A study of the plasma concentrations of lorazepam in mother and neonate. A standard dose of lorazepam 2.5 mg was given i.v. to two groups of mothers: (a) before surgical induction of labour and (b) at the beginning of the second stage of labour. A group of non-pregnant women was studied as control. Plasma concentrations of lorazepam were measured by gas-liquid chromatography, in the mothers before delivery, and in the mother and neonate at delivery and 24 and 48 h thereafter. Concentrations at delivery in the neonates were similar to those in the mothers in group (a), but significantly less in group (b). Fetal concentration rarely exceeded that in the mother. Measurements after delivery indicated that the neonates were able to metabolize lorazepam at the same rate as the mothers. Of the 22 neonates studied only one had an Apgar score of less than 8 at 5 min and this score was 10 at 10 min.


Awareness during surgery--a new approach. With modern light anaesthesia the problem of awareness during surgery has defied analysis, because no physical sign reliably signals the conscious level. A test has been developed which entails direct communication with the patient at the end of surgery, noting the earliest moment after withdrawal of nitrous oxide at which he makes the appropriate response to a verbal request, the "time to correct response" (TCR). This test showed premedication with lorazepam 4 mg/70 kg to be significantly better than morphine 10 mg for ensuring unconsciousness when the main anaesthetic agent was nitrous oxide, in two groups of patients undergoing abdominal surgery (P less than 0.01). All patients who had lorazepam were able, on request, to hold up the head a few minutes after surgery. Thus the benefits of light anaesthesia were retained whilst ensuring unconsciousness.


Maternal blood-gas tensions (PAO2-PaO2), physiological shunt and Vd/Vt during general anaesthesia for Caesarean section. Measurements of maternal blood-gas tensions, (PAO2-PaO2), calculated pulmonary venous admixture (physiological shunt) and deadspace/tidal volume ratio (VD/VT) were made in 14 patients undergoing Caesarean section. Measurements were carried out after induction of general anaesthesia, and before delivery, with the patient tilted to the left. With a mean inspired oxygen concentration of 67.5% mean PaO2 was 44.3 kPa, mean (PAO2-PaO2) 18.4 kPa, mean Vd/Vt 32% and mean physiological shunt 9.5%. The findings are compared with published values for non-anesthetized pregnant patients.


The effect of enzyme induction on diazepam metabolism in man. 1 The elimination and metabolism of diazepam in man was investigated following the induction of the liver microsomal enzyme system by antipyrine. 2 Seven healthy volunteers were given 1200 mg antipyrine as an inducing agent for a period of 14 days. Before and after the induction period the elimination of diazepam and desmethyldiazepam was measured in the plasma by gaschromatography. As parameters of liver microsomal enzyme activity, antipyrine elimination and gamma-glutamyl-transpeptidase in the plasma, D-glucaric acid and 6-beta-hydroxycortisol urinary excretion were measured on both occasions. 3 Following the induction period most parameters of microsomal enzyme activity measured were significantly changed indicating an increase of the microsomal enzyme system. The elimination of diazepam was significantly altered having a half-life of 37 h before and 18 h afterwards combined with a significant increase in total body clearance after the induction period, although the volume of distribution remained unaltered. The formation of the main metabolite N-desmethyldiazepam was not changed, but its elimination was increased having a half-life of 139 or 58 h respectively. 4 The elimination of unchanged diazepam and desmethyldiazepam is significantly increased by the induction of the liver microsomal enzyme system using antipyrine as an inducing agent in healthy volunteers, which might be important under certain clinical conditions.


Resonance Raman studies and structure of a sulfide complex of methemerythrin. The complex of sulfide and methemerythrin has been characterized by resonance Raman spectroscopy. At pH 8.0 the complex contains two irons and one S2- at the active site. The resonance Raman spectrum of the sulfidomethemerythrin complex contains only one vibration, at 444 cm-1. This vibration is assigned to an iron-sulfide stretch. The possibility that sulfidomethemerythrin contains a mu-sulfido bridge. FeIII-S2-FeIII, analogous to the proposed mu-oxo bridge in azidomethemerythrin is discussed.


Variable proton conductance of submitochondrial particles. The relationship between the rate of substrate oxidation and the protonmotive force (electrochemical proton gradient) generated by bovine heart submitochondrial particles has been examined. Unexpectedly, oxidation of succinate generated a higher protonmotive force than the oxidation of NADH, although the rate of proton translocation across the membrane was inferred to be considerably lower with succinate as substrate. The data suggest that the flow of electrons through site 1 of the respiratory chain may increase the conductance of the mitochondrial membrane for protons. Upon reduction of the rate of succinate oxidation by titration with malonate, the protonmotive force remained essentially constant until the extent of inhibition was greater than 75%. The general conclusion from this work is that a constant passive membrane conductance for protons cannot be assumed.


Kinetics of Ca2+ carrier in rat liver mitochondria. The rate of aerobic Ca2+ transport is limited by the rate of the H+ pump rather than by the Ca2+ carrier. The kinetics of the Ca2+ carrier has therefore been studied by using the K+ diffusion potential as the driving force. The apparent Vmax of the Ca2+ carrier is, at 20 degrees C, about 900 nmol (mg of protein)-1 min-1, more than twice the rate of the H+ pump. The apparent Vmax is depressed by Mg2+ and Li+. This supports the view that the electrolytes act as noncompetitive inhibitors of the Ca2+ carrier. The degree of sigmoidicity of the kinetics of Ca2+ transport increases with the lowering of the temperature and proportionally with the concentration of impermeant electrolytes such as Mg2+ and Li+ but not choline. The effects of temperature and of electrolyte do not support the view that the sigmoidicity is due to modifications of the surface potential. Rather, they suggest that Ca2+ transport occurs through a multisubunit carrier, where cooperative phenomena are the result of ligand-induced conformational changes due to the interaction of several allosteric effectors with the carrier subunits. In contrast with La3+ which acts as a competitive inhibitor, Ruthenium Red affects the kinetics by inducing phenomena both of positive and of negative cooperativity. The Ruthenium Red induced kinetics has been reproduced through curve-fitting procedures by applying the Koshland sequential interaction hypothesis to a four-subunit Ca2+ carrier model.


Activation of human brain galactosylceramidase by phosphatidylserine. Assays of sphingolipid hydrolases in vitro generally require bile salts or other detergents. A few 'activator proteins' have been reported that can partially replace the detergents in the assay mixture. We report here that phosphatidylserine from bovine brain is a relatively specific activator of human brain galactosylceramidase in the absence of sodium taurocholate (phosphatidylserine system). Activity similar to that obtained with the conventional assay system containing taurocholate and oleic acid (taurocholate system) could be obtained. Other lipids tested generally gave less than 10% of the taurocholate system activity, but sulfatide could activate human brain galactosylceramidase to 20--30% of the taurocholate system. The properties of the reaction in the phosphatidylserine system were examined with human brain whole homogenate, crude soluble post-concanavalin A preparations, and partially purified preparations as the enzyme source and compared with those obtained with the taurocholate system. The pH optimum shifted from 4.2 in the taurocholate system to 4.7 in the phosphatidylserine system. The phosphatidylserine system was superior in the linearity of the reaction with respect to the enzyme protein. Reasonably linear Lineweaver-Burk plots could be obtained. The Km values for the phosphatidylserine system were greater than those for the taurocholate system. The effect of phosphatidylserine was not additive to that of taurocholate. Additional phosphatidylserine to the taurocholate system was either without effect at lower concentrations or inhibitory at higher concentrations. The assays of galactosylceramidase with phosphatidylserine and without taurocholate do not necessarily provide pragmatic advantages but offer a potentially useful system with which to study the mechanism of in vivo degradation of the membrane-bound glycosphingolipid.


Modulation of purified phospholipase A2 activity from human platelets by calcium and indomethacin. A membrane bound phospholipase A2 (phosphatide 2-acylhydrolase, EC 3.1.1.4) from human platelets has been purified 3500-fold, and partially characterized. Phospholipase A2 activity was assayed using [1(-14)C] oleate-labeled Escherichia coli or sonicated dispersions of synthetic phospholipids. The 2-acyl specificity of the phospholipase activity was confirmed using phosphatidylethanolamine labeled in the C-1 position as substrate. The purified enzyme was maximally active between pH 8.0 and 10.5, and had an absolute requirement for low concentrations of Ca2+. Indomethacin, but not aspirin, inhibited phospholipase A2 activity.


Studies on the subunits of Escherichia coli coenzyme A transferase. Reconstitution of an active enzyme. The alpha and beta subunits of the acetyl-CoA:acetoacetate-CoA transferase were purified by isoelectric focusing of the enzyme in the presence of 6 M urea. The purified beta subunit, in which the active center of the enzyme is located, exhibits low catalytic activity (2% of the specific activity of the native enzyme) which is stimulated 5-6-fold in the presence of an equimolar concentration of alpha subunit. The presence of the substrate,acetoacetyl-CoA, is  required to recover the catalytic activity of the beta subunit and mixtures containing purified alpha and beta subunits. When the enzyme is dissociation in the presence of 6 M urea and the subunits are not fractioned, removal of the urea by dialysis results in the recovery of 88-98% of enzymic activity and the native alpha2beta2 subunit structure. However, analysis of this renatured enzyme by immunochemical techniques shows that the enzyme does not refold to a completely native conformation. This renatured enzyme exhibits an immunological reactivity more closely resembling the isolated alpha subunit. The results indicate that the alpha subunit serves as a structural subunit, or possible a maturation subunit, imposing a conformation on the beta subunit that is catalytically more competent.


Studies on the mechanism of iron release from transferrin. Iron release from human, rabbit, rat and sheep transferrin, chicken conalbumin and human lactoferrin was measured by the change in absorbance of solutions of the iron-protein complexes or by the release of 59Fe from the protein conjugated to agarose. Several phosphatic compounds and iron chelators were able to mediate the process (ATP, GTP, 2,3-diphosphoglycerate, inositol hexaphosphate, pyridoxal 5-phosphate, cytidine 5-triphosphate, pyrophosphate, inorganic phosphate, citrate, EDTA, oxalate, nitrilotriacetate). The greatest rate of iron release was found with pyrophosphate and the least with inorganic phosphate. Different rates of iron release were obtained with the different proteins, greatest with human transferrin and least with lactoferrin. With each of the proteins and the mediators there was a linera relationship between the H+ concentration and the rate of iron release. At any given pH the rate of iron release increased to a maximal rate as the mediator concentration was raised. It is concluded that iron release from transferrin under the conditions of these experiments involves an initial interaction between H+ and the iron-transferrin complex followed by release of the iron under the action of the mediator.


Stability of phage T4 lysozymes. II. Unfolding with guanidinium chloride. The denaturation by guanidinium chloride of three phage lysozymes (wild type and two mutants) was investigated. The study of solvent denaturation permitted the investigation of the relative stabilities of the proteins at neutral pH, in contrast to thermal denaturation studies reported earlier which could only be performed in acid pH. The results were interpreted assuming that the free energy of solution of proteins is a linear function of denaturant concentration. Using standard thermodynamic formulas this permits the calculation of the stabilities of the three proteins in the absence of guanidinium chloride. The single point mutation Trp 138 leads to Tyr leads to relatively large changes in stability and the interaction of the protein with guanidinium chloride. The changes associated with the subsequent double mutation, Trp 126 leads to Tyr, Trp 158 leads to Tyr, are much smaller indicating a relatively smooth adjustment of the protein structure to the changed side chains. Models of the structural effects of point mutations are discussed. It is found that the mutation at position 138 does not fit a model in which the effect of a substitution is to introduce an energetic strain in the structure. It does fit a model in which there is a partial unravelling of the structure as a result of the mutation. However, there are no changes in the backbone circular dichroism spectra associated with the mutation. The two observations are not necessarily in conflict. Further physical studies are required for the resolution of the problem.


Modification of hemoglobin A with dimethyl adipimidate. Contribution of individual reacted subunits to changes in oxygen affinity. The effect of dimethyl adipimidate, a bifunctional imidoester, on the oxygen affinity of hemoglobin A has been studied. Treatment of human oxyhemoglobin with 5 mM dimethyl adipimidate at pH 8.5, room temperature is accompanied by an increase in oxygen affinity in the presence and absence of 2,3-diphosphoglyceric acid. Circular dichroism measurements in the ultraviolet region indicate that dimethyl adipimidate-treated hemoglobin exhibits a reduced conformational change upon deoxygenation. In order to study the contribution of reacted individual subunits, alpha and beta subunits of dimethyl adipimidate-treated and untreated hemoglobin have been separated and reconstituted to form hybrid tetramers containing either the alpha-treated (alpha t beta c) or the beta-treated subunits (alpha c beta t). Electrophoresis on sodium dodecyl sulfate polyacrylamide gels of isolated alpha and beta globin subunits as well as hybrid tetramers from dimethyl adipimidate-treated hemoglobin reveals that 20% of the globin subunits are cross-linked. In the absence of 2,3-diphosphoglyceric acid, modification of alpha subunits increases the oxygen affinity and reduces the conformational change of the tetramer upon deoxygenation whereas modification of beta subunits has no effect. However, treatment of beta subunits decreases the effect of 2,3-diphosphoglyceric acid on the oxygen affinity of the hybrids and reduces the 2,3-diphosphoglyceric acid-induced spectral changes in oxyhemoglobin. Therefore the interaction of dimethyl adipimidate with both the alpha and beta subunits contributes to regulating the oxygen affinity of human hemoglobin.


The formation and thermal stability of in vitro assembled fibrils from acid-soluble and pepsin-treated collagens. The role of the non-helical regions of the collagen molecule in fibrillogenesis has been investigated by comparing the kinetics of fibril formation of pepsin-treated acid-soluble collagen, acid-soluble collagen and mixtures of the two and by comparison of the thermal stabilities of the fibrils formed. The acid-soluble collagen was found to aggregate more rapidly than the pepsin-treated collagen under physiological conditions of pH and ionic strength. Variations in ionic strength, at physiological pH, were found to have differing effects on the aggregation of these two forms of soluble collagen. Fibrils formed from the pepsinized-collagen had a lower thermal stability tha n those formed from the intact collagen. The behavior observed with mixtures of acid-soluble and pepsin-treated collagens was found to be quantitatively consistent with the pepsinized collagen being able to utilize the nuclei formed by the acid-soluble collagen for subsequent growth. However, the use of the acid-soluble nuclei by the pepsinized collagen for growth did not enhance its rate of precipitation during the growth phase, nor did it enhance the thermal stability of the fibrils formed from the pepsinized collagen.


Influence of steric factors on oxygen binding. I. Studies on 2,4-diisopropyldeuteroheme-myoglobin. Sperm whale apomyoglobin was recombined with 2,4-diisopropyldeuterohemin to form 2,4-diisopropyldeuteroheme-myoglobin and its various physico-chemical properties were investigated to get an insight into the structural and functional role of the peripheral vinyl groups. 2,4-Diisopropyldeuteroheme-myoglobin showed a four times lower oxygen affinity at 25 degrees C and larger enthalpy and entropy changes of oxygenation than the corresponding values of native myoglobin. 2,4-Diisopropyldeuteroheme-metmyoglobin shows a pKa value of 9.68 which is higher than those of native metmyoglobin and mesoheme-metmyoglobin. The rate of autooxidation of oxy-form was about seven times larger in 2,4-diisopropyldeuteroheme-myoglobin than in native myoglobin. The electron-donating effect of isopropyl groups does not give straightforward explanation for these anomalous properties of 2,4-diisopropyldeuteroheme-myoglobin. It is proposed that site and stereospecific van der Waals' interaction between the polypeptide side chains and the peripheral 2,4-diisopropyl groups may weaken the interaction between the bound oxygen molecule and the distal His, resulting in the decrease in the stability of oxyform.


Hydrolysis of organophosphate insecticides by an immobilized-enzyme system. An enzyme preparation that could detoxify parathion and eight other organophosphate pesticides was covalently bound to either porous glass or porous silica beads. This immobilized-enzyme system was examined for its use in detoxification of pesticides in production wastewaters. The kinetics of parathion hydrolysis were examined at flow rates up to 96 liter/hr and at influent substrate concentrations ranging from 10--250 mg/liter. The enzyme reactor was able to hydrolyze 95% or more of the parathion added to industrial wastewaters generated during its production, thus reducing the effluent parathion concentration to below 500 ppb. Laboratory continuous-flow experiments were conducted for 70 days with industrial wastewater and indicated no loss in immobilized-enzyme activity. The influence of pH, temperature, solvents, and detergents on enzyme stability and activity and enzyme reactor kinetics will be discussed.


Action of shear on enzymes: studies with alcohol dehydrogenase. Yeast alcohol dehydrogenase (ADH) solutions (approximately 1 mg/ml, pH 7) were sheared in a coaxial cylindrical viscometer. This was fitted with a lid sealing the contents from the atmosphere and preventing evaporation. At 30 degrees C after a total of 5 hr intermittent shearing at 683 sec-1 no losses of activity were observed. No losses were found after 5 hr continuous shearing and in a no-shear control. At 40 degrees C and 683 sec-1 there were only small activity losses in 5 hr. Shearing at 3440 sec-1 no measurable losses of activity were found with a 1.03 mg/ml solution in 5 hr at 30 degrees C, a 1.03 mg/ml solution in 8 hr at 5 degrees C, and with a 3.89 mg/ml solution in 3 hr at 5 degrees C. In all these cases, however, a white precipitate formed that was not observed in zero shear control experiments. The sheared 3.89 mg/ml solution was clarified by centrifugation. It was shown that there were no ADH aggregates in the supernatant and that the precipitate was less than 2% of the original protein. At 30 degrees C under adverse pH conditions (pH 8.8) there was no significant difference in activity losses of an approximately 1 mg/ml solution sheared at 65 and 744 sec-1. An approximately 0.5 mg/ml ADH solution, pH 7, was agitated in a small reactor with no free air-liquid interface. Peak shear rates near the impeller were estimated to be about 9000 sec-1. Only a small decrease in specific activity was observed until over 15 hr total running at 5 degrees C.


Hydrolysis of urea by gelatin-immobilized urease: separation of kinetic and diffusion phenomena in a model immobilized-enzyme reactor system. Experiments and appropriate mathematical models are presented in an attempt to elucidate and separate the effects of mass transfer and immobilization on the apparent kinetics of hydrolysis of urea by urease immobilized within a crosslinked gelatin film. Diffusion of urea through the gelatin matrix appears to exert the major influence on the observed kinetics. Diffusion coefficients are measured, and a model for the "effectiveness factor" is presented, accounting for this aspect of mass transfer control. A secondary, but significant, influence on apparent kinetics arises because the reaction products lead to an increased pH level which, because of diffusion resistance, remains high within the gelatin matrix. For pH levels in the 6.7 to 9.0 range the activity of urease is a strongly decreasing function of pH. An approximate model accounting for ionic equilibrium allows this pH-diffusion effect to be introduced in such a way as to lead to predictions of the apparent kinetics that are compared with experimental observations. Examination of these results indicates that the immobilization procedure leads to some loss of activity due to an interaction of the gelatin crosslinking reaction with the enzyme itself.


[Characteristics of the lymphoid tissue reaction in compensatory reparative growth of the salivary glands in mice]. The capacity of the spleen cells of CBA mice to antibody formation as well as to the "graft-versus-host" (GVH) reaction and the change in the stem cell number determined by the spleen colony method were studied after unilateral removal or burn of the submandibular salivary gland and amputation of lower incisors. It is shown that any of these experimental changes in the salivary gland state causes an increase in the stem cell migration and makes lymphocytes more active in inducing the GVH reaction. The ability of spleen lymphocytes to react on additional antigen stimuli increases after amputation of lower incisors, accompanied by an enlargement of salivary glands, and sharply decreases after the removal or burn of the submandibular salivary gland, not causing hypertrophy of salivary glands.


[Effect of palmitoyl-CoA binding with adenine nucleotide translocase on energization of mitochondria]. Under conditions of inhibiting oxidative phosphorylation of oligomycin palmitoyl-CoA (p-CoA) decreases the rate of energy dependent reduction of acetoacetate and Ca2+-capacity of mitochondria in a phosphate medium. Energy independent osmotic swelling of mitochondria in NH4NO3, which depends on H+ permeability of the inner mitochondrial membrane is inhibited by ADP and acclereated by p-CoA. Carnitin and competitive ADP abolish all the effects of p-CoA. It is concluded that decreased energization induced by p-CoA is related to an increase in the inner mitochondrial membrane permeability b- H+ as a result of the inhibitor bindings with adenine nucleotide translocase.


Presynaptic alpha-adrenoceptor blocking properties among tri- and tetra-cyclic antidepressant drugs. 1 The effect of various antidepressants (5 x 10(-8) to 2 x 10(-5) M) on the resting overflow of tritium, on the evoked overflow and the contractile response to electrical stimulation (2.5 Hz, 2.0 ms) has been determined in mouse vas deferens previously incubated with [(3)H]-(-)-noradrenaline.2 Mianserin and ORG GC 94 produced a concentration-dependent increase of more than two fold in the electrically evoked overflow and the contractile response and, at the highest concentration, slightly increased resting release. These effects were largely unchanged in the presence of a concentration of cocaine effective in blocking noradrenaline uptake (1.1 x 10(-5) M).3 The ability of phentolamine (1 x 10(-5) M) to increase both the evoked overflow of tritium and the contractile response was greatly reduced when these parameters were already elevated by the presence of mianserin or ORG GC 94.4 The inhibitory effect of exogenous (-)-noradrenaline on evoked overflow was greatly reduced in the presence of mianserin or ORG GC 94 (4 x 10(-6) M).5 The inhibitory effect of clonidine on the twitch response of the mouse vas deferens was antagonized by mianserin and ORG GC 94 in a competitive manner (pA(2) values 7.3 and 7.1 respectively).6 Maprotiline, desipramine and nortriptyline (> 3 x 10(-6) M) produced a parallel fall in both evoked tritium overflow and in the contractile response and increased the resting overflow at higher concentrations. These effects were largely unchanged in the presence of cocaine (1.1 x 10(-5) M).7 Doxepin, imipramine and iprindole all increased resting overflow at high concentrations (2 x 10(-5) M) but produced only small changes in evoked overflow and in the contractile response at lower concentrations.8 It is concluded that mianserin and ORG GC 94 produce a blockade of presynaptic alpha-adrenoceptors which could contribute to an antidepressant effect but that this type of action is not common to all antidepressants.


Amino acids as neurotransmitters of corticofugal neurones in the rat: a comparison of glutamate and aspartate. 1 The relative sensitivities to aspartate and glutamate of neurones receiving a corticofugal innervation were examined by microiontophoresis, and compared with the relative sensitivities of neurones not appearing to receive such an input.2 On all the cells tested, glutamate appeared to be a more potent excitant than aspartate in terms of neuronal response size or effective dose.3 DL-alpha-Aminoadipate (alphaAA) reduced the excitatory amino acid responses on all the neurones tested. On many of these cells a control excitation could be produced, by acetylcholine or hydrogen ions, which was in most cases unaffected by doses of alphaAA producing antagonism of amino acid excitation.4 On 70% of the cells, aminoadipate showed no selectivity for aspartate compared with glutamate but a differential action, involving blockade of aspartate but not glutamate, was apparent on the other 30%.5 Doses of alphaAA which selectively reduced responses to aspartate had no effect on short latency evoked spikes, but doses which also reduced responses to glutamate reduced the short-latency synaptic excitation induced by electrical stimulation of either the surface of the cerebral cortex, or of the pyramidal tracts in the medulla.6 These findings suggest that corticofugal neurones having an excitatory action on cells in various parts of the brain may use an amino acid, probably glutamate, as a common neurotransmitter.7 As no significant difference could be demonstrated in the potency ratios of glutamate:aspartate on monosynaptically activated cells compared with other cells, doubt is cast on the validity of drawing conclusions about transmitter identity from potency ratios alone, without the support of antagonist studies.


Selective antagonism by benzodiazepines of neuronal responses to excitatory amino acids in the cerebral cortex. 1 The recently discovered benzodiazepine receptor exists in high concentration in the cerebral cortex. We have, therefore, examined the effects of diazepam and chlordiazepoxide on cortical neurone responses to excitatory and inhibitory amino acids and acetylcholine, in the cortex of rats anaesthetized with urethane.2 Chlordiazepoxide applied by microiontophoresis reduced the responses to glutamate and aspartate but acetylcholine responses were unaffected on most cells even by much higher doses of benzodiazepine. gamma-Aminobutyric acid (GABA) and taurine responses were unaffected on most cells, but were reduced on 4 of 25 units. After intravenous diazepam, responses to GABA and taurine were reduced on 3 cells and unchanged on 11.3 On Purkinje cells in the cerebellum a number of cells (5 of 16) exhibited a substantial increase in responses to GABA and taurine following intravenous or iontophoretic application of benzodiazepines.4 It is suggested that the highly selective reduction of excitatory amino acid responses in the cerebral cortex may be of particular relevance to the behavioural effects of benzodiazepines.


A pharmacological analysis of the contractile action of histamine upon the ileal region of the isolated, blood-perfused small intestine of the rat. 1. The mode of action of histamine was investigated on the rat isolated small intestine perfused at a fixed flow rate through the superior mesenteric artery with blood from the carotid artery of a heparinized donor rat. Compounds were closely injected into the superior mesenteric artery. 2. Increasing doses (1 to 100 micrograms) of histamine caused a monophasic fast contraction of the ileum. 3. The fast contraction was abolished by tetrodotoxin, hexamethonium, morphine or mepyramine, but was not prevented by atropine. 4. The present study indicates that histamine produces the fast contraction of the ileum by primarily acting on the myenteric nerve plexus involving cholinergic interneurones.


Activity, depression, medication and performance on the Revised Kendrick Battery. A theory for the cognitive assessment of the elderly has been previously reported (Kendrick, 1972), in which it was predicted that normal and depressed subjects would not differ on cognitive tests unless 'pseudodementia' was indicated. Recent studies involving the Revised Kendrick Battery have led to a modification of the theory. The theory now has to take into account the effects of activity and medication, the former enhancing performance, the latter decreasing it. The previous studies (Kendrick & Post, 1967; Kendrick, 1972), have been re-examined and explanations given for the differences found between studies.


Adverse reactions to drugs in general practice. Of 817 patients in a general-practice survey of adverse reactions to drugs, 41% were thought to have "certainly" or "probably" had a reaction to the drug prescribed. Adverse effects on the gastrointestinal and central nervous systems were the most frequently reported, and 90% of reactions had occurred by the fourth day of treatment. More patients given drugs acting on the central nervous system and antihistamines reported reactions than those in other categories. A higher incidence of adverse drug effects is shown in this general-practice survey than in other, mainly hospital-based, surveys. Further intensive surveillance for adverse effects of drugs is recommended to provide additional information on the burden of drug-induced disease in the community.


Effect of ergocristine on prolactin secretion in the male rat with pituitaries grafted beneath the kidney capsule. Male rats in which three pituitaries were grafted beneath the kidney capsule showed approximately a fourfold increase in circulating plasma prolactin concentration. The elevated plasma prolactin concentration did not remain at a constant level but fluctuated with time. The elevated prolactin concentration declined immediately after a single bolus injection of ergocristine (30 micrograms/kg). The slope of the prolactin decay curve, determined by sequential blood sampling, was parallel to a theoretical slope having a 7-min half-life. This result indicates that ergocristine blocked prolactin secretion immediately and completely as the decay curve (T 1/2 = 6.5 min, confidence interval 4.5--11.3) resulting from the administration of ergocristine is the same as the endogenous prolactin decay curve (T 1/2 = 7 min).


Effects of microiontophoretically applied flurazepam on responses of cerebral cortical neurones to putative neurotransmitters. Utilizing standard microiontophoretic techniques and recording extracellularly in cats, we studied the effects of flurazepam, a water-soluble benzodiazepine, on the spike activity of single cerebral neurones and its interactions with several excitatory and inhibitory putative neurotransmitters. Large iontophoretic doses (5--30 nA, 0.1 M solution) of flurazepam induced a depression of spike amplitude. Smaller doses (less than 5 nA, 0.1 M solution or 20--50 nA, 20 mM in 0.16 M NaCl) reduced the excitation produced by glutamate, aspartate, and homocysteate, but antagonism of acetylcholine-evoked excitations required large flurazepam doses (up to 30 nA, 0.1 M solution). Even lower doses of flurazepam (less than 10 nA, 20 mM in 0.16 M NaCl) enhanced the inhibitory effect of gamma-aminobutyric acid (GABA) but antagonized that of 5-hydroxytryptamine, and had no effect on dopamine-induced inhibition of firing. Hence, only GABA-evoked inhibitions were significantly potentiated by flurazepam. These results demonstrate the multiple possible interactions between a benzodiazepine and different putative neurotransmitters in the mammalian cerebral cortex.


Use of drugs with dependence liability.

Use of drugs with dependence liability. The term addictive as used by the popular press frequently confuses the more precise concepts of acute and chronic tolerance, physical dependence and withdrawal, and psychologic dependence. Serious physical dependence on psychoactive drugs is rare and is easily managed. In contrast, psychologic dependence, the most important reason for persistent drug use, is much more common and is difficult to treat. Some tactics are available - for example, confrontation and discussion with the patient about how a drug is not going to be effective over long periods. Treating the symptom of a complex problem should, of course, not be expected to solve the problem. The most important tactic is to prescribe dependence-associated drugs only when clearly indicated, when the problem is responsive to drug therapy and for the shortest period necessary, without the option for renewing the prescription. Many problems related to drug use long after the period of expected benefit is past can be avoided by far more restrictive drug prescribing. Barbiturates and nonbarbiturate sedative hypnotics (e.g., ethchlorvynol, glutethimide, meprobamate, methaqualone and methyprylon) should not be prescribed for insomnia, acute reactive anxiety, chronic anxiety neurosis or depressive illnesses, since the safer and equally effective benzodiazepines, which are less associated with dependence, are available.


Neurological soft signs and psychopathology: incidence in diagnostic groups. In earlier studies the authors have reported impairments of cortical function in the parietal and frontal lobes of schizophrenic patients. In this study these results are pursued. The performance of different groups of psychiatric patients with respect to individual neurological soft signs rather than combined cortical function scores, was studied. The potential influence of psychotropic drugs on the significant findings was also analyzed. The results show that specific individual neurologic soft signs are significantly more frequently present in schizophrenics than in either controls or in other psychiatric groups. Additionally, there was no statistical evidence of psychotropic drug effects on the findings.


Pharmacokinetic differences between single and multiple oral dosing with the guidance for beta-adrenoceptor blockade assessment. The disposition profiles of a new beta-adrenergic-blocking drug, timolol, were investigated in healthy subjects after single oral doses, and in patients with mild or moderate essential hypertension given multiple doses. The t1/2 of timolol were different between the two groups, possibly due to the decreased plasma clearance after multiple administration. The dosage regimen calculations for patients indicated to receive the treatment for certain chronic diseases, should be determined by utilizing the disposition data obtained in steady-state conditions. The absolute reduction of exercise heart rate gave the best coefficient as a beta-blockade assessment. Applying a theory for translating the pharmacokinetics to the duration-action course of drug, pharmacokinetic t1/2 was proven to be much shorter than pharmacological t1/2. Timolol given on a twice-daily schedule has shown both antihypertensive effectiveness and plasma-renin-suppressing action in different subject. However, the casual relationship between the drug plasma level, blood pressure fall and change in PRA was not so clearly disclosed. The pharmacokinetics of beta-blockers, particularly with the property of receiving extensive metabolism by the mechanism of hepatic first-pass effect should be studied between single- and multiple-dosing schedules in subjects with diverse clinical conditions.


Capillary filtration coefficient: the technique and its application to the small intestine. In this review, we discuss the physiological basis of the capillary filtration coefficient (Kf,c), and its measurement in the small intestine. First the various techniques by which Kf,c can be measured are discussed and assessed; the second part of the review considers the volumetric method of determining Kf,c in more detail, in an attempt to identify the causes of variability in published values for intestinal Kf,c. Finally, we discuss changes in intestinal Kf,c due to sympathetic nerve stimulation and the administration of drugs and hormones. The majority of estimates of intestinal Kf,c are about 0.38 to 0.60 (innervated) to 0.60 to 0.75 (denervated) cm3 . min-1 . kPa-1 . 100g-1. These values are increased by most vasodilator drugs and hormones, and decreased by sympathetic nerve stimulation and by vasoconstrictor drugs.


Presence in human epidermal cells of a soluble protein precursor of the cross-linked envelope: activation of the cross-linking by calcium ions. Late in the terminal differentiation of epidermis and cultured epidermal cells, a protein envelope located beneath the plasma membrane becomes cross-linked by cellular transglutaminase. The process of cross-linking can be initiated in cultured epidermal cells by agents affecting cell membrane permeability--nonionic detergents, high salt concentrations and ionophores. These agents initiate the cross-linking process by making calcium ions available to the transglutaminase. A soluble precursor of the cross-linked envelope has been identified in crude extracts of cultured epidermal cells by its ability to incorporate labeled amines through the action of transglutaminase. The protein has been purified to homogeneity by gel filtration and chromatography on columns of DEAE-cellulose and hydroxyapatite. Comprising an estimated 5--10% of the soluble cell proteins, it has a molecular weight of about 92,000, is isoelectric at pH 4.5 +/- 0.3 and has an unusual amino acid composition (46% Glx residues). It is chemically and immunochemically unrelated to keratins. The following evidence confirms that the protein becomes incorporated into cross-linked envelopes: first, washed cross-linked envelopes bind antibody to the purified protein, as shown by indirect immunofluorescence; second, absorption of the antiserum with washed envelopes removes all detectable antibodies to the purified protein; and third, the protein cannot be extracted from keratinocytes after their envelopes have become cross-linked. Examination of sections of epidermis by immunofluorescence, using antiserum to the purified protein, reveals that in addition to the stratum corneum, the living cells of the outer half of the spinous layer react strongly. The envelope precursor is present in the cytoplasm, but becomes concentrated at the cell periphery, where it will be cross-linked later, when the cells have passed through the granular layer. The protein is also concentrated in a peripheral location in cultured epidermal cells.


[Comparison of glutamate dehydrogenase and glutamine synthetase activities in the roots and aerial organs of an obligate halophyte: Suaeda maritima var. macrocarpa and a glycophyte: Phaseolus vulgaris, grown in presence of different concentration of NaCl]. The glutamate dehydrogenase and glutamine synthetase activities of an obligate halophyte, Suaeda maritima var. macrocarpa and a glycophyte. Phaseolus vulgaris are compared in function of salinity (increasing concentrations of NaCl) of the culturing solution. In culture, addition of NaCl stimulates glutamine synthetase activity and lowers glutamine dehydrogenase activity in the aerial organs and in the roots of Suaeda as opposed to what is observed in the glycophyte. Hence the obligatory halophily of Suaeda is related to an increase of the glutamine synthetase activity in a sal-trich medium corresponding to the stimulation of nitrate reductase and proteogenesis.


A new phosphatase of human platelets.

A new phosphatase of human platelets. Human platelets contain a phosphatase, which has a pH optimum at 7.0. Ethylenediamine tetraacetate and citrate at 0.01 mol/l concentration and Mg2+ at 0.002 mol/l concentration respectively bring about 7.7-, 3.6- and 2.1-fold increase in its activity. It is thermolabile. About 70% of its activity is lost when held at 50 degrees C for 10 min at pH 7.5. On electrophoresis through polyacrylamide gel at pH 8.3, about 87.8% of the total activity remained at the origin and the rest migrated toward the anode. Sodium chloride, potassium chloride, sodium phosphate, ouabain in the absence or presence of K+, potassium tartarte, phenylalanine, sodium fluoride have no effect on its activity. Urea at 1 mol/l and 0.5 mol/l concentrations respectively inhibited about 76% and 28% of its activity. It has the highest preference for p-nitrophenyl phosphate. Its Km and Vmax respectively are 5.7 x 10(-4) mol/l and 2.9 mumol . min-1. Its activity on beta-glycerophosphate is about 0.7% of that on p-nitrophenylphosphate. Its activity on ribo- and deoxyribonucleotides ranges from 0.4% to 3.0% of that on p-nitrophenylphosphate. Its maximum stimulation by EDTA, its non-dependence on K+ and its insensitivity to inorganic phosphate and ouabain, make human platelet neutral phosphatase herein described, distinct from the membrane bound neutral phosphtases so far reported.


Sleep-wake patterns and integrated values of luteinizing hormone, follicle stimulating hormone, prolactin, growth hormone and thyroid stimulating hormone in normal and cryptorchid pubertal patients. The sleep-wake behaviour of LH, FSH, PRI, GH and TSH was studied in seven cryptorchid patients (four unilateral and three bilateral cryptorchids) average age 12 years and in nine normal pubertal boys of 13 years (mean age). Blood samples were collected by a continuous withdrawal pump, every hour, for 24 h. The hormonal concentration for every fraction of time was measured and related to the sleep (Sc-), wake (Wc-) and total 24 h period (Dc-). The integrated concentrations of the corresponding periods (IS, IW, ID) were calculated as well as their ratios (IS/IW; IS/ID%). For GH and TSH, the data obtained demonstrated no differences between cryptorchid and pubertal subjects. The PRL secretion in cryptorchid patients was moderately increased during the hours of nocturnal sleep. A normal pubertal sleep-wake rhythm was found for gonadotrophins in both groups of subjects. More marked levels of LH secretion were observed in cryptorchid boys compared to normal pubertals. The presence of a sleep-wake rhythm was also found in the cryptorchid patients and normal pubertal subjects in the P 1 stage. These data suggest that the CNS "programme" which controls the onset of puberty may be normal in cryptorchid patients.


Human amniotic fluid alpha-L-fucosidase. The activity and properties of alpha-L-fucosidase in 24 samples of amniotic fluid have been investigated using the 4-methylumbelliferyl substrate. A wide range of fucosidase specific activity (0.20-1.45 nmol/min/mg protein) was found with an average value of 0.62 nmol/min/mg protein. Although no clear-cut correlation exist, there appear to be trends of decreasing fucosidase specific activity with increasing maternal age of donor and increasing gestational time. alpha-L-Fucosidase activity from four amniotic fluids was characterized kinetically and immunochemically and found not to differ in its properties due to maternal age of donor or gestational time. Isoelectric focusing revealed multiple forms between pH 5.0 and 6.8, with the majority of activity present between pH 5.0 and 6.0. The pH optimum is near pH 5.0 with a second optimum suggested at pH 6.2. The apparent Michaelis constant (Km) for the 4-methylumbelliferyl substrate is 0.05 +/- 0.01 mM. The enzyme is completely thermostable at 37 degrees C for at least 4 h but loses 95% of its activity after preincubation at 45 degrees C for 1 h. Double immunodiffusion and immunoprecipitation experiments using anti-liver alpha-L-fucosidase antibody suggest that the amniotic fluid alpha-L-fucosidase is antigenically similar, if not identical, to the human liver enzyme.


The in vivo examination of the irreversible beta-adrenoceptor antagonist Ro 03-7894 on cardiac rate and contractility. 1. Two benzofuran-2-ethanolamines Ro 03-5255 (1-(5-acetylamino-benzofuran-2-yl)-1-hydroxy-2-isopropylaminoethane) and Ro 03-7894 (1-(5-chloracetyl aminobenzofuran-2-yl)-1-hydroxy-2-isopropylaminoethane) which had previously been shown to exhibit respectively competitive and irreversible beta-adrenoceptor antagonism in guinea-pig isolated atria, were compared in vivo using isoprenaline-induced tachycardia of anaesthetized guinea-pigs and heart rate and contractility (dp/dtmax) of open-chest anaesthetized guinea-pigs and of conscious cats. 2. In urethane-anaesthetized guinea-pigs doses of 3 mg/kg, s.c. of both antagonists produced significant blockade of the rate response to an 80% of maximum dose of isoprenaline after 4 h. In other experiments, guinea-pigs were pretreated with the antagonists and the responses to isoprenaline were then monitored. The slopes of the dose-response curves to isoprenaline were depressed for up to 24 h by Ro 03-7894 but this was not so with Ro 03-5255. 3. In conscious cats the course of blockade by Ro 03-7894 was followed in the same animals and was still evident after 48 h. In contrast, the beta-adrenoceptor blockage produced by Ro 03-5255 was not evident 24 h after administration. 4. The persistence of blockade by Ro 03-7894 was consistent with the irreversible mode of action demonstrated in vitro.


The effect of pentobarbitone on plasma and intracellular sodium, potassium and pH in rabbit cardiac and skeletal muscle. 1. Pentobarbitone anaesthesia, in rabbits, produces (i) hypokalaemia, (ii) increased intracellular potassium and reduced intracellular sodium in cardiac and skeletal muscle. 2. These changes suggest that the hypokalaemia which accompanies anaesthesia results from movement of potassium between the extracellular and intracellular compartments.


Pheochromocytoma--recognition and management. Pheochromocytoma is an infrequent cause of hypertension. In spite of its rarity, pheochromocytoma has assumed notorious importance because or a wide variety of clinical features associated with this syndrome. Hypertension remains the most important clinical lead. The presence of other features, such as severe headache, perspiration, palpitations or orthostatic hypotension, makes the diagnosis of pheochromocytoma likely. The diagnosis of this condition can be made with greater certainty than that of any other form of secondary hypertension. Pharmacologic tests are no longer used for evaluation purposes. Biochemical tests are the most important aids to diagnosis, provided highly specific methods are used to determine the levels of urinary catecholamines or their metabolites. Interference by various drugs should be avoided. Most of the pheochromocytomas are found in the abdomen, predominantly in the adrenals. Successful outcome of surgery depends critically on adequate preoperative preparation of the patient with adrenergic blocking drugs and proper intraoperative care. Surgery should only be performed in an institution with experience in treating these tumors. Invasive localizing procedures could be dangerous in patients with pheochromocytoma and are best avoided. Medical therapy proves to be quite successful for those patients who are unable or unwilling to undergo surgery and for those with demonstrated malignant tumor. The postoperative course in most instances is uneventful. The physician should be aware of familial forms of pheochromocytomas and screen all the hypertensive members of the patient's family for the presence of this condition. Pheochromocytoma, with its multiple facets, presents a challenge to the clinician; however, with prompt diagnosis and proper treatment, pheochromocytoma can often be cured. The improved management of patients with this potentially lethal condition is the result of better knowledge of biochemical pharmacology, improved preoperative, surgical and postoperative care.


Diffusion of beta-lactam antibiotics and fosfomycin to interstitial tissue fluid in rabbits. The ability of seven antibiotics (carbenicillin, cloxacillin, ampicillin, cephalothin, cephaloridine, cefoxitin and fosfomycin) to enter interstitial tissue fluid was evaluated. Using rabbits with implanted subcutaneous chambers, antibiotics were given intramuscularly as a single dose of 15 mg/kg, and antibiotic levels in serum and interstitial fluid of the chambers were determined at variously scheduled times after injection. The results indicated that antibiotic concentrations in the two compartments did not run parallel. The pharmacokinetic analysis showed that, in general, antibiotic diffusion from blood to interstitial fluid increased with the concentration gradient and the serum half-life, and there was an inverse relationship to pKa, protein binding and molecular weight of the antibiotic.


The relationships between the cardiovascular effects, alpha- and beta-adrenoceptor blocking actions and plasma concentration of labetalol in doca hypertensive rats. The relationships between the cardiovascular effects, alpha- and beta-adrenoceptor blocking actions and plasma concentration of labetalol have been examined in conscious DOCA hypertensive rats. Labetalol (10, 30 and 100 mg/kg p.o.) reduced resting heart rate; blood pressure was reduced only by the two higher doses. The effects lasted 5-24 hours. There was a highly significant correlation between the plasma labetalol concentration and its cardiovascular effects. During the labetalol-induced hypotension and bradycardia the vasopressor responses to intra-arterial injections of phenylephrine were reduced; the tachycardia and vasodepressor responses produced by intra-arterial injections of isoprenaline were also reduced. It is concluded that alpha- and beta-adrenoceptor blockade probably account for the labetalol-induced decreases in resting blood pressure and heart rate respectively.


[Long-term suppression of H+ secretion through a combination of cimetidine and methanthelinbromide (author's transl)]. Inhibition of acid secretion was investigated in 5 patients with Zollinger-Ellison syndrome and 12 patients with duodenal ulcer after administration of 200 mg cimetidine alone and combined with 50 mg methanthelinebromide. A preinvestigation of 5 patients had not shown any significant decrease of acid secretion after 50 mg methanthelinebromide alone. Compared with a single dose of 200 mg cimetidine, combined drugs' use (200 mg cimetidine and 50 mg methanthelinebromide) led to significant increase of inhibition of secretion both as regards degree and duration. In 6 patients with duodenal ulcer basal secretion of more than 2.0 mmol H+/h 200 mg cimetidine led to inhibition of secretion by 91.4% over 120 min compared to 96.4% over 225 min after combined administration. Similar results were obtained in 6 patients with a basal secretion of less than 2.0 mmol H+/h.


[Studies about influence of food on gastroesophageal reflux. I. pH measurements before and after standardized meal (author's transl)]. Continuous pH measurements were undertaken by 87 patients (17 without, 30 with small, 40 with heavy symptons of reflux) for the study of gastroesophageal reflux 1 hour before and after standardized meal. A significant increase of reflux was shown by 19 patients with reflux under dry conditions, whereas reflux was demonstrated by 47 patients for the first time. After meal provocation of reflux was shown by patients with typical symptoms of reflux. An increase of reflux was shown the heavier reflux sumptoms were. pH measurements of gastroesophageal reflux seem to improve the evidence of results after such standardized meal.


[Effect of antimacrophage serum on the graft vs. host reaction in F1 hybrid mice]. The author carried out experiments on 100 one-week old F1 hybrids (BALB-C C57-BL) and succeeded to obtain moderately manifested CvH reaction, injecting them with peritoneal macrophages from one of the parent's lines-BALB-C, immunized preliminary with lymphocytes from other parentalline. Preliminary incubation of macrophages with AMC without participation of compliment did not affect significantly the manifestations of GvH reaction, while successive incubation of macrophages with AMC and compliment inhibited completely the ability of the cells to induce GvH reaction. This effect was in correlation with the vitality of the cells.


[Chronology of the extrapyramidal effects of neuroleptics, and the nigrostriatal dopaminergic system]. Authors after analysis of the data in literature describe the chronologic appearance of the extrapyramidal effects of neuroleptics. In order to restore a neurophysiological coherence to dissimilar or even contradictory clinical emergences this sequence is analysed in function of the actual data, relative to the mechanism and to the modalities of adaptation of the dopaminergic synapse of the nigro striatal system.


[Tardive dyskinesia induced by neuroleptics. A review of the literature]. Neuroleptics can induce not only early but also tardive extrapyramidal side effects. The former were described as early as in the beginning of the therapeutic era; the latter, known as tardive dyskinesia, are essentially made of bucco-linguomasticatory dyskinesia, sometimes accompanied by other extrapyramidal symptoms, among others choreo-athetoid movements of the limbs. This complication was most often reported in elderly people, when a long-lasting neuroleptic treatment is withdrawn; but it can also appear in young people and after a neuroleptic treatment of only a few weeks duration. The trouble occurs or is worsened when neuroleptics are withdrawn and is reduced when dosage is increased; it responds to the theoretical model of denervation supersensitivity. Symptoms may be reduced by blocking the dopaminergic receptor, or by reducing dopaminergic transmission, or, may be, by increasing cholinergic activity. Now, treatment is first and foremost prevention.


Changes of serum testosterone and of LH-RH test after treatment of cryptorchidism by intranasal LH-RH. The aim of the present investigation was to study, in a collaborative double-blind study, the treatment with intranasal LH-RH application of boys aged 1 1/2 to 12 years, who suffered from unilateral or bilateral cryptorchidism. A total of 88 subjects were randomly and blindly allocated to LH-RH and placebo therapy. Before and after 4 weeks of treatment basal testosterone serum levels were estimated and LH-RH tests were performed. Intranasal treatment with LH-RH resulted in partial or complete descents of testes in 23 out of 88 patients, whereas the position of testes remained unchanged in 17 subjects. 42 boys did not respond to placebo therapy, but complete descents were observed in 6 boys of the placebo group. Hormone analysis data of 4 different laboratories were recorded and statistically evaluated. No changes of LH, FSH and testosterone were found in the placebo groups. Only patients of the Frankfurt group responded to LH-RH test with augmented LH release after therapy (P less than 0.05). All patients treated with intranasal LH-RH showed a significant decrease of FSH release after therapy (P less than 0.05 to P less than 0.01). Basal testosterone serum levels were found to be increased after therapy only in the patients treated at Zürich (P less than 0.05). Data of the present study combine to suggest that chronic application of LH-RH may result in an overstimulation phenomenon, and that LH-RH test as well as basal testosterone levels cannot be used as prognostic index of therapy efficacy.


Developmental studies on gamma-glutamyl transferase in rat intestinal mucosa. The activity of gamma-GT in rat intestinal mucosa has been studied during normal development. No significant differences in enzymatic activity have been recorded between 21-day-old fetuses, neonates tested at 3, 10, 20 and 30 days and older animals (65 days). Only in the period immediately prior to birth did the liver gamma-GT display activity levels similar to those of intestinal gamma-GT. In neonates and in adult rats, the intestinal gamma-GT activity was much higher as compared to the enzymatic activity in the liver, possibly revealing a species feature in rats. The results of the studies show that the rat is particularly suitable for experimental studies on intestinal gamma-GT in pathological conditions.


Characterization and physiological function of rat renal gamma-glutamyltranspeptidase. Rat renal gamma-glutamyltranspeptidase is an intrinsic membrane glycoprotein. The larger of its two subunits is apparently folded into two distinguishable domains which are separated by a protease-sensitive sequence of amino acids. Membrane binding of gamma-glutamyltranspeptidase results from the hydrophobic interaction of the nonpolar domain of the amphipathic subunit with the lipid bilayer. Localization of at least a portion of the gamma-glutamyl binding site on the smaller subunit limits the active site of the enzyme to one side of the membrane. Within the kidney, the enzyme is primarily associated with the luminal surface of the brush border membrane of the proximal straight tubule. Comparison of the kinetic properties of gamma-glutamyltranspeptidase with the pH and the substrates available within the tubular fluid suggests that the physiologically significant reaction catalyzed by the transpeptidase is the hydrolysis of glutathione and its S-derivatives. The glutathionemia and glutathionuria observed in a patient who lacks detectable gamma-glutamyltranspeptidase activity and in mice following specific inhibition of transpeptidase, support the hypothesis that the enzyme plays a major role in glutathione catabolism. It now appears that the activities attributed to the gamma-glutamyl cycle do not participate in amino acid transport, but instead constitute three separate metabolic pathways; the intracellular synthesis of glutathione, the intracellular degradation of gamma-glutamyl peptides and the extracellular hydrolysis of glutathione. The finding that various cells release reduced and oxidized glutathione indicates that glutathione turnover may be a process of intracellular synthesis, excretion and extracellular degradation.


The peroxidase activity of rat uterus.

The peroxidase activity of rat uterus. The peroxidase activity in the uterine extract of rats previously given a low dose of oestradiol has been examined. From sexually mature rats, two peroxidases of apparent molecular weights of 92 000 (peroxidase I) and 40 000 (peroxidase II) and of different mobilities in polyacrylamide disc gel electrophoresis were found. The two peroxidases were separated and characterized in terms of their substrate specificities, kinetics, pH optima for activity, inhibitors and stabilities. Both enzymes appeared to be classic haemoprotein peroxidases of very similar properties. Peroxidase II was further purified.


Stearolyl-CoA desaturase: a control enzyme in hepatic lipogenesis. 1. Hepatocytes were isolated by perfusion of the liver with collagenase/salt solutions and incubated in culture after attachment to plastic culture dishes for periods up to 48 h. 2. The cells, when incubated in serum-free culture medium in the presence of insulin, showed enhanced stearolyl-CoA desaturase activity which was not observed when 50 muM cycloheximide was included. When insulin was omitted from the medium, the cells lost 80% of their original desaturase activity. 3. Cells isolated from animals fed 20% (w/w) sucrose for two weeks prior to sacrifice, showed high levels of fatty acid synthesis, stearolyl-CoA desaturase activity and triacylglycerol synthesis when compared with cells isolated from animals fed a corn oil supplemental diet. 4. The observations are discussed in terms of the influence of stearoyl-CoA desaturase activity on hepatic lipogenesis.


The control of lipogenesis by dietary linoleic acid and its influence on the deposition of fat. The replacement of dietary starch by sucrose results in an increase in hepatic lipogenesis in the rat. When corn oil (4% by weight or 9% of the energy content of the diet) was included with the sucrose (20% by weight, 20% of the energy content) the lipogenic effect of the sucrose was completely suppressed. In contrast, when beef tallow replaced the corn oil, the induced activity caused by the sucrose was reduced by only approximately 20%. No significant differences were observed between males and females. These diets containing sucrose supplemented with either 4% (w/w) corn oil or 4% (w/w) beef tallow, were then used to ascertain whether or not the effects on hepatic lipogenesis were reflected in changes in the amount of fat deposited during growth from 4--24 weeks of age. It was shown that the percentage body fat was only statistically different (P less than 0.05) when animals fed sucrose-supplemented diets were compared with animals fed diets supplemented with sucrose and beef tallow. However, there were no significant differences in total carcass weight of these rats. The results are discussed in terms of the relative contribution of liver and adipose tissue to total lipogenesis and the factors which control the lipogenic activity in the two tissues.


Thymidylate synthetase from Escherichia coli K12. Purification, and dependence of kinetic properties on sugar conformation and size of the 2' substituent. Thymidylate synthetase from Escherichia coli K12 has been purified 3600-fold by a series of chromatographic procedures. The final preparation had a specific activity of 1.47 units/mg protein and was approximately 80% pure. The enzyme is a dimer of relative molecular mass, Mr, 64000 composed of two subunits of Mr 32,000 each. Its isoelectric point is 4.7 and it is stimulated by Mg2+. Michaelis constants for (+)5,10-methylene-5,6,7,8-tetrahydrofolate [(+)CH2H4folate] were 0.014 mM in the case of methylation of 2'-deoxyuridine-5'-phosphate (dUMP) and 0.55 mM when it served as methyl-group donor for 2'-fluoro-2'-deoxyuridine-5'-phosphate (dUflMP); the corresponding Km values for dUMP and dUflMP were 0.01 mM and 0.11 mM, respectively. The activation energies for the two reactions were found to be 72.8 kJ/mol (methylation of dUMP) and 66.1 kJ/mol (methylation of dUflMP). The data support a recognition mechanism between thymidylate synthetase and that fraction of the nucleotide the sugar moiety of which is in the 2'-endo-3'-exo conformation.


Complete inactivation and labeling of methionyl-tRNA synthetase by periodate-treated initiator tRNA in the presence of sodium cyanohydridoborate. Methionyl-tRNA synthetase from Escherichia coli can react with periodate-treated tRNA to form a Schiff's base through the epsilon-amino group of a lysine within the enzymic active center and the 2',3'-aldehyde groups created at the 3'-terminal ribose of tRNA. At alkaline pH, the Schiff's base equilibrium can be continuously and specifically displaced by reduction in situ with sodium cyanohydridoborate, which on the other hand leaves intact the reacting aldehyde groups of oxidized tRNA. The effects of temperature, pH and of reducing agent concentration on the rate and extent of reduction of the Schiff's base are analysed. Conditions are described (37 degrees C, pH 8.0, in the presence of 1 mM cyanohydridoborate) which allowed rapid and complete conversion of the monomeric trypsin-modified methionyl-tRNA synthetase into its 1:1 covalent complex with tRNAfMet.


Crystallization and properties of cathepsin B from rat liver. Cathepsin B from rat liver was purified to apparent homogeneity by cell-fractionation, freezing and thawing, acetone treatment, gel filtration, DEAE-Sephadex and CM-Sephadex column chromatography, and was crystallized. The purified enzyme formed spindle-shaped crystals and its homogeneity was proved by disc gel electrophoresis in the presence of sodium dodecyl sulfate and by ultracentrifugal analysis. Its s20,w value was 2.8 S and its relative molecular mass was calculated to be 22,500 (+/- 900) by sedimentation equilibrium analysis. Crystalline cathepsin B was shown to consist of four isozymes with isoelectric points between pH 4.9 and 5.3, the main isozyme having an isoelectric point of pH 5.0. The enzyme was irreversibly inactivated by exposure to weak alkali. The pH optimum was 6.0 with alpha-N-benzoyl-DL-arginine-4-nitroanilide as substrate. Amino acid analysis showed that the enzyme contained hexosamine, glucosamine and galactosamine. Cathepsin B inactivated aldolase, glucokinase, apo-ornithine aminotransferase, and apo-cystathionase, but the rates of inactivation of glucokinase, apo-ornithine aminotransferase, and apocystathionase were lower than that of aldolase. Studies by polyacrylamide gel electrophoresis in the presence and absence of sodium dodecyl sulfate showed that cathepsin B degraded apo-ornithine aminotransferase to two polypeptide chains differing in relative molecular mass and electrophoretic mobility.


A pathway of polygalactosamine formation in Aspergillus parasiticus: enzymatic deacetylation of N-acetylated polygalactosamine. 1. An enzyme which hydrolyzes the acetamido groups of N-acetylgalactosamine residues in N-acetylated polygalactosamine was found in the supernatant fraction of Aspergillus parasiticus AHU 7165, a polygalactosamine-producing strain. 2. N-Acetylated polygalactosamine was used as a substrate in the purification and characterization of this enzyme. A 140-fold purification was obtained by means of ammonium sulfate fractionation followed by chromatography on carboxymethylcellulose and DEAE-cellulose. 3. The enzyme releases about 60-70% of the acetyl groups of N-acetylated polygalactosamine, giving a product with free amino groups. Whereas the enzyme also deacetylates oligosaccharides with 14 or more N-acetylgalactosamine units at a rate similar to that of deacetylation of the polymer, it deacetylates shorter oligosaccharides (trimer to hexamer of N-acetylgalactosamine) much more slowly and is virtually inactive toward disaccharide. Deacetylation can not be detected with bacterial cell wall peptidoglycan, N-acetylated heparin, partially O-hydroxyethylated chitin or monomeric N-acetylgalactosamine derivatives as substrates. 4. This enzyme shows double pH optima of 5.3 and 9.3. The Km value for N-acetylated poly-galactosamine is 0.15 g/l (or 0.54 mM with respect to monosaccharide residues). 5. The occurrence of this enzyme may account for the formation of polygalactosamine with free amino groups.


Pretest activity and intellectual performance in middle-aged and older persons. The present study investigated the effects of three conditions of pretest activity on the intellectual performance of 90 middle aged (50-61) and elderly (62-72) individuals. The Primary Mental Abilities Test was presented under three pretest conditions: physical, mental and physical, and no activity. Multi- and univariate analyses revealed significant age (or cohort) and sex differences in intellectual performance, but no significant pretest treatment effects. These results, when combined with similar recent findings of other investigators, indicate that pretest activity effects are less powerful than some widely cited previous research has suggested.


Mechanisms of neurohumoral regulation of heart function in aging. Changes in hemodynamics and myocardial contractile capacity following the stimulation of extracardial nerves and administration of various doses of acetylcholine, norepinephrine, propranolol, phentolamin, atropine, serpasil and benzohexonium were studied in albino rats, rabbits and cats of various age. The shifts in cardiac acetylcholine and norepinephrine content and the activity of some enzymes of their catabolism were determined as well. Functional changes were compared with the structural shifts in intramural nervous system. In old animals there was a rise in threshold of voltage, which induced threshold reaction at stimulation of n. vagus and n. sympaticus and there was a change in heart sensitivity to acetycholine and norepinephrine, propranolol, atropine, serpasil and benzohexonium. A relationship was shown between age changes in nervous regulation of heart and transmitter metabolism. The intensity of acetylcholine and norepinephrine synthesis was decreased in old age, the transmitter metabolism in various parts of the heart was not uniformly altered, the sensitivity of epicardial chemoreceptors to nicotine, veratrum, acetylcholine was increased. The reflexes from cardiac mechanoreceptors were diminished.


Accelerated fall in serum bromide level after administration of perchlorate to man. Five patients intoxicated with bromoureide showed accelerated elimination of bromide from serum after a single dose of perchlorate. It was probably due to increased renal excretion of bromide. Perchlorate has been reported to increase the renal clearance of other monovalent anions by inhibiting their tubular reabsorption and a similar interaction between perchlorate and bromide is suggested. Although perchlorate effectively eliminates bromide it should not replace chloride in the treatment of bromide intoxication, because of the side effects of its repeated administration.


Ganglion blocking properties of some bispyridinium soman antagonists. Various doses of several bispyridinium compounds (HS-6, HI-6, HGG-12, HGG-42, and SAD-128) known to protect animals against the irreversible cholinesterase inhibitor soman were examined to determine their effects on the cardiovascular and respiratory system of cats. Although the potency varied considerably all of the compounds tested lowered the blood pressure, which appeared to be the result of ganglion blocking properties as determined by their reduction of the pressor response to dimethylphenylpiperazinium and the blockage of the contraction of the preganglionically stimulated cat nictitating membrane. Some of the compounds caused cessation of respiration at much lower doses than others but did so at doses greater than those causing ganglion blockage.


Presynaptic noradrenergic alpha-receptors and modulation of 3H-noradrenaline release from rat brain synaptosomes. The depolarization (15 mM K+)-induced release of 3H-NA from superfused rat brain synaptosomes and the effects of alpha-noradrenergic drugs thereon were studied. Noradrenaline (NA; in the presence of the uptake inhibitor desipramine) reduced synaptosomal 3H-NA release. Reduction of the concentration of calcium ions in the medium during K+ stimulation greatly enhanced the sensitivity of 3H-NA release to alpha-receptor-mediated inhibition. Under these conditions NA dose-dependently inhibited 3H-NA release from synaptosomes obtained from cortex or hypothalamus, but did not affect 3H-NA release from striatal (i.e dopaminergic) synaptosomes. Adrenaline, clonidine and oxymetazoline potently inhibited 3H-NA release from cortex synaptosomes at concentrations in the nanomolar range. Phentolamine by itself did not affect synaptosomal 3H-NA release, but antagonized the inhibitory effects of both noradrenaline and adrenaline. The data obtained further substantiate the hypothesis that the alpha-receptors mediating a local negative feedback control of NA release are localized on the varicosities of central noradrenergic neurons, Furthermore, noradrenergic nerve terminals in the hypothalamus appear to be less senstive to alpha-receptor-mediated presynaptic inhibition than those in the cortex.


Acid excretion in young and adult Wistar Kyoto and spontaneously hypertensive rats. Wistar Kyoto rats (WKy), the most widely accepted control for SH rats, show an inability to excrete acid appropriately when compared to another normotensive strain, SD. Coupled with the fact than KWy also develops 'sodium-sensitive' hypertension, this makes them a more complex control than realized. At very young ages (less than 10-week-old), neither SH nor WKy show any deficiency in acid excretion.


Immunological blocking of exogenous and endogenous secretin in the dog. In mongrel dogs with chronic gastric and duodenal fistula the biological activity of secretin on exocrine pancreatic secretion could be blocked by preincubating the secretin injected with rabbit antisecretin antibody. In addition, the activity of endogenous secretin released by acid was markedly reduced by application of antibody. Since no such effect was observed after testmeal stimulation, secretin is most probably not released in a significant amount by the liquid meal used in this experiment.


Antihypertensive and cardiac effects of two novel beta-adrenoceptor blocking drugs. Two new beta-adrenoceptor blocking drugs with acute antihypertensive and positive inotropic effects are described: Compound A (2-[4-(3-tert.butylamino-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole) and MK-761 (2-(3-tert.butylamine-2-hydroxypropoxy)-3-cyanopyridine hydrochloride). In SH rats both compounds, given orally, lowered arterial pressure and were more potent than hydralazine. The antihypertensive effect of compound A but not of MK-761 was antagonized by timolol. Both compounds had positive inotropic activity on cat heart papillary muscles; these effects were antagonized by timolol. The pretreatment of animals with reserpine greatly reduced the positive inotropic effect of MK-761 but not of compound A. The acute antihypertensive and positive inotropic effects of compound A are like to be at least partially due to stimulation of beta-adrenoceptors, e.g. intrinsic sympathomimetic activity. The effects of MK-761 on the same parameters appear to be mediated by different mechanisms.


Effect of centrally active drugs on dopamine oxidation by rat brain catecholamine oxidase. Centrally active drugs of the phenothiazine-, butyrophenone- and iminodibenzyl class markedly decreased the rate of dopamine oxidation in the presence of rat brain catecholamine oxidase.


Increased release of tumour cells by collagenase at acid pH: a possible mechanism for metastasis. The ability of collagenase to disaggregate a solid metastasizing lymphosarcoma has been shown to considerably increase with reducing environmental pH. It is suggested that this effect may be operating in vivo to release cells from a primary tumour.


[Effect of vasocative substances on resistance and capacitance vessels under high altitude conditions]. In cats, i.a. administration of adrenaline (10 microgram), serotonin (30 microgram), and acetylcholine (10 microgram) on the 3rd, 15th, and 30th days of animals stay at 3200 m altitude induced different vasomotor responses in precapillary and postcapillary portions of intestine vascular net during different periods of high altitude adaptation. Changes of reactivity in different receptor structures of smooth muscles, the initial tonus of the small intestine resistance vessels associated with the whole adaptive rearrangement of the organism functional state in the high altitude extreme conditions, are the possible mechanisms of detected changes.


An attempt at isolation and partial characterization of specific antibodies from antithymocyte serum. Specific anti-T antibody was isolated from rabbit anti-mouse and anti-rat thymocyte antiserum on immunosorbent prepared by fixation of brain homogenate in glutaraldehyde. Conditions of isolation, purity of obtained antibody and cytotoxic activity were followed. The resulting preparation containing immunoglobulin G is contaminated with beta globulin and albumin, contains non-precipitating proteins originating from brain tissue and is cytotoxic for thymocytes. Cytotoxicity for bone marrow cells was not demonstrated.


Basal cell carcinoma of the vulva.

Basal cell carcinoma of the vulva. Basal cell carcinoma was found in eight of 61 cases of vulvar malignancy occurring over a 20-year period. This incidence of basal cell carcinoma was 13.1%, higher than the expected 2%-5% reported previously in the literature. Symptoms of a mass, usually discharge, pruritus or bleeding, were commonly ignored for long periods of time by the elderly patient. The specific location and size were difficult to ascertain from hospital records. Therapy is always surgical with wide local excision recommended. Local recurrence will be noted in 10%-20%, as vulvar basal cell carcinoma is a multicentric lesion and, therefore, long-term follow-up, as with any malignancy, is mandatory. Adequate identification and reporting may well show that this lesion is more common than has been previously thought.


Choriocarcinoma associated with thyrotoxicosis: a case report. A woman with disseminated choriocarcinoma and with clinical and biochemical evidence of thyrotoxicosis is described. Only a few cases have been previously reported, and works are referred to showing that high levels of human chorionic gonadotropin (HCG) probably are responsible for the thyroid-stimulating activity in patients with trophoblastic disease and clinical signs of thyrotoxicosis.


Early identification, differentiation and treatment of ovarian neoplasia. Among 3205 patients who needed major gynecologic operations, only 250 (7.8%) had significant ovarian cysts or tumors (170 benign, 38 "low malignant potential," 42 gross cancers). Contrary to prior reports, this study show that most patients with ovarian neoplasia had had some symptoms (duration ranged from two weeks to ten years), or a palpable adnexal mass or both. Associated symptoms have been itemized in categories. Procrastination by patients, after occurrence of the first symptoms, resulted in the growth of later-stage cancers and lower survival rates. It may be inferred from age-incidence graphs that some benign cystadenomas may be present in ovaries for long intervals of time and then may become malignant. The importance of (a) careful recording of histories, (b) periodic pelvic examinations, (c) the use of preoperative methods of differential diagnosis and (d) the differentiation between gross tumor characteristics during operations are discussed. Earlier diagnosis and treatment of ovarian neoplasia are possible and will yield better long-term results.


An ultrastructural and clinical study of theca and granulosa cell tumors. To establish the cell type responsible for the production of estrogens in an ovarian tumor, seven thecomas, three granulosa cell tumors and one fibroma were studied with electron microscopy. The secretion of estrogens by the tumor was determined by measuring the plasma levels of estrogens in the ovarian and cubital veins of some patients and examining the histology of the endometria. Polygonal cells with abundant smooth endoplasmic reticulum (SER) at the ultrastructural level were found in the tumors of patients with clinical signs of hyperestrogenism. It is likely that these cells are the site of steroidogenesis, which is known to be reflected by SER in the cells of the human corpus luteum.


Adenocysitc carcinoma of the uterine cervix: a clinicopathologic study. Eight cases of adenocystic carcinoma of the uterine cervix, a rare histologic variant, are presented, with a brief review of 41 cases previously reported in the literature. They represent only 0.27% of 3254 cervical carcinomas that we encountered between 1962 and 1977. In all eight cases, there was early parametrial involvement, and the majority behaved aggressively. All eight patients were multiparas, and six of them were postmenopausal. Interestingly, including this series, 15 of 49 reported cases of this entity have been from India.


Umbilical mass as a presenting symptom of endometrial adenocarcinoma. A case of an umbilical mass as a primary presenting symptom of otherwise asymptomatic endometrial adenocarcinoma is reported. The pertinent literature is reviewed with regard to the relation of the umbilical mass to metastatic carcinoma.


46,XX gonadal dysgenesis associated with congenital nerve deafness. A sporadic case of a woman presenting with the combination of pure 46,XX gonadal dysgenesis and congenital nerve deafness is reported. A similar association had been reported as a rare familial occurrence. The apparent heterogeneity of phenotypic characteristics among the previously reported individuals and the possible genetic implications are discussed.


Concurrent use of PGF2 alpha, vibrations to the cervix uteri and amniotomy to induce labor after intrauterine fetal death. A triad consisting of (a) prostaglandin F2 alpha infusion, (b) dilation of the uterine cervix by low frequency vibrations and (c) early low amniotomy was used to induce labor in ten women after intrauterine fetal death had occurred. Vaginal delivery was successful in all cases, with a mean induction-to-delivery interval of 5.4 +/- 0.8 hours. Vibratory dilation effectively prepares the cervix for the intense prostaglandin-induced uterine contractions and thereby reduces the risk of cervical laceration and fistula. The dilation of the cervical canal also makes an early low amniotomy possible and easy. This study demonstrates a highly effective, safe and relatively nontraumatic method for uterine evacuation after intrauterine fetal death.


Tubal occlusion via laparoscopy in Latin America: an evaluation of 8186 cases. Ease of performance, safety and effectiveness of laparoscopic sterilization techniques are evaluated for 8186 procedures (6995 interval, 680 postabortion and 511 postpartum) performed in Latin America from June 1972 through February 1978. The tubes were occluded via electrocoagulation or application of the spring-loaded clip or the tubal ring. Less than 1% of the procedures were declared technical failures (ie, those which were not completed as planned). For all the tubal occlusion techniques, interval patients had the lowest rate of surgical complications. Pregnancy rates were low for the electrocoagulation and for the tubal ring techniques; patients sterilized by the spring-loaded clip, however, had a significantly higher pregnancy rate.


Variable X chromosomal abnormalities in patients with stigmata of Turner syndrome. Four cases with suspected sex chromosomal abnormalities and clinical features and endocrine data typical of Turner syndrome are presented. Chromosome preparations made from skin fibroblasts and peripheral blood and multiple banding techniques employed to map the genes of their X chromosomes showed variable results. A review of the literature also revealed conflicting findings regarding the mapping of genes on the X chromosome. Despite different cytogenetic findings, the clinical features of the four cases presented were quite similar.


Hyponatremic fits in oxytocin-augmented labors. Case reports of three patients who had fits as a consequence of hyponatremia are presented. Each patient was in spontaneous labor at term and received conventional doses of oxytocin for augmentation. The pathogenesis, diagnosis and treatment of this entirely iatrogenic condition are discussed. The differences between these and similar cases in the literature are stressed.


A comparative study of labor induced by oral prostaglandin E2 and buccal tablets of demoxytocin. A comparative study of the efficacy of oral prostaglandin E2 and buccal tablets of demoxytocin for induction of labor in overdue pregnancies was made in groups of randomly selected patients. Labor was successfully induced in 95.7% of the women in the prostaglandin group and 92.1% of the women in the demoxytocin group. Although the operative delivery rate was low in both groups, it was significantly higher for the demoxytocin group. A low rate of perinatal distress was recorded and there were no serious side effects in either group. The time from start of induction until delivery, as well as the time from amniotomy until delivery, were compared for primiparae and multiparae separately. No significant differences were found. The blood loss during the third stage of labor was lower in the prostaglandin group. We find oral induction of labor in overdue pregnancies effective, safe and convenient.


A new technique for minilaparotomy.

A new technique for minilaparotomy. Female sterilization by minilaparotomy was performed on 500 patients at Kilpauk Medical College Hospital, Madras, India. Access to the Fallopian tubes was achieved by elevating the uterus with the gloved hand of a medical or paramedical assistant. The effectiveness of the fingers for this maneuver in place of various uterine elevators is discussed and its usefulness pointed out in relation to practive in developing countries. The role of paramedical personnel and the hospital's medical staff, in this technique is described.


The history of pregnancies that occur following female sterilization. Data on 208 pregnancies occurring among 20,749 women following sterilization were collected by the International Fertility Research Program and the histories of these pregnancies from conception to termination were analyzed. In the laparoscopic series, the operator's failure to interrupt the tube by electrocoagulation or a tubal occlusion device was the major reason reported for sterilization failure. In the culdoscopic series, operator error or device deficiency were the major reasons for failure. About three quarters of pregnancies in this study were conceived within the first year following sterilization and were confirmed during the first trimester. The rate of ectopic pregnancy occurring in this series was higher than the rate reported for nonsterilized women and was especially high when electrocoagulation was used.


A survey of sterilization acceptors in a family planning program in rural Bangladesh. The results of a survey of 275 Bangladeshi women who were sterilized at a rural family planning clinic are presented. The survey comprised two interviews of each woman: one conducted immediately prior to the sterilization procedure and the second conducted one month after each woman was sterilized. Sociodemographic data were gathered for the survey from the patients' clinic records. Reasons for the choice of sterilization and sociodemographic impact of the procedure are discussed, as are implications of the results on other rural family planning programs.


Active management of high-risk pregnancy. Sixty patients with previous stillbirths were given active antepartum, intrapartum and early postnatal care. A majority (75%) had a history of repeated stillbirths, and responsible pathology was detected in 55% of the cases. In the present pregnancy, 90% of the patients suffered complications, each of which was diagnosed and treated. Most of the group were hospitalized. Tests for serial urinary estrogens were done for 75% of the women. Other special assessments of maturity with amniotic fluid, oxytocin challenges and fetal monitoring were carried out in selected cases. After confirming maturity and degree of antepartum stress, labor was induced when appropriate. There was liberal recourse to cesarean section (18.3%), but no maternal mortality. Overall fetal salvage was 75%.


Hysterectomy following sterilization.

Hysterectomy following sterilization. In a review of 108 cases of consecutively selected women undergoing hysterectomy for nonmalignant disease, it was found that one third of the patients or their husbands had previously been sterilized. In many instances, the gynecologic problem necessitating hysterectomy antedated the sterilizing procedure. It is postulated that, when couples request sterilization, two operations might be avoided if routine consideration were given to any condition that might lead to hysterectomy.


Diazepam therapy in eclampsia.

Diazepam therapy in eclampsia. The single drug therapy of diazepam can be introduced to effectively control convulsions in eclampsia. This treatment will have particular application in rural obstetrics where eclampsia is seen in severe form. The dose schedule of diazepam, as described in this study, shows the therapy to have a stabilizing effect on hypertension and pulse rate. It causes neither respiratory depression nor oliguria. Diazepam is an effective muscle relaxant. Its depressive effect on the newborn is in no way inferior to that of lytic cocktail therapy. The drug is readily available at low cost, even in the remote rural areas, and can be easily administered by any doctor or midwife.


Breech presentations in a sample of Colombian hospitals. All the breech presentations that occurred in a large sample of data on obstetric deliveries from a random sample of urban hospitals in Colombia are examined. The 463 breeches are analyzed by age and parity of the mother, type of breech presentation (frank or footling) and type of delivery (vaginal or abdominal). The data suggest that abdominal delivery reduces perinatal mortality although cell values are too small to adequately control for birth weight.


The outcome of pregnancies subsequent to induced and spontaneous abortion. A study was made of 8982 women who were admitted for delivery over a four-year period to the University of Benin Teaching Hospital, Benin City, Nigeria. Of the 5682 women who had had more than one pregnancy, 14.5% admitted a history of one or more abortions (spontaneous or induced). Of the whole series, 8.8% admitted having had one or more induced abortions. Patients with prior abortions were compared with selected controls, and maternal characteristics were standardized between the two groups. Undesirable outcomes of subsequent pregnancy, such as low birth weight, premature delivery, stillbirth, neonatal death, miscarriage or congenital malformation, did not seem to increase in patients with histories of abortions.


The effect of a single dose of quazepam (Sch-16134) on the sleep of chronic insomniacs. The present study evaluated the efficacy of 25 mg of quazepam, a new benzodiazepine hypnotic, in a population of chronic insomniacs. The results indicate that a single dose (25 mg) administered for one night was efficacious when measured both objectively by polysomnographic recording and subjectively by questionnaire with no reported side-effects. The change in the objective measures paralleled the direction of change in subjective measures. Sleep efficiency and sleep maintenance were improved without EEG changes in Stages 2, 3-4, and REM. Further study is needed to evaluate the effects of chronic administration of different doses of quazepam in chronic insomniacs.


Pentazocine suppositories versus pethidine injections in 500 patients with post-operative pain. Pentazocine (Fortral) suppositories (50 mg) were compared with pethidine (100 mg) by injection in 500 patients after general and gynaecological surgery. Pain was assessed by patients using a pain thermometer, (a modification of a visual analogue scale), and by observers using an adjectival scale. There was a good relationship between these methods. Good pain relief was obtained with both drugs and there was little difference between the treatments in moderate pain. Pethidine was faster and more effective, particularly in severe pain. There were fewer side-effects with pentazocine suppositories. They are a useful alternative to injections, especially in moderate pain.


Antimicrobial activity of amniotic fluid obtained vaginally. Twenty-nine amniotic fluid samples were aspirated from pregnant women at term (38-40 weeks' gestation) by tapping the bulging membrane vaginally, and their effects on Escherichia coli, Staphylococcus aureus and Candida albicans were studied. Inhibition rates were 72.41% for E coli, 68.96% for S aureus and 79.31% for C albicans. Two samples (6.90%) affected only a single organism, 18 (62.07%) affected two organisms and eight (27.59%) affected all three. Only one sample (3.45%) had no inhibitory effect on the microorganisms studied. Thus, 28 of 29 samples (96.55%) inhibited the growth of at least one of the microorganisms tested. These results are also significant because there is a high risk of contamination of amniotic fluid samples obtained through the vaginal route, although they can be obtained easier that way than through amniocentesis.


Dietary iron intake of pregnant Nigerian women with anemia. The daily dietary iron intake of nine pregnant Nigerian women with confirmed iron deficiency anemia was determined. The daily dietary iron intake from hospital meals served to ten other pregnant women was also assessed to serve as a control. The mean daily iron intake of the group of anemic patients on home diet was 14.6 mg (range of individual means = 8.37-25.28 mg), whereas the group of patients served hospital meals had a mean daily dietary iron intake of 36.92 mg (range of individual means = 25.09-46.47 mg). It is, therefore, clear that the etiology of iron deficiency in the patients studied was mainly dietary. Thus, our pregnant patients, many of whom are on diets similar to those of the group studied, should receive iron supplements during pregnancy.


Should we plan a general childhood vaccination against bacterial meningitis? An estimation of the benefits of vaccination against bacterial meningitis are based on the age-specific incidence of meningitis caused by the different groups of meningococci, by Haemophilus influenzae and by pneumococci, and the known efficacy of the present polysaccharide vaccines against these agents. Since the incidence of bacterial meningitis is more than ten times higher below the age of five years that at a later age, vaccination at 1 1/2 years of age could prevent a large fraction of all cases.


Clinical investigation of serum deoxyribonuclease: I. Analysis of serum deoxyribonuclease activity in comparison with normal and after endoscopic retrograde pancreatography. Serum Deoxyribonuclease (DNase) micro-assay method was developed using 32P-labelled E. coli DNA as substrate. The serum DNase showed maximum activity at pH 7.5. It required Mg+ for activity, and was inhibited by EDTA or EGTA. The enzyme was also inhibited by actin (60-65%) or bovine pancreatic DNase I antibody (40-45%). The serum DNase activity was markedly increased following endoscopic retrograde pancreatography (ERP) examination. These results imply that serum DNase activity is mostly at least 60-65% pancreatic DNase I.


International forum update: depot medroxyprogesterone acetate and endometrial carcinoma. In response to a recent report (Fam Plann Perspect 11: 47, 1979) that two of 12 rhesus monkeys given 50 times the human dose of depot medroxyprogesterone acetate (DMPA), by body weight, for ten years had developed endometrial carcinoma (CA), a retrospective survey of all hospital admissions for proven endometrial CA in two Thai provinces where DMPA contraceptive injections have been widely used since 1965 was made. From 1974 through 1978, 16 women were hospitalized with confirmed diagnoses of endometrial CA. None of the nine women successfully followed up had previously used oral or injectable contraceptives, nor has the recorded incidence of endometrial CA increased in these provinces. Base on the available evidence, the authors conclude that (a) the data on monkeys given very large doses of DMPA for ten years do not apply to women given normal doses of DMPA for prolonged periods and (b) widespread and long-term use of DMPA can and should be continued.


Effects of bucolome and related barbiturate derivatives on the displacement of bilirubin from plasma albumin in vivo and in vitro. Bucolome, one of barbiturate derivatives, lowers plasma bilirubin in Gilbert's syndrome without inductive effect on liver microsomal enzymes. To clarify the mechanism of this action, the study was performed concerning the effects of bucolome and five other closely related barbiturate derivatives including phenobarbital (PB) on plasma bilirubin in homozygous Gunn rats and on albumin-bilirubin binding in vitro. When 15 mg/100 g of bucolome was administered to Gunn rats, remarkable drop in plasma bilirubin continued for more than 48 hrs. This decrease of bilirubin was returned to preinjection level after intravenous injection of albumin. Three Gunn rats died as a result of administration of 30 mg/100 g. This dose caused no pathological change in control rats. In in vitro study, bucolome displaced bilirubin from human albumin strongly. PB had almost no effect on the plasma bilirubin in Gunn rats and the in vitro action was very small. Among the barbiturate derivatives, compounds which have cyclohexyl radicals in N position showed stronger plasma bilirubin decreasing effects in Gunn rats. From these results, a strong action to displace bilirubin from plasma albumin is concluded as the mechanism of bucolome to decrease plasma bilirubin.


Aortitis syndrome associated with ulcerative colitis: report of a case. A 43-year-old Japanese woman with asynchronous onset of ulcerative colitis and aortitis syndrome (Takayasu's arteritis) is reported. The possible relationship between the two disorders is discussed.