Hemodynamic and metabolic changes induced by temporary clamping of the thoracic aorta. Numerous authors reported a significant deterioration of heart function induced by aortic cross-clamping. Nevertheless, the aorta has been clamped during various surgical procedures without any complication. We studied the hemodynamic and metabolic variations induced by 20 min thoracic aorta cross-clamping in 6 open-chest dogs. During clamping the most striking modifications were an increase in coronary blood flow of over 65%, an increase in cardiac work of over 77% and an increase in total peripheral resistances of over 68% compared to base values. No significant variations were found in the heart rate and cardiac index. Metabolic parameters, such as O2 consumption and lactate consumption increased significantly during the clamping period. The increase in lactate consumption and the progressive and continuous improvement in oxygenation indexes (lactate/pyruvate, redox potential, excess of lactate) proved the absence of any myocardial anoxia during this period. Within 15--30 min after declamping all hemodynamic and metabolic parameters reverted to values close to basal values. These data strongly suggest that the mammalian heart can tolerate this procedure satisfactorily for a limited period of time. In clinical settings, one should consider the base conditions of the cardiovascular system before transposing these conclusions.


Climbing behaviour induced by apomorphine in mice: a potential model for the detection of neuroleptic activity. Apomorphine and the putative dopamine agonist, 2-(N, N-dipropyl)-amino-5, 6-dihydroxytetralin induced dose-dependent climbing behaviour in the mouse which was measured in wire mesh lined cages as the percentage of time spent climbing in the 30 min period following the first climb and as the maximum time spent in a single climb throughout the drug effect. These These two measures were generally found to parallel excepting when the interacting agent caused muscular hypotonia. All potential interacting agents were given as pretreatments to determine changes in motor function which may interfere with the climbing induced by 1.0 mg/kg s.c. apomorphine. The possibility of a change in the apomorphine response to a sterotyped biting, which would also interfere with climbing, was also considered. Excluding these non-specific changes, climbing behaviour was shown to be antagonised, dose-dependently, by low doses of typical and atypical neuroleptic agents (haloperidol, fluphenazine, loxapine, pimozide, oxiperomide, clozapin, thioridazine, sulpiride, tiapride and metoclopramide) but not specifically by other psychoactive agents. Climbing behaviour was modified by serotonergic agents; the agonist quipazine reduced or abolished, whilst the antagonists, methysergide and cyproheptadine, enhanced the response. Picrotoxin specifically reduced climbing behaviour but sodium valproate exerted non-specific effects, precluding conclusions as to a GABA involvement. Cholinergic and noradrenergic involvements with climbing were also apparently eliminated by the ineffectiveness of atropine, aceperone, piperoxan and propranolol. The involvement of serotonin with climbing was extended to the actions of the neuroleptics: the antagonistic effects of typical neuroleptics (haloperidol, fluphenazine, loxapine) were markedly enhanced by combination with methysergide or cyproheptadine whilst the effects of clozapine, sulpiride and thioridazine were significantly reduced. The actions of metoclopramide, oxiperomide, pimozide and tiapride were not generally modified by such combinations. These differences are discussed in terms of differential abilities to induce extrapyramidal disturbances and the mouse climbing model is forwarded as a test with potential to detect antipsychotic agents of different activity spectra.


The influence of heart rate on ouabain cardiotoxicity in cats with spinal cord transection. The dose, serum level and ventricular content of ouabain needed to produce cardiotoxicity were examined in control cats, cats with transected spinal cords and cats with transected spinal cords whose heart rates were restored to control values by artificial pacing. The lethal dose of ouabain was higher in cats with transected spinal cords and not paced than it was in the control group. However, the lethal dose of ouabain in spinal-sectioned cats with ventricular pacing was no different from that in controls. However, in both groups of spinal-sectioned cats, death was associated with higher ventricular and serum levels of ouabain than in controls. The ventricular ouabain content of paced animals with transected spinal cords was higher than that of controls and lower than that of unpaced spinal cats. Thus, restoration of heart rate to control levels in spinal animals appeared to accelerate myocardial ouabain uptake. The lower myocardial ouabain content in the spinal-sectioned animals which were paced suggests that pacing sensitizes the heart to cardiotoxicity. Spinal section itself appears to decrease the sensitivity to ouabain partly through a decrease in cardiac rate and partly through a loss of neurogenic influence.


Halothane-induced sleeping time in the mouse: its modification by benzodiazepines. The conditions under which prolongation of halothane-induced sleeping time in the mouse may be used as a test for centrally acting drugs are described. The test can be recommended for its practical advantages over methods using barbiturates to induce hypnosis; due cognizance must be taken of a diurnal variation in the response of mice to halothane. To assess the usefulness of the test the effects of amphetamine, chlorpromazine, histamine, morphine, nikethamide, pentobarbitone and SKF 525A have been investigated. The interaction between 5 benzodiazepines and halothane has been studied in particular. Results from sleeping time experiments, measurements of body temperature and of brain halothane concentrations suggest that the halothane-benzodiazepine interaction is due to additive CNS depressant effects. It was found that nitrazepam and diazepam were clearly more potent than chlorodiazepoxide, medazepam and oxazepam in respect of their interactions with halothane.


Relaxation of depolarized guinea pig taenia caecum induced by some antispasmodics. Taenia isolated from the guinea pig caecum were used for the experiments. No inhibitory response of the depolarized taenia to isoprenaline was observed during the significant increase of cyclic AMP level. These observations suggest that the total tissue level of cyclic AMP is not an important determinant of relaxation in the depolarized taenia. Antispasmodics, such as papaverine, benactyzine and Aspaminol (1,1-diphenyl-3-piperidino-butanol hydrochloride) relaxed the depolarized taenia, while the depolarized taenia was not relaxed by concentrations of dibutyryl cyclic AMP sufficient to relax the polarized taenia. Ca uptake by the depolarized taenia was inhibited by papaverine, benactyzine and Aspaminol but not by isoprenaline and dibutyryl cyclic AMP. These results indicate that relaxation of the depolarized taenia induced by the antispasmodics used was mainly due to inhibition of Ca uptake.


Steric aspects of dopaminergic drugs.

Steric aspects of dopaminergic drugs. There are a variety of molecule species of dopamine avaialable at physiological pH. The predominant form available at physiological pH is the phenolic ammonium salt. However, at the present time the molecular form that is optimum for producing dopaminergic activity is unknown. In attempting to delineate the conformational requirements of dopaminergic agonists, a variety of conformationally restricted analogs and complex molecules possessing a dopaminergic segment have been investigated. It appears at this time that the trans extended form of dopamine is the optimum form for binding to dopamine receptors. The rotameric forms of dopamine are also important considerations when examining a molecule for dopaminergic agonist activity. A high degree of stereospecificity has been shown in different dopaminergic systems.


[Several new inhibitors of gastric secretion]. In experiments on dogs, milid (proglymid) entailed a weak inhibition of the 2nd phase of the gastric secretion leaving intact the 1st phase. The action of LS-519 was obvious in the 1st phase, having entailed a significant inhibition. The glycomacropeptid exerted a strong inhibiting effect both on the 1st and the 2nd phases, the effect lasting longer than that of the first two drugs. All the three drugs not only inhibited the gastric secretion but increased pH, reduced the gastric juice acidity while exerting no significan effect on concentration of common proteinases.


Ergonomics. Reducing mental and physical fatigue in the dental operatory. The work output and the mental and physical fatigue generated by a dental procedure is affected by the length and type of operation, physical facilities, the amount of cooperation given by the patient, operating techniques, and the effective teamwork and rapport of the operatory dental team. Fatigue is also generated by stresses that arise outside of the office and which, when superimposed over the normal operating stresses of the office, can have a cumulative effect of decreasing output and increasing mental and physical fatigue for the dentist, the assistant, and the patient. Probably the three most important means to compensate for both routine and nonroutine physical and mental stresses of any type or origin are: (1) learn to cope with or resolve the origin of the stress; (2) develop a pattern of healthy living; (3) cultivate job satisfaction.


Adenylate cyclase of human gastric mucosa. Stimulation of enzyme activity by histamine and catecholamines. Human gastric mucosal adenylate cyclase has been shown to be sensitive to histamine and catecholamines. Stimulation of enzyme activity by histamine and catecholamines were selectively blocked by cimetidine and propranolol, respectively. Combination of both hormones at maximally effective concentrations were additive, indicating that human gastric mucosa contains at least two separate hormone-sensitive adenylate cyclases.


Fecal chymotrypsin: study on some characteristics of the enzyme. A Lineweaver-Burk plot demonstrated that the apparent Michaelis constants are identical for chymotrypsin (CT) in duodenal juice and in feces of the same patient. CT in fecal homogenates exhibits exhibits a remarkable stability and is bound to particles to a considerable but variable extent. The pH optimum of CT in human feces is somewhat higher as compared to pure bovine pancreatic CT. All measurements of fecal CT activity should, therefore, be performed at pH 9.0. The distribution of CT among the fecal mass has been investigated. There were considerable differences between CT activities in random fecal specimens and in the corresponding stool collections. However, if the results were expressed in terms of 'normal' and 'abnormal', 113 out of 120 random fecal specimens gave the same results as the corresponding stool collections. It is concluded that the risk of 'false-normal' values cannot be effectively reduced by determination of CT outputs in stool collections (or by using continuous markers) instead of CT activities in random stool specimens.


Polyarteritis nodosa causing severe intestinal bleeding. Rupture of an aneurysm of the mesentergic artery caused severe intestinal hemorrhage in a 50-year-old woman with polyarteritis nodosa. Abdominal angiography not only established diagnosis of polyarteritis nodosa by demonstrating multiple visceral aneurysms but also localized the site of bleeding.


Non-beta islet cell tumor calcification assoicated with Zollinger-Ellison syndrome and multiple endocrine adenomatosis. The radiographic triad of a calcified pancreatic mass, duodenal ulcers, and nephrocalcinosis should suggest the Zollinger-Ellison syndrome, as part of the multiple endocrine adenomatosis complex. The clinical and radiographic features of the entity are described in this case report.


Recognition of alcoholic liver disease in a district general hospital. Two-hundred-and-two patients with alcoholic liver disease whose investigations included a liver biopsy were seen in a district general hospital over a seven year period. Thirty-five percent presented with general gastrointestinal symptoms rather than with overt liver disease or previously recognised excess consumption of alcohol. Recognition of the alcohol problem was assisted by the finding of a raised mean corpuscular volume (MCV) and/or gammaglutamyl transpeptidase (GGTP). The use of these methods of detection is discussed in relation to the rapid rise in alcohol consumption in the United Kingdom, and the high mortality of cirrhosis reported from special centres. Twnety-two per cent of the patients were found to have an established cirrhosis, and there was some evidence that the women were more susceptible to some of the toxic effects of alcohol. Early detection can be enhanced by a high level of suspicion, wider recognition of the significance of a high MCV, and the greater use of GGTP estimations.


Postprandial duodenal function in man.

Postprandial duodenal function in man. Duodenal function was studied in 11 healthy volunteers after intragastric instillation of a mixed semi-elemental meal. The duodenum accepted chyme of varying pH, osmolality, and nutrient concentration; and, as a result of biliary, pancreatic, and enteric secretion as well as absorption, it delivered chyme with nearly constant pH, osmolality, and nutrient concentration to the jejunum. The flow rate and nutrient load of jejunal chyme varied. The duodenum absorbed more carbohydrate than lipid and less protein, taking up each nutrient at a constant rate during most of the postprandial period. The percentage of nutrient load absorbed was greatest in the late postprandial period, when flow rate, nutrient load, and concentrations were low.


Acid microclimate in coeliac and Crohn's disease: a model for folate malabsorption. The surface pH of human proximal jejunum was measured in biopsy samples and found to be more acid than the phosphate buffer in which they were incubated. The in vitro jejunal surface pH was 5.93 +/- 0.05 in control subjects and 6.19 +/- 0.09 in treated coeliac patients. A group of untreated coeliac patients with a surface pH of 6.56 +/- 0.14 had a significantly less acid surface pH compared to controls, as did a group of Crohn's patients with a surface pH of 6.21 +/- 0.04. These two groups with a significantly raised surface pH were subdivisible into 'high' and 'low'groups. Surface pH was found to remain low in the treated coeliac and control groups but became more acid over the incubation period reaching almost normal values in the Crohn's group and the untreated coelic initial surface pH. The raised surface pH in untreated coeliac disease and Crohn's disease would alter the amount of a weak acid available for non-ionic diffusion. Therefore the present results may help to explain the folate malabsorption known to occur in untreated coeliac disease and the frequently seen low serum folate levels in Crohn's disease.


Effects of phospholipase A and triton x-100 on guanylate cyclase activity in mammary gland homogenates from mice. The effects of a variety of agents on guanylate cyclase activity were tested in broken cell preparations of mammary glands from midpregnant mice. Of the agents tested, only phospholipase A, triton X-100, and an impure egg lysolecithin preparation enhanced the activity of guanylate cyclase in mammary gland homogenates; other agents, including sodium azide and phospholipase C, and purified egg lysolecithin had no effect. Phospholipase A increased the activity of guanylate cyclase in the 150,000 g pellet fractions of mammary gland homogenates, bud did not consistently enhance guanylate cyclase in the 150,000 g supernatant fractions. Phospholipase A did not appear to enhance guanylate cyclase activity by solublizing the enzyme from the 150,000 g pellet. Triton X-100, in contrast, appeared to act by solubilizing guanylate cyclase from the material present in the 150,000 g pellet. Triton X-100 increased by several fold guanylate cyclase activity in the tissue homogenates and the 150,000 g pellets, but did not consistently enhance enzyme activity in the 150,000 g supernatant. Triton X-100 had no effect on the apparent Km of guanylate cyclase.


Rapid formation of N-nitrosamines from nitrogen oxides under neutral and alkaline conditions. The formation of carcinogenic N-nitrosamines in neutral and alkaline aqueous solutions (pH 6-14) at 25 degrees C is reported using dissolved N2O3 and N2O4 gases. These reactions are very much faster than those with acidified nitrite: typically, 2 X 10(-3) M amine gives ca. 10-50% N-nitrosamine in a few seconds with 5-20 fold excess of nitrogen oxide. The N-nitrosamine yield in 0.1 M sodium hydroxide is independent of amine basicity from pKA 11.2-0.99, but decreases with decreasing pH of the reaction solution for the more basic amines. Significantly, N-nitrosamine yields are not lowered with diluted nitrogen oxides (1000 ppm) and moderately basic amines (eg. N-methylpiperazine) react readily at physiological pH. The mechanism by which these reactions occur is discussed, with particular reference to the existence of two reactive tautomeric forms of N2O3 and N2O4. The formation of carcinogenic N-nitrosamines from NO in ethanol at 25 degrees C is also reported. These reactions are slow in the absence of air (oxygen), I2 or metal salts. Oxygen accelerates nitrosation by converting NO via NO2 to either N2O3 or N2O4, but both I2 and metal salts are effective under anaerobic conditions, where reaction rates are virtually independent of amine basicity but depend on the nature of the added reagent. The most effective substance is I2, which gives quantitative yields of N-nitrosamine in a few minutes at 25 degrees C by forming the reactive nitrosyl iodide (NOI) reagent. Acceleration in ethanol at 25 degrees C is also observed with AgI, CuI, CuII, ZnII, FeIII and CoII salts, among others, with substantial amounts of N-nitrosamine being produced in ca. 30-300 min. Metal iodides intervene by way of the NOI reagent, as for I2, but other salts require a mechanism involving reaction between a metal-amine complex and NO, itself. The results show that carcinogenic N-nitrosamines may form under a much wider range of experimental conditions than suspected hitherto. Their relevance to human exposure is discussed, with particular reference to urban pollution and the effect of dietary antioxidants.


Mechanism of N-nitrosodimethylamine formation from trimethylamine and trimethylaminoxide. The kinetics of nitrosation of trimethylamine (TMA) and trimethylaminoxide (TMAO) to give N-nitrosodimethylamine (NDMA) have been studied. The nitrosation rates of TMA and TMAO, when determined at 100 degrees C in sealed tubes, showed maximum values at about pH 3, while at temperatures lower than 75 degrees C the pH dependence of the nitrosation of these compounds was similar to that observed with alkylamides. The initial rate of NDMA formation from TMAO determined at pH 3.0 and 25 degrees C was found to be proportional to the TMAO and nitrite concentrations, not to the square of the nitrite concentration. In contrast, the rates of NDMA formation from TMA and TMAO when reacted at pH 3.0 and 100 degrees C in sealed tubes were found to be proportional to the square and the cube, respectively, of the nitrite concentration. These results strongly suggest that the NDMA formation at higher temperatures involves the oxidative cleavage of tertiary amines to produce secondary amines (dimethylamine, DMA) which may react with nitrite to form NDMA. On the other hand, at lower temperatures, NDMA may be formed from TMA or TMAO by a pathway not involving DMA.


Some effects of phenol- and thiol-nitrosation reactions on N-nitrosamine formation. C-Nitrosophenols, produced by the nitrosation of phenols, catalyse N-nitrosamine formation. The rate of N-nitrosation of pyrrolidine, catalysed by p-nitroso-o-cresol, is fastest at about pH 5. The catalytic species is thought to be the quinone monoxime tautomer of the nitrosophenol. A possible mechanism for the catalysis is proposed. A reaction of pyrrolidine with nitrite at pH 5.0 is described, which gives enhanced N-nitrosation in the presence of p-cresol. The yield of N-nitrosopyrrolidine (NPYR) is further enhanced when this reaction is carried out under anaerobic conditions. Nitrosocysteine hydrochloride reacts with N-methylaniline at pH 2.65, 5.5 and 9.75 in the absence of nitrite to give N-nitroso N-methylaniline. The N-nitrosation of morpholine and pyrrolidine at pH 9.75 is also effected by nitrosocysteine hydrochloride. The rate of N-nitrosation at this pH decreases with increasing amine basicity. The reaction of nitrosocysteine with N-methylaniline at pH 9.75 under anaerobic conditions leads to a significant reduction in the yield of N-nitroso-N-methylaniline.


Alpha-tocopherol: uses in preventing nitrosamine formation. alpha-Tocopherol has been evaluated as a nitrite scavenger for the prevention of nitrosamine formation in a model system and under practical conditions. alpha-Tocopherol was found to react with nitrosating agents in both lipophilic and aqueous environments. The use of alpha-tocopherol was shown to inhibit aminopyrene-nitrite induced hepatotoxicity in rats and to reduce the amount of NDMA formed in cigarette smoke. Of primary interest is the finding of a significant reduction of NPYR formation in fried bacon. Nitrosamine inhibition was greater with alpha-tocopherol used in combination with sodium ascorbate than with sodium ascorbate alone.


Acceleration of nitrosamine formation at pH 3.5 by microorganisms. Rate enhancements of from 12 to 49-fold occurred when dihexylamine was nitrosated at pH 3.5 in the presence of bacteria and yeast cells at a concentration of 12 mg/ml. Rates were similar in the presence of either boiled or unheated cells. The magnitude of the rate enhancement for nitrosation of other amines depended on the alkyl chain length. A nonenzymatic mechanism involving hydrophobic interactions of the precursor amines and cellular constituents is proposed.


Preliminary observations on amines and nitrosamines in non-normal human gastric contents. Gastric contents from fasting humans were pooled and analysed for amines. Volatile amines present were dimethylamine, trimethylamine and histamine; non-volatile amines found were cadaverine, putrescine, ethanolamine and tryptamine. Gastric contents from 35 patients, some before and/or after gastric stimulation with histamine or pentagastrin, were analysed for nitrosamines. N-Nitrosodiethylamine (NDEA) (5-30 microgram/kg) was present in four samples, N-nitrosodimethylamine (NDMA) (2 microgram/kg) in two samples and N-nitrosopyrrolidine (NPYR) (6 microgram/kg) in one sample. pH, nitrite and nitrate determinations were made on some samples. Medical diagnosis of patients could not be correlated with the presence of nitrosamines in the gastric contents.


Homologous and cross-reactive precipitins in anti-pneumococcal sera raised in mules. Serial bleedings were obtained from two mules during prolonged immunization, one with type XXV the other with type VIII pneumococcal vaccine. IgGa, IgGb, IgGc, IgB, IgG(T) and IgM present among purified Pn anti-XXV and Pn anti-VIII immunoglobulin isolated from various bleedings were identified by use of rabbit anti-equine heavy chain specific reagents. Radioimmunodiffusion with 14C-labelled type XXV pneumococcal capsular polysaccharide and horse and donkey reagents with species specificity directed against donkey or horse IgGa respectively, demonstrated both parental horse and donkey IgGa heavy chain isotypes among the anti-PnXXV antibodies of the interspecies hybrid. Qualtitative and quantitative examination of the cross-precipitation of mule anti-PnXXV sera with the capsular polysaccharides of pneumococcal types IV, X and XA, with birch sap, ketha gum, and with polysaccharides of E. coli, Klebsiella and Rhizobium was carried out and compared with data obtained with anti-PnXXV raised in a horse. Analysis of supernatants from the cross-reactions showed that distinct subfractions had reacted. indicating a marked heterogeneity of the antibodies.


Ionic binding of aminoglycosides to human serum albumin in the absence of divalent cations. IV. Effect of structure, ph and concentration. The binding of sisomicin and streptomycin to human serum albumin was studied in the absence of divalent cations by means of the dialysis method. Hydrophobic bonds between albumin and sisomicin or streptomycin can be excluded by nuclear magnetic resonance measurements. The presence of hydrogen bonds is made unlikely according to the result that the binding of the aminoglycosides decreases with increasing number of OH groups in the aminoglycoside molecule. The pH dependence of protein binding suggests that ionic bonds are involved in the binding of aminoglycosides. On the basis of the concentration dependence of the albumin binding of sisomicin and streptomycin we determined the binding affinities delta F degrees, the binding constants K1, and the maximum number n of aminoglycoside molecules that can be bound by a molecule of albumin in the absence of Ca++ ions. The results were as follows: Sisomicin: delta F degrees = -4189 cal/mole, K1 = 900 1/mole, n = 12; Streptomycin: delta F degrees = 3512 cal/mole, K1 = 300 1/mole, n = 17.


Factors affecting in vitro lipid peroxidation of rat brain homogenate. Peroxidation of the unsaturated lipid of tissue homogenates is an established method to assess the antioxidant or vitamin E status of animals. In the present study the spontaneous lipid peroxidation in air of rat brain homogenates is reported. The effects of various factors like pH, time, concentration of tissues, temperature, ferrocompounds and catalysis by added tissues like liver are described. Rat brain homogenates appear to be a suitable preparation for in vitro studies of lipid peroxidation.


Enhancement of insulin hypoglycaemia by beta adrenoceptor antagonists. Interaction of insulin with beta-adrenoceptor antagonists was studied in conscious rabbits. Propranolol and metoprolol did not modify the peak of insulin hypoglycaemia but delayed its recovery. Practolol, sotalol and 1-INPEA enhanced the peak effect and delayed the recovery of insulin-induced hypoglycaemia. H 35/25 and d-INPEA did not modify insulin hypoglycaemia. The beta-blockers did not produce significant hypoglycaemia per se. Since sotalol, 1-INPEA (specific beta-adrenoceptor antagonists devoid of local anaesthetic activity); practolol and metoprolol (selective cardiac beta-1 adrenoceptor antagonists) enhanced hypoglycaemic action of insulin and H 35/25 (a selective beta-2 adrenoceptor antagonist) failed to affect it, it seems that selective beta-adrenoceptor blockade (similar to cardiac beta-1 adrenoceptors) mediates enhancement of insulin hypoglycaemia. Caution should, therefore, be exercised in administering beta-adrenoceptor antagonists and insulin together. A reduction in the dose of insulin may be necessary.


Acetylcholine: a possible neurotransmitter in Setaria cervi. The total and free acetylcholine (Ach) and cholinesterase (CHE) content of adult Setaria cervi were estimated. The Ach was estimated by bioassay on rectus abdominis muscle of frog and the CHE by measuring the drop in pH following incubation of worm homogenate with Ach chloride. The free and total Ach contents (4.0 +/- 0.57 and 6.0 +/- 0.48 microgram/g wet weight of worms respectively) were as high as found in mammalian brain cortex. The cholinesterase activity was found to be 5.57 +/- 0.6 units/g wet weight of worms. It is possible that there may exist a well developed system responsible for the synthesis, storage, release and destruction of Ach and that Ach may be acting as an excitatory neurohormone in S. cervi.


Inhibition of allergic reactions by a new antiallergic drug, LC-6 (trans-2,3b,4,5,7,8b,9,10-octahydronaphthol[1,2-c:5,6-c'] dipyrazole). I. Inhibition of the rat reaginic passive cutaneous anaphylaxis. A new synthetic compound, LC-6, has been shown to inhibit the passive cutaneous anaphylaxis reactions induced in rats by mouse reaginic antibody. In this system, the ED50 was 35 mg/kg body weight of LC-6 administered per os. LC-6 prevented neither histamine skin reactions nor the reactions to histamine and other chemical mediators released by 48/80. Therefore, its inhibitory activity is comparable to that of the model anti-allergic compound, disodium cromoglycate (DSCG). In contrast to DSCG, the new drug exhibits the distinct advantage of being active per os and over prolonged periods of time. Its activity has been shown to persist for at least 6 h when doses 4 times higher than the ED50 were administered. The duration of the drug effect was clearly dose-dependent. Predoses of the compound increased its effectiveness. The long-lasting association of LC-6 with mast cells, as indicated by its prolonged inhibitory activity, makes it a valuable tool in the search for receptors involved in anaphylactic reactions.


Effect of light and exhaustive ergometric exercise on blood sugar, total cholesterol and pH in untrained young human subjects. Light and exhaustive ergometric exercise in untrained male and female medical students in the age group 18-21 years resulted in significant lowering of the blood sugar, cholesterol and pH. Females exhibited hypoglycemia of slightly greater magnitude as compared to male subjects and during both the exercises, however, such sex differences were not observed for changes in cholesterol and pH.


Immunological nature of the inhibition of BLV-induced early polykaryocytosis by bovine sera. A quantitative in vitro assay (EPI) was developed for the serological detection of bovine leukemia virus (BLV) infection in cattle. Positive sera inhibit early polykaryocytosis (EP) induced by BLV. We report herein experiments which demonstrate that BLV-induced antibodies are responsible for this inhibition. Serum fractionation by gel filtration and affinity chromatography indicate that EP-inhibiting activity is mediated only by immunoglobulins of the IgG class. Furthermore, on the basis of their ion-exchange chromatographic behaviour, these antibodies were classified as IgG1. We also ruled out the participation in the EP inhibition reaction of the other compounds such as polypeptides, including serum complement and interferon or DNA and RNA. These results demonstrate that EP inhibition by bovine sera is specific to BLV-induced antibodies.


The dissociation of b-TSH. The effect of sodium dodecyl sulfate, pH, urea and temperature. In the present study SDS polyacrylamide gel electrophoresis was used to reinvestigate the conditions under which b-TSH dissociates into its constituent subunits. The effects of SDS, itself, urea, acid pH and temperature were assessed by the decrease in the amount of undissociated TSH and the increase in the dissociated components as revealed by SDS gel electrophoresis. In SDS alone 25--30% dissociation occurred. Pre-treatment with increasing concentrations of urea up to 7.1 M increased the degree of dissociation to 70% after h at room temperature. Maximum dissociation was achieved by treatment at pH 2.5 and 37 degree C for 1 h. In 1 M propionic acid approximately 10% of the TSH was still undissociated after 18 h at 25 degree C.


Assessment of long-acting neuroleptics. Methods and problems. Long-acting neuroleptics, without offering a therapeutic breakthrough in the treatment of schizophrenia, are nevertheless a definite step in the management of patients with this disorder. The adequate assessment of these agents necessitates methodological considerations to ensure first, just and adequate patient selection, secondly, adaptations to the drug's characteristics, thridly, sufficient duration of the study and finally, special precautions in the assessment of toxicity. Furthermore, the patient management in these studies must ensure continued and easy accessibility of the simultaneously investigating and treating team.


The pH dependency of sodium and chloride transport in the isolated human cornea. Sodium and chloride net transport in isolated human cornea preparations were found to be pH dependent. Sodium net transport was directed from aqueous humor to tear side at pH 7.6 and 8.6. At pH 7.4, net sodium flux did not differ significantly from zero, and at pH 7.0, net sodium transport was directed toward the aqueous humor side. Chloride net flux at pH 8.6 and 7.6 was also directed from aqueous humor to tear side. Acidification of the bathing solution to pH 7.4 and 7.0 was followed by a decrease in chloride net fluxes to values not significantly different from zero.


Variability of oxygen affinity of normal blood: an automated method of measurement. Oxygen equilibrium curves of 48 healthy adult subjects have been measured by the method of Rossi-Bernardi et al. (Clin. Chem. 21: 1747, 1975), in which H2O2 is gradually added to a sample of deoxygenated blood that contains an excess of catalase. The mean P50 for nonsmokers was 26.9 Torr and the distribution of values was slightly skewed to the right (range 24.2--29.9 Torr). The method differs from others previously available in that pH, PCO2, and HCO3-- are constant during oxygenation. The system for control of the experiment and data collection and processing has been automated by the use of a microprocessor so that the equilibrium curve can be obtained quickly, reproducibly, and relatively simply. With the aid of a digital computer, the parameters of the generalized Adair equation can also be estimated.


Alpha-adrenergic receptors in human and canine tracheal and bronchial smooth muscle. We studied the reactions of human tracheal and bronchial smooth muscle and canine trachealis muscle to adrenergic agonists. Human tissue was obtained from recent autopsies of patients with normal lungs and patients with respiratory disorders, and canine tissue was obtained from animals used in other experiments. The muscle was mounted in tissue baths fitted with platinum wire electrodes and the mechanical activity was recorded. Norepinephrine added to the normal human or canine tissue in concentrations up to 10(-5) M caused no reaction. In the normal human and in the dog, pretreatment with histamine or KCl changed this response and when norepinephrine was added the tissue contracted. This contraction was blocked by phentolamine or N,N'-bis-(O-methoxybenzylaminohexyl)-cystamine tetrahydrochloride (BHC). In diseased tissue, the addition of norepinephrine resulted in a contraction that was blocked by phentolamine or BHC and no pretreatment with histamine or KCl was required. These findings demonstrate alpha-receptors in human and canine airway smooth muscle, and there is a difference between normal and diseased human tissue in the reaction of these tissues to alpha-adrenergic agonists.


Rapamycin (AY-22,989), a new antifungal antibiotic. III. In vitro and in vivo evaluation. The activity of rapamycin, a new anti-Candida antibiotic, was not affected by pH values between 6 and 8; at pH 4, however, activity was abolished. The MIC of rapamycin did not vary drastically with the size of inoculum: a ten-fold dilution of the inoculum reduced the MIC only two-fold. Serum binding was extensive. Serum levels obtained in mice were higher on subcutaneous injection than with oral administration. Dogs absorbed rapamycin after oral administration. Rapamycin cured systemic candidosis in mice: PD50 s.c. was 9.5 mg/kg: PD50 p.o. was 11 mg/kg. In the same experimental infections amphotericin B and nystatin exhibited PD50 values of less than 0.25 mg and greater than 4,000 units/kg respectively. Rapamycin and amphotericin B, administered at 1, 4 and 24 hours after infection, gave approximately the same percent survival after 30 days of observation. When the above treatment was extended by an additional daily treatment for 6 days, rapamycin by the subcutaneous route yielded a higher percentage of survival than either rapamycin or amphotericin B, administered orally, after a 30-day observation period. Vaginal candidosis in female rats was treated efficiently (91% cure) by rapamycin administered orally. No increase of resistance of C. albicans was observed during treatment.


Specificity and regulation of gamma-aminobutyrate transport in Escherichia coli. A specific gamma-aminobutyrate (GABA) transport system in Escherichia coli K-12 cells with a K(m) of 12 muM and a V(max) of 278 nmol/ml of intracellular water per min is described. Membrane vesicles contained d-lactate-dependent activity of the system. Mutants defective in GABA transport were isolated; they lost the ability to utilize GABA as a nitrogen source, although the activities of glutamate-succinylsemialdehyde transaminase (GSST) (EC 2.6.1.19) and succinylsemialdehyde dehydrogenase (SSDH) (EC 1.2.1.16), the enzymes that catalyze GABA utilization, remained as high as in the parental CS101B strain. The ability to utilize l-ornithine, l-arginine, putrescine, l-proline, and glycine as a nitrogen source was preserved in the mutants. The genetic lesions resulting in the loss of GABA transport, gabP5 and gabP9, mapped in the gab gene cluster in close linkage to gabT and gabD, the structural genes of GSST and SSDH, and to gabC, a gene controlling the utilization of GABA, arginine, putrescine, and ornithine. The synthesis of the GABA transport carrier is subject to dual physiological control by (i) catabolite repression and (ii) nitrogen availability. Experiments with glutamine synthetase (EC 6.3.1.2)-negative and with glutamine synthetase-constitutive strains strongly indicate that this enzyme is the effector in the regulation of GABA carrier synthesis by route (ii).


Structural basis of the thermostability of monomeric malate synthase from a thermophilic Bacillus. Malate synthases from a thermophilic Bacillus and Escherichia coli have been isolated in a high state of purity. Molecular weights of these two proteins determined in the native state and after denaturation in sodium dodecyl sulfate-mercaptoethanol show that the enzymes are monomeric. This conclusion is supported, for the thermophile enzyme, by the result of an electrophoretic analysis of that protein after treatment with dimethylsuberimidate and denaturation. The thermophilic Bacillus malate synthase is considerably more thermostable than its mesophilic counterparts from E. coli, Bacillus licheniformis, and Pseudomonas indigofera. It is, however, markedly labilized by an increase in the ionic strength of the medium brought about by the addition of 0.2 M potassium chloride or in pH above 9. Increased ionic strength has little effect on the thermostability of the mesophilic bacterial malate synthases. These observations provide strong support for the idea that monomeric proteins in thermophiles owe their unusual heat stability to the presence of salt bridges in their tertiary structure.


High-dose benzodiazepines in the treatment of severe neurotic anxiety. There has been a paucity of research in the use of high-dose benzodiazepines in the treatment of severe neurotic anxiety. The author presents five cases, three with excellent and two with poor outcomes. The English and Fench language literature is reviewed and reveals evidence that high-dose benzodiazepines may be useful in the treatment of certain neurotic patients. However, the lack of controlled studies is noted. The author poses several questions important to the future of research on benzodiazepines.


Multi-clinic double-blind comparison of triazolam (Halcion) and placebo administered for 14 consecutive nights in outpatients with insomnia. In this multi-clinic double-blind study, patients suffering from insomnia were treated with triazolam 0.5 mg (Halcion) or placebo for 14 days. Four investigators treated 239 patients, 122 on triazolam and 117 on placebo. Thirty-nine patients, 10 on triazolam and 29 on placebo, dropped out for ineffectiveness of the medication and 32 patients, 16 in each group, dropped out for side effects. Analysis of pooled efficacy data showed that triazolam was significantly better than placebo on all efficacy parameters measured, including how much the medication helped the patients sleep, onset of sleep, duration of sleep, duration compared to usual, number of nocturnal awakenings, and feeling of restfulness in the morning. Triazolam did not produce evidence of tolerance development after 2 weeks of treatment. The same variety of side effects occurred on each treatment and primarily included drowsiness, grogginess, headaches, impaired coordination nausea, and dizziness.


A microelectronic pH sensor.

A microelectronic pH sensor. This paper presents preliminary data on a new integrated circuit microelectronic pH sensor. The device is extremely miniaturized by the use of integrated circuit technology, and uses the intrinsic hydrogen ion selective properties of the gate insulator material. In order to make the device compatible with aqueous solution monitoring, the silicon dioxide-silicon nitride gate insulator structure is used. The integrated circuit chip was designed, processed, and packaged by a variety of techniques which protect all metal parts from the aqueous solution. Test data are reported on leakage current, sensitivity, reproducibility, linearity, stability, response time, and life. The results indicate that this type of pH sensor may have many significant advantages for biomedical research and application.


Fabrication of pH-sensitive implantable electrode by thick film hybrid technology. We report preliminary results of our experiments directed at fabricating pH-sensitive electrodes suitable for in vivo use by means of thick film screening techniques. Our results show that glass membranes of suitable thickness and possessing nearly theoretical sensitivity to pH can be fabricated by this process. A hybrid electrode structure permits the incorporation of a source follower FET amplifier directly adjacent to the pH membrane, significantly reducing response time and noise pick-up. Extension of the basic electrode structure to accommodate membranes sensitive to other ions is discussed.


Use of enzymolysis techniques in studying the mechanical properties of connective tissue components. The optimum conditions for the selective removal of elastin from connective tissues are described. The process, elastolysis, consists of incubating small samples of connective tissue in buffered saline at ph=8.6 containing 300 microgram/me of a 50-50% mixture of elastase with trypsin inhibitor, for 5-6 hours at room temperature. This process, complimented with other processes for selective removal of lipids, or mucopolysaccharides, or collagen, enables one to examine the contribution of the various components of the connective tissue to its mechanical function. The elastolysis was tested with aortic, valvular and tendon tissues from human, bovine and canine species and it was found that in tensile stress experiments, collagen was unaffected while the low-stress contribution of elastin disappeared.


Diffusion of fluoride ions in dental enamel at pH 7. The penetration and uptake of both radioactive (18F) and stable fluoride (19F) in bovine enamel were investigated. Buffered pH 7 NaF solutions were employed. Penetration profiles of both 18F and 19F in enamel were determined by using a sectioning technique. 18F and 19F concentrations decreased exponentially with increasing penetration distance. The uptake of 18F in enamel can be described by a power function of the immersion time, with an average power of 0.76. The results agree reasonably with our previously published theoretical model for the diffusion in enamel, based on simultaneous diffusion in enamel pores and in the hydroxyapatite crystallites. The diffusion coefficients of fluoride ions in enamel obtained from the application of the model to the results presented here, were: D = 0.9 x 10(-17) cm2/s in the crystallites and D' = 3.3 x 10(-10) cm2/s in the enamel pores. An average penetration depth of fluoride ions at pH 7.0 of 8 micron in 4 hours has been calculated.


Characterization of ionomycin as a calcium ionophore. The ionophorous properties of a new antibiotic, ionomycin, have been studied. It was found that the antibiotic is capable of extracting calcium ion from the bulk of an aqueous phase into an organic phase. The antibiotic also acts as a mobile ion carrier to transport the cation across a solvent barrier. The divalent cation selectivity order for ionomycin as determined by ion competition experiments was found to be: Ca greater than Mg greater than Sr = Ba, where the binding of strontium and barium by the antibiotic is insignificant. The antibiotic also binds La3+ to some extent, but its complexation with monovalent alkali metal ions is negligible. Measurement of the binding of ionomycin with Ca2+ indicates that ionomycin complexes and transports calcium ion in a one to one stoichiometry.


Evidence for thyroid hormone-dependent and independent glucocorticoid actions in cultured cells. Studies on the induction of growth hormone and glutamine synthetase in GH1 cells and tyrosine aminotransferase in Reuber H-35 cells. The induction of growth hormone synthesis and mRNA by thyroid hormone in cultured GH1 cells is mediated by the thyroid hormone nuclear receptor. In addition, the regulation of the growth hormone response by glucocorticoid is highly dependent on the action of thyroid hormone. To clarify whether thyroid hormone has a general influence on glucocorticoid action in GH1 cells, the glucocorticoid induction of growth hormone and glutamine synthetase was simultaneously examined. In contrast to the growth hormone response, the induction of glutamine synthetase by glucocorticoid was not influenced by thyroid hormone. Both responses appear to be modulated by the glucocorticoid receptor, and thyroid hormone had no influence on nuclear-associated glucocorticoid receptor levels. These results suggest that the thyroid hormone control of glucocorticoid induction of growth hormone may be a selective process, and the nuclear associated receptors for both thyroid and glucocorticoid hormones interrelate to control the growth hormone response.


Purification and properties of prolylcarboxypeptidase (angiotensinase C) from human kidney. Prolylcarboxypeptidase was purified from human kidney 1200-fold with 18% yield. The enzyme had no cathepsin A activity and appeared to be homogeneous in gel electrophoresis. The molecular weight of prolylcarboxypeptidase was estimated to be 115,000 by gel filtration. Under denaturing conditions the enzyme dissociated into subunits of 45,000 and 66,500 molecular weight. The enzyme cleaved benzyloxycarbonyl (Cbz)-Pro-Phe, representing the COOH-terminal end of angiotensin II and des-Asp1-angiotensin II (angiotensin III), at a rate of 31 micronmol/h/mg of protein. The rate of hydrolysis increased when phenylalanine in the N-protected dipeptide was replaced with alanine, valine, or leucine or when the octapeptide angiotensin II or the heptapeptide angiotensin III were the substrates. The enzyme also cleaved the angiotensin II antagonist saralasin (Sar1-Ala8-angiotensin II). The Km values were 1 mM, 2mM, and 0.77 mM with Cbz-Pro-Phe, angiotensin II, and angiotensin III, respectively. The enzyme had an acid pH optimum (4.5 to 5.5), but hydrolyzed angiotensin III at pH 7 at 50% of the optimal rate. Prolylcarboxypeptidase was inhibited by diisopropyl phosphorofluoridate and pepstatin, but not by sequestering agents or -SH reagents.


Regulation of glutamine synthetase by dexamethasone in hepatoma tissue culture cells. In certain lines of hepatoma tissue culture (HTC) cells, glutamine synthetase (EC 6.3.1.2) specific activity is increased 2.5- to 3-fold by the addition of glucocorticoids to the growth media. Actinomycin D blocks both the induction and deinduction of glutamine synthetase by glucocorticoids, suggesting a requirement of RNA synthesis for both processes. Using an antiserum raised against purified rat liver glutamine synthetase, we have precipitated radiolabeled glutamine synthetase from HTC cells. Electrophoresis of the immunoprecipitates on sodium didecyl sulfate-acrylamide gels isolates the subunit of glutamine synthetase and permits the radioactivity in the glutamine synthetase band to be quantitated. Using this technique, we have investigated the effect of dexamethasone, a synthetic glucocorticoid, on the rates of synthesis and degradation of glutamine synthetase. Dexamethasone (10(-7) M) increases the rate of synthesis of glutamine synthetase 2- to 3-fold but has no effect on the rate of glutamine synthetase degradation. The rates of total cell protein synthesis and degradation are not significantly affected by dexamethasone. The presence of actinomycin D at the time of removal of dexamethasone from induced cells prevents the fall in the induced rate of synthesis of glutamine synthetase normally seen when the inhibitor is removed from the culture medium. The regulation of glutamine synthetase by dexamethasone has been compared to the regulation of another dexamethasone-inducible enzyme in HTC cells, tyrosine aminotransferase, and been found to be similar in all parameters studied.


Biosynthesis in Escherichia coli of sn-glycerol 3-phosphate, a precursor of phospholipid. Kinetic characterization of wild type and feedback-resistant forms of the biosynthetic sn-glycerol-3-phosphate dehydrogenase. Homogeneous wild type and feedback-resistant forms of the biosynthetic sn-glycerol 3-phosphate (glycerol-P) dehydrogenase of Escherichia coli (EC1.1.1.8) were subjected to two-substrate kinetic analysis. The kinetics of the NADPH-dependent reduction of dihydroxyacetone phosphate (dihydroxyacetone-P) and of the NADP-dependent oxidation of glycerol-P indicate that these reactions proceed by a sequential mechanism. Glycerol-P was a competitive inhibitor with respect to dihydroxyacetone-P for both enzymes. The wild type and feedback-resistant glycerol-P dehydrogenases had Ki values for glycerol-P of 4.4 micrometer and 43 micrometer, respectively. Therefore, the sensitivity of the wild type activity and reduced sensitivity of the feedback-resistant activity, both noted previously in crude extracts, were inherent properties of the enzymes. The patterns of product inhibition for both enzymes were identical, and the difference in the inhibition constants for glycerol-P occurred without significant alteration of any other kinetic constant determined. Kinetic mechanisms consistent with the patterns of product inhibition violated Haldane relationships and other kinetic relationships. These discrepancies suggest that glycerol-P inhibition occurs at a site distinct from the active site. The pH dependencies of the Km for dihydroxyacetone-P and the Ki for glycerol-P were markedly different suggesting the existence of an allosteric site. The addition of glycerol-P in the presence of NADPH stabilized both enzymes against thermal inactivation. Half-maximal stabilization was provided by 5 micrometer and 50 micrometer glycerol-P for the wild type and feedback-resistant enzymes, respectively. These kinetic data, considered in conjunction with previous physiologic and genetic data, indicate that the synthesis of glycerol-P is regulated in vivo by glycerol-P inhibition of the glycerol-P dehydrogenase. The data suggest that glycerol-P inhibition occurs at an allosteric, regulatory site.


Bovine thymus poly(adenosine diphosphate ribose) polymerase. About 1,300-fold purification of poly(adenosine diphosphate ribose) polymerase has been achieved from the extract of bovine thymus with a recovery of 10 to 20%. The final preparation has a purity of 99%, and the enzyme is composed of a single peptide with a molecular weight of 130,000. The purified enzyme required NAD+, Mg2+, a thiol compound, DNA, and histones for full activity. Whereas DNA is essential for activation of the enzyme, histones are not. The observed stimulation of the reaction by histones is shown to be due to masking of the inhibitory effect of contaminating denartured DNA in native DNA preparation. The concentration of DNA required for half-maximal enzyme activity (apparent Km for DNA) is proportional to the concentration of enzyme in the reaction mixture. The minimum estimation of the number of nucleotide pairs of DNA required for half-maximal activation of one enzyme molecule is 220 to 240 for bulk of calf thymus DNA, while the value is 10 for a calf thymus DNA fraction, "active DNA," which was separated from the enzyme fraction in a stage of the purification. These results suggest that the enzyme is activated by binding to a specific site on calf thymus DNA. The apparent Km for NAD+ and the maximum velocity of the enzyme are estimated to be 60 micrometer and 0.91 mumolper min per mg, respectively.


Actin filament destruction by osmium tetroxide. We have studied the destruction of purified muscle actin filaments by osmium tetroxide (OsO4) to develop methods to preserve actin filaments during preparation for electron microscopy. Actin filaments are fragmented during exposure to OsO4. This causes the viscosity of solutions of actin filaments to decrease, ultimately to zero, and provides a convenient quantitative assay to analyze the reaction. The rate of filament destruction is determined by the OsO4 concentration, temperature, buffer type and concentration, and pH. Filament destruction is minimized by treatment with a low concentration of OsO4 in sodium phosphate buffer, pH 6.0, at 0 degrees C. Under these conditions, the viscosity of actin filament solutions is stable and actin filaments retain their straight, unbranched structure, even after dehydration and embedding. Under more severe conditions, the straight actin filaments are converted into what look like the microfilament networks commonly observed in cells fixed with OsO4. Destruction of actin filaments can be inhibited by binding tropomyosin to the actin. Cross-linking the actin molecules within a filament with glutaraldehyde does not prevent their destruction by OsO4. The viscosity decrease requires the continued presence of free OsO4. During the time of the viscosity change, OsO4 is reduced and the sulfur-containing amino acids of actin are oxidized, but little of the osmium is bound to the actin. Over a much longer time span, the actin molecules are split into discrete peptides.


Interference in word associations in schizophrenia. Assessed the effect of response interference on the word associations of male and female process and reactive schizophrenics in two studies that used the difference in associative disturbances between high and low interference (low and high commonality stimulus words) as the measure. The reactives showed a significantly greater increase in disturbances in the high interference condition than did process schizophrenics in both studies. These results occurred in process and reactive groups that did not differ in age, IQ, institutionalization, and current level of physiological arousal and symptom severity in Study I. Findings supported predictions from a qualitative differences theory of cognitive deficit in schizophrenia.


Psychophysiological responses to presentation of a caged snake among behaviorally avoidant and non-avoidant college students. Sixty-six coeds who reported fear of snakes on a paper-and-pencil fear inventory were exposed to a Physiological Response Test, during which their electrodermal and cardiac responses to a neutral stimulus and a caged snake were recorded. Half of these coeds then were exposed to a representative Behavioral Avoidance Test, on the basis of which they were classified as avoidant, as non-avoidant, or as neither. Those remaining were classified similarly with an Incentive Behavioral Avoidation Test, before which each was offered an incentive for displaying non-fearfulness. The electrodermal response data showed that students classifed as avoidant had not been more responsive to snake confrontation than the the students classified as non-avoidant. The cardiac response data showed that avoidant Ss had been relatively more responsive to the snake cue, but that differential responsiveness was not robust. These results held for both behavioral avoidance tests.


Facilitating and debilitating test anxiety among college students and volunteers for desensitization workshops. Administered the Alpert-Haber Achievement Anxiety Test (AAT) to 54 students who expressed interest in participating in a test anxiety desensitization workshop. In addition, 182 students from the general college population were tested. Results indicated that both the debilitating and facilitating (AAT) scales were higher for the self-referred volunteer group. These data indicate that these scales are useful in distinguishing self-referred volunteers for behavior modification workshops from a general college population. In addition, the scales of the AAT were correlated with the number of sessions attended by those students who enrolled in the desensitization groups. Results indicated no relationship between attrition and debilitating anxiety. There was a correlation of r = .318 p less than .15 between facilitating anxiety scores and number of sessions attended. It is suggested that facilitating anxiety can function as a measure of S's ego strength in predicting workshop attendance.


Reduction in enamel dissolution by liquorice and glycyrrhizinic acid. Liquorice extracts and confections reduced enamel dissolution in acidic buffers and saliva/glucose incubations by a direct effect on solubility, and by inhibiting the fall in pH on incubation. These actions may be attributed to the solubility-reducing, glycolysis-inhibiting, and buffering properties of glycyrrhizinic acid, a constituent of liquorice.


An electrochemical study on the human dental enamel with special reference to isoelectric point. In an attempt to make a dynamic study of the isoelectric point and the chargeability of human dental enamel, an electrochemical approach was utilized. Zeta potential of three kinds of the enamel was measured by a streaming potential method. As a result, these isoelectric points could be decided.


Effect of 4.5--year use of xylitol and sorbitol on plaque. The pH values of xylitol-containing plaque suspensions of persons who habitually used xylitol and sorbitol during 3.2 to 4.5 years did not significantly differ from those observed with suspensions containing no added carbohydrates. Sorbitol produced in 22-hour incubations pH values as low as 3.9 to 5.5. The activity of plaque xylitol dehydrogenase was almost nil, whereas sorbitol dehydrogenase activity was higher. The nonacidogenic nature of xylitol in relation to plaque did not change in prolonged use of xylitol.


Effect of progestins on androgen delta4-3-ketosteroid-5alpha-A-ring reductase system in rat oral mucosa. Rat oral mucosa microsomal delta4-3-ketosteroid-5alpha-A-ring reductase enzyme system, reducing testosterone and 4-androstenedione, was found to be inducible by systemic administration of medroxyprogesterone acetate (MPA). MPA, when used in a mixture with testosterone and/or 4-androstenedione in vitro, acted as a competitive inhibitor of the reduction of these substrates.


Child abuse and dentistry: orofacial trauma and its recognition by dentists. Orofacial trauma was found in 49% of 260 documented cases of child abuse seen during of five-year period at the Children's Hospital Medical Center, Boston. An additional 16% of the cases involved head trauma; the total percentage of head and facial trauma was 65%. Head or facial trauma was the principal reason for admission to the hospital in 45% of the cases. A survey of 537 dentists in Massachusetts showed that the majority were unaware of their legal and social responsibilities to report suspected cases of child abuse. Eleven percent of all dentists surveyed saw orofacial trauma cases that were of a suspicious nature, by only 22 confirmed cases of child abuse were noted by the dentists. Of these, only four were reported to social agencies. In general, oral surgeons and pedodontists saw a higher percentage of these cases and were more aware of their responsibilities than were general practitioners.


[A new instrument for measurement of actual instantaneous pH in obstetric (author's transl)]. The authors present a new instrument for measurement of actual instantaneous pH in obstetrics. It has been developped to avoid most errors of the usual scalp-blood sampling. Its advantages are:--Aspiration is manual and controlled.--Results are obtained within 10--15 seconds. A comparative study with two other pH-meters has demonstrated an excellent correlation and reliability of this new instrument. The authors consider the method as simple, functional and reliable, all favourable factors for routine use.


Polyarteritis: A cause of nerve palsy in the extremity. The association between polyarteritis and peripheral neuropathy may be overlooked in the clinical assessment of nerve lesions in the extremity. Nerve palsy may be the initial presenting complaint in polyarteritis nodosa. A case is presented which demonstrates the pathological process. A method for early recognition and treatment is suggested.


Low molecular weight C1q-precipitins in hypocomplementemic vasculitis-urticaria syndrome: partial purification and characterization as immunoglobulin. A lupus-like syndrome involving chronic urticaria with cutaneous vasculitis, systemic symptoms, hypocomplementemia with preferential depletion of C1q, and low m.w. (7S) C1q-precipitins has recently been defined. The C1q-precipitin activity (C1q-p) seems to represent a diagnostic marker of the disease, but its chemical nature is not yet clear. We have partially purified and characterized C1q-p from the serum of two patients with this syndrome and compared its activity with the C1q-precipitating activity of aggregated human gamma-globulin (AHGG) anti-C1q antibodies, and several polynucleotides including DNA and polyinosinic acid. C1q-p was found to partition with IgG during precipitation by ammonium sulfate and low ionic strength buffer as well as during column chromatography on DEAE-cellulose and G-200 Sephadex. Like AHGG, but in complete contrast to the polynucleotides, the C1q-precipitating activity of C1q-p was sensitive to pepsin, trypsin, and acidic conditions, but unaffected by DNAse or RNAse; the C1q-precipitating activity of anti-C1q antibody was not diminished by any of these procedures. Thus, C1q-p consists of gamma-migrating protein of low m.w., and its C1q-precipitating activity is indistinguishable from that of AHGG. These results are consistent with the concept that C1q-p is comprised, at least in part, of IgG that binds C1q via the Fc portion of the molecule.


Characterization of human hairbulb tyrosinase: properties of normal and albino enzyme. Human hairbulb tyrosinase from normally pigmented and tyrosinase-positive oculocutaneous albino (TPA) hairbulbs was studied by single hairbulb and by pooled hairbulb assay procedures. The response to temperature and pH was the same for TPA and normal enzyme. The Km for tyrosine as substrate and the Km or dopa as cofactor was the same for TPA and normal enzyme. These studies show that TPA tyrosinase is kinetically normal and that the defect with this form of albinism must be elsewhere in the melanin pathway.


Endogenous angiotensin I concentration in human plasma. A reliable radioimmunoassay of endogenous angiotensin I concentration in plasma, extracted on a Dowex-resin at pH 7.4, is described. The concentration of angiotensin I in the pH 7.4-extracted plasma samples is significantly correlated with the angiotensin I concentration in the samples extracted at pH 5.5, the pH optimum of the in vitro reaction of human renin with human renin substrate. The presence of immunoreactive angiotensin I-like material in plasma and the relatively high cross-reaction of renin substrate with the anti-angiotensin I antiserum necessitates a chromatographic purification on a Dowex resin. The normal range found for angiotensin I in venous blood of apparently normal, male subjects was 25 to 143 pg/ml. A significant correlation (r = 0.78; p less than 0.001) between PA-I and PRA was found in normal subjects. No differences (p greater than 0.10) between arterial and venous angiotensin I concentration were observed in hypertensive patients.


Supersaturation of urine with uric acid and urate: response to a uricosuric diuretic. In order to assess the possibility that treatment with the uricosuric diuretic ticrynafen (tienilic acid) could lead to UA or MSU crystalluria, the degree of urinary supersaturation with respect to these crystalloids was assessed in persons receiving the diuretic for 1 week, and the results were compared with similar data generated from the use of probenecid. Initially, only probenecid significantly increased the degree of urinary suspersaturation with respect to MSU, and after adjustment of urine pH values to 5.5, probenecid also increased the degree of urinary supersaturation with respect to nonionized UA. At a pH of 5.5, the urine was significantly more supersaturated with nonionized UA after a single dose of probenecid than after ticrynafen (tienilic acid). Ticrynafen never significantly affected the degree of urinary supersaturation with respect to UA or MSU. Neither agent affected small amounts of "colloidal" or "bound" urinary urate. Insofar as the degree of urinary supersaturation with these crystalloids predisposes to crystalluria and calculus formation, ticrynafen (tienilic acid) appears to present no increased risk.


Renal regulation of acid-base balance in a freshwater fish (1). Intra-arterial injection of a fixed acid load caused only a short-lived (less than 2h) disturbance of blood pH but a long lived (2-3 days) elevation of urinary acid excretion in freshwater trout (Salmo gairdneri). The renal response comprised an immediate increase in acid output in the form of titratable acidity minus bicarbonate, and a slower rise in acid output in the form of ammonia. The total elevation in urinary acid efflux over 72h was such that no other mechanism besides renal function is needed to explain the ultimate compensation of this experimental acid-base disturbance.


The isolation of a Bwamba virus variant from man in Western Kenya. A bwamba group virus was isolated from the blood of a febrile child on the Kano Plain, Kenya. The isolate (NY-45), closely resembling Bwamba, established infection in both Anopheles gambiae and Mansonia uniformis. Neither the Bwamba nor the Pongola prototype strains grew in both species. In gel-diffusion tests NY-45 virus passaged through mosquitoes exhibited a line of identity with Pongola antiserum. In contrast no cross-reaction was observed with NY-45 virus which had not previously been passaged through mosquitoes.


Effect of a new benzodiazepine bromazepam on locomotor performance and brain monoamine metabolism. Administration of a single dose (10 mg/kg) of a relatively new benzodiazepine, bromazepam to rats markedly suppressed their spontaneous locomotor activity. Hypomobility became apparent 15 min after the injection and remained significantly lower during the period of observation for 6 hours when locomotor activity was 27% of controls. Following 2 hours after bromazepam treatment, no change was noted in tyrosine levels and tyrosine hydroxylase activity in striatum or rate of catecholamine synthesis in synaptosomal preparation (P2 pellet). However, the endogenous levels of norepinephrine, dopamine and 5-hydroxytryptamine were significantly increased not only in several brain areas examined, but also in P2 pellet. Bromazepam failed to change 3H-norepinephrine and 3H-5-hydroxytryptamine uptake in synaptosomes suggesting that the increased levels of monoamines are not related to laterations in uptake mechanisms, but probably to a diminished release. This is supported by the data on striatal homovanillic acid and whole brain 4-hydroxy-3-methoxyphenyl glycol whose concentrations were significantly lowered following a single injection of this benzodiazepine. However, bromazepam increased 5-hydroxyindole-acetic acid levels in hypothalamus, mid-brain and pons-medulla. The present study demonstrates that bromazepam elicits its tranquilizing action by lowering the release of catecholamines in brain; however, its anti-anxiety action might be associated with a reduction in 5-hydroxytryptamine turn over. Our data also suggest that bromazepam is almost as potent as diazepam in altering the metabolism of certain putative neurotransmitters in brain.


Biosynthesis and processing of presumed neurosecretory proteins in single identified neurons of Aplysia californica. The biosynthesis and processing of low molecular weight protein (presumed neurosecretory protein) in cells R15, R14 and L11 of Aplysia californica was studied at high resolution by polyacrylamide slab gel electrophoresis in sodium dodecylsulfate. The number of low molecular weight proteins detected in each cell ranges from 3 in R14 and L11 to 5 to 6 in R15. In each of the cells studied, the low molecular weight protein consists of a primary precursor of ca. 12,000 daltons, and its proteolytic processing products. In each cell, the smallest protein, or in the case of R14, one of the two smallest proteins, accumulates to a significant extent, suggesting that it might correspond to a final processed neurohormone. In cell R15, the biosynthesis of the primary precursor and its subsequent processing to smaller peptides is largely unaffected by removal of extracellular calcium, by replacement of calcium with cobalt or by inhibition of spontaneous bursting via stimulation of the brachial nerve.


Evidence for a change in neurotransmitter affecting oesophageal motility in Parkinson's disease. In a study of oesophageal motility in 20 patients with Parkinson's disease, intravenous atropine produced marked disruption of co-ordination in response to swallows, when compared with control subjects. This suggests that cholinergic rather than dopaminergic mechanisms are more important in the control of swallowing in patients with Parkinsonism. No conclusive evidence of peripheral dopamine depletion or autonomic neuropathy was found, although minor changes suggestive of the former were found in severely affected patients.


Radioiodinated derivatives of beta adrenoceptor blockers for myocardial imaging. Four new beta-adrenoceptor blocking agents carrying tyramine as the amino moiety were synthesized and the distribution of their I-125-tagged derivatives evaluated in rats. This distribution was compared with the distribution of various agonists and antagonists labeled with H-3 and C-14, and with the in vitro binding affinity of the new derivatives. A radioiodinated derivative of a cardioselective blocker, alprenolol, showed poor blood clearance and no cardiac selectivity. A derivative of another cardioselective blocker, practolol, showed a promising heart-to-blood ratio (ca. 19) and cardioselectivity with a heart-to-lung ratio of ca. 2. Two additional practolol analogs showed no improvement over the practolol derivative; because of the increased lipophilicity of these derivatives, blood clearance and cardioselectivity were diminished. An inverse correlation is suggested between the dissociation constant for the beta adrenoceptor in the lung and the heart-to-blood and heart-to-lung values. We conclude that polarity plays an important role in the blood clearance and cardioselectivity of these beta-adrenoceptor derivatives.


Experimental cross infections of Fasciola hepatica in lambs and calves. The effects of experimental infections with Fasciola hepatica of ovine and bovine origin in homologous and heterologous hosts and in uninfected controls were compared; groups comprised 5 animals each. The effects of the infections were monitored by biweekly determinations of packed cell volumes (PCV), serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), gamma glutamyl transpeptidase (GGT), serum iron, bilirubin levels, alkaline phosphatase (AlP) and total serum protein levels. Infected animals showed changes in SGOT, SGPT and GGT activity levels, and GGT activity levels, and infected lambs showed changes in PCV and AlP. However, no no significant differences in these serum levels between infected host groups were attributable to fluke strain. At necropsy, calves infected with ovine and bovine strains on an average had about the same number of flukes, but lambs infected with a high dose of the bovine strain on the average had nearly twice the number of flukes as those infected with ovine strain. Weight gains did not differ within host groups; liver damage was extensive in all infected animals. On the basis of these experiments, the pathogenicity of the ovine and the bovine strains of F. hepatica appears to be the same.


Isolation and partial characterization of trehalase from Ascaris muscle. The tissues of female Ascaris suum were assayed for alpha,apha'-glucoside 1-D-glucohydrolase (trehalase) activity. A soluble from of the enzyme was isolated from muscle tissue and purified approximately 37-fold. The enzyme was specific for trehalose as substrate. The pH optimum for enzymatic activity was found to be 6.0, and the apparent Km for trehalose was estimated to be 2.1 x 10-4 M. The product of the reaction was identified as D-glucose by chemical, chromatographic and enzymatic methods.


The interaction of preservatives with polyhydroxyethylmethacrylate (polyHEMA). The interaction of the four most commonly used preservatives in contact lens solutions (chlorbutol, thiomersal, chlorhexidine gluconate and benzalkonium chloride) with polyhydroxyethylmethacrylate (polyHEMA), has been examined. Benzalkonium chloride and chlorhexidine gluconate show typical high affinity type isotherms. The interaction of benzalkonium chloride with polyHEMA from aqueous solution was reversible whereas that of chlorhexidine was only reversible in the presence of electrolyte or surfactant. Chlorbutol showed a typical reversible linear isotherm. Thiomersal does not interact with polyHEMA above pH 5.0. The extent of chlorhexidine--polyHEMA interactions in increased by the presence of formulatory adjuvants such as electrolyte and hydrophilic polymers. PolyHEMA lenses that apparently have been equilibrated with chlorhexidine gluconate will, on the addition of fresh preservative solution, bind further quantities of chlorhexidine above that which would be predicted from the sorption isotherm.


Theory of the mean absorption time, an adjunct to conventional bioavailability studies. The theory is outlined of a procedure for characterizing the time-course of drug absorption by determining the mean absorption time. The procedure requires data of the type normally collected in bioavailability studies.


Bioavailability of griseofulvin from a novel capsule formulation. The in vivo availability of griseofulvin from a novel formulation has been compared with the micronized powder. The formulation technique involves the conversion of the hydrophobic surface of the drug to a hydrophilic one by treatment with a film forming polymer. This enhances the wettability of the power, and increases its dissolution rate. The results of the in vivo study show the formulation technique has increased the rate and extent of bioavailability of griseofulvin when compared with the non-treated powder.


The relation between molecular connectivity and gas chromatographic retention data. The recently developed topological index, molecular connectivity (chi), has been correlated using multiple regression analysis with gas chromatographic retention time (Rt) for various series of compounds. For saturated and unsaturated aliphatic hydrocarbons, and aliphatic aldehydes, good correlation with log Rt was achieved by one-parameter linear equations in terms of the first-order conncectivity index. (1chi). The equation for aliphatic alcohols required an additional parameter, the valence connectivity (vchi) for satisfactory correlation. One-parameter equations using 1chi also good correlation with log Rt for three series of drug molecules, amphetamines, barbiturates and phenothiazines. In all cases the equations generated gave good agreement between calculated and observed log Rt values.


The percutaneous absorption of phenolic compounds: the mechanism of diffusion across the stratum corneum. The effect of temperature on the permeation of phenolic compounds from aqueous solution through excised human skin has been examined. From a thermodynamic analysis of the data, a mechanism is postulated by which these solutes penetrate through human skin. For the more polar solutes it is suggested that the main resistance to penetration is the lipid barriers in the stratum corneum. Diffusion of these substances through the stratum corneum appears to depend on the breaking of hydrogen bonds in the desolvation of the solute during this penetration process and by the overall 'viscosity' of the stratum corneum. With non-polar solutes, the aqueous boundary layers appear to provide an additional barrier to the penetration of phenolic compounds.


The character of the antagonism by polyphloretin phosphate of contractions to prostaglandins E1 and F 2alpha in guinea-pig ileum. Polyphloretin phosphate (PPP) produced a dose-dependent decrease in the tone and reduction of the spontaneous phasic contactions of the longitudinal muscle of guinea-pig isolated ileum. PPP (100 microgram ml-1) after a 2 min contact with the ileum decreased the contractile effects of PGE1 0.1 micron by 40.6 +/- 7.4%, of PGE1 0.01 micron by 86.7 +/- 3.3% and of PGE2alpha 0.1 micron by 62.2 +/- 8.6%. After 10 min contact of PPP the contractile effect of PGE1 0.1 micron was decreased by 47.7 +/- 4.7% and that of PGE2alpha 0.1 micron by 89.6 +/- 1.7%. When the contact was longer, PPP showed a pronounced after-effect in respect to the effects of PGE1 and particularly of PGF2alpha. PPP signicantly reduced contractions to 5-HT and BaCL2, but not to acetylcholine, histamine or substance P. The type of antagonism of PGE1 by PPP was examined using cumulative concentration-effect curves for PGE1 in the presence of increasing concentrations of PPP. We conclude that on guinea-pig ileum PPP acts as a non-competitive antagonist of PGE1 and PGF2alpha.


Direct effect of a nomifensine derivative on dopamine receptors. A study was made of the effects of nomifensine, 4'-hydroxynomifensine and 3',4'-dihydroxynomifensine on dopamine receptors in rat striatum and nucleus accumbens, using the dopamine-sensitive adenylate cyclase assay. Nomifensine and its 4'-hydroxy metabolite were both inactive as dopaminergic agonists. 3',4'-dihydroxynomifensine was, however, a potent agonist, being approximately 2 to 4 times less active than dopamine. The effects of dopamine and of 3',4'-dihydroxynomifensine were blocked by fluphenazine. It is concluded that the dopaminergic activity of 3',4'-dihydroxynomifensine is dependent upon the presence of the two hydroxyl groups.


The influence of methysergide on 5-hydroxytryptamine-induced changes in regional distribution of blood flow. Systemic and regional haemodynamic variables were measured at the baseline and after saline or 5-HT infusions (5 microgram kg-1 min-1, i.v.) or methysergide injections (0.5 mg kg-1, i.v.). Cardiac output and its complete distribution were measured by the radioactive microsphere (15 micrometer diam) technique. Although 5-HT did not change the systemic variables, methysergide caused a moderate increase in systolic and mean blood pressure and heart rate. 5-HT caused a substantial increase in gastric and a moderate increase in cerebral and myocardial blood flow at the expense of that to the lungs (arteriovenous shunt + bronchial flows), kidneys and skin. While methysergide was able to reduce the vascular responses to 5-HT in stomach, skin, kidneys, heart, lungs and brain, the drug itself, like 5-HT, decreased the number of microspheres reaching the lungs. Since a large number of 15 micron microspheres can escape through the arteriovenous anastomoses to lodge in the lungs it seems likely that both 5-HT and methysergide can reduce the 'non-nutrient' flow through these anastomoses.


Pharmacology of 6,7-dihydroxy-2-dimethylaminotetralin (TL-99). I. Cardiovascular activity in the dog and cat. 6,7-Dihydroxy-2-dimethylaminotetralin (TL-99), the 5,6-dihydroxy isomer (M-7) and dopamine were studied for cardiovascular activity in the cat and dog. TL-99 was found to be the most active of these compounds. Some of the more striking actions of TL-99 and M-7 were bradycardia, hypotension and complete blockade of norepinephrine-induced reflex activation. A detailed study of these compounds showed that they were most likely exerting their effects by inhibiting sympathetic nervous system activity. Whether these compounds were activating dopamine receptors or alpha adrenergic receptors is not entirely clear from this study.


Withdrawal of clonidine: effects of varying dosage or duration of treatment on subsequent blood pressure and heart rate responses. The influence of the dosage or duration of treatment on the incidence and severity of clonidine withdrawal responses was examined in normotensive rats. Clonidine (0.01 or 0.1 mg/kg i.m.) was administered either in single doses, or twice daily for 3 days or 3 weeks. Rats were then anesthetized and arterial catheters were inserted. Significant overshoots in blood pressure and heart rate, reaching peak values 16 to 26 hr after the last injection, occurred in all clonidine-treated rats, but in no control rats. The overshoots after single injections of clonidine were as great as those after suspension of sustained treatment. Moreover, withdrawal responses were as great after the low dose as they were after the 10-fold greater dose. Only plasma renin activity showed a significantly greater elevation during withdrawal of the high dose of clonidine. Since ganglionic blockade reduced blood pressures and heart rates to the same levels in rats with clonidine withdrawal hypertension as in control rats, the withdrawal overshoots appear to be nervously mediated. Neither the dosage nor the duration of treatment could be shown to determine the magnitude of the response to withdrawal of clonidine.


The black physician's assistant: problems and prospects. This is a report on a study of the social origins, attitudes, and anticipated practice settings of black and white recruits to the physician's assistant occupation. Recruits are generally representative of the larger black and white communities in their values; however, black recruits are more likely than their white counterparts to value the status, income, and stability perceived to be associated with the occupation. At the same time, blacks are more likely to favor national health insurance and to look forward to servicing the poor. These liberal social attitudes and the finding that blacks are more likely than whites to desire to practice in ghetto areas provide some support for affirmative action policies in dealing with the health manpower needs of medically underserviced areas.


Suppression of mitogen responses and graft-versus-host reaction by splenocytes from mice bearing Lewis lung carcinoma. The presence of suppressor cells in the spleens of C57BL/6 mice bearing Lewis lung carcinoma was investigated with the use of the in vitro lymphoproliferative response to mitogens and the graft-versus-host reaction (GVHR) as test systems. Splenocytes from tumor-bearing mice showed a lower response to mitogens when obtained 15-27 days after tumor transplant. In parallel, these cells were capable of suppressing the response of normal spleen cells to mitogens and their capacity to mount a GVHR in allogeneic hosts. Treatments with procedures known to remove adherent phagocytes, but not treatments with anti-Thy 1.2 serum plus complement, removed the suppressive activity observed.


Transfer of viable putative preneoplastic hepatocytes to the livers of syngeneic host rats. A new approach was developed by which freshly isolated, chemical carcinogen-altered hepatocytes with the positive marker gamma-glutamyl transpeptidase (gamma-GT) could be transferred from adult donor F344 rats to the livers of syngeneic, adult host rats. Selective proliferation of gamma-GT-positive hepatocytes was induced in host rat livers, such that large, macroscopic colonies of altered hepatocytes could be generated within 10 days of the cell transfer operation. Quantitation of the number of gamma-GT-positive hepatocyte colonies (foci) appearing per square centimeter of host liver section area on day 10 following cell transfer revealed that prior treatment of host rats with a low dose of 2-acetylaminofluorene was essential for the appearance of large numbers of foci. In addition, the appearance of foci on day 10 depended on the presence of intact, gamma-GT-positive hepatocytes in the infused (transferred) cell suspensions.


Prostatic maldevelopment in the prune belly syndrome: a defect in prostatic stromal-epithelial interaction. The prune belly syndrome consists of a triad of abdominal wall musculature deficiency, cryptorchidism and urinary tract anomalies. A rarely described but fairly constant component of the syndrome is the lack of development of the epithelial elements of the prostate. We wish to suggest that this is a further expression of a postulated arrest in mesenchymal development responsible for other features of the syndrome.


Bone marrow transplantation for acute myeloblastic leukemia. Fifty-seven patients with end-stage acute myeloblastic leukemia (AML) received a total of 65 bone marrow transplants between 1968 and 1976. Marrow from HLA genotypically identical allogeneic donors was administered to 32 patients, 13 received marrow from HLA-incompatible donors, donor-recipient HLA compatibility was undetermined for eight patients, and identical twins were marrow donors for four patients. None of the patients  in the three latter groups survived beyond 9.4 months after transplantation. Two patients treated with marrow transplants from HLA-compatible donors currently are alive and free of leukemia with functioning grafts 13 and 38 months after transplantation. The 32 patients in the Registry series who received marrow from HLA-compatible donors were compared with a similar series of 46 patients in Seattle. Data for these 78 patients were pooled and analyzed for pretransplant factors that might have prognostic value. Patients with end-stage AML had approximately a 10% chance of surviving 20 months after high-dose chemoradiotherapy plus marrow transplantation. Patients younger than 21 years had a higher six-month survival rate than patients older than 30 years. Patients in the Registry series who received transplants with HLA-compatible marrow within eight months of diagnosis had a higher survival experience than patients who received transplants later.


Single-mouse urine collection and pH monitoring system. A glass cage with minimal surface area was designed and used to house mice for 24-hour urine collections. An experiment was performed with a radio-labeled compound excreted in the urine to assess the collection efficiency of the cage. In this experiment 74.2 +/- 6.5% of the excreted radioactivity was recovered in the urine, with 25.8 +/- 6.5% found adhering to the cage surfaces. When a flow-through pH electrode, meter, and recorder were attached, the system provided a continuous pH versus time urination record.


Effects of two adrenergic beta-receptor blockers on the sleep cycle of the cat. Sixteen hour polygraphic recordings (EEG, EOG and EMG) were obtained from 14 adult cats after intraperitoneal injections of propranolol (5 mg/kg) or pindolol (0.1 or 0.5 mg/kg). All injections moderately increased waking, which consisted mainly of a sedated drowsy stage. Both drugs also decreased deep slow wave sleep, while light slow wave sleep remained at control levels. The changes were more marked after propranolol, which also significantly reduced paradoxical sleep (PS). The decrease in the deeper stages of sleep and PS is suggested as being due to blockade of the central adrenergic beta-receptors per se and/or antagonistic effects of the beta-blockers on 5-HT receptors. The results agree with the finding that beta-blockers cause insomnia in susceptible patients, but they do not suggest that intensified dreaming or nightmares reported by others are likely to be caused by increased PS.


[Sialographic findings in inflammations of the salivary glands (author's transl)]. The greatest part of all diseases of salivary glands are caused by inflammations. The differential diagnosis to other diseases, e.g. tumors, if of great importance. The sialography has hereby developed to an important diagnostic measurement. There is a discussion about the technique of the sialography and its simple performance as well as the high effectiveness of this X-ray examination. The X-ray morphology of different kinds of inflammations is various. The acute inflammations are characterized by narrowing of ducts, the subacute inflammations by the pathological staining of the parenchyma, and the chronic by the increased changes of the Stenon's or Wharton's duct, respectively of ducts with superior range.


[Disorders of motility of the stomach and pylorus: pathological significance (author's transl)]. Five different disorders of motility of the pyloric region may be distinguished if direction and velocity of chyme passing through the pylorus are taken into account: 1. Accelerated emptying of food and overacidification of the bulbus duodeni: 2. Bolus emptying of the stomach and rapid increasing hyperosmolarity in the small intestine: 3. Delayed emptying of the stomach and gastric retention: 4. Duodeno-gastric reflux and inflammatory lesions of the gastric mucosa: 5. Other disorders causing pain. Gastric disroders cannot yet be classified on the basis of abnormal motility patterns. It is well known, that the gastric and duodenal motility are regulated by two separate pacemakers located in the distal corpus area and in the bulbus duodeni. Thus it may be speculated that distrubed motility patterns may be due to abnormal pacemaker function.


[Methods and problems of investigation of psychopharmacological effect illustrated by the comparison of a novel pyridylbenzodiazepine with diazepam (author's transl)]. Comparison of two compounds being investigated should take into consideration the most comprehensive spectrum of all psychic variables affected. Consequently, besides 15 standardized investigational methods, three open methods, history, observation of behavior and in particular free exploration were used. The investigation was carried out in 18 ambulant patients who were given the preparations under investigation in a double-blind cross-over trial. Particular problems of the method were the interference of psychotherapeutic effect of the intensive exploration discussions on the action of the preparations, which could be controlled by comparison with a placebo phase, and the effects of learning and stereotype on repeated presentation.


[Effect of anions on inhibition of lactate dehydrogenase by pyruvate]. The effect of anions Cl- and I- on structural and kinetic properties of LDH was investigated. It was shown that anions are specific inhibitors of LDH competing with pyruvate in the active ternary complex, LDHNADHpyq. The following dissociation constants for the anions were obtained from inhibition data: 0.4 +/- 0.02 and 0.07 +/- 0.01 M for Cl- and I-, respectively. The slope of Hill plot are near 1.0. The anions abolished the inhibition of LDH at high pyruvate concentrations. The following dissociation constants were obtained from these data: 0.1 and 0.015 M for Cl- and I- respectively. The inhibition by anions and the abolishing of substrate inhibition by anions were studied also for the lactate oxidation reaction. The dissociation constants for anions obtained from these data are in good correlation with the constants obtained for the pyruvate reduction reaction. It was concluded that anions do not interact with the group at the catalytic site with pK approximately 7.8, presumably His-195. The degree of pyruvate inhibition does not depend on the buffer system. The differences in the degree of inhibition obtained previously in phosphate, imidazole and tris-buffer systems can be explained by the presence of Cl- anions in the last two buffer. The rate constants of hydroxy leads to keto pyruvate transition was obtained in various buffer systems. It was shown that the hydroxy-form of pyruvate does not cause the inhibition of LDH.


[Acid-base properties and secondary structure of DNA in isoionic solutions]. Potentiometric titration of DNA in the isoionic solutions has been investigated at different concentrations of the polymer. The intrinsic constants pKo of titrable groups corresponding to the two inflections in the titration curves were calculated by taking into account the electrostatic potential of the macroion. The number of ionogenic groups was evaluated from curves of titration. It has been found that the constants of ionization of both ionogenic groups increased with DNA concentration. The number of ionogenic groups corresponding to the first inflection in titration curves is significantly decreased when the concentration of DNA increases. On the other hand, the number of groups corresponding to the second inflection is slightly increased. Spectrophotometric investigations of isoionic solutions of DNA showed that the molar extinction coefficient increases with the concentration of the polymer. The results are discussed in view of the change of the secondary structure of DNA caused by an increase of its concentration in isoionic solutions.


[Isolation of matrix RNA coding a tyrosine aminotransferase isoenzyme induced by hydrocortisone from rat liver polyribosomes]. Messenger RNA (mRNA) capable of coding hydrocortisone induced isoenzyme of tyrosineaminotransferase (TAT) was isolated and purified approximately 5000 times. Highly specific rabbit antibodies to the isoenzyme were obtained. Using these antibodies a specific antibody immunoadsorbent with a high capacity for specific binding to TAT was prepared. From total rat liver polyribosomes induced by hydrocortisone a specific fraction synthesising TAT was isolated by fractionation on the antibody immunoadsorbent. Affinity chromatography using poly(U)--Sephadex 4B allowed to isolate a poly(A)-containing RNA from this polyribosome fraction. The mRNA (15-16S) acts as a matrix in a cell-free protein synthesising system. The extent of purification of the mRNA was estimated by the synthesis of specific protein TAT in the cell-free system.


[Acid-base equilibrium of yellow lupine ferrileghemoglobin. potentiometric studies]. Dissociation of ionizing groups in leghemoglobin from Lupinus Luteus in the wide pH range was studied by potentiometric titration. 16 + 8 groups were shown to the titrated at acid pH. One part of them are normally titrating groups and the other one is associated with some details of protein structure. At neutral pH 4 groups are titrated, the titration of 3 of the show histeresis. Five lysins are normally titrated at the alkaline pH. among them one is possibly responsible for an alkaline dissociation. 13 charged groups take part in the dissociation, 3-4 are titrated inreversibly. The experimental results are analyzed in terms of Linderstrom-Lang-Tanford representation and are discussed on the basis of primary and three-dimentional leghemoglobin structure.


[Nature of the easily melted portions of DNA with a quasi-random base sequence]. The influence of denaturation conditions upon the character of partial denaturation of DNA with random base distribution were thoroughly studied. Maps of partial DNA denaturation were obtained at T less than TAT for phage phiB DNA at pH 10.7 and 5.5; Tg9 DNA at pH 8.8; at T less than TAT for phiB DNA at pH 10.9 and Tg9 DNA at pH 8.8. The map quality was better when obtained at higher pH values; the peaks became sharper and higher against the background. We failed to obtain maps of partial denaturation at pH 5.5, T less than TAT. The improvement of the map quality and existence of the partial denaturation maps at T less than TAT at pH 10.9 were explained by the increase of primary melting probability of AT-rich DNA regions. At high pH the denaturation map quality was temperature independent. This was explained by a very weak temperature dependence of primary melting probability for all maps of equal quality. The map quality became worse, when the quantity of loops was increased.


Impaired antibody response to pneumococcal vaccine after treatment for Hodgkin's disease. To determine if a normal antibody response can develop after therapy for Hodgkin's disease, we immunized 53 patients and 10 normal controls with dodecavalent pneumococcal vaccine. Antibody concentrations three weeks after immunization (geometric mean of 11 serotypes) were 1566 ng of protein nitrogen per milliliter in controls, 963 ng per milliliter after subtotal radiation (P less than 0.05 compared to controls), 658 ng per milliliter after chemotherapy (P less than 0.05), 377 ng per milliliter after subtotal radiation plus chemotherapy (P less than 0.01) and 283 ng per milliliter after total nodal radiation plus chemotherapy (P less 0.001). Low levels of antibody before immunization correlated with a poor response (r = +0.73, P less than 0.001). The ability to respond to immunization improved significantly but did not return to normal as long as four years after combined therapy. The antibody response to pneumococcal vaccine is profoundly impaired in patients who have received intensive treatment for Hodgkin's disease: the ability of this vaccine to protect them from overwhelming postsplenectomy infections remains in doubt.