmented the vasodilator responses to bradykinin and kallikrein but not that to lingual nerve stimulation.10 The results suggest that neither kallikrein nor*kinin (including bradykinin) is responsible for the parasympathetically induced vasodilatation in the tongue.


Feigned bereavement: twelve cases.

Twelve patients who feigned bereavement are described. Most appeared depressed on admission, and in over half bereavement was erroneously believed by staff to be an important cause of their depression. This type of behaviour, leading to admission to hospital, may be regarded as abnormal illness behaviour, and reasons are given for considering most of the cases as variants of the Münchausen syndrome. Motivation for these deceptions is discussed, and reference is made to features which might arouse suspicion that bereavement is feigned.


The Münchausen syndrome as a psychiatric condition.

In this presentation of two cases it is suggested that many Münchausen syndrome patients present with psychiatric symptoms. This syndrome, however, should be differentiated from other clinical psychiatric conditions.


Physical disorder among day hospital patients.

During a six-month period, physical disorder was found among 50 per cent of the 133 patients at a day hospital. Few of these cases (5) had organic brain syndromes. Among the remainder (62) physical disorder was not associated with sex, formal psychiatric diagnosis or time of referral to the hospital; of those 33 patients with a neurological disorder, one-third had previously been diagnosed to be hysterical. For this 'hysterical' group, however, associations with folate deficiency, organic brain disease, and depression were noted. The need is demonstrated for routine investigations among day hospital patients with particular attention for those with atypical features.


Suicide in psychiatric patients.

The study relates to suicides occurring in Shropshire during 1965 to 1973 inclusive. Psychiatric patients who had committed suicide were compared with others, matched by sex and age who had not done so. The suicide group included a higher proportion of members who had behaved violently, experienced a broken marriage (through death, separation or divorce) or earlier had deliberately harmed themselves, often by dangerous means. Of the psychiatric patients who committed suicide 63 per cent had seen a doctor within a month beforehand, yet very few were receiving adequate physical treatment for depressive illness at the time of their death. Immigrants from eastern Europe were found to be particularly prone to suicide.


Classification of suicide attempters by cluster analysis.

Cluster analytic procedures for classification were carried out on a sample of 236 suicide attempters. Rating variables concerned previous suicidal behaviour, details of the recent attempt and its motivation, mental state, and demographic characteristics. Results suggested the existence of three groups of attempters. The first comprised patients taking overdoses, on the whole showing less risk to life, less psychiatric disturbance, and more evidence of interpersonal rather than self-destructive motivation. The second groups, fewer in number, made severe attempts with more self-destructive motivation, by violent methods rather than overdose. The third and smallest group had a previous history of many attempts and gestures, made relatively mild attempts and were overtly hostile, engendering reciprocal hostility in the treating psychiatrist. These groups show some resemblance to those found in other studies.


Multivariate statistical methods and problems of classification in psychiatry.

This paper is concerned with the use of multivariate statistical methods in relation to classification in psychiatry. There are two aspects of classification: the classification of symptoms to form syndromes and of patients into diagnostic groups. Critical papers are reviewed, and proposed severe limitations on the methods answered. The use of multivariate methods has increased objectivity and agreement between investigators, but differences remain, largely on issues in statistical logic, which must be resolved.


Ancestral secondary cases on paternal and maternal sides in bipolar affective illness.

An analysis of the distribution of ancestral secondary cases of affective illness in families of patients with bipolar manicdepressive disorder was undertaken. Twenty probands with at least two affectively ill second degree relatives were available for study. Probands with both parents affected were excluded. The distribution of unilateral to bilateral pairs of all affected relatives, both excluding and including parents, of probands showed no significant differences from that expected in polygenic inheritance. However, separation into bipolar family history, positive or negative, showed significant differences from the expected ratio of unilateral to bilateral pairs in a bipolar family history positive group consistent with a single dominant gene inheritance.