NADPH cytochrome P-450 reductase activation of quinone anticancer agents to free radicals. With NADPH as the electron donor, rat liver NADPH cytochrome P-450 reductase (NADPH:ferricytochrome oxidoreductase, EC 1.6.2.4) catalyzes the single-electron reduction of several quinone antibiotics to a semiquinone or free radical state. The benzanthraquinones adriamycin, daunorubicin, carminomycin, 7-O-methylnogalarol, and aclacinomycin A and the N-heterocyclic quinones streptonigrin and mitomycin C are activated to free radical intermediates which can transfer their single electron to molecular oxygen to form superoxide. The overall Km range for this electron transfer is 0.4 to 42.1 X 10(-4) M. We postulate that the formation of the "site-specific free radical/ intermediate is central to the cytotoxic action of these antibiotics.


Immunity to malaria.

Immunity to malaria. Malaria remains prevalent throughout tropical and subtropical regions and almost a third of the World's population is exposed to the risk of infection. There is currently a serious resurgence of the disease in Asia and Central America. The failure of global eradication measures based upon the use of insecticides and chemotherapy has resulted from difficulties of practical implementation compounded by the spread of insecticide and drug resistance. Repeated natural infection does not produce detectable resistance to the exo-erythrocytic cycle of malaria in man. Irradiated sporzoite vaccines do, however, induce stage specific immunity in murine malaria and in a proportion of human subjects. Vaccinated individuals remain susceptible to blood stage infection which causes clinical malaria. In addition the vaccine is unstable and must be administered by intravenous inoculation. Since neither sporogonic nor exo-erythrocytic parasite development is cyclical in human malarias, there is little prospect for vaccine production through cultivation of these stages. The inhabitants of hyperendaemic areas become increasingly resistant to malaria during childhood and adolescence, through the slow development of specific, acquired immunity to asexual blood stage parasites. Immunity is mediated by antibody, which blocks merozoite invasion of red cells, as well as by cell mediated mechanisms and non-specific cytotoxic agents. Vaccination with merozoites induces long lasting immunity of broad serological specificity active against the blood-stage of the parasite. Merozoite vaccines can be preserved by freeze drying and harvested from continuous cultures of blood stage parasites. The major problem in development of a human merozoite vaccine concerns the requirement for Freund's complete adjuvant which is not acceptable for man. The effective immunity induced by vaccination contrasts with the slow development of incomplete resistance which follows repeated natural infection. The latter is associated with the generation of immune suppressor cells, lymphoid cell mitogens and soluble antigens, and in some species by the occurrence of antigenic variation--all of which may favour parasite survival. It is probable that vaccination with non-viable antigen of appropriate composition, induces immune effector processes without activating mechanisms which allow parasites to escape the consequences of immunity. Many effective vaccines such as those against measles, poliomyelitis, tetanus and rabies are commercially available but barely used in the developing world. The affected nations cannot afford their purchase, nor do the means exist for their distribution. It follows that if a safe and effective malaria vaccine were to be developed, its bulk manufacture and administration would require massive international support and cooperation.


The correlation between discharge times of neighbouring neurons in isolated cerebral cortex. The purpose of the experiments was to find out whether neighbouring neurons in chronic preparations of neurally isolated cerebral cortex are more likely to fire synchronously than are similar neurons in the intact brain. Chronically implanted extracellular microelectrodes were used to obtain simultaneous records of the spontaneous discharges of neighbouring neurons in the suprasylvian gyrus of the unanesthetized, unrestrained cat. We have examined multi-unit records obtained from neurons in islands of neurally isolated cortex; these records have been compared with similar records from neurons in the same cortical region of the intact brains of control animals. In isolated cortex, neighbouring neurons showed a tendency to discharge in near synchrony. In contrast, there was a random temporal relation between the firing times of adjacent nerve cells of intact cortex, provided the cat was awake. These results, taken together with the relevant observations of other workers, may indicate the manner in which biologically important information is transmitted within the mammalian brain.


The eye of the soldier beetle Chauliognathus pulchellus (Cantharidae). The soldier beetle eye is unusual in having large optically isotropic corneal cones which project inwards from a thick isotropic cornea. Refraction is mainly at the corneal surface. Calculation shows that the first focal plane is near the tip of the cone, from which the optical pathway continues as a crystalline tract. At the distal end of the crystalline tract, 3 micrometer in diameter, the four cone cells enclose the proximal tip of the corneal cone; at the proximal end they enclose the distal tip of a long fused rhabdom rod. The eye is remarkable in that there are two classes of retinula cells; four cells contribute to the long thin axial rhabdom, 2 micrometer in diameter and 120 micrometer long, and the other four cells form two rounded rhabdoms, 10 x 4 micrometer in cross-section and 20 micrometer deep, which lie to one side of the optical axis. The physiological properties of individual retinula cells were measured by intracellular recording. The retinula cells are of three spectral types with peaks near 360, 450 and 520--530 nm. Except by the criterion of spectral sensitivity, the retinula cells sampled could not be sorted into more than one class. The measured value of the acceptance angle, near 3 degrees in the dark-adapted state, is consistent with the hypothesis that all sampled cells were of the anatomical type that participate in the central rhabdom rod. A calculation of the theoretical field size of individual retinula cells from measurments of refractive index and lens dimensions predicts that cells which participate in the central rhabdom will have acceptance angles near 3 degrees. The conclusion, therefore, is that only one anatomical type of cell has so far been sampled.


A search for causes of polymorphism in Clithon oualaniensis (Lesson) (Gastropoda; Prosobranchia). Western Clithon from India and Ceylon differs from eastern Clithon from the Malay Peninsula and Hong Kong as regards shell pattern and coloration (Grüneberg 1976, 1978). The western form lives in regions with high surface salinity whereas the eastern form lives in regions with low surface salinity. This situation may either reflect a causal relation, or it may be the result of a coincidence. The evidence presented in this paper speaks against a causal relation and suggests that other factors with a similar geographical distribution may be at work.


Hyperaccumulation of nickel by Alyssum Linnaeus (Cruciferae). Herbarium specimens of all except one of the 168 recognized species of Alyssum Linnaeus have been analysed for their nickel content in order to identify hyperaccumulators (greater than 1000 microgram per g dry mass) of nickel. A further 31 hyperaccumulators (all in section Odontarrhena) were discovered in addition to the 14 European species reported earlier. Pot trials on the non-accumulator A. serpyllifolium Desfontaines and the hyperaccumulator A. pintodasilvae Dudley in ed. involving addition of nickel to the medium in which the plants were growing, showed that not all species of of section Odontarrhena were able to act as hyperaccumulators of nickel. Hyperaccumulation occurred almost exclusively in the eastern Mediterranean area and Turkey. There appeared to be a definite correlation between species diversity, proliferation and endemism on the one hand, and extremely high nickel concentrations (greater than 1%) on the other.  The data have been used to assess the evidence for promoting section Odontarrhena to generic rank.


The interpretation of structure from motion. The interpretation of structure from motion is examined from a computional point of view. The question addressed is how the three dimensional structure and motion of objects can be inferred from the two dimensional transformations of their projected images when no three dimensional information is conveyed by the individual projections. The following scheme is proposed: (i) divide the image into groups of four elements each; (ii) test each group for a rigid interpretation; (iii) combine the results obtained in (ii). It is shown that this scheme will correctly decompose scenes containing arbitrary rigid objects in motion, recovering their three dimensional structure and motion. The analysis is based primarily on the "structure from motion" theorem which states that the structure of four non-coplanar points is recoverable from three orthographic projections. The interpretation scheme is extended to cover perspective projections, and its psychological relevance is discussed.


Ionic basis of different synaptic potentials mediated by an identified dopamine-containing neuron in Planorbis. A specified dopamine neuron in Planorbis corneus produces dopamine-mediated e.p.s.ps, i.p.s.ps or biphasic, depolarizing-hyperpolarizing p.s.ps in different follower neurons. The excitatory potentials were of three types. Some follower neurons exhibited slow e.p.s.ps (ca 1 s), and a long-lasting, slowly desensitizing, depolarizing response to iontophoresed dopamine. Others showed rapid (ca. 150 ms) e.p.s.ps, often of variable amplitude, and a rapid, quickly desensitizing, response to iontophoresed dopamine. The rapid e.p.s.ps were sometimes followed by the inhibitory response (biphasic potential). The e.p.s.ps  were potentiated by hyperpolarization and reduced by depolarization, though they could not be inverted. The slow e.p.s.p. was shown to be associated with an increase in membrane conductance, but it has proved difficult to elucidate the ions involved. A third type of e.p.s.p. was produced by electrical transmission. The inhibitory potentials were generally reduced in amplitude by artificial hyperpolarization but could rarely be inverted. This is probably due in part to the presence of of electrotonic coupling between these follower neurons. The i.p.s.ps were associated with an increase in conductance which appeared small when measured in the cell body. However, the i.p.s.ps produced considerable shunting of electrotonic transmission between coupled followers indicating a large increase in conductance at the synapse. I.p.s.ps were unaffected by Cl-free solution but they were greatly reduced, though rarely inverted, by increasing the external K concentration. They were blocked by intracellular tetraethylammonium, or cooling.  The effects on corresponding responses to iontophoresed dopamine were in each case the same as on the i.p.s.ps. It is concluded that the i.p.s.ps mediated by the dopamine neuron are produced by an increase in permeability to K+. On a few occasions i.p.s.ps mediated by the dopamine neuron were potentiated by hyperpolarization. This appeared to be caused by a sharp increase in membrane resistance with hyperpolarization of these particular neurons. However, mediation by a mechanism of conductance decrease could not be completely excluded.


Local development of action potentials in slow muscle fibres after complete or partial denervation. Pyriformis muscles of Rana temporaria were completely or partially denervated by cutting the sciatic nerve or some of the small nerve branches entering the muscle. One stimulating and one to three recording microelectrodes were inserted along the fibres in order to compare the electrical activity at these points. In an early period following denervation action potentials of variable size and shape could be observed; these action potentials were often composed of two, sometimes of three or four, components. The size of individual components depended on the position of the recording microelectrode. Individual components could occasionally be triggered separately by adjusting the strength of the stimulating current pulse; propagation of these "all or none" responses was absent. In other fibres one component of the action potential could trigger another one several millimetres apart, thus indicating propagation. Conduction velocities were approximately 0.4 m/s. In partially denervated slow fibres, endplate potentials were confined to one lateral segment of the fibres, while the action potential occupied the denervated part of the membrane. The amplitudes of endplate and action potentials varied inversely with distance. Rough estimates of the length constant of the slow fibre membrane were calculated from the spatial decay of action potentials, endplate potentials and hyperpolarizing electrotonic potentials; mean values obtained were 2.5, 4.8 and 7.7 mm respectively. The results suggest that following denervation Na channels are built into discrete areas of the slow fibre membrane and that this process depends on the amount of denervation in individual fibres.


Drug interactions with nerve membrane components regulating ionic permeability: action of tetrodotoxin, procaine, pentobarbital, and ethanol. The interaction of neuroactive agents with surface membrane ionizable groups which regulate passive ionic  permeability in crayfish giant axons was examined. Every ionizable membrane group was found to contribute in various degrees to regulating membranes ionic permeability. However, some membrane ionizable groups have dominant control over specific ions. Thus potassium and sodium passive permeability is predominantly activated by deprotonation of imidazole on  protein and the secondary ionization of phosphatidic acid. Chloride permeability appears activated almost entirely by protonation of amino side groups on protein. The conformational state of membrane protein which regulates ionic permeability changed when the axon was potassium depolarized. The effects of tetrodotoxin, ethanol, and the amphipathic molecules procaine and pentobarbital, on the passive ionic conductances were determined. Both procaine and pentobarbital could, when charged, alter specific ionic conductances through their effects on surface double layer potentials although protein conformational changes were also involved. Studies on animals made dependent with ethanol showed an increased passive sodium conductance which further increased following ethanol withdrawal. A physical mechanism for ethanol dependency is suggested. Although the above four agents show differences in how they alter specific ionic conductances of nerve, their common mode of action, at concentrations which block the action potential, is to prevent a normal conformational change in membrane protein from occurring when nerve is depolarized.


Effects of lesions in the ventral noradrenergic bundle on behavior and response to psychotropic drugs in rats. Bilateral lesions of the ventral noradrenergic bundle (VB) decreased concentration of noradrenaline within the mesendiencephalon but not in the cortex. Lesioned rats showed increased activity measured in the open field test. Cataloptogenic effects of chlorpromazine and haloperidol were almost completely abolished in VB-lesioned animals. The stereotypy induced by both--amphetamine and apomorphine was, however, unchanged. It is supposed that lesions of the VB lead to increased activity in dopaminergic neurons in the brain.


Enhancement of 3H-diazepam binding by SQ 65,396: a novel anti-anxiety agent. SQ 65,396, a clinically active anti-anxiety agent, enhanced the binding of 3H-diazepam at 1.5 nM. This effect was due to an increase in the affinity for the ligand, without a change in the number of 3H-diazepam binding sites. This action of SQ 65,396 may mediate its anti-anxiety effects by affecting the action of an endogenous modulator of the "benzodiazepine receptor." Several other substances and treatments increase the affinity of 3H-diazepam for its receptors by mechanisms which may be related to the effect produced by SQ 65,396.


Relationship between benzodiazepine receptors and experimental anxiety in rats. The in vitro and in vivo ability of benzodiazepines to inhibit specific 3H-diazepam binding correlated with their ability to increase punished responding in a conflict situation. Conflict and foot shock, the punishing stimulus used in most conflict procedures, also altered 3H-diazepam binding. These data implicate 3H-diazepam binding sites in mediating at least some of the anxiolytic properties of benzodiazepines and suggest the existence of some endogenous substance which might be involved in the etiology of anxiety.


Effects of urotensin I on the isolated rat tail artery. Urotensin I (UI) was found to elicit dose-related relaxation responses in isolated helical strips of the rat tail artery. The responses were not prevented by adrenergic, cholingergic or histaminergic blocking agents. Competitive and non-competitive components of antagonism were observed to noradrenaline-, 5-hydroxytryptamine-, and arginine vasopressin-induced contractions. Atropine caused a direct relaxation of the isolated vascular tissues, as well as a significant potentiation of UI responses.


The constitutive heterochromatin in chromosomes of Fritillaria Sp., as revealed by Giemsa banding. The incidence of C-bands (constitutive heterochromatin), as determined by differential Giemsa staining, was studied in the chromosomes of 56 species, varietal forms and subgenera of Fritillaria and 30 of them are illustrated. With the exception of the subgenera Korolkowi, a supposed link between lilies and fritillaries, and chromsome complements of all plants contained bands. There were wide differences in the size and number of these bands among species both within and between groups. In those with the largest and most abundant bands, there was a pronounced tendency for centromeric localization, both in Old and New World species. The Giemsa positive centromeres were masked when this occurred. Heteromorphy in respect of banding occurred in most species. The relation of repetitive DNA sequences with heterochromatin is discussed, as is also the problem of evolution in Fritillaria.


Selected soft-tissue research: an overview from carville. Studies are underway on the effect on insensitive feet of repeated, "normal," nonischemic pressure, such as that caused by walking. Although such stress does not harm normal tissues, it can lead to soft-tissue damage in the insensitive foot. This research is trying to determine such information as the amount of energy input required to damage soft tissue, microscopic and macroscopic changes that occur during early soft-tissue damage, importance of time sequence of energy input, and amount of energy input that causes hypertrophy rather than ulceration. The progress of these studies is reported.


Management of the insensitive limb.

Management of the insensitive limb. The limb or part of a limb that becomes insensitive often is destroyed or must be amputated. This is largely due not to intrinsic weakness of the limb but to damage from external forces that would normally be avoided by the person experiencing a warning pain. When the lack of pain sensation can be compensated for, the insensitive limb need not become damaged. Techniques for protecting the insensitive foot and hand are presented.


Antipsychotic effect of propranolol on chronic schizophrenics: study of a gradual treatment regimen. Ten chronic treatment-resistant schizophrenic patients were treated in a single-blind trial for six weeks with propranolol in daily doses increasing up to 3 g in order to evaluate a modified dose regimen of propranolol treatment in these patients. Four of the patients improved significantly and could be released from the hospital, regaining premorbid social and work adjustments. The modified regimen proved safe as long as the dose increment was not more than 80 mg/day. The mean therapeutic level of propranolol was 1600 mg/day, which proved to be a safe dose. Although three patients with hypertensive encephalophaty responded, their response was related not to the maximum dose but to a drastic change in the rate of the dose increase. It seems that on the basis of these results a double-blind comparative study would be worthwhile.


Individual variations in the effects of flurazepam, clorazepate, L-dopa and thyrotropin-releasing hormone on REM sleep in man. The comporative effects of flurazepam, clorazepate, L-dopa, and thyrotropin-releasing hormone (TRH) on REM sleep were investigated in normal, healthy adults. A single dose of each drug was given orally to the subjects 30 min before bedtime. A dose of 30 mg flurazepam significantly decreased REM sleep-time when compared to the mean baseline record. No change was noted in REM sleep-time on the clorazepate (15 mg) night, L-dopa (1000 mg) night, or TRH (2 mg) night, when compared to the mean baseline record. Because large individual variations were found in REM sleep time on each drug night, and in percentage increase in REM sleep following partial differential REM deprivation (PDRD), correlation was investigated between them. The percentage decrease in REM sleep during flurazepam was found to have a significant negative correlation with the percentage increase in REM sleep after PDRD in individual subjects. Although there was no significant change in REM sleep on TRH night when compared to the mean baseline record, a similar significant negative correlation was noted. On the L-dopa night, there was a tendency toward a negative correlation between them. No significant correlation was noted on the clorazepate night.


Comparison views in extremity injury in children: an efficacy study. Routine comparison views in cases of suspected extremity injury in children have not been adequately substantiated, in the authors' opinion. Three hundred such cases were reviewed, with pediatric radiologists requesting comparison views of the uninjured side in 8%. In no case did the comparison view change the initial diagnosis. When the initial interpretation is made by pediatric radiologists, selective use of comparison views is more cost-efficient and delivers less radiation to patients and personnel, compared to obtaining them routinely in all cases.


[Pharmacological treatment of syndromes of aggressivity]. In the treatment of violent-aggressive behavior, four major groups of drugs emerged: 1. Major tranquilizers in the treatment of aggressive-violent behavior associated with psychotic syndromes. 2. Anti-epileptic drugs such as diphenylhydantoin and barbiturates in the treatment of aggressive-violent behavior within the epileptic syndrome. 3. Psychostimulants in the treatment of aggressive behavior of adolescents and children within behavior disturbances. 4. Anti-male hormones such as cyproterone acetate in the treatment of violent-aggressive behavior associated with pathological sexual hyperactivity. Whereas each category of drug is predominantly effective in one type of aggressive syndrome, it may also be effective in other conditions as well. Aggression as a result of a personality disorder is most difficult to treat with drugs.


Physiological significance of secretin in the pancreatic bicarbonate secretion. I. Responsiveness of the secretin-releasing system in the upper duodenum. In nine normal subjects intraduodenal pH was measured by means of a glass electrode placed in the passage from the first to the second part of the duodenum. The physiological variations in pH were simulated by intraduodenal injection of 2.5, 5, or 10 ml of 0.1 mol x 1(-1) HCl and subsequent neutralization by injection of bicarbonate. A total of 26 injections of acid was followed by a pH spike from a median pH of 7.0 to a median of pH 2.1 Median spike duration was 45 sec. The concentration of secretin in plasma increased from a median of 1.2 pmol x 1(-1) to a peak value of 2.2 pmol x 1(-1) after 4 min. It is concluded that the secretin response to a brief acidification of the first 4--6 cm of the duodenum is sufficient to explain the physiological variations in the concentration of secretin in human plasma.


Long-term prognosis and followup in schizophrenia. The long-term course or natural history of schizophrenia is correlated with differing diagnostic criteria and commonly agreed upon prognostic variables. A review of 38 long-term followup studies of hospitalized schizophrenics reveals that unspecified or Kraepelinian-type schizophrenia has a much worse prognosis than atypical schizophrenia, schizoaffective psychosis, reactive psychosis, or other good premorbid types. Diagnoses based on longitudinal as well as cross-reactional data are more predictive of outcome than cross-sectionally based diagnoses. Drug and psychosocial treatment results must be evaluated in terms of prognostic variables, many of which are incorporated in some currently employed diagnostic criteria. There is no firm evidence that maintenance medication is indicated in some good prognosis patients. The paucity of long-range followups, the inadequacies of outcome assessments, and diagnostic disagreements limit our understanding of the effects of drug treatment, a treatment which is not without dangerous neurological side effects in many patients.


Therapeutic antagonism between anticholinergics and neuroleptics: possible involvement of cholinergic mechanisms in schizophrenia. We have answered technical criticisms of our work in which anticholinergic agents were added to ongoing neuroleptic treatment in an ABA' research design. The suggested analysis of variance for repeated measures of the three periods is inappropriate because of the expected carryover effects from continuous neuroleptic treatment. The multivariate analysis of various parameters seems unsuitable because homogeneity of covariance cannot be ensured due to the heterogeneity of schizophrenia and the diverse factors represented in the psychopathology measures. We have summarized the results of recent parametric and nonparametric analyses of combined data from our three studies to show that the significant effects clearly pointed to therapeutic antagonism between anticholinergic agents and neuroleptics. We suggest that cholinergic neurons may be part of some crucial discriminative control mechanisms in the brain organization that are ineffective in schizophrenia and lead to a relative overactivity of the opposing catecholaminergic neurons in the midbrain-limbic circuitry which promote repetition of behaviors in goal-directed activity.


Social influences on the prognosis of schizophrenia. Literature relating to social influences on prognosis of schizophrenia is selectively reviewed. The influence of the care system is considered separately from other social influences such as business cycle fluctuations, community organization and attitudes, social class membership, independent events in the patient's life, and expression of emotion by the patient's family members. Several studies of milieu indicate that milieu can influence course of illness for better, or for worse. One study of group psychotherapy suggests that groups help improve social function of schizophrenics in the community. Studies of individual psychotherapy fail to demonstrate its efficacy. Business cycle fluctuations clearly relate to admission rates of schizophrenics to hospitals; independent life events are associated with onset and relapse. Community attitudes and family emotional expression relate to relapse and rehospitalization. Clearly, social events, especially those occurring outside the care system, do influence the course of illness. There is also evidence for the influence of psychosocial treatment but at the present time is less consistent the evidence for the influence of other social events on the prognosis and course in schizophrenia.


[Antimicrobial resistance and serotypes of Streptococcus pneumoniae in Switzerland]. One hundred and eighty strains of Streptococcus pneumoniae were isolated from various materials at the Institute of Medical Microbiology in Zurich between March and October 1978. Examination of these isolates for resistance to 6 standard antimicrobials revealed that 17 (9.4%) strains were resistant to the tetracyclines, 2 strains to sulphamethoxazole/trimethoprim and 1 strain to both tetracycline and chloramphenicol. All strains were highly sensitive to benzylpenicillin, cephalothin and erythromycin. Serotyping of the pneumococci was done by the capsular quellung reaction. The prevalent serotypes in the entire collection of strains were Nos. 6, 23, 19, 3, 9, 14 and 7. The prevalent serotypes of strains isolated from blood, cerebrospinal fluid, pus, and bronchial secretions were Nos. 4, 8, 7, 14, 9, 3, 19 and 6. Vaccination with PneumovaxTM, a vaccine containing 14 capsular antigens, should provide protection against 75% of pneumococci identified as true pathogens in this study. Pneumococci are rather rarely isolated in our laboratories. For this reason, and because the strains isolated are still sensitive to antibiotics in conventional use, mass vaccination of the population in Switzerland is not recommended. Vaccination should be carried out in certain high risk groups of patients.


[Use of frozen thrombocytes for the determination of von willebrand factor with the aid of ristocetin]. The quantitative assay of von Willebrand factor using ristocetin aggregation is simplified and improved by the use of frozen normal platelets. The main advantages of the method described are excellent reproducibility, maintenance of a stable optimal pH and the possibility of eliminating interfering factors, such as inhibitors, by dilution.


Phosphorylation of Isocitrate dehydrogenase of Escherichia coli. Addition of acetate to a stationary phase culture of Escherichia coli in glycerol mineral salts medium containing phosphorus-32-labeled orthophosphate results in rapid loss of isocitrate dehydrogenase activity and concomitant incorporation of phosphorus-32 into the enzyme. This is the first example of protein phosphorylation in a bacterium in which the endogenous substrate for the protein kinase has been identified.


Mediatory role of calcium and guanosine 3', 5'-monophosphate in adrenocorticotropin-induced steroidogenesis by adrenal cells. When incubated in a calcium-free medium, isolated rat fasciculata cells showed neither an increase in the concentration of guanocine 3',5'-monophosphate (cyclic GMP) nor an increase in corticosterone production in response to adrenocorticotropic hormone (ACTH). In response to submaximum and maximum steroidogenic concentrations of ACTH, corticosterone formation was directly proportional to increases in calcium concentration ranging from 0 to 2.5 mM. Higher concentration of calcium, however, inhibited maximal ACTH-induced steroidogenesis. In the absence of ACTH, calcium did not stimulate cyclic GMP accumulation and corticosterone formation. ACTH-induced corticosterone synthesis, preceded by an increase in cyclic GMP, was restored when ACTH and calcium were both present in the medium. Cyclic GMP or dibutryl cyclic GMP-induced steroidogenesis was substantially reduced in the absence of calcium, but in contrast to the ACTH effect a significant amount of corticosterone formation occurred without calcium. It is proposed that at the physiological concentrations of the hormone, calcium regulates the transduction of information between hormone receptors and guanylate cyclase.


[Sultopride: a new powerful neuroleptic (author's transl)]. The authors have used sultopride as a treatment for twenty-five hospitalized psychiatric patients whose states of agitation belonged to different nosographic kinds. They could notice the remarkable efficacy previously stated. Interesting results have been obtained in behaviour disorders in epileptics and oligophrenic patients. Sultopride at low dosage also seems to have favourable effects on the agitation of the demented states and in the case of late delirante psychose.


[Dietary and drug treatments of calcium nephrolithiasis (author's transl)]. Dietary and drug treatments of calcium nephrolithiasis depend mainly on the mineral composition of renal stones: calcium oxalate, phosphate or mixed stones. The association with an hypercalciuria is an important factor which must be taken into account because oxalates and phosphates precipitate as calcium crystals in case of urinnary oversaturation. Despite many therapies have been proposed, their efficiency seems to be rather small when they are used alone. Usually, it is necessary to act on several factors with a combination of therapeutic methods. Absorptive hypercalciuria are improved with both low calcium diets and inhibitors of calcium absorption. In renal hypercalciuria, the treatment is based on the administration of thiazide diuretics which enhance calcium renal tubular reabsorption. The other therapeutic methods depend on the nature of renal stones: urinary acidification for calcium phosphate; administration of succinimide, oral phosphate or organic phosphonates for calcium oxalate stones; association with purine biosynthesis inhibitors in case of the presence of urates in renal calculi.


[Present-day treatment of dyskinesias (author's transl)]. The physiopathological processes involved in the production of dyskinesias will become clearer as our knowledge of neuromediators and their receptors increases. Among centrally-acting molecules, pimozide and the substituted benzamides block dopaminergic receptors only. Tiapride, which is a substituted benzamide, has an original neurotropic action expressed as relaxant and antidyskinetic activity. It is perfectly well-tolerated and is simple to prescribe, which has made it a product for use in general practice where very encouraging results have been obtained, especially in the two cases reported: an elderly patient with buccofacial dyskinesia often seen in this age group, and a patient with severe dopa-induced dyskinesias.


[Cases of abnormal movements].

[Cases of abnormal movements]. Four patients with abnormal movements were treated with tiapridal. Very good results were obtained in a case of buccofacial dyskinesia associated with an extrapyramidal syndrome and dementia, and in another patient with middle-of-the-dose dyskinesias induced by L-dopa treatment for Parkinson's disease. No effect was observed, however in a case of beginning of the dose dyskinesias, and the extrapyramidal symptoms increased in severity. A dopadecarboxylase-inhibitor was associated with the L-dopa treatment in these three cases. In the fourth case, there was an increase in the spasms of the medial part of the face.


General anaesthesia with intravenous flunitrazepam, continuous ketamine infusion and muscle relaxant. A preliminary report. We present a preliminary report of an anaesthetic technique for abdominal surgery involving a combination of flunitrazepam induction and continuous ketamine maintenance of anaesthesia, specifically avoiding the use of any inhalational agents. Standard techniques of muscle relaxation, intubation and ventilation with oxygen-enriched air were employed.


Fetal heart rate in the second stage of labour and fetal outcome. Fetal heart rate tracings were obtained in 50 patients who had a normal 1st stage of labour until delivery of the baby. Fetal condition at birth was assessed by umbilical cord artery (UCA) pH and Apgar scores. Forty-eight of the 50 fetal heart tracings showed frequent, marked, early decelerations throughout the 2nd stage of labour. These tracings, when not accompanied by other pathological features, were associated with a good fetal outcome at birth.


Hypothesis: volatile anaesthetic agents enhance transplacental exchange between mother and fetus. A preliminary study of fetal scalp blood gas changes associated with enflurane anaesthesia. A hypothesis that volatile anaesthetic agents, represented by enflurane, facilitate transplacental exchange was tested by simultaneous blood sampling of both mother and fetus. A trend towards improved fetal scalp blood gas status and maternal-to-fetal acid-base matching was observed with enflurane. Our results encourage further research into the feasibility of intra-uterine fetal resuscitation by anaesthetically induced promotion of intervillous perfusion.


Persistent gastric mucosal hypoxia and interstitial edema after hemorrhagic shock: prevention with steroid therapy. To define the role of the nutrient microvasculature in the pathogenesis of acute gastric mucosal erosions, a correlation was performed of changes in intracellular oxygenation (ICPO2) and intracellular potential difference (ICPD) in surface epithelial cells with the histological alterations in the apices of the faveoli of canine gastric mucosa after 3 hours of hemorrhagic shock. ICPO2 fell from 16.7 +/- 0.8 mm Hg before shock to 5.4 +/- 0.9 mm Hg at the end of shock. Ninety minutes after reinfusion of blood and restoration of total gastric blood flow to baseline levels, ICPO2 was 5.8 +/- 0.7 mm Hg. ICPD changes were similar, but more gradual. Treatment with methylprednisolone (30 mg/kg) 30 minutes after hemorrhage ameliorated mucosal hypoxia during shock (10.9 +/- 1.0 mm Hg) and prevented it after resuscitation (15.4 +/- 0.8 mm Hg). The microscopic anatomy of untreated gastric mucosae showed severe subepithelial edema with dialted capillaries in the lamina propria; methylprednisolone treatment prevented these changes. We conclude that pathophysiological arteriovenous shunting occurs in the microcirculation of the apical faveoli and speculate that it is caused either by redistribution of nutrient blood flow away from the surface epithelium or by increased permeability of the microvascular endothelium with concomitant mucosal interstitial edema. These findings suggest an explanation for the paradox between restoration of mucosal blood flow and continued mucosal injury which occur after shock.


[Genetically conditioned variability of metabolic profile parameters in dairy cows]. Individual heritability and differences in the concentration of the chemical components of the blood were studied in the dairy cows of the Slovak Spotted breed. The experiment was performed with 166 cows. The set comprised six groups of half-sisters from three stocks. The differences among the cows were statistically significant (alpha = 0.01) in the majority of the parameters studied: haematocrit, haemoglobin, pH, PO2, oxygen saturation of the blood; plasma potassium, phosphorus, magnesium, calcium, total protein, urea, glucose, alkaline phosphatase, and esterified fatty acids. The coefficients of repeatibility for the mentioned parameters ranged from 0.19 to 0.75. The heritability coefficients were calculated for the parameters in which the inter-group differences were significant: total protein (0.62), magnesium (0.57), potassium (0.51), urea (0.49), glucose (0.45), phosphorus (0.43), calcium (0.39), haematocrit (0.37), haemoglobin (0.35), pO2 (0.29). The results suggest that some of the parameters under study are under certain genetic control.


[Evaluation and comparison of acid-base findings obtained using the partial and Astrup's technic in cattle]. The aim of the study was to compare the acid-base (AB-) findings in cattle obtained parallelly by the equilibration method after Astrup and the partial method (titration determination of total carbon dioxide in blood plasma) and at the same time to determine pH, net acid-base exudate in urine and the specific weight of urine. Altogether we made 65 parallel examinations in three groups of cows according to phases of reproduction. In 70.8% of cases correlation between the two results was very good or good, however under the condition that in many cases it was necessary to know also blood pH for the employment of the partial method. Without the knowledge of the blood pH good correlation would be obtained only in 33.8% of all cases. The partial method does not provide satisfactory results mainly in diagnosing respiratory disturbances and in determining compensatory degree of acid-base disturbances. We analysed two alternative values for the top, reference limit of vol. % CO2 in plasma: 60.0 or 55.0. The results imply that from the aspect of correct partial method interpretation it is more accurate to use the value 60.0. A high interpretation correlation between pH and net acid-base urine exudate was also confirmed and that independent urine pH values may be used in a complex acid-base examination to obtain acid-base findings. The representation of the basic types of acid-base disturbances indicates that metabolical acidoses are most frequent in highly pregnant cows (36.9%) mostly without proved compensation. The largest proportion of normal acid-base findings (43.4%) was determined in cows after calving in which also the compensatory mechanisms were most often activated. In connection with these findings the possibilities of impaired health of calves are discussed.


[Microbiology of various liver products]. The proportions of mesophilic, thermophilic and psychrophilic microorganisms were investigated in the total number of microbes and aerobic sporogenic microorganisms in delicatessen liver sausages and liver cheeses. At the same time the content of ammonia and the pH of the products were determined. The largest part of the microflora comprised mesophilic microorganisms, 10 to 25% of which belonged to the sporogenic microflora. The incidence of staphylococci, enterococci and coliform microorganisms was also studied. The total number of microbes contributed to the ammonia content in the products, however, no intercorrelation was statistically proved. In the case of pH no relationship between its value and the number or kind of investigated microorganisms was found. All the indicators were followed in the raw material, in the finished products after heat processing and in products stored at refridgerator and room temperatures for one week.


[Cholestatic hepatosis caused by Talinolol (Cordanum)?]. It is reported on a 38-year-old female patient who was treated for 18 days with 150 mg cordanum (talinolol) each and then fell ill with a dyspeptic clinical picture and signs of cholestase. The result of a liver biopsy was the picture of a cholestatic hepatosis. According to the results of the lymphocyte transformation test and the monocyte test as well as to the reexposition with following clinical recidivation the talinolol medication is to be regarded as cause. Pathogenetically is referred to the structural relations of talinolol to substances with paragroups as well as to a possible summation of different loads of the liver function.


[pH measurements following delivery from breech presentation (author's transl)]. In 1977 the adaptation capability of 22 out of 89 breech presentation new-borns was studied by way of punctual pH-measurements within the first 30 minutes after birth. Thus, it was possible to gain an insight into the extra-uterine adaptation, especially with respect to the mode of delivery. Further points of comparison were parity, maturity and a possible correlation with the Apgar Score. The study included a comparison with identical measurements of 20 spontaneous head position new-borns. According to the results under certain preconditions a vaginal delivery in breech presentation is also today by all means to be justified.


[Comparison of k therapies after determination of success and failure]. To compare k therapeutic methods, N patients are suggested to be assigned to k therapies at random. The effect of each therapy is rated to be present or absent. The resulting k x 2 contingency table is evaluated according to one of the following questions: 1) Do the k therapies differ in their effects? 2) Is a given therapy more effective than the k-1 remaining therapies? 3) Is a given therapy more effective than a competitive therapy? The methods are exemplified by a numerical example from treatments of schizophrenics.


Deviated lysis: lysis of unsensitized cells by complement. V. Generation of the activity of low pH or low ionic strength. In serum exposed to acid pH (6.4), a serum activity was generated which lyzed unsensitized erythrocytes in the presence of EDTA. It was similar to the d.l. activity found following serum activation by inulin (2). In contrast to the d.l. generation by the classical or by the alternative pathway of C activation, the generation of d.l. by acid pH did not require C4 plus C2 or C3 plus factor B resp. It was, thus, not dependent on any hitherto known pathway of C activation. A similar activity appeared when NHS was centrifuged in a sucrose gradient at low ionic strength. Physicochemical alterations of the component proteins which influence their affinity for each other are seen as the basis for the activation of the attack phase of C.


Thymic stromal alterations in mice undergoing a chronic graft-versus-host reaction. Graft-versus-host induced immunosuppression has previously been shown to be accompanied by severe morphological changes in the thymus; furthermore chronic GvH could become acute by grafting a normal syngeneic thymus, suggesting a functional defect in the autologous thymus. In this work, we monitored the changes occuring in two biologically active thymic stromal fractions during a state of chronic GvH reaction. It was thus observed that a soluble thymic factor (STF), normally found in the reticuloepithelial cells, was lost, and that an insoluble thymic fraction (ITF) found in a double basement membrane surrounding medullary blood vessels, became markedly hypertrophied. These changes are interpreted as being possibly related to the state of immunosuppression by interfering with normal T cell differentiation and traffic through the thymus.


[Teaching of microbiology at medical institutes (on the results of the XVI All-Union Congress of Microbiologists and Epidemiologists)]. Data on teaching microbiology, virology, and immunology to students of the 2nd and 3rd course of medical institute are presented. A number of recommendations of the improvement of bacteriology and virology teaching at the sanitary-hygienic faculties are given; in particular it is suggested to introduce into the teaching plan for students of the 6th course of sanitary-hygienic faculties specialization on medical microbiology and virology. For the general view on virology the author considers it necessary to begin study of the viruses by delivery of individual lectures in the general course of microbiology during the 4th semester; it is recommended to present the main virology course during the 5th semester.


[Autolysis of hemolytic streptococcus group A]. As revealed, autolytic enzymatic system of hemolytic streptococcus, group A, expressed the maximal activity at the end of the exponential growth phase. Autolysis was accompanied by the release of N-acetylaminosugars and of free amino group. Optimal conditions for the lytic system function were chosen (composition, ionic strength, and buffer pH). The activating action of trypsin and chemotrypsin was demonstrated.


[Makeup of a population El Tor vibrios according to their agglutinability by type-specific sera]. The authors studied population composition of 14 strains of EL Tor vibrios. Of 7 strains of Ogava serological type the population composition was homogeneous in 2, and heterogeneous in 5. All the 7 strains of EL Tor vibrios of Inaba serological type had homogeneous population composition. Changes of the existence conditions of EL Tor vibrios of Ogava serological type, containing in their population 5% cells of Hikoshima serological tupe, led to separation of the cells of Inaba serological type; under the same conditions, in El Tor vibrios of Ogava and Inaba serological type with homogeneous population the latter was stable.


[Differential diagnosis of enterococci]. The most stable differential signs of enterococci are: growth in the medium at pH 10.2, growth in broth containing 40% bile, citrate utilization, resistance to 0,05% potassium tellurite, 2, 3, 5-triphenyltetrazolium chloride (TTC) reduction, the staining of colonies (plaques) on a medium with manganese, iron and zinc salts, glycerine fermentation under anaerobic conditions, mannite fermentation, the presence of hemolysin, of the proteolytic enzyme, and mobility. Combined differential-diagnostic nutrient medium permits to determine simultaneously 5 enterococci signs--resistance to nalidixic acid and to crystal violet, TTC reduction, hemolytic and proteolytic activity. The suggested scheme of enterococci laboratory diagnosis including a set of hard nutrient media poured into multisection Petri dish is simple reliable and accessible for any bacteriological laboratory.


[Correlations between chemical structure and cardiac effectivity of a group of beta-receptor blockaders]. 13 compounds from the families of halogenated phenylethanolamines and phenoxypropanol-amines were tested for their antagonistic effect against an isoproterenol-induced increase in heart rate and lowering of blood pressure, and the AD50 values were determined. All the substances had beta-adrenolytical effects. 2.4-Difluoroisoproterenol and 1-(2.4-dichlorophenoxy)-3-t-butylaminopropanol-(2) showed a higher affinity to the beta1-receptors of the heart than to the beta2-receptors of the vessels. Correlations existing between chemical structure and action on the adrenergic beta-receptors are described.


A sensitive method for the assay of guanylate cyclase activity. A method for the assay of guanylate cyclase is described utilizing alpha-[32P]-GTP as substrate for the enzyme reaction. 100-150 microgram of enzyme protein is incubated in a 15.6 mM Tris-HCl buffer incubation mixture, pH 7.6. The reaction is stopped by the addition of EDTA. The [32P]-cyclic GMP formed is separated by a two-step column chromatography on Dowex 50W-X4 ion-exchange resin and neutral alumina. The recovery for cyclic GMP was about 70%. The blank values ranged from 0.001-0.003% of the added alpha-[32P]-GTP which had been purified by Dowex 50W-X4 column chromatography. This method was employed for the assay of guanylate cyclase activities in different tissues.


Spontaneous non-aneurysmal rupture of the renal pedicle artery due to acute vasculitis in polyartheritis nodosa--with survival. The first published case is presented of survival following a ruptured renal artery due to acute vasculitis in polyarteritis nodosa (PAN). Spontaneous, massive retroperitoneal hemorrhage was the presenting symptom in this case. Emergency nephrectmoy was carried out as a life-saving procedure. Postoperative studies revealed that only the kidneys and joints were involved in the disease.


Pancreatic bicarbonate response to a meal. In dogs with gastric and pancreatic fistulas, the rate of delivery of acid from the stomach to the duodenum and the rate of pancreatic bicarbonate secretion were measured in response to a meal of liver extract. The time course of changes in quantity of bicarbonate secreted per minute closely paralleled that of changes in quantity of hydrogen ions delivered to the duodenum per minute. For each mole of hydrogen ion entering the duodenum, about 5 moles of bicarbonate were secreted.


Hemodynamic effects of prenalterol, a beta1-adrenoreceptor agonist, in hypotension induced by high thoracic epidural block in man. The hemodynamic effects of prenalterol, a new beta1-adrenoreceptor agonist, on hypotension induced by a thoracic epidural block extending between T1 and T12 and thereby blocking the cardiac sympathetic supply have been studied in eight patients scheduled for abdominal aortic aneurysm resection. The thoracic epidural block induced a drop in blood pressure, due to a reduction in cardiac output and systemic vascular resistance. Intravenous infusion of 10 mg of prenalterol rapidly and effectively reversed the hypotension by an increase in cardiac output without any effects on systemic vascular resistance or heart rate. The results indicate that prenalterol is a pure beta1 agonist with a marked inotropic but no chronotropic property.


Characteristics of gastric secretion in suckling calves. In the investigations on five calves with fistulae in the abomasum and oesophagus the secretion of gastric juice as well as its content of proteolytic enzymes and hydrogen ions were measured. It was found that the gastric juice of calves possessed a fairly high proteolytic activity (about 6 UP/l) and hydrogen ion level already on the 3rd day of life. Sham feeding produced two different types of gastric secretion response, depending on the age of calves. In the first week of life sham feeding caused an inhibition of secretion which became more intensive only about 30 min following food administration. In the second week of life gastric juice secretion increased immediately after feeding.


Serum free fatty acid level and body temperature changes in emotional stress in rabbits. Effect of hydroxydial. Fourteen New Zealand rabbits were immobilized for 75 minutes During this time the ear (Te) and rectal (Tre) temperatures were measured at 5 min intervals. Immediately before immobilization, and then in the 35th, 55th, and 75th min of immobilization blood samples were taken for determinations of the serum free fatty acid (FFA) levels. A statistically significant fall of Tre and a significant rise in the serum FFA levels were observed at the end of immobilization. The ear temperature in these animals exceeded considerably the values as normal. Intravenous administration of hydroxydial 0.1 mg/kg before repeated immobilization prevented body temperature changes and blood FFA level rise in half the animals. In the remaining animals the changes became more intensive. It is supposed that the tested rabbits differed in their reactivity to stressful stimuli, and this hypothesis was confirmed by experiments in which weaker stimuli were used. Repetition of stressful stimuli increased the intensity of these autonomic responses in all animals.


Presence of a lipolytic factor in the gastric juice of calves. In experiments performed on 5 calves the lipolytic activity of pure gastric juice obtained from the abomassum was investigated during the first 2 weeks of life. It was found that the gastric juice of suckling calves possesses the ability of releasing free fatty acids from all triglycerides present in the milk. The highest activity was observed, however, using monoglyceride--Tween 80 as a substrate. The optimum pH for the lipolytic reaction approached 3.0.


Bone marrow transplantation.

Bone marrow transplantation. Bone marrow transplantation can be considered in any disease state resulting in the malfunction or absence of part or all bone marrow elements. Diseases such as aplastic anemia, leukemia, and immunodeficiency disease are being treated with bone marrow transplantation. As with any organ transplant, graft rejection is a possibility. In bone marrow transplantation, there is the additional, unique problem of graft versus host disease. In order to prevent or minimize graft rejection, the immunocompetence of the recipient and the degree of disparity between donor and recipient at the major histocompatibility complex (MHC) loci are considered. The results of bone marrow transplantation are variable, and the mortality rate is still relatively high. However, progress is being made, and in many instances, normal bone marrow function can be restored in patients with whom other treatment has failed.


5 alpha-Reductase activity in human placenta. The concentration of 5 alpha-pregnane-3,20-dione in peripheral blood of pregnant women is higher than that found in blood obtained from nonpregnant women throughout the luteal phase of the ovulatory cycle. The in vitro synthesis of 5 alpha-reduced pregnanes from [3H]progesterone by placental tissue was investigated using tissue minces and homogenates in the presence of added nicotinamide-adenine dinucleotide phosphate. The metabolites, [3H]5 alpha-pregnane-3,20-dione and [3H]3 beta-hydroxy-5 alpha-pregnan-20-one, were isolated and characterized employing a combination of chromatographic techniques, derivative formation, and crystallization with authentic [14C]5 alpha-pregnane-3,20-dione and [14C]3 beta-hydroxy-5 alpha-pregnan-20-one to constant 3H:14C ratios. In short-term incubations with placenta homogenates, the apparent pH optimum for the synthesis of 5 alpha-pregnane-3,20-dione was 8.8. There was no evidence for the formation of 5 beta-reduced pregnanes from [3H]progesterone by placental tissue. The in vitro metabolism of [3H]progesterone by minces of five term placentas, during 1 hour incubations at pH 7.4, was studied. The rate of formation of 5 alpha-pregnane-3,20-dione varied from 109 to 197 pmoles/gm placental tissue/hr.


Determination of liver intracellular pH in vivo and its homeostasis in acute acidosis and alkalosis. An in vivo method is presented for the determination of liver intracellular pH (pHi) using [14C]dimethadione (DMO) in dogs. This method differs from those previously published in that hepatic venous and portal venous blood pH were selected as the extracellular reference pH, and liver blood space corrections are applied to whole liver tissue [14C]DMO activity. Using these corrections, a normal liver pHi of 6.99 +/- 0.03 (SE) was obtained. During acute metabolic acidosis and alkalosis, as well as during acute respiratory acidosis and alkalosis, the liver pHi remained normal; metabolic acidosis was 7.04 +/- 0.04; metabolic alkalosis was 6.92 +/- 0.08; respiratory acidosis was 6.98 +/- 0.04; and respiratory alkalosis was 7.00 +/- 0.10. None of these values was significantly different from normal (P greater than 0.05). Changes in intracellular bicarbonate and lactate appeared to account in part for the observed stability of the liver pHi despite acute manipulations resulting in a range of pH values between 7.09 and 7.63 in arterial blood.


Treatment of tardive dyskinesia and mania with RBC lithium determinations. The authors report the usefulness of RBC lithium determinations in managing the treatment of tardive dyskinesia. They present a case report in which manic manifestations and tardive dyskinesia symptoms paralleled the rise and fall of RBC lithium and plasma lithium levels were constant during the period of symptom improvement. They conclude that RBC lithium levels appeared to reflect toxicity, control of mania, and symptom suppression of tardive dyskinesia better than plasma lithium levels alone.


Neuromuscular blocking potency of fazadinium in man. The study was designed to compare the recovery rates of fazadinium and four other commonly used competitive muscle relaxants in forty patients and eight volunteers. One-fifth to 1/10 of the clinical doses of the muscle relaxants were diluted in 20 ml of saline and injected intravenously at the wrist after inflation of a pneumatic tourniquet on the upper arm. After 3 min the tourniquet was released and the recovery time of twitch tension from 25 to 75% of the control determined. Evoked force of middle finger adduction was measured at a frequency of 0.2 Hz. The mean 25-75% recovery times of twitch tension for tubocurarine, pancuronium, alcuronium, gallamine and fazadinium were 14.20 +/- 1.42, 12.30 +/- 1.02, 10.12 +/- 0.77, 10.07 +/- 1.12 and 9.90 +/- 0.87 min, respectively. The authors conclude that the dissociation rate of fazadinum from the receptor of the motor endplate appears to be the fastest among the competitive muscle relaxants studied in man.


Beta-adrenoceptor blockade and anaesthesia. Beta-adrenoceptor antagonism during anaesthesia for coronary artery surgery. Twenty-six patients with severe coronary artery disease, receiving long term beta-adrenoceptor blocking drugs were anaesthetised for aorto-coronary bypass operations. Beta-adrenoceptor blocking drugs were withdrawn 2 to 8 days before surgery in ten patients only. In the remaining sixteen patients there were no serious complications due to the presence of a degree of beta-blockade during anaesthesia and surgery. The undesirable cardiovascular responses to laryngoscopy and tracheal intubation were diminished in these patients, and the rise in heart rate/systolic pressure product, and indicator of myocardial oxygen consumption, was less in this group. The need for peripheral vasodilators to treat systemic arterial pressure rises in response to surgery was also reduced. There appeared to be no contraindication to the continuation of beta-adrenoceptor blockade before operation in patients undergoing aorto-coronary bypass procedures when suitable anaesthetic agents were selected and when an appropriate blood volume was maintained.


[Rapid preparation of ornithine carbamyl transferase without carbamyl phosphate synthetase activity (author's transl)]. A rapid method of preparation of ornithine carbamyl transferase from rat liver is described. The enzyme preparation obtained is lacking in carbamyl phosphate synthetase activity. It may thus be used for the estimation of this enzyme on liver fragments obtained by needle biopsy of the liver in the diagnosis of neonatal hyperammonemia.


Impaired renal tubular potassium secretion in sickle cell disease. We examined renal tubular function in six patients with sickle cell hemoglobin. All had normal inulin and para-aminohippurate clearances and impaired urinary concentrating and acidifying abilities. After intravenous potassium chloride administration, maximum excretion of potassium (U,V) was significantly lower in sickle cell patients than in control subjects, and the percentage of potassium load excreted in 5 h was markedly reduced. Urinary potassium excretion after sodium sulfate infusion was also markedly reduced in sickle cell patients compared to control subjects. After 40 mg of oral furosemide, U,V was also diminished in sickle cell patients. Plasma aldosterone response to ACTH and intravenous potassium was similar to that of control subjects. Plasma renin activity increased normally after volume contraction. We conclude that sickle cell patients have a defect in their ability to excrete an acute potassium load that cannot be attributed to abnormal renin or aldosterone secretion. Overall potassium homeostasis is maintained by extrarenal mechanisms during acute potassium loading.


Diagnosis and treatment: drugs five years later. Amoxicillin. Amoxicillin is an aminopenicillin available in the United States only for oral use. It has an antibacterial activity and spectrum similar to that of ampicillin and is destroyed by gram-positive and gram-negative beta-lactamases. It is more active against enterococci and salmonellae than ampicillin, but less active against Shigella. It is better absorbed than ampicillin from the gastrointestinal tract with blood levels two to two and one half times those of ampicillin. Amoxicillin is an excellent agent to treat otitis media, bacterial sinusitis, bacterial exacerbations of bronchitis, acute lower-urinary-tract infections, gonorrhea, and typhoid. In special settings it may be useful as oral therapy of endocarditis, septic arthritis, and osteomyelitis and as prophylaxis to prevent endocarditis. When the cost of amoxicillin approaches that of ampicillin, it should replace that agent as the oral aminopenicillin of first choice.


[Trial of Idarac in stomatology and maxillofacial surgery (author's transl)]. In the light of a study involving a group of 50 patients hospitalised or seen on an ambulatory basis in a department of Stomatology and Maxillofacial surgery, Idarac (floctafenine) was felt to be an effective analgesic, at an average dose of 4 tablets. Tolerance was excellent from a clinical standpoint, rendering the drug easy to use, both on an out-patient basis as well as postoperatively.


[Clinical, hormonal and spermiologic evaluation in 25 crytorchids patients (author's transl)]. To obtain as many informations as possible about the degree of their fertility, 25 patients treated with gonadotropin or surgically for unilateral or bilateral cryptorchidism, were submitted to clinical examination, to evaluation of the endocrine testicular function, and to detailed sperm analysis. With respect to the serum gonadotropin levels, it is possible to distinguish three groups of patients : some with normal FSH and LH, some with increased FSH and normal LH, and some with increased FSH and LH. It appears that the tubular cells exerce a feed-back control on the FSH level, probably through a substance called "inhibin". The possibility is suggested that some feed-back control on the LH level is equally exerced from the tubular cells.


[Growth hormone specific binding sites : characteristics of lactogenic receptors induced by estrogens (author's transl)]. In vitro binding of growth hormone was characterized in rat liver. Microsomal preparations were found more active than membranes purified with an aqueous two-phase polymer system. Binding conducted at 4 degrees C was found optimal after 72 hours of incubation in 5 mM Tris-Maleate buffer pH 6.4 with 25 mM CaCl2. Injecting estrone (25 microgram/100 g B.W.) for one week induced the formation of lactogenic receptors, and increased the specific binding of hGH from 2.8 +/- 1.9 to 22.3 +/- 7.1%. Prolactin and hGH, but not rGH or other pituitary hormones, could displace radioactive hGH. With incubations conducted at 37 degrees C, equilibrium was reached more rapidly but at the cost of a more extensive degradation. The presence of membrane receptors in the medium partly protected the hormone against aggregation and degradation. Scatchard plots were obtained from experiments conducted under optimal conditions and analyzed on computer using a program based on an iterative method. Data indicated that lactogenic receptors possessed a single specific binding site for hGH with a constant (Ka) of 2.18 +/- 0.22 x 10(9) M-1 and a binding capacity of 304 +/- 91 fm/mg proteins.


Palatal myoclonus and denervation supersensitivity in the central nervous system. We postulate that palatal myoclonus after infarction of the brainstem or cerebellum, or both, is the manifestation of denervation supersensitivity secondary to lesions involving the dentatorubroolivary system. Two cases of our own and 31 from the English and French literature were analyzed in order to determine the delay between the occurrence of presumed anatomical lesions and the recognition of palatal myoclonus. The intervals varied from 2 to 49 months with the median between 10 and 11 months. The natural history of palatal myoclonus following brainstem infarction seemed consistent with the hypothesis.


Postvaccinal encephalomyelitis without cutaneous vaccination reaction. A 5-year-old girl developed a progressive febrile neurological illness consisting of right focal seizures, right hemiparesis, and stupor evolving over a period of six weeks. During the month preceding the onset of her illness she had received two apparently unsuccessful smallpox vaccinations without a skin lesion. Elevation of cerebrospinal fluid gamma globulin and findings on brain biopsy were consistent with postinfectious encephalitis, and a simultaneous increase in serum vaccinia antibody titer suggested that the illness was postvaccinial encephalitis. Clinically, the child developed a severe extrapyramidal movement disorder during the acute phase followed by nine months of stuporous unresponsiveness, yet subsequently made a substantial recovery.


[Effect of triterpene glycosides on plasma membrane permeability for UV-absorbing substances in Saccharomyces carlsbergensis yeast cells]. The effect of triterpene glycosides of cauloside C from Caulophyllum robustum M, stichoposide A from Stichopus japonicus S. and theasaponine from Thea sinensis Z. on permeability of plasmic membranes of Saccharomyces carlsbergensis for UV-absorbing substances was studied. It was found that incorporation of 14C-uridine from the endocellular pool into the yeast acid-insoluble fraction decreased under the effect of the triterpene glycosides as a result of the precursor leakage from the cell into the medium. It was found that the triterpene glycosides stimulated the leakage of the UV-absorbing substances with an absorption maximum at 260 nm from the cells. The maximum membranotropic effect was observed at 30--40 degrees C and in the presence of monovalent potassium, sodium, ammonium and lithium ions in the medium. Cauloside C and theasaponine, pentacyclic glycosides had the highest effect on the permeability at pH 4.8--5.6, while stichoposide A, a tetracyclic glycoside, had the highest effect at pH 7.0.


Effect of ampicillin and chloramphenicol against Streptococcus pneumoniae and Neisseria meningitidis. Antagonism, determined by isobolograms constructed from data from combinations of ampicillin and chloramphenicol at or below the minimal inhibitory or bactericidal concentrations, was observed against 13 clinical isolates of meningococcus and against one isolate of pneumococcus. Synergy occurred against six strains of pneumococcus and three of meningococcus. Additive effects were noted against 14 isolates of pneumococcus and 5 of meningococcus. There was no relationship between the minimal inhibitory or bactericidal concentrations for the isolates and the occurrence of antagonistic, additive, or synergistic effects. These data indicate that ampicillin and chloramphenicol may be antagonistic in vitro against some strains of pneumococcus or meningococcus.


Application of oxygen-enriched aeration in the production of bacitracin by Bacillus licheniformis. The physiological effects of controlling the dissolved oxygen tension at 0.01, 0.02, and 0.05 atm by the use of oxygen-enriched aeration were investigated during growth and bacitracin production by Bacillus licheniformis ATCC 10716. Up to a 2.35-fold increase in the final antibiotic yield and a 4-fold increase in the rate of bacitracin synthesis were observed in response to O(2)-enriched aeration. The increase in antibiotic production was accompanied by increased respiratory activity and an increase in the specific productivity of the culture from 1.3 to 3.6 g of antibiotic per g of cell mass produced. Oxygen enrichment of the aeration decreased medium carbohydrate uptake and the maximum specific growth rate of B. licheniformis from 0.6 h(-1) to as low as 0.15 h(-1), depending upon the level of enrichment and the conditions of oxygen transfer rate (impeller speed). The response of this culture to O(2) enrichment suggests that this method of controlling the dissolved oxygen tension for antibiotic-producing cultures may simulate conditions that would occur if the carbon source were fed slowly, as is often employed to optimize antibiotic production. Analysis of the biologically active bacitracins produced by B. licheniformis ATCC 10716 suggested that the ratio of biologically active peptides was not changed by O(2) enrichment, nor were any new biologically active compounds formed.


Milk pH, acid base status, and growth in babies. Metabolic acidosis is common in babies fed cows' milk-based formulae. Therefore the effects of adding alkaline salts (sodium and potassium citrate) to a demineralised whey formula were studied in vitro and in 26 low birthweight babies fed on the formula or formula plus citrate. The alkali altered the pH and titratable acidity to a value nearer human milk but it increased the buffering capacity to a value further away. This may effect the bacterial flora of the intestine. The babies fed on formula plus citrate did not make greater gains in weight, length, head circumference, skinfold thickness, or midarm muscle circumference, although they had a greater blood base excess. Some of these babies developed a mild metabolic alkalosis and 3 had hyponatraemia despite their increased sodium intakes. These babies also had lower levels of plasma transferrin but showed no differences in urea, albumin, cholesterol, and calcium levels. No baby fed on the demineralised whey formula without added citrate had a base deficit exceeding 5 mmol/l; late metabolic acidosis is less common in babies fed on this formula and the routine addition of alkali can have untoward metabolic effects.


Differential neurohumoral modulation of myoclonic and clonic seizures. Differential effects of neuropharmacological drugs upon susceptibility to flurothyl-induced myoclonic and clonic convulsions were assessed in two selectively bred lines of mice. Dopaminergic drugs (apomorphine and haloperidol) only affected myoclonus, whereas cholinergic (pilocarpine and scopolamine), gabaergic (AOAA and bicuculline), and serotonergic (PCPA) compounds principally influenced clonus. Noradrenergic drugs (clonidine, phentolamine and sotalol), however, altered the expression of both types of seizures. The apparent differential neurohumoral modulation of myoclonus and clonus is discussed in light of previous suggestions that these behaviors have separate neural substrates.


Effects of terbutaline, a synthetic beta adrenoceptor agonist, on in vivo erythropoietin production. Terbutaline sulfate, a new synthetic beta2-adrenoceptor agonist, was found to produce a dose-related increase in 59Fe-incorporation into newly formed red blood cells of exhypoxic polycythemic mice. This effect was blocked by prior treatment of the polycythemic mice with the potent beta-adrenoceptor antagonist, DL-propranolol. Terbutaline was also infused (i.v.) (500 microgram/kg/min) into restrained unanesthetized rabbits for a period of 5 hr with constant monitoring of arterial blood pressure and periodic blood Po2, Pco2, and pH analyses. Terbutaline was found to significantly elevate plasma erythropoietin titers in rabbits while producing a slight but nonsignificant decrease in mean blood pressure. Terbutaline did not produce a significant effect upon blood gases or blood pH. These data suggest a possible involvement of beta2-adrenoceptor activation of erythropoietin production.


Adenovirus aggregation and preservation in extracellular environment. The conditions of adenovirus aggregations are analyzed. Adenovirus type 2 was propagated on Hep2 cells; virion aggregation analysis was performed by sedimentation velocity on sucrose gradients. The results show that aggregation depends on: 1) Ionic strength: aggregate formation was verified between 0.005 M and 0.05 M NaCl; 2) pH: at pH 7.1 virus particles are dispersed, 90 per cent of particles are aggregated at pH 4--5; at pH lower than 4 aggregation is not reversible; 3) Particle concentration: the dilution of a stock containing 5 X 10(11) particles/ml decrease rate of aggregate formation until all aggregation is inhibited; 4) Temperature: the degree of aggregation in the 25 to 37 degrees C range is constant but decreases when the temperature falls below 20 degrees, at +4 C there is no aggregation. The aggregation reaction presents a positive deltaH of 17.9 Kcal/mol and a deltaG of --1.32 Kcal/mol.


[Histoenzymological characteristics of changes in the thymus gland in xenogenous form of graft vs host reaction]. The structural and functional lesions in the thymus of newborn animals in which xenogeneic graft versus host reaction was produced. Against the background of thymus hypoplasia, a decrease in mitogenesis and a reduction in the number of metabolically active lymphocyte forms were found. At the same time, activation of reticuloepithelial cells, macrophages, and giant cells was observed. It is assumed that such changes in the thymus may reflect an adaptative reaction of the host directed at making up the deficiency of peripheral T-lymphocytes developing in GVHR.


[Changes in the pulmonary artery in collagen diseases]. Morphological changes in the pulmonary artery and its major branches were studied histologically and histochemically on autopsy cases of polyarteritis nodosa (23), systemic lupus erythematosus (10), systemic scleroderma (12), and rheumatoid arthritis (5). The ages of the fatalities ranged from 9 months to 77 years. An identical type of lesions was revealed: disorders of the connective tissue, destruction of elastic fibers, alterations of vasa vasorum, with cellular reactions typical of each nosological form reflecting the peculiarities of the immunological processes. The initial stage in the genesis of lesions in the vascular walls of the major pulmonary arteries is the involvement of vasa vasorum as a regular disorder of the microcirculatory ways in all collagen diseases.


Acetoacetate metabolism in rat brain. Development of acetoacetyl-coenzyme A deacylase and 3-hydroxy-3-methylglutaryl-coenzyme A synthase. 1. Data are provided that indicate that the rat brain acetoacetyl-CoA deacylase is almost exclusively mitochondrial. Developmental studies show that this enzyme more than doubles its activity during suckling (0--21 days) and then maintains this activity in adults (approx. 1.1 units/g wet wt.). 2. Kinetic studies (on the acetoacetyl-CoA deacylase) in a purified brain mitochondrial preparation give a Vmax. of 47 nmol/min per mg of protein, and a Km for acetoacetyl-CoA of 5.2 micron and are compatible with substrate inhibition by acetoacetyl-CoA above concentrations of 47 micron. 3. The total brain 3-hydroxy-3-methyl-glutaryl-CoA synthase remains constant in the developing and adult rat brain (approx. 1.2 units/g wet wt.). This enzyme is located in both the mitochondrial and cytosolic fractions. During suckling (0--21 days) the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase represents approx. one-third of the total, but this increases markedly to about 60% of the total in the adult. The cytosolic enzyme correspondingly falls to approx. 40% of the total. 4. The role of the acetoacetyl-CoA deacylase in providing cytosolic acetoacetate for biosynthetic activities in the developing brain is discussed.


Purification and properties of four species of lysyl oxidase from bovine aorta. Lysyl oxidase of bovine aorta was resolved into four enzymically active species by elution from DEAE-cellulose with a salt gradient in 6m-urea, consistent with purification results obtained with enzyme of other tissues [Stassen (1976) Biochim. Biophys. Acta438, 49-60]. In the present study, each of the four peaks of activity was purified to apparent homogeneity by subsequent chromatography on gel-filtration media in 6m-urea. Each enzyme is eluted as a species with mol.wt. approx. 30000 under these conditions, although lysyl oxidase polymerizes to a series of multimers with molecular weights ranging up to 1000000 in the absence of urea. The apparent subunit molecular weight of each enzyme species determined by electrophoresis in sodium dodecyl sulphate and 8m-urea is approx. 32000-33000. The amino acid compositions of the purified forms of lysyl oxidase are similar to each other, although sufficient differences exist to conclude that each is a unique molecular species. Incorporation of alpha-toluenesulphonyl fluoride into the purification scheme does not alter the resolution of enzyme into four species, suggesting that proteolysis during isolation is not the basis of the heterogeneity. The similar sensitivities of each form of enzyme to chelating agents and to semicarbazide and isoniazid indicate that each requires the participation of a metal ion, presumably Cu(2+), and of a carbonyl compound for enzyme function. The present study describes a method for the purification of multiple species of lysyl oxidase and reveals that significant chemical differences exist between the different enzyme forms.


Interaction of dinitrophenyl groups bound to bovine serum albumin with univalent fragments of anti-dinitrophenyl antibody. Two lysine residues of bovine serum albumin reacted with 1-fluoro-2,4-dinitrobenzene with apparent second-order rate constants approx. 500-times greater than those observed in similar reactions with low-molecular-weight lysine derivatives. A series of dinitrophenyl (Dnp)-bovine serum albumins were prepared and their ability to bind univalent fragments of anti-Dnp antibody was measured by fluorescence-quenching titrations. Compared with the Dnp group of the free hapten, 6-N-Dnp-aminohexanoate, the majority of the protein-bound Dnp groups were unavailable to the antibody at pH8.0. When the same Dnp-albumins were titrated at pH3.0 the availability of the Dnp groups increased approx. 3-fold. Dnp-albumins were treated with pepsin at pH3.0 and Dnp-containing fragments isolated by chromatography on DE-52 DEAE-cellulose. Fluorescence-quenching titrations showed that the Dnp groups on the fragments behaved like the free hapten with respect to quenching efficiency, although with an increased dissociation constant. The association between the Dnp-albumins and the antibody was measured also by difference-spectral titrations at high protein concentrations. Antibody binding was increased under these conditions, but the Dnp group of mono-Dnp-albumin remained unavailable to antibody. We propose that the reactive lysine residues are located in clefts between the globular sub-domains of the single polypeptide chain. Dnp groups attached to these lysine residues are fully exposed to the solvent, but binding of the macromolecular probe, anti-Dnp antibody, is sterically hindered by the adjacent surface of the albumin molecule.


The role of link-protein in the structure of cartilage proteoglycan aggregates. Proteoglycan fractions were prepared from pig laryngeal cartilage. The effect of link-protein on the properties of proteoglycan-hyaluronate aggregates was examined by viscometry and analytical ultracentrifugation. Aggregates containing link-protein were more stable than link-free aggregates at neutral pH, at temperatures up to 50 degrees C and in urea (up to 4.0M). Oligosaccharides of hyaluronate were able to displace proteoglycans from link-free aggregates, but not from the link-stabilized aggregates. Both types of aggregate were observed in the ultracentrifuge, but at the concentration investigated (less than 2 mg/ml) the link-free form was partially dissociated and the proportion aggregated varied with the pH and temperature and required more hyaluronate for saturation than did link-stabilized aggregate. The results showed that link-protein greatly strengthened the binding of proteoglycans to hyaluronate and suggest that under physiological conditions it 'locks' proteoglycans on to the hyaluronate chain.


Derivation of molecular pK values from pH-dependences. If the titration pK values of a dibasic acid are called pK +/- logp, then its molecular pK values are pK +/- log(p+1/p). If the pH values at which the concentration of its monoprotonated form is half-maximal are called pK +/- logq, then its molecular pK values are pK +/- log(q-4+1/q).


Properties of the cupric sites in bovine superoxide dismutase studied by nuclear-magnetic-relaxation measurements. Proton nuclear-relaxation rates have been measured as a function of frequency, temperature, pH and cyanide concentration in aqueous solutions of superoxide dismutase from bovine erythrocytes. The results show that, whereas for pH less than or equal to 9 only one water molecule is bound to each Cu2+ ion, at higher pH a second co-ordination site for OH- becomes available; it is proposed that this involves cleavage of the bond between Cu2+ and the histidine residue that bridges to Zn2+.


The multiple forms and kinetic properties of the N-acetyl-beta-D-hexosaminidases from colonic tumours and mucosa of rats treated with 1,2-dimethylhydrazine. The separation and purification of the N-acetyl-beta-D-hexosaminidase activities from tumours induced by 1,2-dimethylhydrazine in the rat colon and from colonic mucosa of tumour-bearing animals are reported. Mucosa contained N-acetylhexosaminidases A and B, as well as a third form whose properties with regard to electrophoretic mobility and thermostability lay between those of A and B. Tumours contained only N-acetylhexosaminidase A and B activities. Each form possessed both N-acetylglucosaminidase (EC 3.2.1.30) and N-acetylgalactosaminidase (EC 3.2.1.53) activities, which could not be separated by a variety of techniques. The alteration of the ratio of the two specific activities in each form during purification, together with differences in the kinetic inhibition constants and behaviour during inactivation by various reagents or a temperature of 50 degrees C, supported the belief that each form contains the two enzyme activities, glucosaminidase and galactosaminidase, at separate active sites. This model is in contrast with that reported for these activities from a number of other sources. A variety of treatments reported to cause the conversion of form A into a form resembling B failed to produce such an effect on the rat colonic hexosaminidases.


Acetyl-coenzyme A deacylase activity in liver is not an artifact. Subcellular distribution and substrate specificity of acetyl-coenzyme A deacylase activities in rat liver. Whole liver and isolated liver mitochondria are able to release free acetate, especially under conditions of increased fatty acid oxidation. In the present paper it is shown that rat liver contains acetyl-CoA deacylase (EC 3.1.2.1) activity (0.72mumol/min per g wet wt. of liver at 30 degrees C and 0.5mm-acetyl-CoA). At 0.5mm-acetyl-CoA 73% of total enzyme activity was found in the mitochondria, 8% in the lysosomal fraction and 19% in the postmicrosomal supernatant. Mitochondrial subfractionation shows that mitochondrial acetyl-CoA deacylase activity is restricted to the matrix space. Mitochondrial acetyl-CoA deacylase showed almost no activity with either butyryl- or hexanoyl-CoA. Acetyl-CoA hydrolase activity from purified rat liver lysosomes exhibited a very low affinity for acetyl-CoA (apparent K(m)>15mm compared with an apparent K(m) value of 0.5mm for the mitochondrial enzyme) and reacted at about the same rate with acetyl-, n-butyryl- and hexanoyl-CoA. We could not confirm the findings of Costa & Snoswell [(1975) Biochem. J.152, 167-172] according to which mitochondrial acetyl-CoA deacylase was considered to be an artifact resulting from the combined actions of acetyl-CoA-l-carnitine acetyltransferase (EC 2.3.1.7) and acetylcarnitine hydrolase. The results are in line with the concept that free acetate released by the liver under physiological conditions stems from the intramitochondrial deacylation of acetyl-CoA.


Effect of age on amnesia and sedation induced by flunitrazepam during local anaesthesia for bronchoscopy. Bronchoscopy was undertaken in 79 outpatients using local anaesthesia plus an i.v. injection of flunitrazepam 0.01 mg kg-1. The co-operation of the patients and the ease of bronchoscopy were good regardless of the age of the patient. There was an increase in amnesia for the bronchoscopy with increasing age, but the most distinct difference between different age groups was that the amnesic action of flunitrazepam was evident earlier and persisted longer in patients of more than 60 yr. Eye co-ordination and ability to stand steadily and walk on a line returned to normal more slowly in patients more than 60 than in those less than 60 yr, but no differences in recovery were noted between patients less than 40 and those of 40--59 yr, or between those 60--69 and those more than 70 yr.


Effects of glycopyrrolate and cimetidine on gastric volume and acidity in patients awaiting surgery. Glycopyrrolate or cimetidine was administered before operation to patients undergoing elective surgery. After the induction of anaesthesia, the stomach contents were retrieved and the volume and pH measured. Neither drug diminished the volume of gastric contents compared with control. Glycopyrrolate produced little diminution in hydrogen ion concentration. Cimetidine caused a marked increase in pH with a mean [h+] 3.2 x 10(-3) g litre-1 compared with 1.4 x 10(-2) g litre-1 in the controls and 1.1 x 10(-2) g litre-1 in the glycopyrrolate group. Seventy-seven per cent of the patients receiving cimetidine had a pH greater than 2.5.


Effects of H1- and H2-receptor blocking agents on histamine-induced bronchoconstriction in non-asthmatic subjects. 1 Two studies have been carried out to investigate the effect of H1- and H2-receptor blocking agents on histamine-induced bronchoconstriction in non-asthmatic subjects. 2 The H2-receptor blocker cimetidine administered orally had no effect on histamine-induced bronchoconstriction on any of the subjects tested. In three of four subjects, the H1-receptor blocker, chlorpheniramine given orally, inhibited the effect of the histamine in the lung. 3 The effects of intravenous chlorpheniramine and cimetidine, both alone and in combination, upon histamine-induced bronchoconstriction, were also studied. Chlorpheniramine inhibited the effect of the histamine and this was significantly dose related. This was not so with cimetidine and there was no evidence that the dose response curve to chlorpheniramine was affected by the additional administration of cimetidine. 4 The results show that histamine-induced bronchoconstriction in non-asthmatic subjects is not mediated by H2-receptors, but it is likely that H1-receptors are involved.


Study of urinary excretion of butobarbitone in man in relation to the percentage of ideal body weight. 1 Thirty-three patients with no evidence of endocrine disease, hepatic or renal insufficiency or sleep disorders, were classified in groups 1 to 4 in order of increasing of percentage of ideal body weight (IBW) respectively: less than 90% of IBW, 90--120%, 120--180%, and greater than 180% of IBW. After oral administration of 200 mg butobarbitone, concentration of the intact drug was measured by gas liquid chromatographic assay in urine samples collected during 72 h and at three times in blood. 2 A highly significant negative relationship was found between the cumulative excretion of butobarbitone with urine and the logarithm of the percentage of IBW. In contrast for a given weight, excretion of the drug with urine was found to be weakly correlated with the diuresis. 3 The cumulative urinary elimination of butobarbitone was significantly different between the groups studied, except of the difference between the group 2 and 3 of the patients. No significant difference was found between the renal clearances of butobarbitone in the four groups of subjects. 4 We conclude that redistribution of butobarbitone into adipose tissues can explain the obtained results and that obesity modifies the pharmacokinetics of the drug.


The separate effects of H+ and 2,3-DPG on the oxygen equilibrium curve of human blood. Addition of non-saturating amounts of 2,3-DPG (2,3-diphosphoglycerate) within the red cell (2,3-DPG/haemoglobin less than 1) initially reduces Hill's parameter, n. With increasing 2,3-DPG/haemoglobin, n increases until a maximum is reached at 2,3-DPG/haemoglobin greater than 1. Thus, 2-3-DPG influences the shape as well as the position of the whole blood oxygen equilibrium curve (OEC). The importance of this effect on the oxygen carrying capacity of the blood is considered. The effect of 2,3-DPG on the position of the OEC (p50, the pO2 at one-half maximal O2 saturation) is via its allosteric effect on haemoglobin at 2,3-DPG/haemoglobin less than 1. Above the ratio, its effect is to reduce intracellular relative to the extracellular pH.


The influence of diet and diabetes on stearoyl Conenzyme A desaturase (EC 1.14.99.5) activity and fatty acid composition in rat tissues. 1. Rats were given low-fat diets for 3 d in which the carbohydrate source was starch. The livers of animals given the fructose or sucrose had increased hepatic activities of the fatty acid synthetase and stearoyl CoA desaturase (EC 1.14.99.5) enzyme complexes: in those given fructose there was a lower activity of the enzymes in adipose tissue. 2. Similar results were obtained in rats given fructose diets for 30 d, but in animals which had previously been made diabetic with streptozotocin, the activities were lower. The dietary treatment made little difference to the fatty acid profiles of the tissue lipids. The diabetic condition on the other hand produced considerable changes in fatty acid profile. 3. With diets containing approximately 200 g fat/kg in the form of butter or of polyunsaturated margarine, the tissue lipids from rats given sucrose had less linoleic acid than those from rats given starch. In addition, there was the expected difference between the rats given butter or margarine. The results are discussed in relation to the current literature.


The behaviour of thiomolybdates in in vitro systems. The stability of potassium tetrathiomolybdate was studied in vitro using solutions with molybdenum, hydrogen ion and phosphate concentrations similar to those normally found in the rumen. Under these conditions K2[MoS4] hydrolysed rapidly and as a result the solution contained [moS4]2-, [MoOS3]2-, [MoO2S2]2-, [HS]- and H2S in equilibrium. In view of this hydrolysis, in vivo studies of thiomolybdate on copper metabolism of sheep should not exclude the possibility that either sulphide or molybdate is responsible for any observed effect.


Fluorescence studies of native and modified neurophysins. Effects of peptides and pH. The effect of neurophysin-hormone interaction on the environment of the single tyrosine of bovine neurophysin (Tyr-49) and on that of the tyrosine of oxytocin and vasopressin was studied by fluorescence; tyrosine-free peptides were used to determine effects on Tyr-49, and acetylated neurophysin was used to determine effects on the hormone tyrosine. Binding increases the fluorescence intensity of Tyr-49 by 130% while the fluorescence of the hormone tyrosine is almost completely quenched. Correlation of these results with those obtained on binding oxytocin or vasopressin to native neurophysin indicates that in the hormone complexes less than half of the fluorescence of Tyr-49 is lost by Förster energy transfer to the quenched hormone tyrosine. These results support spin-label studies in indicating that the distance between Tyr-49 and the tyrosine of hormone bound to the strong hormone binding site is greater than 5 A. In the absence of peptides, the fluorescence of Tyr-49 increases by 40% on lowering the pH from 6.2 to 2. Titration of the acid fluorescence transition in bovine neurophysins-I and -II, and in bovine neurophysin-II treated with carboxypeptidase B to remove the Arg-Arg-Val sequence at the carboxyl terminus, indicates that this transition is due to titration of a side-chain carboxyl with an intrinsic pK of 4.6. The effects of guanidine, glycerol, and disulfide cleavage on the magnitude of the acid transition indicate that the conformational information necessary for the transition resides within the amino acid sequence adjacent to Tyr-49. Accordingly, the fluorescence acid transition is attributed to decreased quenching by Glu-46 or Glu-47 upon protonation. Glycerol is shown to perturb the glutamate-tyrosine interaction in the absence of general conformational effects. Comparison of the fluorescence low-pH transition with that of the low-pH circular dichroism transition of nitrated neurophysins suggests that the fluorescence and CD transitions reflect related, but not necessarily identical, phenomena. In an appendix, evidence is presented which suggests that the products of carboxy-peptidase digestion of bovine neurophysin-II are the same as two minor bovine neurophysin components, one of which is neurophysin-C.


CO and O2 complexes of soybean leghemoglobins: pH effects upon infrared and visible spectra. Comparisons with CO and O2 complexes of myoglobin and hemoglobin. The effects of pH upon infrared spectra [CO stretching frequency (vco) region] and visible spectra of the CO complexes of soybean leghemoglobins a, c1, and c2, sperm whale myoglobin, and human hemoglobin A  are reported. The vco for leghemoglobin--CO complexes was 1947.5 cm-1 at neutral pH. At acid pH myoglobin-- and hemoglobin--CO complexes developed vco bands at 1966--1968 cm-1, whereas leghemoglobin--CO complexes developed vco bands at approximately 1957 cm-1. All pKapp co values determined by pH-dependent variation of vco fell in the range 4.0--4.6. The pKapp co values determined from visible spectra were consistent with vco-determined values except for that of myoglobin--CO (visible pKapp co = 5.8). The pKapp co values in the 4.0--4.6 range appear to be pK values of the distal histidines, while the visible pKapp co of myoglobin--CO appears to be the pK of a group other than the distal and proximal histidines. The data are consistent with a model in which protonation of the distal histidine permits protein-free heme FeCO geometry in leghemoglobin--CO complexes but not in myoglobin-- or hemoglobin--CO complexes. Thus the heme pockets of leghemoglobins appear to be more flexible than the heme pockets of myoglobin and hemoglobin. The effects of pH upon visible spectra of the O2 complexes of soybean leghemoglobins a, c1, and c2, sperm whale myoglobin, and human hemoglobin A also are reported. pKapp o2 values of approximately 5.5 (leghemoglobins) and 4.4 (hemoglobin) are probably the pK values of the distal histidines. Comparisons of pKapp o2 values with pKapp co values indicate a more flexible heme pocket in leghemoglobins than in hemoglobin. The O2 complex of leghemoglobin c2 differed significantly from the O2 complexes of leghemoglobins a and c1 in visible spectra and titration behavior. These differences  might be associated with the small structural differences in the region between the E and F helixes of leghemoglobins.


Electrostatic interactions at charged lipid membranes. Electrostatically induced tilt. The changes in bilayer structure induced by surface charges in the case of an ionizable lipid were studied by X-ray diffraction, Raman spectroscopy, and film-balance measurements. With increasing surface charge in the ordered phase, the X-ray results show a decrease in bilayer thickness, whereas the hydrocarbon chain packing stays essentially constant, the Raman data signify that the internal chain ordering does not change, and the monolayer studies show a lateral expansion of the bilayer. These results are interpreted in terms of a tilt of the chains caused by the surface charges on the polar heads. The tilt angle between the direction of the chains and the bilayer normal is obtained by a detailed theoretical evaluation. The tilt allows for a better understanding of the electrostatically induced shift of the phase transition temperature and of the shift induced by the binding of water in the case of lecithin in contrast ethanolamine.