Effect of cholesterol feeding on tissue lipid perioxidation, glutathione peroxidase activity and liver microsomal functions in rats and guinea pigs. The effect of cholesterol feeding on liver and aortic nonenzymatic lipid peroxidation and glutathione peroxidase activities, and on liver microsomal NADPH-dependent lipid peroxidation, codeine hydroxylation and cytochrome P-450 levels was examined in rats and guinea pigs. One percent cholesterol was added to a casein-sucrose-soybean oil basal diet for rats or a stock diet with 2% soybean oil for guinea pigs. The effect of vitamin E and cholestyramine was also examined in some experiments. Cholesterol feeding increased the rate of lipid peroxidation in liver and aortic homogenate both in rats and guinea pigs when fed non-vitamin E supplemented basal diets. Vitamin E supplementation prevented the increase in the aorta, but not as completely in the liver in rats, while the reverse was true in guinea pigs. The effect of cholestyramine was dependent on the level of vitamin E in the diet. Cholesterol feeding decreased glutathione peroxidase activities in rats and guinea pigs. In guinea pigs, cholesterol feeding also markedly decreased liver microsomal NADPH-dependent lipid peroxidation, codein hydroxylation and cytochrome P-450 levels especially when fed non-vitamin E supplemented basal diets. In rats, cholesterol feeding reduced liver microsomal NADPH-dependent lipid peroxidation and in some cases, increased microsomal codeine hydroxylation activities, but had no effect on microsomal cytochrome P-450 levels. Vitamin E supplementation increased liver and serum cholesterol levels in guinea pigs, but had no such effect in rats. Results of this study indicate that cholesterol feeding can result in various metabolic alterations in rats and guinea pigs. The implication of these alterations in atherogenesis requires further investigations.


Role of ascorbic acid on tyrosine hydroxylase activity in the adrenal gland of guinea pig. The decrease of tyrosine hydroxylase activity in adrenal homogenate in scurvy was recovered after the administration of ascorbic acid. The causes of the increase in the enzyme activity after the administration of ascorbic acid have been studied. 1. No significant elevation in the enzyme activity was observed after the administration of reserpine to the scortutic guinea pig. 2. A dose of metal chelating agent, alpha, alpha'-dipyridyl, prevented the ascorbic acid-induced or reserpine-induced increase in enzyme activity in the scorbutic and the non-scorbutic guinea pigs, respectively. 3. Tyrosine hydroxylase activity was partially recovered by the administration of FeSO4 to the scorbutic guinea pig. From these results, it became clear that the induction of tyrosine hydroxylase which was not observed in scurvy was due to the deficiency of Fe2+. These results suggested that ascorbic acid affected the induction of this enzyme via Fe2+.


The effect of C.P.A.P. upon pulmonary reserve and cardiac output under increased abdominal pressure. The cardiopulmonary effects of CPAP under conditions of increased intra-abdominal pressure were studied using the rabbit as an experimental model. Central venous pressure and cardiac output were reduced when the intra-abdominal pressure was increased. Addition of CPAP caused a further reduction in C.V.P. and C.O. Despite these reductions CPAP significantly improved arterial PaO2 without significant effects on pH and PaCO2. The use of CPAP in conditions associated with pulmonary dysfunction secondary to increased intraabdominal pressure may be a definite therapeutic modality.


Oral factitious injuries.

Oral factitious injuries. The subject of oral factitious injuries is reviewed and four cases are reported. It is noted that self-inflicted oral injuries are not limited to the soft tissue but may result in destruction of bone and tooth structure. While children are more often the subjects of self-injurious behavior about the oral cavity, adults may also exhibit similar conduct. Emotional problems are often co-existent with self-inflicted oral injuries, however, in some cases there does not seem to be a readily descernible emotional disturbance. Since factitious injuries often pose diagnostic problems for the dentist, some diagnostic suggestions are included.


Acute anti-inflammatory effects of aspirin and dexamethasone in rats deprived of endogenous prostaglandin precursors. Paw oedema, induced by carrageenan, was potentiated in normal rats by arachidonic acid and bishomo-gamma-linoleic acid, but not by 5,8,11-eicosatrienoic acid. The latter is not an endogenous prostaglandin precursor, but replaces the other two in essential fatty acid deficient (EFAD) rats. Carrageenan oedema was partially suppressed in these EFAD rats. Aspirin exhibited equal suppression of carrageenan oedema in both normal and EFAD rats, despite the fact that, in the latter, prostaglandins are of negligible importance. The anti-inflammatory effect of dexamethasone was also identical in both normal and EFAD rats. The view that interference with the prostaglandin-system explains the acute anti-inflammatory effects of the two drugs, is discussed, in relation to the present results.


Dihydroxylated metabolites of cannabinol formed by rat liver in vitro. Cannabinol (CBN) was metabolized in vitro by a 10,000 g supernatant from rat liver. After removal of unchanged CBN and its monohydroxylated metabolites four dihydroxylated metabolites were isolated. By nuclear magnetic resonance and mass spectrometry the compounds were identified as 1'',7-dihydroxy-CBN. Side chain hydroxylation occurred predominantly at C-4'' anc C-3''.


Oxidation of aliphatic hydroxylamines in aqueous solutions. The effects of pH, buffer constituents, duration of storage, presence of air, heavy metal ions, extracting solvents and various additives and cofactors on the aerial oxidation of some aliphatic primary and secondary hydroxylamines were investigated. Copper ions were particularly effective catalysts of the oxidation reaction. Conditions to minimize this transformation are described.


Black lipid membranes as a model for intestinal absorption of drugs. Black lipid membranes were generated in isotonic buffer (pH 4-5 and pH 6-5) from egg phosphatidylcholine and intestinal lipid, and the permeability to salicylamide, salicylic acid, p-aminobenzoic acid and tryptophan of these membranes was studied. Electrical resistance of intestinal lipid membranes was higher than that of phosphatidylcholine membranes. The presence of cholesterol produced an increase in the electrical resistance of black lipid membranes and a small decrease in the permeability of membranes to drugs. The permeability coefficient of salicylamide, an uncharged drug, was much larger than the coefficients of the charged drugs examined. The values for salicylic acid and p-aminobenzoic acid were much larger than comparable values predicted from their partition coefficients. Intestinal lipid membranes were more permeable to acidic drugs than phosphatidylcholine membranes. It is suggested that phospholipids and other lipid components of the small intestine may play an important role in the membrane permeability to acidic drugs. This method may be of interest in studying the complex processes of drug absorption from intestine.


Hydrolysis of digoxin by acid.

Hydrolysis of digoxin by acid. Predictable hydrolysis of [3H]digoxin-12alpha occurred in vitro with incubation in HCl or gastric juice. Hydrolysis varied with pH, time, temperature and agitation. Digoxin, the bis- and mono-digitoxosides of digoxigenin and digoxigenin were separated by silica gel thin-layer chromatography using chloroform-ethyl acetate-glacial acetic acid (25:25:1 v/v) and were quantitated by liquid scintillation spectrometry. Hydrolysis with incubation at 37 degrees and pH 3 for 90 min was minimal, but increased with increasing acidity until greater than 70% was hydrolysed at pH 1-2 after 30 min and greater than 96% after 90 min incubation. At pH 0-9, 87% was hydrolysed after 30 min. In vitro hydrolysis in gastric fluid was slightly less than in HCl at the same pH. A volunteer was given 150 muCi[3H]digoxin-12alpha by nasogastric tube during a pentagastrin infusion when gastric pH was 0-94. He remained on his left side and samples were aspirated at intervals and immediately neutralized. Ethanol-chloroform 50-50 (v/v) extracts of the gastric fluid aspirated after 90 min and of all the urine specimens collected for 5 days were applied to a DEAE Sephadex LH-20 column. The radioactivity appeared in a single peak as digoxigenin in the 90 min gastric aspirate and in all urine specimens. Extensive intragastric hydrolysis of digoxin may occur under conditions of maximum acid output.


The effect of compression on some physical properties of microcrystalline cellulose powders. Tablets have been prepared from previously characterized microcrystalline cellulose (Avicel) powders, using an instrumented single station tablet machine. The regenerated particle size was found to increase in compaction pressure. Compaction caused a slight initial decrease in B.E.T. surface area, followed by an increase mainly as a result of elastic recovery of the particles. The intra-particulate pore size distribution showed no change throughout the range of compaction pressures studied, demonstrating that the internal pores did not collapse. Measurement of the interparticulate porosity by mercury porosimetry, liquid penetration techniques and scanning electron microscopy showed a decrease in this parameter with increase in compaction pressure. The dissolution behaviour from the compacts showed in general a decreased rate with increase in compaction pressure, that from the cellulose grade PH 105 being slower than from the remaining grades.


The action of colloidal silicon dioxide as a glidant for lactose, paracetamol, oxytetracycline and their mixtures. Anomalies are observed in some of the physical and mechanical properties of mixtures of lactose, paracetamol and oxytetracycline when small amounts of colloidal silicon dioxide are added to them. Owing to its differing propensities to coat the particles of the host powders, the silicon dioxide acts as a glidant for the lactose and paracetamol, but as an antiglidant for the oxytetracycline.


Brain areas involved in the catecholamine mediated regulation of electroshock seizure intensity. Selective treatments which alter the catecholamine content of discrete areas of the brain were tested for their effect on electroshock seizure intensity in the rat. The data indicate that depletion of noradrenaline and dopamine in near ventricular areas by the intracerebroventricular administration of the benzoquinolizine, Ro 4-1284, enhances electroshock seizure intensity. The enhancement of seizure produced by systemic Ro 4-1284 was antagonized by the intracerebroventricular injection of noradrenaline or dopamine which do not appear to penetrate more than 1 mm into the brain. Further, pretreatment with systemic iproniazid and L-dopa completely antagonized the increased seizure intensity produced by intracerebroventricular Ro 4-1284 and repleted brain catecholamines in both near and far ventricular areas. Thus, the effects of both noradrenaline and dopamine in attenuating electroshock seizure intensity appear to be exerted principally through periventricular structures.


Simultaneous determination of 4-nitroanisole, 4-nitrophenol, and 4-nitrocatechol by phase-sensitive ac polarography. Phase-sensitive ac polarography was applied to the simultaneous quantitative determination of 4-nitroanisole, 4-nitrophenol, and 4-nitrocatechol in alkaline solutions. Certain experimental precautions are necessary to determine each compound in the presence of the other two. Thus, 4-nitrocatechol is determined indirectly by forming a yellow ratio chelate with cupric ions, wheras 4-nitroansole is determined directly by the reduction waves of the nitro group. For the determination of 4-nitrophenol, the interferency by the simultaneously present 4-nitrocatechol must be eliminated by masking it by the addition of magnesium ions. The method described permits a qualitative and quantitative analysis of all three compounds in one solution since linear calibration curves are obtained.


Kinetics of hydrolysis of fenclorac.

Kinetics of hydrolysis of fenclorac. The kinetics of hydrolysis of fenclorac were studied to determine its stability in aqueous solution at different pH's and temperatures. For this study, a stability-specific liquid chromatographic assay method was developed to separate fenclorac from its hydrolysis product, alpha-hydroxy-3-chloro-4-cyclohexylbenzeneacetic acid. The k-pH profile in the 0-12 pH range in various buffer solutions shows that fenclorac is stable in its undissociated form in strongly acidic media and is unstable in neutral and alkaline media. The instability of fenclorac in aqueous solution is proportional to the degree of ionization of the carboxyl group in the 1-4 pH range and is independent of pH above 4. The rate-determining step in the mechanism of hydrolysis of fenclorac involves ionization of the carbon-chlorine bond. The ionization is catalyzed by an intramolecular necleophilic attack on the alpha-carbon by the dissociated carboxyl group, resulting in the formation of an unstable intermediate, a three-membered ring lactone. This unstable intermediate rapidly hydrolyzes to the final hydrolysis product. This mechanism is supported by experimental evidence such as the medium effect, positive salt effect, common ion effect, and substituent effect. Arrhenius parameters for the hydrolysis of fenclorac and its 3-nitro substituted analog were obtained.


The interaction of histamine and guanylnucleotides with cardiac adenylate cyclase and its relationship to cardiac contractility. Histamine stimulates adenylate cyclase activity in a washed membrane preparation from guinea-pig ventricle. Marked synergistic effects are observed with histamine and GTP. In the absence of GTP, the degree of stimulation of the enzyme by histamine is slight and occurs only in the presence of relatively high concentrations of ATP suggesting that ATP, or contaminating GTP in commercial preparations of ATP, may partially satisfy the guanylnucleotide requirement. The GTP analog, GppNHp, strongly and irreversibly activates the cardiac enzyme. Preincubation studies, in which the membranes are treated with GppNHp alone or in combination with histamine followed by estensive washing, indicate that histamine markedly increases the rate of activation of the enzyme by the guanylnucleotide. It is suggested that the mechanism of action of histamine on adenylate cyclase involves a facilitation of the interaction of guanylnucleotides with the regulatory site of the enzyme. The relative activities for stimulation of adenylate cyclase of a series of histamine analogs correlate quite well with the activities of these derivatives on four H2-receptor systems, including atrial rate and ventricular contractility and do not correlate with the activities on H1-receptors. The H2-receptor antagonists, burimamide and metiamide, competitively inhibit hitamine-stimulated adenylate cyclase and the dissociation constants for these antagonists on the enzyme agree with the pharmacological data on the H2-receptors in the atria and ventricles. Our results suggest that histamine-stimulated cardiac adenylate cyclase can be classified inotorpic and chronotropic effects of histamine on the intact heart.


Pharmacologically induced changes in the 3':5'-cyclic guanosine monophosphate content of rat cerebellar cortex: difference between apomorphine, haloperidol and harmaline. Harmaline increases cerebellar 3':5'-cyclic guanosine monophosphate (cGMP) content in a dose-related manner; this increase is prevented by a pretreatment with 3-acetylpyridine (3-AP) (0.66 mmol/kg) which destroys climbing fibers and inhibits harmaline-induced tremor. The cerebellar cGMP content increases after isoniazid; this response remains unchanged in rats pretreated with 3-AP. Since isoniazid decreases cerebellar gamma-aminobuturic acid (GABA) levels, the increase in cGMP content might reflect a reduction in the availability of GABA at the level of postsynaptic receptors. Apomorphine (a dopamine receptor agonist) and haloperidol (a dopamine receptor blocker) increase or decrease the cGMP content of cerebellar cortex, respectively. Neither drug changes the guanylate cyclase activity of cerebellar homogenates; moreover their action on cerebellar cGMP content persists after 3-AP. Chloropromazine, like haloperidol, decreases the cerebellar cGMP content. The increase in cerebellar cGMP content elicited by apomorphine can be differentiated from that elicited by harmaline or isoniazid; presumably apomorphine indirectly activates mossy fibers. The decrease in cerebellar cGMP content elicited by haloperidol can be differentiated from that elicited by diazepam; perhaps haloperidol reduces the mossy fiber input to the cerebellum. We suggest that the cGMP content of cerebellar cortex fluctuates in response to changes in the afferent stimulatory input to the cerebellum; it increases when the activity of either climbing or mossy fibers is increased; it decreases when either of these two stimulatory inputs is reduced.


Propoxyphene and norpropoxyphene: pharmacologic and toxic effects in animals. alpha-d-Propoxyphene and its principle metabolite, alpha-d-norpropoxyphene, were compared pharmacologically to establish their relative opioid profiles as defined by naloxone reversal. Propoxyphene exhibited opioid activity in the following tests: mouse abdominal constriction and rat tail heat analgesic tests, inhibition of the twitch of the guinea-pig ileum and acute lethality in rodents. Norpropoxyphene also showed opioid activity in the rat tail heat and guinea-pig ileum tests, but exhibited nonopioid activity in the mouse abdominal constriction and acute toxicity studies. Jumping in mice, precipitated by naloxone, suggests the following order for liability to produce physical dependence after repeated administration: morphine greater than codeine greater than propoxyphene greater than norpropoxyphene approximately saline. Propoxyphene and norpropoxyphene depressed axonal conduction in isolated peripheral nerve and were comparable in potency to standard local anesthetic agents. The nonopioid actions of norpropoxyphene might be due in part to its local anesthetic properties.


Reduction of tertiary amine N-oxides by rat liver mitochondria. Reduction of tertiary amine N-oxides by the mitochondrial fraction of rat liver was investigated. NADPH was required as a cofactor. The rate of reaction was faster with the NADPH-generating system than with NADPH. Isocitrate in the NADPH-generating system revealed the maximum stimulation. A little less activity was observed when NADH was used as a cofactor instead of NADPH. The reductase activity was markedly inhibited under aerobic conditions. The rates of mitochondrial tertiary amine N-oxide reduction expressed in nanomoles per milligram of protein per minute were: N,N-dimethylaniline N-oxide, 4.3; tiaramide N-oxide, 0.47; and imipramine N-oxide, 0.14. The activity for N,N-dimethylaniline N-oxide was comparable to the microsomal activity, but the activity for imipramine N-oxide was much less than that in microsomes. Isocitrate and alpha-ketoglutarate were found to stimulate mitochondrial tertiary amine N-oxide reduction more efficiently than other Krebs cycle intermediates. Oxalacetate, on the other hand, was the least effective intermediate. ATP together with NADPH and NADP stimulated the reaction efficiently, probably due to the energy-dependent intramitochondrial transhydrogenation. Antimycin, rotenone and cyanide had little or no effect on isocitrate-dependent N-oxide reduction, whereas an inhibitory effect was observed on succinate-supported N-oxide reductase. N-oxide reductase activity in mitochondria was partially suppressed under an atmosphere of carbon monoxide, althouth no increase of the activity was observed by phenobarbital pretreatment, nor inhibition by 2,4-dichloro-6-phenylphenoxyethylamine. Experiments with digitonin-treated mitochondria demonstrated that mitochondrial N-oxide reductase was bound to mitochondrial inner membrane or its matrix.


In vitro inhibition of rho-aminohippurate transport by halogenated anesthetics. The effects of four commonly used halogenated anesthetic agents (methoxyflurane, halothane, enflurane and fluroxene) on rho-aminohippurate (PAH) uptake by rabbit renal cortical slices were examined. All agents depressed PAH uptake in a linear dose-dependent manner after 60 minutes of incubation and the effect was reversible. When the data were normalized for anesthetic potency, all agents exhibited a parallel dose-response curve. Since these agents do not share a common metabolite, it is concluded that the depression of PAH transport is mediated primarily by a direct effect of the agents acting through a common pathway. Exposure of kidney slices to perithreshold concentrations of halothane and enflurane for 180 minutes did not result in a cumulative inhibitory effect on PAH transport. A slight time-dependent effect was seen with methoxyflurane. It is suggested that with prolonged exposure metabolic conversion of methoxyflurane may occur leading to further inhibition of PAH uptake.


Intracellular pH of single crustacean muscle fibres by the DMO and electrode methods during acid and alkaline conditions. 1. The intracellular pH of intact single muscle fibres of the giant barnacle was measured directly with a glass micro-electrode following prolonged (2-5 hr) equilibration in one of three solutions: normal Ringer, CO2 Ringer and NH4+ Ringer. 2. The intracellular pH of identically-prepared fibres from the same specimen was measured indirectly from the distribution of DMO following prolonged equilibration in the same solutions. 3. The DMO-pH compared favourably with the electrode-pHi provided DMO-pHi was calculated from the values of the indicator compounds, [14C]DMO and [3H]inulin, obtained by extrapolating the slow uptake phase to time zero. 4. Following prolonged equilibration, the transmembrane H+ ion distribution was found to vary with the membrane potential but not in accordance with a simple Gibbs-Donnan equilibrium. 5. A model which recognizes the existence of two independent net fluxes for H+ across the membrane in developed to explain the results. One of the fluxes represents passive diffusion and the other represents the so called H+-pump. The model predicts the H+-pump rate increases by two orders of magnitude when pHi is reduced from 7-2 to 6-7.


Chloride transport in human erythrocytes and ghosts: a quantitative comparison. 1. Homogeneous preparations of resealed ghosts with intracellular KCl concentrations between 15 and 900 mM could be prepared. Virtually all ghosts sealed to chloride. The chloride transport system was found not to be damaged: a quantitative comparison of the self-exchange of 36Cl- across intact and resealed membranes showed that both the transport capacity and a number of characteristic properties were identical (saturation kinetics, temperature dependence and the effect of inhibitors). 2. Due to the absence of intracellular titratable buffers intracellular chloride concentration in ghosts vary only slightly between pH5 and 11. The unidirectional exchange flux was constant between pH 7 and 11, showing that the transport system does not have a functionally important titratable group in the alkaline range, as previously assumed. The decrease of transport below pH 7 is similar in intact erythrocytes and ghosts. 3. Mean cellular volume of the resealed ghosts was a function of the amount of KCl added at 'reversal', before the ghosts are sealed. The ghosts shrank by osmosis when KCl was added to the suspension of 'unsealed' ghosts. The reflexion coefficient of sucrose (and therefore the osmotic effect) is larger than that of KCl. It was, therefore, possible to demonstrate that volume changes do not affect the chloride transport across the human red cell membrane. Unidirectional chloride fluxes at a KCl concentration of 165 mM were independent of ghost volume (100-40 mum3).


Direct measurement of the intracellular pH of mammalian cardiac muscle. 1. The intracellular pH (pHi) of sheep heart Purkinje fibres and rat, ferret and guinea-pig ventricle has been measured using recessed-tip pH-sensitive micro-electrodes. 2. In the absence of CO2 the pHi was approximately 7-2 in all the preparations used. In 5% CO2 the mean pHi was 7-14 in rat and ferret ventricle and 7-02 in sheep Purkinje fibres. 3. The pHi response to an increase or a decrease in the CO2 level (at constant external pH) was biphasic with a large transient change followed by a partial recovery to a new sustained pHi. 4. The intracellular buffering capacity was 34-8 +/- 2-7 m-equiv H+/pH unit per l. (+/- S.E. of mean) in sheep Purkinje fibres, 76-6 +/- 13-6 in rat ventricle and approximately 69 in ferret ventricle. 5. The pHi of all the preparations tested indicated that H+ ions were not passively distributed across the cell membrane. There was also little or no pHi change produced by depolarization with high K solutions. 6. Short exposures to hypertonic solutions (100 mM sucrose or 50 mM-KCl) produced a decrease in pHi of approximately 0-1 pH units. 7. Acetazolamide slowed the pHi response to CO2 changes. 8. Restoration of the pHi after displacement by increasing the CO2 was not blocked by ouabain or SITS. 9. The relationship between pHi and cardiac contractility is discussed.


[Dietary protein level and circadian variation of enzyme activities for glucose metabolism and lipogenesis in male rats (author's transl)]. One hundred and seven Wistar rats, 8 weeks old and weighing 180-200 g, were housed under conditions of controlled temperature (22 plus or minus 2 degrees) and lighting (light on from 07:00 to 19:00). They were divided into 2 groups and fed diets containing either 15 per cent cas-protein for 23 days. Food consumption was recorded every 2 hours for each animal during 48 hours. Four or five rats from each group were killed every 2 hours for 24 hours and the hepatic activities of PK (EC.2.7.1.40),G6P-DH (EC1.1.1.49), ME (EC1.1.1.40), Acetyl-CoA-carbox (EC.6.4.1.2.),PC(EC.6.4.1.1.), PEP-CK(EC.4.1.1.32), G6Pase (EC.3.1.3.9) and GPT (EC.2.6.1.2.) were measured...


Studies on antianaphylactic agents. 5. Synthesis of 3-(1H-tetrazol-5-yl)chromones, a new series of antiallergic substances. A number of 3-(1H-tetrazol-5-yl)chromones were synthesized and found to have antiallergic activity in the rat passive cutaneous anaphylaxis (PCA) test. These compounds are active when administered orally in rats and of possible value for the treatment of asthma.


Use of distribution coefficients in quantitative structure-activity relationships. The use of distribution coefficients (log D) for the analysis of structure-activity relationships of ionizable compounds is described. (D is the ratio of the equilibrium concentration of compound in an organic phase to the total concentration of un-ionized and ionized species in the aqueous phase at a given pH.) Simpler equations, often with improved correlations, have resulted. This method has the advantage that the influence of pKa or equivalent electronic factors on distribution can be distinguished from electronic effects related to mechanism of action. Several absorption studies are reanalyzed as well as studies on membrane conductance and uncoupling of oxidative phosphorylation.


5,11-dimethyl-2,9-bis(phenylacetyl)-5,11-diazatetracyclo[6.2.2.0(2,7).0(4,9)]dodecane, a potent, novel analgesic. 5,11-Dimethyl-2,9-bis(phenylacetyl)-5,11-diazatetracyclo[6.2.2.0(2,7)90(4,9)]dodecane (2a) has been found to be a potent narcotic analgesic of unusual structure. All of the analgesic activity was attributable to the levorotatory isomer 2b which was approximately three times as potent as morphine in the rat. Removal of one N-methyl group from 2a reduced, but did not abolish, the analgesic activity. However N-allyl analogues were neither agonists nor antagonists. Replacement of one of the phenyls of 2a with a cyclohexyl group yielded an analogue with considerable activity. Structural similarities with derivatives of ethenooripavine are noted.


Ergoline congeners as potential inhibitors of prolactin release. 3. Derivatives of 3-phenylpiperidine. In a continuation of our attempts to elucidate the prolactin release inhibiting pharmacophore within the ergoline structure, we have prepared several derivatives of 3-phenylpiperidine. These congeners have been evaluated for inhibition of prolactin release in vivo and are for the most part inactive.


Esters of 4-[3-[2-(trifluoromethyl)phenothiazin-10-yl]propyl]-1-piperazieneethanol and related compounds as long-acting antipsychotic agents. Synthesis of the 1-adamantoate, the first crystalline base. A number of new esters of fluphenazine are described: among these was the 1-adamantoate, 1h, the first highly crystalline ester of that drug. The 1-adamantoate of pipotiazine, 2b, typically, was an oil. Following a single subcutaneous or intramuscular injection of 25 mg/kg of either 1h or 2b, dissolved in sesame oil, each ester was found to be a potent and long-acting inhibitor of conditioned avoidance behavior in the rat.


Relationships between opiate receptor binding and analgetic properties of prodine-type compounds. The receptor binding affinities of some diastereoisomeric prodine analgoues have been compared with their analgetic activities determined by the hot-plate test in mice. The close correlation found between these potencies indicates that the relative analgetic activities of the alpha/beta isomers are determined primarily by the appropriate association to the receptor sites.


Electrochemical potential of protons in vesicles reconstituted from purified, proton-translocating adenosine triphosphatase. Measurements were made of the difference in the electrochemical potential of protons (delta-mu H+) across the membrane of vesicles restituted from the ATPase complex (TF0.F1) purified from a thermophilic bacterium and P-lipids. Two fluorescent dyes, anilinonaphthalene sulfonate (ANS) and 9-aminoacridine (9AA) were used as probes for measuring the membrane potential (delta psi) and pH difference across the membrane (delta pH), respectively. In the presence of Tris buffer the maximal delta psi ans no delta pH were produced, while in the presence of the permeant anion NO-3 the maximal delta pH and a low delta psi were produced by the addition of ATP. When thATP concentration was 0.24 mm, the delta psi was 140-150 mV (positive inside) in Tris buffer, and the delta pH was 2.9-3.5 units (acidic inside) in the presence of NO-3. Addition of a saturating amount of ATP produced somewhat larger delta psi and delta pH values, and the delta -muH+attained was about 310mV. By trapping pH indicators in the vesicles during their reconstitution it was found that the pH inside the vesicles was pH 4-5 during ATP hydrolysis. The effects of energy transfer inhibitors, uncouplers, ionophores, and permeant anions on these vesicles were studied.


Electrical hemolysis of human and bovine red blood cells. The external electric field strength required for electrical hemolysis of human red blood cells depends sensitively on the composition of the external medium. In isotonic NaCl und KCl solutions the onset of electrical hemolysis is observed at 4 kV per cm and 50 per cent hemolysis at 6 kV per cm, whereas increasing concentrations of phosphate, sulphate, sucrose, inulin and EDTA shift the onset and the 50 per cent hemolysis-value to higher field strengths. The most pronounced effect is observed for inulin and EDTA. In the presence of these substances the threshold value of the electric field strength is shifted to 14 kV per cm. This is in contrast to the dielectric breakdown voltage of human red blood cells which is unaltered by these substances and was measured  to be approximately 1 V corresponding in the electrolytical discharge chamber to an external electric field strength of 2 to 3 kV per cm. On the other hand, dielectric breakdown of bovine red blood cell membranes occurs in NaCl solution at 4 to 5 kV per cm and is coupled directly with hemoglobin release. The electrical hemolysis of cells of this species is unaffected by the above substances with exception of inulin. Inulin suppressed the electrical hemolysis up to 15 kV per cm. The data can be explained by the assumption that the reflection coefficients of the membranes of these two species to bivalent anions and uncharged molecules are field-dependent to a different extent. This explanation implies that electrical hemolysis is a secondary process of osmotic nature induced by the reversible permeability change of the membrane (dielectric breakdown) in response to an electric field. This view is supported by the observation that the mean volumes of ghost cells obtained by electrical hemolysis can be changed by changing the external phosphate concentration during hemolysis and resealing, or by subjecting the cells to a transient osmotic stress immediately after the electrical hemolysis step. An interesting finding is that the breakdown voltage, although constant throughout each normally distributed ghost size distribution, increases with increasing mean volume of the ghost populations.


Effects of parathyroid hormone on H+ and NH+4 excretion in toad urinary bladder. The urinary bladder of Bufo marinus excretes H+ and NH+4, and the H+ excretion is increased after the animal is placed in metabolic acidosis. The present study was done to determine if parathyroid hormone could stimulate the bladder to increase the excretion of H+ and/or NH+4. Parathyroid hormone added to the serosal solution in a final concentration of 10 mug/ml was found to increase H+ excretion by 50 per cent above the control hemibladders, while there was no effect on NH+4 excretion. Parathyroid hormone had no effect on H+ excretion when added to the mucosal solution. We also performed experiments utilizing theophylline and dibutyryl cyclic AMP which mimicked those of the parathyroid hormone experiments. A dose-response analysis was performed and the results indicate that 1 mug/ml of parathyroid hormone was the minimal effective dose. These results suggest that parathyroid hormone can stimulate H+ excretion in the toad urinary bladder and this effect seems to be mediated by cyclic AMP. In addition, it was found that parathyroid hormone has no effect on NH+4 excretion.


The possible role of solid surface area in condensation reactions during chemical evolution: reevaluation. Published data on adsorption and condensation of amino acids, purine and pyrimidine bases, sugars, nucleosides, and nucleotides are analyzed in connection with Bernal's hypothesis that clays and other minerals may have provided the most likely surface for adsorption and condensation of these molecules in prebiotic times. Using surface concentration and reaction rate as the main criteria for the feasibility of condensation reactions, four types of prebiotic environments were analyzed: (1) an ocean-sediment system, (2) a dehydrated lagoon bed produced by evaporation, (3) the surface of a frozen sediment, and (4) a fluctuating system where hydration (rainstorms, tidal variations, flooding) and dehysration (evaporation) take place in a cyclic manner. With the possible exception of nucleotides, low adsorption of organomonomers on sediment surfaces of a prebiotic ocean (pH 8) is expected, and significant condensation is considered unlikely. In dehydrated and frozen systems, high surface concentrations are probable and condensation is more likely. In fluctuating environments, condensation rates will be enhanced and the size distribution of the oligomers formed during dehydration may be influenced by a "redistribution mechanism" in which adsorbed oligomers and monomers are desorbed and redistributed on the solid surface during the next hydration-dehydration cycle.


Some aspects and implications of coital physiology. A review of some experiments in human coital physiology in the home setting considers their possible value to the sex therapist. Blood pressure changes are described in normal subjects with reference to their relevance in patients with heart disease or high blood pressure. Respiratory patterns and intravaginal and intrauterine pressure changes are described during coitus, and their significance in different types of female orgasm are discussed. It now appears that a specific deeply satisfying and terminative female orgasm is associated with a particular type of respiratory pattern and intrauterine pressure change. The use of radiotelemetry devices to measure pressure and pH changes during coitus makes home studies possible. Further projects and areas for future study are considered.


Role of endogenous murine leukemia virus in immunologically triggered lymphoreticular tumors. I. Development and use of oncogenic cellfree preparations serially passaged in vivo. Cellfree extracts (CFEs) prepared from (BALB/cJ X A/J)F1 (CAF1) and (BALB/cJ X C57BL/6J)F1 (CB6F1) mice in which a graft-versus-host reaction (GVHR) has been induced are known to be oncogenic, but only after a protracted latent period (mean, 16 mo). Serial passage of such CFEs in successive generations of syngeneic mice inoculated at birth led to the development of two separate oncogenic preparations, the CA serioes in CAF, mice and the CB series in CB6F, mice, in which the mean latent period was reduced to 6 and 12 months, respectively. Both oncogenic preparations contained infectious B-tropic murine leukemia virus (MuLV) and particles with the ultrastructural characteristics of MuLV. No other kind of virus particle was seen. When these preparations were injected into infant syngeneic mice, B-tropic MuLV could be detected in the reticular tissues as early as 2 weeks thereafter. The virus persisted in the reticular tissues and was present in the lymphoreticular tumors that subsequently developed. However, if the same preparation was injected into young adult recipients, there may have been transient MuLV replication, but the virus subsequently disappeared from the reticular tissues and no lymphoreticular tumors developed. Previous experiments showed that MuLV was present in CFEs prepared from CAF, animals with the GVHR but absent in those of normal control mice. Since the lymphoreticular tumors arising in mice with the GVHR were the same as those induced by the CA and CB MuLV preparations, it was concluded that tumorigenesis in mice with the GVHR was caused by endogenous B-tropic MuLV activated by the immunologic disturbance.


Neurotransmission and glial cells: a functional relationship? The investigations reported here demonstrate high affinity transport systems localized in glial cells which appear to be specific for amino acid neurotransmitter candidates. Data on uptake of gamma-aminobutyric acid (GABA), glutamate, glycine, and taurine, show transport systems with KT'S in the range of 10(-5) M. In addition, the distribution of the glial transport system for glycine is shown to parallel the presumed distribution of glycine as an inhibitory neurotransmitter. Results of these studies also suggest that transport studies on brain homogenates or synaptosomal preparations do not serve to localize these functions to synaptic elements as is widely believed. This report shows that glia can form vesicles during homogenization which band which synaptosomes in density gradients, and retain transport activity. Glia also may contribute to the release of neurotransmitters via control of the extracellular Ca++ concentration. This is shown by the ability of GABA in the extracellular media to cause release of Ca++ by glia.


Role of the pneumococcal autolysin (murein hydrolase) in the release of progeny bacteriophage and in the bacteriophage-induced lysis of the host cells. The pneumococcal bacteriophage Dp-1 seems to require the activity of the N-acetylmuramic acid-L-alanine amidase of the host bacterium for the liberation of phage progeny into the medium. This conclusion is based on a series of observations indicating that the exit of progeny phage particles is prevented by conditions that specifically inhibit the activity of the pneumococcal autolysin. These inhibitory conditions are as follows: (i) growth of the bacteria on ethanolamine-containing medium; (ii) growth of the cells at pH values that inhibit penicillin-induced lysis of pneumococcal cultures and lysis in the stationary phase of growth; (iii) addition of trypsin or the autolysin-inhibitory pneumococcal Forssman antigen (lipoteichoric acid) to the growth medium before lysis; (iv) infection of an autolysin-defective pneumococcal mutant at a multiplicity of infection less than 10 (treatment of such infected mutant bacteria with wild-type autolysin from without can liberate the entrapped progeny phage particles); (v) release of phage particles and culture lysis can also be inhibited by the addition of chloramphenicol to infected cultures just before the time at which lysis would normally occur. Bacteria infected with Dp-1 under conditions nonpermissive for culture lysis and phage release secrete into the growth medium a substantial portion of their cellular Forssman antigen in the form of a macromolecular complex that has autolysin-inhibitory activity. We suggest that a phage product may trigger the bacterial autolysin by a mechanism similar to that operating during treatment of pneumococci with penicillin (Tomasz and Waks, 1975).


Prazosin-new hypertensive agent. A double-blind crossover study in the treatment of hypertension. Prazosin hydrochloride, a new antihypertensive agent, is said to be of mild-to-moderate potency when used as a sole agent in mild-to-moderate hypertension and when used in conjunction with other agents in severe hypertension. In our study of 14 patients comparing hydrochlorothiazide with prazosin, the antigypertensive effect of prazosin was less than that of hydrochlorothiazide. The greatest application of prazosin may be in conjunction with thiazide diuretics and beta-adrenergic blocking agents as the second or third drug.


Hemodialysis in methyprylon overdose. Some pharmacokinetic considerations. Serial measurements of serum methyprylon concentration were made in the case of a 14-year-old girl who ingested an overdose of the drug. Our data indicate that, in the presence of high plasma levels of the drug, much longer half-lives than the usually reported four hours may be observed. It is postulated that saturation kinetics may be a possible mechanism for this observation. The striking clinical improvement after six hours of hemodialysis demonstrated the efficacy of this mode of treatment in our patient.


Effects of subcutaneously administered adrenaline on human eccrine sweating, with special reference to the physiological significance of the adrenergic sweating mechanism. The effects of a small dose (3-6 mug/kg) of subcutaneously administered adrenaline on thermal sweating were studied while subjects were at rest and during or after excerise by means of continuous monitoring by resistance hygrometry of the sweat rate in the forearm area. In most cases, the sweat rate either decreased or did not change significantly following the adrenaline injection, however, among athletic subjects it showed a mild increase in a few cases, mostly during or after exercise. In the area receiving the intradermal injection of an alpha-adrenergic blocking agent, tolazoline, phentolamine or dihydroergotoxine, subcutaneous adrenaline consistently caused an increase in sweat rate. Adrenaline (15 mug) was injected intravenously with similar results. Noradrenaline was used in place of adrenaline in some cases, and the results were essentially the same as, but less distinct than, those with adrenaline. The results indicate that a small dose of subcutaneous adrenaline has dual effects, with the sweat-inhibitory effect generally predominating over the sweat-facilitatory one, with occasional exceptions in association with exercise and/or physical training. The former effect is largely secondary to its vasconstrictive effect, whereas the latter appears to be secondary to its systemic effects, such as central and calorigenic ones. It is concluded that adrenaline within a physiological range exerts no direct action on human eccrine sweat glands.


Jimson seed poisoning-- a new hallucinogen on the horizon. Of 27 patients with Jimson seed poisoning recently treated in the University of Cincinnati Medical Center, 15 were admitted to the hospital, while 12 were treated and released. The patients ranged in age from 13 to 21. The dose was between 2 gm and 25 gm. Time from ingestion to arrival in the emergency department averaged 12.1 hours for those admitted and 10 hours for those who were not. All patients had altered mental status. Twenty-five of the 27 received Ipecac and all but one received at least 2 mg of physostigmine, which produced dramatic improvement in central nervous system symptoms. The authors have developed a management protocol based on physiologic criteria.


[Use of beta-stimulators in chronic ischemic heart disease with complete atrioventricular block complicated by congestive circulatory insufficiency]. In 23 patients with full atrioventricular block and congestive heart failure developing against the background of chronic ischaemic heart disease Isuprel was injected intravenously at a speed of 1 to 3 muG/min. A positive chronotropic effect of the drug was observed and attributed to the dose employed. Isuprel produced a positive dynamics in the structure of the cardiac cycle in the treated patients. A course of such therapy resulted in a reduction, or even disappearance of the circulatory insufficiency signs in the majority of patients, but sinus rhythm could not be restored in either of them. The noted side effects were typical of beta-stimulators. Two patients developed anginal pains in the zone of the heart when the drug was given intravenously.


Isolation and characterization of uricine from uric acid stones. Uricine was found to be present in all uric acid stones tested, although another physiochemically related pigment was occasionally present. Uricine is of low molecular weight (28.2) and a preliminary analysis of its structure suggests that it is formed by two pyrrolic rings. It is a yellow pigment whose color is pH-dependent, shifting from reddish-yellow to green at pH 1.0. It is water soluble, but its solubility increases in alkaline solutions. Preliminary evidence suggests that uricine is related metabolically to bilirubin-like compounds.


[The influence of plasma protein binding on distribution and pharmacological activity of tranquilizers of the benzodiazepine group (author's transl)]. This paper discusses the problem if the plasma protein binding of benzodiazepine derivatives can influence distribution and pharmacological activity of the drugs. The distribution of the benzodiazepines in the organism is influenced not only by the plasma protein binding of the drugs, but also by several other factors, especially since the drugs are mostly lipophilic. Thus, an effect of the plasma protein binding on the distribution can only be expected if the benzodiazepine derivative is highly bound to the plasma proteins. Thus results have been shown only for diazepam and chlordiazepoxid, which indicate an effect of the plasma protein binding on distribution and pharmacological activity, for example the existence of a direct correlation between unwanted CNS depressions and low plasma albumin concentrations and a direct correlation between the plasma protein binding and the biological half-life. There are no observations available on a displacement of other drugs from their binding to plasma proteins by benzodiazepines. The observed displacement of thyroid hormones from their binding to plasma proteins seems to have only a significance for thyroid function tests in vitro. It was shown that benzodiazepines decrease the amount of L-tryptophan bound to serum albumin in vitro and in vivo and increased therewith the L-tryptophan concentration in the brain. At present it can not be confirmed if these observations bear any significance on the pharmacological activity of the drugs. But these experiments demonstrate the significance of the use of albumin as a model for the interaction of drugs with tissue or receptorproteins.


Reoperations for myocardial revascularization. Reoperations solely for myocardial revascularization were performed in 219 consecutive patients (1967 to 1975). Indications were (1) graft failure, 46 (21 per cent); (2) progressive atherosclerosis, 42 (19 per cent); (3) incomplete revascularization, 39 (18 per cent); and (4) combinations, 92 (42 per cent). Primary operations included bypass grafts in 100 patients; mammary artery implants, 87; and combinations of direct and indirect procedures, 32. Reoperations performed were single bypass, 141 patients; double, 61; and triple or other coronary artery operations, 17. Eight patients died within 30 days of operation (3.7 per cent). Major postoperative complications included hepatitis, 24 (11 per cent); myocardial infarction, 19 (9 per cent); bleeding, 21 (10 per cent); and respiratory insufficiency, 12 (5 per cent). Follow-up for 202 long-term survivors was complete (mean 29 months). In patients who originally underwent direct revascularization, Class I or II (N.Y.H.A.) was attained in 35 of 43 (81 per cent) of those reoperated upon for primary graft failure, in 14 of 15 (93 per cent) of those with progressive atherosclerosis, and in 27 of 33 (82 per cent) of patients with combined indications. Arteriography was performed after the reoperation in 55 patients (mean interval 17 months), and 65 of 77 (84 per cent) grafts were patent. Nineteen of 22 grafts performed for primary graft failure were patent. We have made the following conclusions: (1) Reoperation for direct myocardial revascularization can be accomplished with low mortality rates although morbidity is high; (2) complete relief of symptoms was achieved in 65 per cent of survivors; (3) results in patients reoperated upon for graft failure alone were similar to results in those operated upon for progressive atherosclerosis or combined indications; and (4) high graft patency was found in secondary grafts constructed to arteries involved with primary graft failure.


[Relationship of the content of carboxyhemoglobin in the blood and of carbon monoxide in the expired air of test subjects to the CO concentration in the air of a hermetic chamber]. Four manned experiments (4 test subjects participating in each) were carried out in a chamber of 24 m3. The effect of CO at a concentration of 10 to 45 mg/m3 on the content of carboxyhemoglobin in the blood, nonhemoglobin iron in the plasma, CO in the breathing air, catalase and peroxidase activity was studied. A correlation was found between these parameters and CO concentration in the atmosphere and exposure time. It was demonstrated that a continuous exposure (up to 90 days) to CO at a concentration of 10 mg/m3 under favorable microclimatic conditions produced no significant effect on the above mentioned biochemical paramters.


[Study of the possibility of utilizing the transpired mositure condensate from sweet potato for growing plants in biological life support systems]. The effect of nonpurified condensate obtained during prolonged cultivation of batata in a sealed chamber upon batata cuttings and seedlings of garden cress, radish and Chinese cabbage was studied. It was shown that nonpurified condensate produced an inhibitory effect on the formation of roots in batata cuttings and on the growth of previously developed roots of batata cuttings and seedlings. The studies which used a chemical model of 3,4-dihydroxy phenylalanine indicated that the condensate contained biologically active substance of organic origin. However, only experiments with the real continuous culture of batata, using real dilutions of the condensate that depend on the size of the greenhouse and the amount of the nutrient solution would clarify wheather condensate of transpiration water of batata plants can be repeatedly utilized in life support systems.


[Hygienic evaluation of experimental samples of antimicrobial underwear containing hexachlorophene]. The hygienic examination of 12 samples of knitted underwear which contained hexachlorophene added during fiber formation allowed the selection of four types that can be used under poor sanitation conditions. Taking into consideration possible changes in the proportion of various micoorganisms during prolonged space flights, it is recommended to carry out a complex investigation in order to allow the use of the antimicrobial underwear by specific crewmembers during a certain period of time.


[Assessment of the quality of relcaimed water by total organic carbon]. The paper discusses possible application of the method of measuring the total content of organic carbon to evaluate the quality or reclaimed water. The paper gives data on the content of organic carbon, ratio of chemical consumption of oxygen and carbon in the atmospheric condensate, urine, condensate of urine low-temperature evaporation and portable water reclaimed from these sources.


A multiple-parameter comparison of immunocompetence and tumor resistance in aged BALB/c mice. Several parameters of cell-mediated and humoral immunity were measured in young-adult and aged BALB/c mice and compared with resistance to the ascites form of intraperitoneal induced P815 mastocytoma. It was found that the age-related decline of in vitro phytohemagglutinin (PHA) responsiveness by spleen cells approximated the marked decrease of old mice to tumor-cell challenge and approached that characteristically seen in humoral immunity. Thus, decreased PHA responsiveness of splenic lymphocytes provided as sensitive an estimate of the age-related decline of immunocompetence in old mice as other classical parameters of cell-mediated immunity (e.g. graft-vs-host reaction or in vivo cellular proliferation of parental spleen cells in lethally-irradiated F1 recipients). Results could be interpreted to represent a decreased ability of noncycling T-cells to be released to a functional cycling state.


Hyperlipoproteinemia, diabetes, and oxygen affinity of hemoglobin. Oxyhemoglobin dissociation curves (ODC) were performed on blood from diabetic and nondiabetic subjects with and without hypertriglyceridemia. P50 at in vivo pH was slightly lower than normal in normolipemic diabetics (25.7 versus 26.6 mmHg, p less than 0.05), in spite of increased red cell 2,3-diphosphoglycerate concentration (15.4 versus 14.4 mumole/g Hg, p less than 0.025). P50 at in vivo pH in diabetics with moderately elevated very low density lipoproteins (VLDL)--Type IV hyperlipoproteinemia (HLP)--was likewise found to be slightly lower than normal (25.5 versus 26.6 mmHg, p less than 0.05). In contrast, diabetics with pronounced hyperlipemia due to accumulation of chylomicrons (type I HLP) or due to accumulation of chylomicrons (type I HLP) or due to accumulation of chylomicrons as well as VLDL (type V HLP) showed markedly increased hemoglobin--oxygen affinity (P50:21.1 versus 26.6 mmHg, p less than 0.001). The change in the ODC of normolipemic diabetics is considered to be an expresssion of the presence of an increased proportion of a hemoglobin fraction (Hb Alc) with increased oxygen affinity. The additional change in the ODC of the hyperlipemic patients is thought to be secondary to accumulation of triglyceride-rich particles for the following reasons: (1) a similar increase in oxygen affinity of hemoglobin was demonstrated in familial type I HLP of nondiabetic subjects; (2) normal red cells increased their oxygen affinity when incubated in lactescent plasma; (3) in both acquired types I and V HLP the disappearance of HLP was followed by a normalization of the ODC.


Effects on the diet on brain neurotransmitters. The synthesis of neurotransmitters in mammalian brain responds rapidly to changes in precursor availability. Serotonin synthesis depends largely on the brain concentrations of L-tryptophan, its precursor amino aicd. This relationship appears to be physiologic: when brain tryptophan levels vary because of insulin secretion or meal ingestion, corresponding alterations occur in the rate of serotonin formation. The ability of any food to modify brain tryptophan (and serotonin) depends on how its ingestion changes the serum concentration of not only tryptophan, but also several other large neutral amino acids that compete with tryptophan for uptake into the brain. Such precursor-induced changes in brain serotonin appear to be functionally important: animals having a reduced level of brain serotonin (caused by the chronic ingestion of a naturally tryptophan-poor diet, such as corn) demonstrate a heightened sensitivity to painful stimuli; this pain sensitivity can be acutely restored to normal values by a single injection of L-tryptophan, which rapidly elevates brain serotonin. The synthesis of catecholamines (e.g., dopamine, norepinephrine) in the brain also varies with the availability of the precursor amino acid L-tyrosine. Single injections of this amino acid increase brain tyrosine levels and accelerate brain catechol synthesis, while injections of a competing neutral amino acid (e.g., leucine, tryptophan) reduce brain tyrosine and its rate of conversion to dopa. The rate of catecholamine synthesis, however, appears to be influenced less by precursor levels than is serotonin formation: tyrosine hydroxylase, whcih catalyzes the rate-limiting step in catecholamine synthesis, responds strongly to end-product inhibition and to other controls that reflect variations in neuronal activity. The synthesis of acetylcholine in brain responds to substrate (choline) availability much like serotonin synthesis. Short-term alterations in brain choline levels are mirrored by similar changes in brain acetylcholine concentration. Variations in the daily dietary intake of choline also modify brain choline and acetylcholine. The relationship between choline availability and acetylchyoline synthesis has already foudn a cletween choline availability and acetylchyoline synthesis has already found a clinical application: choline has been used successfully in the treatment of tardive dyskinesia, a disorder of the central nervous system thought to reflect a deficiency in cholinergic transmission. These relationships between precursor availability from the periphery and brain neurotransmitter synthesis may ultimately provide the brain with information about peripheral metabolic state.


Heritable catabolic and anabolic disorders of lipid metabolism. The principal manifestations and metabolic defects in ten heritable disorders of lipid metabolism are discussed. Facile procedures have been developed for the diagnosis of patients with these conditions, the identification of heterozygous carriers, and the prenatal detection of any of these diseases. Enzyme replacement appears promising for patients with Fabry's disease and Gaucher's disease who do not have central nervous system damage. The clinical and biochemical abnormalities that occur in patients with a novel inherited disorder of ganglioside anabolism are described.


[Transitional state of Candida utilis chemostat culture after shock caused by a low pH value of the medium during 1 generation]. Transitional states of Candida utilis BKM Y-1668 were found during its growth in conditions of chemostat at D of 0.1 hr(-1) and glycerol limit after a shock caused by an extreme pH value (2.2). The optical density of the cells, the amount of dry biomass and protein, the activity of respiration, the content of ATP, and the activity of ATPase decreased, the character of the decrease being that of damped oscillations. Qualitative changes were detected in the activity of respiration, oxygen uptake was not inhibited by cyanide. More glycerol and phosphorus are utilized in processes of vital activity. Therefore, a sharp change of pH values causes profound changes in the metabolism of the yeast cell.


[Chitinase of Bacillus thuringiensis].

[Chitinase of Bacillus thuringiensis]. Strains of Bacillus thuringiensis were shown to hydrolyse various forms of chitin around growing colonies on a solid medium. In conditions of submerged cultivation on a medium containing demineralized crab shells, Bac. thuringiensis var. caucasicus INMI Arm. 837 manifests the chitinolytic activity at the beginning of the stationary growth phase. The activity of chitinase which is of a constitutive nature increases when the bacterium is cultivated at pH 7.2. The maximum rate of hydrolysis of colloid chitin by chitinase prepared from the cultural broth is displayed at pH 8.0 and 60 degrees C.


Two membrane sites for DNA synthesis in Pneumococcus. A DNA membrane fraction extracted from pneumococci can be separated into two subfractions with respect to macromolecular composition and DNA synthesis by centrifugation in a 30-60% w/v neutral sucrose gradient. Each fraction can be rebanded in a sucrose gradient or centrifuged to equilibrium in a CsCl density gradient without altering the ability of the fractions to synthesize DNA. The fast sedimenting (heavy) fraction contains 45% of the DNA, and the bulk of the phospholipid, protein, and RNA. The light fraction contains 50% of the DNA, and lower, but significant amounts of phospholipid, RNA, and protein. Both fractions contain a DNA replication complex consisting of a number of enzymes involved in synthesizing DNA or DNA precursors, as well as RNA polymerase activity. However, the specific activity of DNA polymerase in the light fraction is much greater than that in the heavy fraction. In addition, the following results suggest that the former is concerned primarily with replication of the genome while the latter has characteristics of a repair function for the genome. (1) newly synthesized DNA can be detected within 30 s in the light fraction but not until 4 min in the heavy fraction. (2) an RNA-DNA single-stranded hybrid can be demonstrated during initial stages of DNA synthesis in the light, but not heavy fraction. (3) extensive semiconservative DNA replication occurs in the light fraction, whereas little such replication is detected in the heavy fraction. (4) DNA polymerase activity in the light fraction has several of the characteristics of a polymerase identified by others as being concerned with normal DNA replication, such as inhibition by N-ethylmaleimide, and relatively high rates of chain elongation (4.9 x 10(4) nucleotides/min). In contrast, DNA polymerase activity in the heavy fraction has characteristic properties associated with DNA polymerase I, a possible repair enzyme. These include higher activity for a d(A-T)n template than that detected in the light fraction, no effect of N-ethylmaleimide, and relatively low rates of chain elongation (9 x 10(3) nucleotides/min).


Biochemical, genetic, and regulatory studies of alanine catabolism in Escherichia coli K12. E. coli K12 was found to utilise both D-and L-stereoisomers of alanine as sole sources of carbon, nitrogen and energy for growth. This capability was absolutely dependent upon the possession of an active membrane-bound D-alanine dehydrogenase, and was lost by mutants in which the enzyme was defective. The Michaelis constant for the enzyme with D-alanine as substrate was 30 mM, and the pH optimum about 8.9. D-alanine was the most active substrate, L-alanine was inactive and several other D-amino acids were 10--50% as active as D-alanine. Oxidation of D-alanine was linked to oxygen via a cytochrome-containing respiratory chain. Synthesis of the dehydrogenase was induced 16 to 23-fold by incubation with D- or L-alanine, but only D-alanine was intrinsically active as an inducer. L-alanine was active either as a substrate or inducer only in t he presence of an uninhibited alanine racemase which converted it to the D-isomer. The map-location of their structural genes between ara and leu, together with other similarities, indicate that D-alanine dehydrogenase and the "alaninase" of Wijsman (1972a) are the same enzyme. Both D- and L-alanine were intrinsically active as inducers of alanine racemase synthesis. The synthesis of both D-alanine dehydrogenase and alanine racemase was found to be regulated by catabolite repression.


[Treatment of ischemic heart disease with "coronary drugs" (author's transl)]. The standard treatment of ischemic heart disease consists in the administration of nitrates and beta-sympathicolytic agents. Calcium antagonists are likewise promising. They should be used particularly if beta-sympathicolytic agents are contraindicated. In the beginning special caution should be exercised on combining a beta-sympathicolytic agent with a calcium antagonist. This is best done under clinical supervision since sudden cardiac decompensation, extreme bradycardia and/or disturbed atrioventricular conduction is to be expected. Today the administration of "coronary dilators" is no longer a part of the standard treatment but can at best be regarded as supplementary therapy.


Lytic enzymes in the autolysis of filamentous fungi. The degrees of autolysis attained by five different genera of filamentous fungi during an incubation period of 60 days, under the same culture conditions were: 87.3% for Penicillium oxalicum; 65.9% for Neurospora crassa; 62.7% for Polystictus versicolor; 51.7% for Aspergillus niger and 23.5% for Nectria galligena. N. crassa, A. niger and P. versicolor reached the end of the autolysis during this incubation period (60 days), whereas P. oxalicum and N. galligena did not. The excretion of the lytic enzymes beta-N-acetylglucosaminidase, beta -1-3 glucanase, chitinase, invertase and acid phosphatase into the culture medium during growth and autolysis was investigated. The excretion of these enzymes was consistent with the degree of autolysis reached, the maximum excretion belonging to P. oxalicum and the minimum to N. galligena. The N. crassa invertase was excreted into the culture liquid at levels very much higher than the other enzymes studied, and at levels very much higher than the invertases excreted by the other fungi.


Methylation and aging in Rhizoctonia solani. Our earlier studies had shown that as fungi age, many of their vital functions decrease; in Rhizoctonia solani, protein synthesis is one of the functions so affected. We now find that the ability to methylate tRNA, a vital component of the protein synthesizing system, also decreases with age. This methylation of Escherichia coli tRNA by R. solani methylase preparations increased with the concentration of enzyme and with time of incubation; in both cases the rate of increase was considerably higher for preparations from young cells than for those from old cells. The methylation reaction also increased with the concentration of substrate tRNA, with temperature, at least to 45 degrees C, and with pH to 9.0. Methylase preparations from R. solani methylated both exogenous E. coli tRNA and yeast tRNA, but were only weakly active on isolated R. solani tRNA. However, acid-precipitated methylases from R. solani were very effective in methylating the homologous exogenous tRNA. Regardless of the source of the tRNA used as substrate, the methylases from older cells were always less active than those from young cells from the same mycelium. No methylase inhibitor was detected in the fungus.


Development of Chronomers for narcotic antagonists. The object of this program is to prepare a bioerodable naltrexone delivery system which can be implanted subcataneously in human and which can relieve the narcotic antagonist over 1-6 months at relatively constant and sufficient rates to block the euphoric effect of morphine based drugs. The system is composed of naltrexone uniformly dispersed in a solid hydropholic CHRONOMER matrix which undergoes predictable surface erosion when exposed to an aqueous medium. Kinetic studies in vitro have been carried out during the course of the program to determine the best composition for the system. Toxilogical studies conducted at ALZA during the past 2 years have not revealed limiting adverse effects of either the CHRONOMER materials or their hydrolysis products. The tail-flick test procedure was used to measure the effectiveness of naltrexone to antagonize the analgesis of morphine in rats. Naltrexone infused intravenously at doses of 4 and 16 ug/kg/hr resulted in, after 6 hours, 54 and 89 per cent antagonism, respectively, against a 63.5 per cent effective dose of morphine. Preliminary sterilization studies showed that no adverse effects to CHRONOMER/naltrexone systems occurred after exposure to 2.5 or 5.0 mrads of 60Co irradiation.


Octopamine.

Octopamine. Octopamine is highly concentrated in neurones of several invertebrate species. Unlike in mammals, octopaminergic neurones in invertebrates are spatially separated from catecholaminergic neurons. In identified nerve cells of Aplysia, however, this amine coexists with other putative neurotransmitters. Octopamine is synthesized in nerves from tyrosine and tyramine and metabolised mainly by monoamine oxidase. When lobster nerves are depolarized, octopamine is liberated by a Ca2+-dependent process. A specific adenylate cyclase is stimulated by octopamine in several invertebrates to activate phosphorylase in the cockroach, induce a light-flash in firefly lattern or inhibit rhythm contractions in locust muscle. All of these observations provide compelling evidence that octopamine is a neurotransmitter in invertebrates. In mammals octopamine is localised in nerves in peripheral tissues and brain where it seems to coexist with noradrenaline, the catecholamine being present in much higher concentrations. Octopamine is released from nerves together with noradrenaline and it may under certain conditions modify the actions of the adrenergic neurotransmitter. Octopamine is present in unusually high concentrations in certain neurological and hepatic diseases and may have a pathophysiological role.


Effects of two benzodiazepines, phenobarbitone, and baclofen on synaptic transmission in the cat cuneate nucleus. The effects of diazepam, flunitrazepam, phenobarbitone and baclofen on excitatory as well as on pre- and postsynaptic inhibitory processes in the cuneate nucleus were studied in decerebrate cats. Afferent presynaptic inhibition in the cuneate nucleus, evoked by volleys in the median nerve, and assessed by the size of the positive cuneate surface potential (P wave), the dorsal column reflex (DCR), and the increased excitability of primary afferent terminals of the ulnar nerve, was markedly enhanced by diazepam (0.1-3.0 mg/kh i.v.) and flunitrazepam (0.01-0.3 mg/kg i.v.), slightly enhanced by lower doses of phenobarbitone (3-20 mg/kg i.v.), but depressed by baclofen (1-10 mg/kg i.v.). Diazepam, flunitrazepam and phenobarbitone also increased postsynaptic inhibition in the cuneate nucleus which was measured by the decrease after conditioning volleys in the median nerve of the short-latency lemniscal response to cuneate stimulation. The GABA receptor blocking agent, picrotoxin, antagonized the effects of diazepam on pre- and postsynaptic inhibition in a surmountable way. After thiosemicarbazide (TSC), an inhibitor of GABA synthesis, both pre- and postsynaptic inhibition were greatly reduced and the augmenting effect of diazepam on both types of inhibition was nearly abolished. Aminooxyacetic acid (AOAA), an inhibitor of GABA degradation, slightly enhanced pre- and postsynaptic inhibition; the effects of diazepam were unaffected by AOAA. Diazepam, flunitrazepam and phenobarbitone did not alter the resting excitability of primary afferent endings or of cuneo-thalamic relay (CTR) cells in the cuneate nucleus. After higher doses (30 mg/kg i.v.) of phenobarbitone pre- and postsynaptic inhibition, which were enhanced by 10 mg/kg of this drug, tended to return to pre-drug values or below. Phenobarbitone, in contrast to benzodiazepines, also depressed in a dose-dependent way the N wave, which is an index of the orthodromic excitation of the CTR cells. Baclofen strongly depressed the cuneate N wave, decreased the excitability of CTR cells, reduced pre- and postsynaptic inhibition, but had no effect on the resting excitability of primary afferent endings. Our findings suggest the following modes of action of the above mentioned drugs: 1. benzodiazepines enhance selectively the GABA-mediated pre- and postsynaptic inhibition in the cuneate nucleus; 2. phenobarbitone slightly enhances pre- and postsynaptic inhibition only in a narrow dose range, and in addition reduces the excitatory processes in the cuneate nucleus; 3. baclofen seems to depress the excitation of cuneate relay cells and interneurones postsynaptically; the depression of relay cells is probably nonspecific.


The effect of tris(2-chloroethyl)amine on human hemoglobin. The reaction of tris(2-chloroethyl)amine (TCEA) with purified hemoglobin and its effect on properties of hemoglobin was studied using 14C-labeled TCEA. Hemoglobin remained soluble after binding as much as 4 TCEA per heme. In concentrations which did not denature hemoglobin TCEA reacted only with a small proportion of the free SH groups; blockade of the SH groups with PMB did not noticeably affect the binding of TCEA to hemoglobin. Hydrolysis by trypsin or chymotrypsin of hemoglobin which had reacted with TCEA yielded radioactive peptides besides not radioactive peptides and radioactive compounds not reacting with ninhydrin. The reaction with TCEA caused a change in electrophoretic mobility of hemoglobin and prevented its complete disintegration by PMB into subunits. After reaction with TCEA the affinity of hemoglobin for oxygen was strongly increased and the heme-heme interaction strongly diminished. The Bohr effect and the effect of 2,3-diphosphoglycerate on oxygen affinity remained unchanged. The effect of TCEA on the properties of hemoglobin points to specificity in its reaction with functional groups of hemoglobin.


Effects of cimetidine on adenylate cyclase activity of guinea pig gastric mucosa stimulated by histamine, sodium fluoride and 5'-guanylylimidodiphosphate. Cimetidine, a recently developed histamine H2-receptor blocking agent has been shown to be a potent inhibitor of histamine-stimulated gastric acid secretion in rat, cat, dog and man. To study the mode of action of cimetidine the modification of stimulatory effects of histamine, sodium flouride and 5'-guanylylimidodiphosphate by cimetidine on the adenylate cyclase activity of guinea pig gastric mucosa was studied. The effect of cimetidine was also compared to that of metiamide, an older histamine H2-receptor antagonist. The effect of cimetidine was qualitatively similar to that of metiamide, i.e. a selective blockade of histamine H2-receptors. Quantitatively cimetidine was about 10-fold more potent than metiamide.


Beta-adrenergic receptors in guinea-pig myocardial tissue. Stereospecific binding sites for (-) [3H]-alprenolol, a beta-adrenergic antagonist, have been identified in guinea-pig myocardial broken cell preparations. The concentration of the sites was 0.3 pmoles per mg of protein and the dissociation constant (at 37 degrees C) 10(-8) M. A close correlation between the ability of various beta-adrenergic antagonists to compete with tracer alprenolol binding and to block the response of isoprenaline-stimulated myocardial adenylate cyclase has been found. Low affinity sites for the labelled beta-adrenergic antagonist in contrast to stereospecific sites are heat stable and do not discriminate between the (-) and the (+) forms of the beta-adrenergic antagonists. Adenylate cyclase in guinea-pig myocardial tissue is poorly stimulated by isoprenaline or 5'-guanylylimidodiphosphate. This is attributed to a high basal activity which could be lowered by a preincubation at 37 degrees C.


Dopaminergic neurons: an in vivo system for measuring drug interactions with presynaptic receptors. An in vivo system has been used to investigate the ability of dopamine agonists and antagonists to alter dopamine synthesis by acting at what appear to be presynaptic dopamine receptors. In order to eliminate postsynaptically induced changes in dopamine synthesis caused by the effects of these drugs on the firing rate of dopamine neurons, gammabutyrolactone was administered to block impulse flow in the nigro-neostriatal pathway. The accumulation of Dopa in the rat striatum after administration of Dopa decarboxylase inhibitor was used as an index of striatal tyrosine hydroxylase activity. It was found that administration of the dopamine agonists, apomorphine or ET-495 [1-(2-pyrimidyl)-piperonyl-piperazine], modified the apparent activity of striatal tyrosine hydroxylase when impulse flow was blocked in dopamine neurons. This presynaptic effect of apomorphine could be prevented by low doses of loxapine haloperidol and spiroperidol. Chlorpromazine, fluphenazine, and thioridizine were much less effective than the butyrophenones in blocking the effects of apomorphine. Molindone and (+) butaclamol, but not (-) butaclamol, reversed the presynaptic agonist effects, pimozide was a weak blocker and clozapine had no effect at all. All these neuroleptics except (-) butaclamol caused a significant increase in Dopa accumulation when impulse flow was intact. Compared with haloperidol the phenothiazines and pimozide appeared less potent in reversing the presynaptic effects of apomorphine than in blocking the behavioral effects of this agonist. Possible functional significance of the presynaptic dopamine receptors are considered.


Electromechanical studies of an Anemonia sulcata toxin in mammalian cardiac muscle. 1. In guinea-pig papillary muscles toxin II isolated from the sea anemone Anemonia sulcata (ATX) enhanced the force of contraction without changing the time-to-peak tension. ATX increased the relaxation time. The positive inotropic effect was accompanied by a prolongation in action potential duration. The action potential amplitude and the resting membrane potential remained essentially unchanged. The velocity of depolarization (dV/dtmax) decreased slightly. The effects werenot modified by pretreatment of the animals with reserpine. 2. In preparations partially depolarized by elevated extracellular potassium (14.7 mM KCl) a concentration of 1 X 10(-8) M ATX was ineffective with respect to increase in force of contraction or delay of repolarization. The effects of 1 X 10(-8) M ATX could be reversed by 5 X 10(-7) M tetrodotoxin. 3. Our results suggest that ATX affects the action potential duration by delaying the inactivation of the fast sodium permeability change which initiates the action potential. It is not clear, however, in which manner this effect is related to the increase in force of contraction.


Analysis of the actions of cimetidine and metiamide on gastric acid secretion in the isolated guinea pig gastric mucosa. Cumulative dose-response curves for histamine were determined on acid secretion from the isolated guinea pig gastric mucosa. Two H2-receptor antagonists-metiamide and cimetidine-behaved like competitive antagonists to histamine on gastric acid secretion in vitro. The isolated guinea pig gastric mucosa seems to be a suitable in vitro model for analysing the action of compounds on receptors involved in acid secretion.


[Effect of pH on properties of the cholinoreceptive membrane of snail neurons]. The influence of pH on acetylcholine (ACh)-induced responses in completely isolated neurons of Lymnaea stagnalis was studied under voltage clapm conditions. The pH drop lead to a decrease in sensitivity of cholinoreceptive membrane; at pH 5.8-6.0 ACh-responses were eliminated completely. When raising the external pH (up to 10.6) there were no changes in the ACh effect. A group responsible for sensitivity changes of the cholinoreceptive membrane appears to have pK about 6.7. It is shown that the pH drop does not influence the ionic channel functional groups. The results can be explained in the assumption that some functionally important groups in the cholinoreceptor active site are protonated at low pH.


Immune system to uremia.

Immune system to uremia. Pneumonia [4,9] and septicemia are still the principle causes of the high mortality in acute renal failure. Moreover, according to the EDTA report, 19% of chronic intermittent dialysis patients die from infection [17]. The resulting conclusion, that cellular and humoral immune responses are suppressed in renal insufficiency, is further supported by experimental evidence.


In vitro release of ACTH from dispersed rat pars intermedia cells. II. Effect of neurotransmitter substances. Studies were carried out to test the responsiveness of dispersed pars intermedia (PI) cells to a number of neurotransmitter substances known to be present in the PI. These substances were tested over an extended dose range. The catecholamines, adrenaline, noradrenaline, and dopamine inactivated PI ACTH at high concentrations; at lower concentrations, they were without effect. Histamine and carbachol had no effect on ACTH release. 5-hydroxytryptamine stimulated ACTH release in a dose-related manner, from 10(-6) to 10(-3)M, while having no effect on ACTH release from the pars distalis (PD). We conclude that the release of ACTH from the PI may be controlled by direct serotonergic innervation.


Mental disturbed violent offenders in Sweden. Among perpetrators of crimes of violence against persons submitted to psychiatric examination, 16 men with severe mental disorder have been examined by standardized psychologic tests and clinical interviews. Objective anamnestic data have been used to assess social background, individual development and onset of mental disorder. Psychotic as well as nonpsychotic men reacted with violence against threat to the offender's physical existence of his self image. In most instances ego weakness or depleted mental energy exaggerated the feeling of threat or stymied the ability to choose alternative solutions. Abuse of alcohol and narcotics and acute inebriation often weakened self-control and triggered of the act of violence.


Cerebrospinal fluid changes in experimental cardiopulmonary bypass using hemodilution with glucose water. Cardiopulmonary bypass using hemodilution with isotonic glucose water was performed on seven dogs. Intense systemic metabolic acidosis, hyponatremia, hypochloremia, and hyperglycemia were accompanied by only comparatively small changes in the corresponding cerebrospinal fluid values. The data suggested that in the present study, cardiopulmonary bypass was not associated with gross disruptions of the barriers for bicarbonate, sodium, chloride, and glucose between blood and cerebrospinal fluid.


The association of umbilical cord complications and variable decelerations with acid-base findings. Variable decelerations during the last 2 hours of labor were associated with an abnormally positioned umbilical cord at delivery in 52% of cases. In cases where an abnormally positioned umbilical cord was seen at delivery, 89% had been preceded by variable decelerations. Cord compression resulted in an A-V difference in pH that was significantly increased when compared to a control group. This was mainly due to a decrease in the pH of the umbilical artery. The pathophysiology of cord compression is discussed.


Dental management of patients undergoing bone marrow transplantation for aplastic anemia. Acquired aplastic anemia is a rare hematologic disease characterized by a hypoplastic bone marrow and peripheral pnacytopenia. In severe cases, where conservative medical management has been unsuccessful, bone marrow transplantation is now being performed. Between the years 1971 and 1975, twenty-two patients with severe aplastic anemia were seen at the Children's Hospital Medical Center. This article discusses the oral presentations of aplastic anemia and the dental management of nine patients without and thirteen with transplantations.


Hormone production in ovarian carcinomas. Histochemical approach in stroma reaction. Enzymatically active stromal cells (EASC) in different ovarian tumors are concerned with hormon production. 198 cases of ovarian tumors were investigated by different histochemical methods. Distribution of lactate-and glucose-6-phosphate-dehydrogenase was investigated by plaimetric measurement.--EASC were found in benign ovarian tumors in 48%, in malignant in 30%. They are found exclusively in ovarian tumors and are completely absent in metastases. Incidence is dependent on histological type of tumor. With regard to untreated ovarian carcinoma containing EASC, these cells cover an aerea of 1.9% (0.5-5.9%). EASC occur in a very high percentage after menopause and are reduced by chemotherapy or radioation. Incidence of EASC in ovarian tumors is in relation with postmenopausal bleeding. Glandular-cystic endometrium is noticed only in connection with EASC. There is a positive relation between the quantity of EASC and the incidence of bleeding.--EASC are characterized by a strong NADP-dependent-dehydrogenase-reaction and reactions for lactate-, malate-dehydrogenases and alcaline phosphatases. Apart from that these cells are not all uniform. It seems that the enzymatically active fibrocytes are the first step of theca-like cells which are then luteinized and finally filled up with cholesterol. Histochemistry of EASC in comparison with other steroid-producing tissues make possible, that these cells have an estrogenic and more seldomly also an androgenic activity.


Preponderance of beta adrenergic receptors in the gastric fundus of the rat. There are two kinds of adrenergic receptors in rat fundus (stomach), the alpha receptors are stimulated with adrenaline and noradrenaline and can be blocked effectively with azapetine and the beta receptors are stimulated with isoprenaline and adrenaline and can be blocked effectively with propranolol. Adrenaline, noradrenaline and isoprenaline all produce inhibition of acetylcholine induced contractions in both untreated and reserpinized tissues that can be antagonized with azapetine and propranolol on its specific receptors but propranolol has a greater capacity to decrease the sensitivity of both untreated and reserpinized tissues to isoprenaline and adrenaline than azapetine can in case of noradrenaline and adrenaline.


Methods in coccidiosis research: separation of oocysts from faeces. Factors which may be important in the large-scale extraction of coccidial oocysts from faeces ha.ve been investigated with Eimeria tenella. Age of bird, inoculum, feeding status at the time of inoculation, period of collection, feeding status during collection, collection medium, homogenization and sieving, flotation, washing, sporulation and further purification have all been considered. The aim has been to establish a method to produce the maximum number of oocysts of a required degree of purity and viability, with the expenditure of the minimum amount of physical effort, time, animals and chemicals. In our method, groups of chickens 3-4 weeks of age are inoculated with 5000 oocysts of E. tenella and food is supplied ad lib. Over the period 5-8 days after inoculation, faeces are collected in trays containing 2% (w/v) potassium dichromate solution, while food intake is restricted. The faecal material is homogenized, passed once through 40 and 100 mesh sieves, centrifuged and the oocysts recovered from the sediment by 3 flotations in saturated salt solution. Following washing, oocysts are sporulated by forced aeration at 30 degrees C and may be further purified by hypochlorite treatment, or passage in 5% Tween 80 solution through a glass bead column followed by sucrose density gradient centrifugation. Routine passages along these lines over a 5 year period have given a recovery of 46% of the oocysts excreted by over 7000 birds.


[Synovial fluid. Review of international literature from 1972 to 1975 (author's transl)]. The tremendous increase in the number of articles from the world scientific literature dealing with the synovial fluid in recent years, reflects the growing interest of research on that subject. The current review summarizes the scientific works published during the period of 1972 to 1975. This review deals with fundamental as well as applied research or clinical reports adding some diagnostic hints in the knowledge of diseases involving joints. The content of the review is divided in two major chapters. 1) The Physico-Chemical Properties of the Synovial Fluid (viscosity, pH,...); 2) The Composition of the Synovial Fluid (proteins, carbohydrates, lipids, prostaglandins, cells, crystals, micro-organisms).


Three group treatments for reduction of speech anxiety among students. Conditions of group systematic desensitization (n = 8), group flooding (n = 7), and a group discussion-placebo control treatment (n = 4) were employed to reduce anxiety about public-speaking in university students. Three 90-min. sessions were provided. Pre- and posttreatment assessments employed self-report and behavioral measures. The desensitization group showed significant pre- to posttreatment change across all self-report measures, whereas the flooding and control groups showed similar improvement on only one such measure. No group showed significant improvement on the behavioral measure. Groups did not exhibit significant intergroup differences in improvement on any measure.


Lactate content and pH in muscle obtained after dynamic exercise. Analyzes were made on muscle samples taken from the lateral part of the m. quadriceps femoris of man (lactate, pyruvate, and pH) on venous blood (lactate, pyruvate) and on capillary blood (pH). Samples were taken at rest, immediately after termination of dynamic exercise and during 20 min recovery from exhaustive dynamic exercise. Muscle pH decreases from 7.08 atrest to 6.60 at exhaustion. Decrease in muscle pH was linearly related to muscle content of lactate + pyruvate. The relationship was slightly different from what has been obtained after isometric exercise and this difference was ascribed to acid-base exchange with the blood during dynamic exercise. Lactate content was highly elevated in muscle after exercise and the concentration was 2-3 times higher than in blood. Pyruvate content was, however, only slightly higher than that at rest. During recovery, lactate content of muscle decreased exponentially with respect to time, whereas pyruvate content increased. The half-time of lactate decrease was 9.5 min. From the lactate dehydrogenase equilibrium relative values on NADH/NAD ratio could be calculated. It was found that NADH/NAD was highly increased after exercise and that it had not returned to the basal value after 20 min recovery.


The interstitial pH of the working gastrocnemius muscle of the dog. In isolated gastrocnemius muscles from 19 dogs the interstitial H+ activity ([H+]int) was measured with bulb-type buffer-filled glass minielectrodes. The muscles were working isotonically and perfused with blood. In addition arterial and venous pH, venous O2 saturation, muscle temperature, and blood flow were meausred continuously at rest, during 12 min of sustained exercise, and in the recovery period. Lactate (LA-) release and O2 consumption were calculated by the Fick principle. The experiments were performed under normal acid-base conditions and during artificially induced metabolic acidosis and alkalosis. 1. In normal acid-base balance [H+]int at rest was 54 +/- 3.3 neq/l (= pH 7.24), while venous H+ ([H+]ven) was 45 +/- 4.7 neq/l (= pH 7.34) A[H+] gradient was always observed between interstitial fluid and venous blood. 2. Immediately after onset of exercise [H+]int decreased transiently. After about 15 s [H+]int increased rapidly up to values of 105 +/- 7 neq/l (= pH 6.98). In the recovery period [H+]int diminished and reached control values after about 20-30 min. [H+]ven increased up to 74.4 +/- 8.4 neq/l (= pH 7.13). Maximal gradients between [H+]int and [H+]ven were 36 neq/l (= pH 0.2). 3. During repeated exercise the decrease in [H+]int at the onset of exercise was more extensive, while the subsequent increase was lowered. These changes correspond to a smaller LA- release. 4. During metabolic alkalosis at the onset of exercise [h+]int decreased less, during metabolic acidosis more than under normal acid-base conditions. Thereafter during metabolic alkalosis maximal values of 95.4 +/ 2 neq/l (= pH 7.03), during metabolic acidosis of 180 +/- 8.6 neq/l (= pH 6.74) were reached. This led to [H+] gradients between interstitial fluid and venous blood which were much higher in metabolic acidosis than in normal acid-base balance or in metabolic alkalosis. In metabolic acidosis [H+]int decreased very sle rapidly than during metabolic alkalosis or during normal acid-base conditions. It is concluded that the H+ activity measured is that within the interstitial space. Exercise hyperemia is not caused by changes of [H+]int. Mechanisms are discussed which may explain H+ gradients between interstitial fluid and venous blood and rapid changes of [H+]int at the onset of exercise.


Phosphate transfer and tubular pH during renal stopped flow microperfusion experiments in the rat. The loss of 32P-phosphate salts by the luminal compartment of cortical tubules was studied in control and in acetazolamide-infused rats, during stopped-flow microperfusion with 100 mM phosphate-raffinose solutions. When the initial pH of the perfusion solution was low (5.5), phosphate was lost more rapidly from proximal tubules than at high initial pH (8.2). The average half-time of phosphate loss was 31.9 s during acid, and 66.0 s during alkaline perfusion in proximal tubules of control rats; in acetazolamide-infused rats half-times were 77.0 and 86.6 s for acid and alkaline perfusions. Thus acetazolamide infusion slows the rate of phosphate loss by proximal tubules, when the perfusion solution is acid, but has no significant effect if its pH is alkaline. These half-times compare to proximal acidification rates of 7.23 s in control and 13.2 s in acetazolamide-infused rats. In distal tubules of control rats no significant loss of phosphate was observed during the period of perfusion. It is concluded that the loss of phosphate, in proximal tubules, is markedly slower than the changes in tubular pH and so its effect on tubular acidification must be of minor importance. In distal tubules changes in pH are not due to transepithelial phosphate movement.


Studies on the lithium transport across the red cell membrane. II. Characterization of ouabain-sensitive and ouabain-insensitive Li+ transport. Effects of bicarbonate and dipyridamole. In studies on Li+ net-transport across the human red cell membrane following results were obtained: 1. In K+- and Na+-free choline chloride media, Li+ is transported into the erythrocytes against an electrochemical gradient. This Li+ uphill transport as well as Li+ downhill transport into the cells is inhibited by ouabain, ATP-depletion, and by external K+ and Na+. The effects of K+ and Na+ are relieved at high Li+ concentrations. 2. Ouabain-sensitive Li+ uptake, determined at 10 mM external Na+, does not obey simple Michaelis-Menten kinetics and exhibits a maximum at about pH 7. 3. Ouabain-resistant Li+ downhill transport into erythrocytes increases with rising pH. It is comprised of a saturating component and a component linearly dependent on external Li+. The linear component is partly inhibited by dipyridamole and accelerated by bicarbonate. The bicarbonate effect can be completely blocked by dipyridamole, phlorizin and phenylbutazone. 4. Li+ release is not inhibited by ouabain, ATP-depletion and external K+. It increases with external Na+ concentration, tending to saturate at 150 mM Na+. Na+-independent Li+ release is stimulated by bicarbonate. It is concluded that ouabain-sensitive Li+ uptake is mediated at the K+-site(s) of the Na+-K+ pump. Li+, K+ and Na+ appear to compete for a common site (or sites). The stimulation of Li+ transfer by bicarbonate and the inhibition by dipyridamole suggest a participation of anionic species in ouabain-resistant Li+ transfer. The Na+-dependent Li+ release and the "saturating component" of Li+ uptake are ascribed to the Na+-dependent Li+ countertransport system.


The influence on breeding, production, and acid-base balance when mink are fed on acidified feed. It has been shown, partly in an investigation in which female mink were subject to increasing quantities of acid in their feed, and partly in an investigation of experimental animals which were fed with various concentrations of acid-preserved fishsilage, that there is a marked risk for a change of the acid-base balance to a metabolic acidosis when pH in the feed comes lower than 5. These investigations are also considered to show that mink's reproductive ability and general welfare is considerably affected when fed with large quantities of acid-preserved fish feed over a longer period, possibly because of alterations in the acid base balance. It is possible to reduce or avoid metabolic acidosis in mink by neutralizing silage or feed.


Surface activity of some psychotropic drugs. Diazepam was found to be the most surface active substance in aqueous solutions, chlorpromazine was less active and the lowest activity was found for haloperidol. The surface activity in blood was similar. The effect of pH on the surface activity of chlorpromazine solutions was observed.


Kinetics and mechanism of degradation of some 2-sulfanilamidopyrimidine derivatives. Part 1. Log k--pH profile for sulfadimidine solvolysis. The degradation of sulfadimidine (SDMP) in the pH range 5-83--10-0, at 403, 411 and 418 K, was investigated by UV spectrophotometry. Semilogarythmic plots (A242--A') vs. time in 0-1 M HCl for the degradation of SDMP in the above pH range were linear. The log k--pH profile constructed from the experimental results served for estimation of specific rate constants and pKa values. These, in turn, were used to calculate the theoretical log k--pH profile, acc. to the equation for the rate of reaction proportional to the concentration of the dissociated form of SDMP, in the pH range 5-8--10. Thermodynamic parameters of the reaction--energy, entropy and enthalpy of activation and the frequency factor for the specific rate constants were determined.