Allosteric modifiers of fish hemoglobins: in vitro and in vivo studies of the effect of ambient oxygen and pH on erythrocyte ATP concentrations. Fundulus heteroclitus decreases erythrocyte adenosine triphosphate and increases blood hematocrit when acclimated to hypoxic conditions. A defined medium has been developed which allows isolated F. heteroclitus erythrocytes to be maintained for several hours without an appreciable loss of cellular ATP. The effect of oxygen tension, pH and metabolic inhibitors on the cellular concentration of ATP of fish red cells has been investigated as an in vitro model to explain in vivo responses to environmental changes. The isolated red cells significantly decrease their ATP/Hb molar ratio when exposed either to anaerobiosis or metabolic inhibitors. It is concluded that the in vivo response is mediated at the red cell level via decreased oxidative phosphorylation in the presence of low environmental oxygen. The length of time necessary to elicit the responce both in vivo and in vitro is also discussed.


Stronglyoides ransomi: factors influencing the in vitro development of the free-living generation. Among the progeny of parasitic females of Strongyloides ransomi, ransomi, males did not appear in significant numbers until the 7th week of infection in cases of simple infection, and until the 3rd week of infection in cases of multiple infection. The appearance of males was attributed to the effect of host immunity, the physiological ageing of the parasitic females, or both. Type of culture substrate and other cultural conditions did not influence the percent of larvae developing into males. Sex of larvae was determined prior to hatching, probably during oogenesis or embryogenesis. Culture conditions influenced the direction of development of female larvae. An initial pH below 5.9 or above 7.2 favored differentiation of larvae into infective larvae, whereas, intermediate initial pH levels favored development of free-living females. Baby pig substrate, autoclaved substrate, and substrate washed free of soluble chemicals (adverse cultural conditions)  promoted differentiation toward infective larvae. Adult pig substrate, nonautoclaved substrate and unwashed substrate promoted differentiation toward free-living females. In general, adverse conditions inside the host and favor an indirect life cycle.


A simple quantitative technique for testing behavioral responses of Schistosoma mansoni miracidia to chemicals. We describe a new technique for testing responses of Schistosoma mansoni miracidia to chemicals. Miracidia in spring water were placed in a chamber shaped like the Greek letter phi. Small volumes of test chemicals were inoculated into one side of the chamber. After 30 sec a dam was inserted to bisect the chamber and the percentage of miracidia on the inoculated side was calculated. Reproducible quantitative results were obtained using the known miracidial stimulants, snail-conditioned water (Biomphalaria glabrata) and Mg2+; up to 80% of the miracidia were recovered on the inoculated side of the chamber. Other substances also stimulated miracidia: several inorganic cations, 4 neurotransmitters, 3 acetycholine antagonists, and 1 acetycholine agonist. Modifying the technique by testing stimulants in altered chemical "backgrounds" allowed us to test for inhibitors of miracidial responses. Assays of the Mg2+ content of several of the test solutions indicated that their stimulatory or inhibitory effects could not be ascribed to Mg2+ contamination. However, results obtained with neurotransmitters and drugs were not sufficiently consistent to implicate specific neurotransmitters in the mechanism by which miracidia detect and respond to stimulants in snail-conditioned water.


Effect of diamfenetide on experimental infections of Fasciola hepatica in lambs: anthelmintic and clinical investigations. The activity of diamfenetide (N,N'-[oxybis(2,1-ethan diyloxy-4,1-phenylene)] bis acetamide) was studied in lambs experimentally inoculated with Fasciola hepatica. The drug was given orally at a dose level of 100 mg/kg either 1,3,5,7, or 9 weeks postinoculation. It was 100% effective 1, 3, and 5 weeks postinoculation, 73% effective 7 weeks postinoculation, and 57% effective 9 weeks postinoculation. Serum gamma-glutamyl transpeptidase activity remained normal in all lambs for 5 weeks after infection; it then began to increase in infected, untreated lambs at 6 weeks, and had increased 5- to 6-fold 9 weeks postinoculation in infected lambs. This enzyme activity was the most sensitive hematologic parameter used in this test to detect hepatobiliary damage by the parasite. The drug was well tolerated at the dose level used.


Effect of vehicles and other active ingredients on stability of hydrocortisone. The stability of hydrocortisone in various types of vehicles, aqueous, water-washable (polyethylene glycol ointment base), and oil in water or water in oil-type emulsified vehicles, and in the presence of other ingredients, iodochlorhydroxyquin, menthol, and phenol, was studied under normal conditions (room temperature and weakly acidic pH). The study was conducted using a stability-indicating assay method, high-pressure liquid chromatography. The hydrocortisone was very unstable in water and water-washable ointment base. The addition of alcohol and glycerin to water had a stabilizing effect. Under drastic conditions (very acidic or very basic pH), hydrocortisone proved to be unstable only on the basic side. The data at higher temperatures confirmed that the decomposition in water and polyethylene glycol was pseudo-first order. The decomposition process appears to be different in the highly basic solution versus weakly acidic media or in water versus polyethylene glycol ointment base.


Demonstration of penicillamine as a product in benzylpenicillenic acid degradation in neutral media using differential pulse polarography. During the study of the temporal changes of benzylpenicillenic acid in aqueous buffers using differential pulse polarography, penicillamine was found to be a degradation product at neutral pH. Since this result was not previously reported, the effects of pH and buffer concentration on penicillamine formation were investigated. The amount of penicillamine produced was greatest under conditions producing maximum benzylpenicillenic acid stability. Penicillamine was not obtained from benzylpenicilloic acid, the reported degradation product of benzylpenicillenic acid at neutral pH. Penicillamine also was detected in penicillin G solutions of neutral pH. Therefore, it is suggested that penicillamine found in penicillin G solutions arises from benzylpenicillenic acid degradation which, in turn, is produced from penicillin G isomerization. A pathway is proposed to show that penicillamine originates from the UV-absorbing isomer of benzylpenicillenic acid.


Effect of ionization on absorption of cephalosporins. To explore the relative absorbabilities of different ionic forms of cephalosporins, the absorption rates of four compounds were measured in the pH 5-9 region using an in situ rat gut technique. Cephalexin, cephradine, and cephaloglycin have some oral activity, while 3-[(acetyloxy)methyl]-8-oxo-7-[[(4-oxo-1(4H-pyridinyl)acetyl]-amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (I) has insignificant oral activity. The pH-species profiles calculated from their ionization constants showed that cephalexin, cephradine, and cephaloglycin have a large proportion of uncharged molecules plus zwitterions in the pH range of the small intestine, while I exists as the anion throughout this range. When the species profiles are compared with the pH-absorption rate profiles for cephalexin, cephradine, and I, the results are consistent with a model in which the zwitterionic and/or uncharged forms of the molecules are well absorbed, whereas the anions show little or no absorption. Although it has a pH profile for zwitterions plus uncharged molecules similar to cephalexin, cephaloglycin shows poor absorption, suggesting that the ratio of uncharged molecules to zwitterions may be important in absorption.


Kinetics of digoxin stability in aqueous solution. Digoxin hydrolysis was studied as a function of pH. Conversion of digoxin to digoxigenin was followed by high-pressure liquid chromatography and shown to proceed by the initial loss of one, two, or three sugars. The hydrolysis rate was directly proportional to parent drug concentration and hydrogen-ion activity. The individual hydrolysis rate constants of digoxin, digoxigenin bisdigitoxoside, and digoxigenin monodigitoxoside were determined by a simplex fitting procedure. Data are presented suggesting that at least some variation in the bioavailability of orally administered digoxin arises from observed variations in gastric pH; these variations influence the extent to which hydrolysis occurs and, thus, modify the composition of digoxin species available for absorption.


Spectroscopic approach to estimation of microequilibrium constants of prototropic reactions of aminobenzoic acids. The microequilibrium constants of protolytic dissociation of diprotic acids, dihydric bases, or ampholytes such as the aminobenzoic acids, with dissimilar ionizing groups, can be estimated by spectrophotometric titration and measurement of the molar absorptivity at the long wavelength absorption maximum of simple alkylated derivatives. The method is applicable when the long wavelength absorption spectral bands of the tautomeric species are well resolved. Compared to the traditional method of estimating microequilibrium constants using the dissociation constants of alkylated derivatives, the proposed method is simpler, faster, and more accurate.


Characterization of impurities in sulfasalazine. The chemical structures of four impurities isolated from sulfasalazine were determined. Three impurities are the by-products of the reaction process in drug synthesis, i.e., during diazotization of sulfapyridine and during coupling with salicylic acid. Only one contaminant was identified as a starting material, sulfapyridine, in the drug synthesis. The four impurities were characterized as 2-[[p-(2-pyridylsulfamoyl)-phenyl]azo]hydroxybenzene (I), 3-[[P-(2-pyridylsulfamoyl) phenyl]-azo]salicylic acid (II), 5-[[p-[4-(2-pyridylanilino)]-N-phenyl]azo]salicylic acid (III), and sulfapyridine (IV). Compounds I-III are novel molecules, and IV is the precursor of sulfasalazine. The isolation of the impurities was accomplished by TLC and liquid extraction procedures. The methods used to characterize the impurities were a combination of IR, UV, and NMR spectroscopy, mass spectrometry, and TLC. For I and III, comparisons also were made with the synthesized materials to supplement the evaluation.


In vitro evidence for ipecac inactivation by activated charcoal. The in vitro adsorption of the alkaloid emetine, a primary constituent of ipecac, on activated charcoal was studied. The results support the supposition that syrup of ipecac should not be given to counteract poisonings if activated charcoal is also to be administered.


Determination of desmethyldiazepam in plasma by electron-capture GLC: application to pharmacokinetic studies of clorazepate. Plasma desmethyldiazepam concentrations were quantitated by a rapid and sensitive technique using electron-capture GLC. Following addition of diazepam as the internal standard, plasma is extracted at physiological pH into benzene-isoamyl alcohol. The extract is evaporated to dryness and reconstituted with toluene-isoamyl alcohol prior to chromatography. Both diazepam and desmethyldiazepam are quantitatively extracted. The variation of identical samples is 5%, and the sensitivity is 5 ng of desmethyldiazepam/ml of original sample. The method is applicable to pharmacokinetic studies of clorazepate, a benzodiazepine derivative transformed to desmethyldiazepam prior to absorption.


In vitro evaluation of three commercial sustained-release papaverine hydrochloride products. Three commercial sustained-release papaverine hydrochloride products in the form of microencapsulated pellets were evaluated. Three different dissolution apparatuses were used: a continuous flow apparatus, the USP rotating basket apparatus, and a modified reciprocating basket apparatus. The frequency rate of the reciprocating basket apparatus could be varied from 0 to 31 strokes/min. Salicylic acid compacts were used as a standard to characterize each apparatus. A linear log--log correlation between dissolution rate and apparatus speed or flow rate was obtained. Release of papaverine hydrochloride from the commercial preparations was affected significantly by the pH of the dissolution media but not by the agitation intensity.


Prodrug approaches to enhancement of physicochemical properties of drugs IX: acetaminophen prodrug. The synthesis, hydrolysis rate, and bioavailability of 1-(p-acetaminophenoxy)-1-ethoxyethane, an acetaminophen prodrug, are described. The prodrug is less soluble than acetaminophen and stable at neutral pH. However, in an acidic environment, the compound cleaves rapidly, generating acetaminophen. When both the prodrug and acetaminophen were administered to dogs in equivalent amounts, the blood acetaminophen levels were comparable.


Hydrolysis kinetics of the monophosphate ester triclofos sodium. The hydrolysis kinetics of the monophosphate ester triclofos sodium were studied in the pH 0.00--7.80 range, the 80.1--98.4 degrees range, and ionic strengths of 0.02--1.50. The pK1 and pK2 values for triclofos were 1.00 +/- 0.05 and 5.80 +/- 0.05, respectively. The pH dependency observed was consistent with a theory in which the hydrolysis rates of the triclofos species follow the order: monoanion greater than unionized greater than dianion. The apparent first-order rate constants at 80.1 degrees associated with each species were 6.4 +/- 0.6 X 10(-3), 28.0 +/- 0.5 X 10(-3), and 0.3 +/- 0.1 hr-1, respectively, Different Arrhenius activation energies were observed at pH 0.00, 3.50, and 7.80, at which values the unionized, monoanion, and dianion forms were the dominant species present, respectively. The reaction showed a modest positive kinetic salt effect at pH 3.50 and a modest negative effect at pH 7.80. Various mechanistic possibilities are discussed.


Determination of serum nadolol levels by GLC--selected ion monitoring mass spectrometry: comparison with a spectrofluorometric method. A method to determine the serum concentration of the beta-adrenergic receptor blocking agent, nadolol, by GLC--selected ion monitoring mass spectrometry of the tri(trimethysilyl) ether derivative is described. A basic solution of serum was extracted, known amounts of internal standard were added to the extract, and the extract was back-extracted into acidic media and lyophilized. The resulting solids were reacted with N-trimethylsilylimidazole. Coded serum samples of 12 subjects, given nadolol alone or in combination with a second drug, were analyzed. The ions at m/e 86 and 100 were monitored to establish the relative concentration ratio of nadolol and the internal reference N-methylnadolol. No interferences from blood components or other administered drugs were observed. A detection level of 6.95 ng/ml of serum was found.


Microionization constants of commercial cephalosporins. The equilibrium constants of five commercial cephalosporins were determined. Two are monoacidic and possess one Ka while three are amphoteric and have four microconstants. Although several assumptions were made in the calculations, good agreement was found between the compounds and with previously reported macroionization constants. By utilizing the microionization constants, the ratios of zwitterion to unchanged species were calculated to be in the 900-50,000 range and to have a maximum concentration between pH 3.5 and 5.


Pharmacokinetic studies on ditazole, a novel inhibitor of platelet aggregation. The distribution of ditazole in blood and tissues of rats was determined by a simple GLC technique. Ditazole, after intravenous injection in rats (20 mg/kg), entered preferentially into the brain, the liver, and the heart in decreasing order. In the epididymal adipose tissue, the drug was present only in small amounts. Ditazole disappeared from the rat organs 4 hr after the treatment. The apparent ditazole half-life in rat blood was 41 min, the volume of distribution was 2.068 liters/kg, and the body clearance was 0.0345 liter/kg/min.


Differential spectrophotometric determination of tyrosine and tryptophan in pharmaceutical amino acid solutions. A method is proposed for the simultaneous determination of tyrosine and tryptophan in solutions by differential spectrophotometry. The concentrations are calculated from the measurement of the absorbance of the amino acid mixture in an alkaline medium and from the differential absorbance of the alkaline solution against the acid solution at 294.4 nm. A comparison with three other well-known methods is discussed.


Rat jugular vein relaxes to norepinephrine, phenylephrine and histamine. Circular muscle of the rat external jugular vein contracted to serotonin, angiotensin and potassium chloride but not to norepinephrine, phenylephrine, histamine or carbamylcholine. In contrast, rabbit and guinea-pig jugular veins contracted to norepinephrine, phenylephrine and histamine, although contractions to norepinephrine were small in guinea-pig jugular veins. Norepinephrine, phenylephrine and histamine produced a concentration-dependent sustained relaxation of serotonin-induced contractions in the rat jugular vein, as did isoproterenol, nitroglycerin and papaverine. Propranolol blocked relaxation to norepinephrine, phenylephrine and isoproterenol whereas metiamide, a H2 receptor antagonist blocked relaxation to histamine. alpha adrenergic receptor blockade with phentolamine or prazosin resulted in greater relaxation to norepinephrine whereas cocaine did not enhance norepinephrine-induced vasodilation. This study supports the premise that norepinephrine may exert prominent beta adrenergic receptor stimulation in some blood vessels and that this effect may be more apparent in veins than arteries.


Nucleoside transport in mammalian cell membranes. IV. Organomercurials and organomercurial-mercaptonucleoside complexes as probes for nucleoside transport systems in hamster cells. Organomercurials form stable stoichiometric complexes with thiolated nucleosides. The complexes inhibited uptake of ribonucleosides and cytosine arabinoside (CAR) in various types of normal and transformed cells. The inhibition was competitive and reversible (Ki = 3--6 micrometer). The interaction between complexes and transport system displayed a 1:1 stoichiometry. Chemical factors which contributed to the inhibitory power were evaluated with a series of S-alkylated derivatives and S--Hg--R complexes of mercaptonucleosides. The inhibitory potency was not determined exclusively by the hydrophobic nature of either the S-alkylated or the S--Hg--R moieties. Chemical modification of cells with penetrating and nonpenetrating organomercurials lead to stimulation of nucleoside uptake and to an increase in its susceptibility to inhibition by S--Hg--R complexes or S-aklylated derivatives of mercaptopurine ribosides. The kinetic and chemical data obtained with nucleoside analogs and with chemical modifiers suggested complex features of nucleoside transport systems. Four distinct classes of sites were implied: (i) a substrate binding site susceptible directly to competitive inhibition by organomercurial-mercaptonucleoside complexes, (ii) an additional site susceptible either to S-arylalkylated or S-mercuriated derivatives of 6-mercaptopurine ribosides, (iii) SH-containing modifier sites which stimulate uridine uptake upon binding of organomercurials, and (iv) SH-containing modifier sites which inhibit the function upon binding of organomercurials. From the observation that only SH sites related to stimulation were susceptible to modification by macromolecular-SH modifier probes, some conclusions can be drawn regarding the disposition of the various sites in the cell membrane in general and among membrane components in particular.


Hypertonic cryohemolysis: ionophore and pH effects. Human erythrocytes suspended at 37 degrees C in hypertonic solution of either electrolytes or nonelectrolytes undergo hemolysis when the temperature is lowered toward 0 degrees C (Green, F.A., Jung, C.Y. 1977 J. Membrane Biol. 33:249). In the present studies this hypertonic cryohemolysis was profoundly affected by the pH of incubation, and was completely abolished at ph 5. In hypertonic NaCl, there was an apparent pH optimum at 6--6.5. In hypertonic sucrose, on the other hand, hemolysis increased progressively with increasing pH between 6 and 9. Amphotericin B inhibited hypertonic cryohemolysis in NaCl or KCl solution. No inhibiting effect of amphotericin B was observed when hypertonicity was due to sodium sulfate or sucrose. Valinomycin also inhibited hypertonic cryohemolysis in KCl, but did not affect the process in NaCl or sucrose solution. SITS (4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonate) and phloretin interfered with this valinomycin effect, whereas phlorizin did not. These results indicate that dissipation of an osmotic gradient across membranes may be responsible for the inhibition of the hemolysis by these inophores. Iso-osmotic cell shrinkage induced by valinomycin in 150 mM NaCl solution did not result in cryohemolysis.


Current-voltage relationships for the plasma membrane and its principal electrogenic pump in Neurospora crassa: I. Steady-state conditions. The nonlinear membrane current-voltage relationship (I-V curve) for intact hyphae of Neurospora crassa has been determined by means of a 3-electrode voltage-clamp technique, plus "quasi-linear" cable theory. Under normal conditions of growth and respiration, the membrane I-V curve is best described as a parabolic segment convex in the direction of depolarizing current. At the average resting potential of - 174 mV, the membrane conductance is approximately 190 micronhos/cm2; conductance increase to approximately 240 micronhos/cm2 at -300 mV, and decreases to approximately 130 micronhos/cm2 at 0 mV. Irreversible membrane breakdown occurs at potentials beyond this range. Inhibition of the primary electrogenic pump in Neurospora by ATP withdrawal (with 1 mM KCN) depolarizes the membrane to the range of -40 to -70 mV and reduces the slope of the I-V curve by a fixed scaling factor of approximately 0.8. For wild-type Neurospora, compared under control conditions and during steady-state inhibition by cyanide, the I-V difference curve--presumed to define the current-voltage curve for the electrogenic pump--is a saturation function with maximal current of approximately 20 muA/cm2, a half saturation potential near -300 mV, and a projected reversal potential of ca. -400 mV. This value is close to the maximal free energy available to the pump from ATP hydrolysis, so that pump stoichiometry must be close to 1 H+ extruded:1 ATP split. The time-courses of change in membrane potential and resistance with cyanide are compatible with the steady-state I-V curves, under the assumption the cyanide has no major effects other than ATP withdrawal. Other inhibitors, uncouplers, and lowered temperature all have more complicated effects. The detailed temporal analysis of voltage-clamp data showed three time-constants in the clamping currents: one of 10 msec, for charging the membrane capacitance (0.9 muF/cm/2); a second of 50-75 msec; and a third of 20-30 sec, perhaps representing changes of intracellular composition.


Bloody pericardial fluid. The value of blood gas measurements. Clinically notable pericardial effusions developed in three patients with renal failure. Pericardiocentesis showed hemorrhagic fluid, the source of which was not apparent. Simultaneous determinations of PCO2, PO2, and pH values showed a substantial increase in PCO2 levels and decrease in PO2, pH, and bicarbonate levels in the pericardial compared with the intracardial aspirates. This was true when pericardial fluid PCO2, PO2, and pH values were compared with mixed venous samples. Determination of PO2, PCO2, pH, and bicarbonate values in pericardial aspirates may determine the source of the fluid.


Some new or poorly recognized physical and graphic findings in various forms of pericardial disease. The eight new items concerning pericarditis (acute pericarditis, acute or chronic pericardial effusion, and constrictive or sero-constrictive pericarditis) were demonstrated based on the clinical observation of 115 patients. Pericarditis, a disease of remote antiquity, still has many fascinating and unrecognized aspects, which will be uncovered by the meticulous observation of the patients.


[Use of beta-adrenergic blockaders in the treatment of arterial hypertension]. The results of treatment of over 300 patients suffering from hypertensive disease with beta-blocking agents Obsidan and Visken are analysed and the place of these agents among other hypotensive drugs is discussed. The therapeutic effect was most evident in patients with the early stages of the disease and hyperkinetic type of circulation. The daily doses were from 60 to 240 mg. The hemodynamic shifts were displayed by a decrease in the cardiac output and rate of cardiac contractions and reflex, ususlly moderate, increase in general peripheral resistance, as a result the arterial pressure decreased gradually. In 1 to 6 months general peripheral resistance diminished in half of the patients, evidently due to the gradual adaptation of the vascular tone to the chronic reduction of the cardiac output. Treatment with beta-blocking agents led to non-uniform changes in regional hemodynamics: the tone of the cerebral arteries significantly reduced, the tone of the arteries of the lower extremities had a tendency to increase. This gives rise to the conclusion that alpha-adrenergic receptors predominate in the vessels of the lower extremities. In the treatment of patients with high and stable hypertension, it is advisable to combine beta-blocking agents with saluretics, vasodilators, hemiton, and other hypotensive drugs.


[Coronary circulation under alpha-adrenergic blockade]. In canine experiments with coronary catheterization and perfusion, catheterization of the heart cavities and great vessles, and with thermodilution it was demonstrated that the alpha-adrenergic blocker Phentolamine causes a regular flow resistance in the coronary vessels. The maximal depressor effect was observed with 0.3 mg/kg (intravenously), and it did not grow under higher doses of the drug. The reduction of coronary resistance under the effect of Phentolamine was realized, firstly, by way of a moderate activation of myocardial beta-receptors, and secondly, by way of a specific block of alpha-adrenergic receptors of the heart vessels. Phentolamine inhibited the pressor reactions of the coronaries to mesatone, adrenalin, noradrenalin, and limited the manifestations of the pressor effects in the coronary vessels during systemic sinocarotid reflexes.


[The different effects of fe(II)- and fe(III)-ions on the hyaluronic acid of the vitreous body (author's transl)]. Fe(II)-ions reduce the viscosity of a hyaluronic acid solution but do not form a precipitate. Fe(III)-ions only slightly lower the viscosity of hyaluronic acid solutions but cause a brown, water-insoluble iron-hyaluronic acid precipitate. After adding ascorbic acid--concentrate the pH-value as in vitreous body--to the reaction solution, Fe(III)-ions reduce the viscosity too. The iron-hyalurnic acid complex is also destroyed by ascorbate. Therefore, the ascorbate of the vitreous humor plays an important role in the generation of siderosis bulbi.


[Possibility of conserving the heat balance of the human organism in an extremely rarefied atmosphere by vacuum evaporation of sweat from the surface of the body]. As a result of 64 experiments carried out on 24 test subjects, it has been shown that extreme overwarming due to moderate and heavy thermal loads can be prevented with the aid of heat release through sweat evaporation from the surface of the body under the action of a rarefied atmosphere (termed vacuum sweat evaporation). The test subjects wearing altitude suits remained in a thermal altitude chamber at 40 and 55 degrees C for 8 to 3 hours at rest and doing light work at altitudes of 7 to 25 km without marked signs of overwarming. The entire heat release occurred only through vacuum sweat evaporation from the surface of the body that was under the altitude suit during a gradual decrease of the chamber pressure to 20 mm Hg (equivalent to an altitude of 25 km). The findings give support to the hypothesis that heart release via vacuum sweat evaporation from the surface of the body can be used as a method of controlling thermal homeostasis during high altitude and space flights.


[Experimental substantiation of the maximum permissible concentrations of acetone and acetaldehyde in regenerated drinking water]. The paper presents experimental data indicating maximum permissible concentrations of acetone and acetaldehyde in reclaimed potable water used for different periods of time--up to 1, 3 or 12 months. The recommended concentrations for reclaimed water used for a year are 14.0 mg/l and 0.2 mg/l for acetone and acetaldehyde, respectively. The recommended levels for reclaimed water used for 1--3 months are 39.6 mg/l and 0.2 mg/l for acetone and acetaldehyde, respectively.


Submandibular salivary pH as a diagnostic aid for prognosis of facial palsy. The present paper aims at introducing a new method of testing the function of the chorda tympani with the aid of submandibular salivary pH. This method has several advantages: (1.) it enables the measurement of the function of only the paralyzed side; (2.) it accurately predicts the outcome of facial palsy at an early stage; and (3.) the method is simple and inexpensive.


[Effect of soap and detergents on the restitution of acidity and lipids of the skin surface]. A comparative evaluation of the effects of soaps and detergents on pH behaviour and lipids level on the skin surface and duration of their restitution was carried out. The studies were conducted in two groups. The first group of 32 persons used 1% solution of "BHP" soap, whereas the other one, composed of 31 persons, 0,5% solution of detergentpowder "POLLENA". PH measurements of skin were performed using pH--meter of Radelkis firm with a combined glass and calomel electrode. Lipids on the skin surface were determined by the Hodgson--Jones and Wheatly's gravimetric method. The evaluation of soap and detergent's effects on skin was based on the mean output and direct pH values of the skin surface, accidental and residual level of lipids, and comparison of the duration of these parameters restitution. The soap was found to alkalyse stronger than the detergent, and duration of pH restitution is longer after using the soap, whereas the detergent degreases the skin more intensively than the soap. Also restitution of lipid's jacket is slower after using the detergent.


An affinity-column procedure for the purification of veratrate O-demethylase from fungi. An affinity column procedure is reported for purifying veratrate O-demethylase from higher fungi. The procedure is based on the affinity of the fungal demethylases for veratrate, which was coupled to AH-Sepharose 4B. An over 300-fold purification of the enzyme from an Ascomycete (Chaetomium piluliferum), and a lower degree of purification (20-fold) from a Basidiomycete (Xerocomus badius), were obtained. The O-demethylases from higher fungi require NADH and oxygen. The enzyme activity is sensitive to exposure to oxygen. The pH optima are 5 for enzyme from Chaetomium, and 7 for demethylase from Xerocomus, respectively. The enzymes are not specific for veratrate. They also demethylate p- and m-anisate and 3,4-dimethoxycinnamate, but to a lower degree.


Specific agglutination of Escherichia coli O128B12 by the mannose-binding proteins of Pseudomonas aeruginosa. The mannosephilic haemagglutinins of Pseudomonas aeruginosa were found to agglutinate cells of Escherichia coli O128B12, to be adsorbed onto them and to attach peroxidase to them. These reactions were specifically inhibited by D-mannose. No agglutination by this Pseudomonas haemagglutinin was obtained when several other enteropathogenic types of Escherichia coli and some other Gram-negative bacteria were examined. Concanavalin A, which also reacted with Escherichia coli O128B12 cells, interacted with some of the other bacteria examined, too. Escherichia coli O128B12 was not agglutinated by the Pseudomonas galactosephilic haemagglutinins and those of the plant Phaseolus vulgaris. Its maximal agglutination by the Pseudomonas mannosephilic haemagglutinins was obtained employing cells grown for 4-6 h in conventional media. The growth temperature, aeration and presence of certain amino acids, but not D-mannose, in the culture medium had some effect on the agglutination in tensity; pH 6-8 was optimal for it and only at pH 3.0-3.2 no agglutination was observed. Treatment of the bacteria by proteolytic enzymes, ethanol or formaldehyde did not alter their agglutinability by either the Pseudomonas lectin or by antibodies produced against them in rabbits. Heating of the bacteria to 100 degrees C prevented their agglutination by the Pseudomonas lectin and lowered their ability to adsorb it, but did not significantly affect their reactions with the rabbit antibodies.


[X-ray examination of the abdomen in hypnotic-sedative drug poisoning--casuistical contribution (author's transl)]. By means of an impressive example the significance of abdominal X-ray examination in cases of intoxication with hypnotic-sedative drugs is pointed out. Apart from the qualitative diagnosis (drug containing bromide) the radiological proof of shadow-giving substances also permits a quantitative clinical assessment and has prognostical as well as therapeutical consequences.


A solution to the graft-versus-host problem in bone marrow transplantation to humans. Many clinical situations arise where it would be desirable to transplant bone marrow to a marrow function deficient patient. However, bone marrow is immunologically competent by virtue of its content of lymphocyte precursors. Marrow transplantation in these patients is followed by the graft's immunological rejection of the patient - a fatal disease. A system for specific abrogation of this graft-versus-host disease after xenogeneic bone marrow transplantation to humans is presented. In this system, prospective patient cells are removed by skin biopsy for example, and injected into a fetal chimpanzee. The fetal chimpanzee becomes tolerant to this patient's antigens and will not attack or reject them when its bone marrow is removed after birth and injected into the specific patient from whom the tolerogenic cells were obtained. A simple and straightforward experimental test of this system's clinical applicability is also presented.


Release of [14C]tyrosine from tubulinyl-[14C]tyrosine by brain extract. Separation of a carboxypeptidase from tubulin-tyrosine ligase. The carboxypeptidase previously described that releases tyrosine from tubulinyl-tyrosine was obtained from rat brain preparation free of tubulin-tyrosine ligase. The enzyme was purified 24-fold. Its activity was increased by 2 mM MgCl2 or 30 mM KCl. Mercaptoethanol (50 mM), colchicine (0.2 mM) and tyrosine (0.2 mM) showed practically no effect on the release of tyrosine whereas iodoacetate (2 mM), deoxycholate (0.5%), CuCl2 (0.1 mM), ZnCl2 (0.1 mM) and NaCl or KCl (240 mM) had a strong inhibitory effect. The optimal pH of this enzyme was 6.3--7. A preparation containing tubulin-tyrosine ligase free of carboxypeptidase was also obtained. This preparation catalyzed the release of tyrosine from tyrosinated tubulin in the presence of ADP, Mg2+, K+ and Pi and the incorporation of tyrosine into tubulin. For the releasing activity the optimal concentration of MgCl2 was 3--20 mM and of KCl was 10--30 mM. For ADP the maximal act;vity was at 0.3 mM or higher. An important difference between the activities of the carboxypeptidase and the ligase was that the former was active on denatured tubulin whereas the latter was not.


Reversible inhibition of cyclic AMP-dependent protein kinase by insulin. Extracts of fasted rat diaphragms, previously treated with or without insulin were assayed for glycogen synthase, protein kinase and cyclic [3H]-AMP binding. Treatment with insulin produced an elevation in the % of glycogen synthase I and a concurrent decrease in cyclic AMP-dependent protein kinase activity and cyclic [3H]-AMP binding. Analysis of extracts by disc gel electrophoresis demonstrated the inhibition of cyclic [3H]-AMP binding to involve the Type I protein kinase holoenzyme. Inhibition of protein kinase activity was most apparent in the presence of 0.2 micrometer cyclic AMP, with enzymatic activity of the insulin-treated extracts typically 60--65% of control. Higher assay concentrations diminished the difference between control and insulin-treated extracts and concentrations greater than 20 micrometer abolished it. The inhibition of cyclic AMP-dependent protein kinase activity after insulin was a transient and labile phenomenon. The effect was independent of ATP concentration in the assay, but was sensitive to the pH of tissue extraction, requiring a pH of 7.0 to 8.4 to be observed. Insulin-mediated inhibition of protein kinase activity was reversed upon preincubation of extracts at 0--2 degrees. Relatively concentrated homogenates (less than 4 microliter buffer/mg tissue) yielded extracts which exhibited little or no inhibition of protein kinase activity compared to extracts prepared from more dilute (6--10 microliter/mg) homogenates. A model for the inhibition of the cyclic-AMP dependent protein kinase by an insulin-generated inhibitor which becomes directly associated with the Type 1 holoenzyme is proposed.


Antacid titration in the prevention of acute gastrointestinal bleeding: a controlled, randomized trial in 100 critically ill patients. We randomized 100 critically ill patients at risk of developing acute gastrointestinal ulceration and bleeding into two groups. One (51 patients) received antacid prophylaxis, and the other (49 patients) received no specific form of prophylaxis. Hourly antacid titration kept the pH of the gastric contents above 3.5. Two of the 51 patients who received antacid prophylaxis and gastrointestinal bleeding. Twelve of the 49 control patients bled (P less than 0.005). Of the 12 patients in the control group who bled, seven were placed on antacid medication, and all seven apparently stopped bleeding. Analysis of all the patients showed that an increasing prevalence of respiratory, failure, sepsis, peritonitis, jaundice, renal failure and hypotension was correlated with a greater frequency of bleeding. No patients required operative treatment to control bleeding. These data indicate that the occurrence of acute gastrointestinal bleeding in critically ill patients can be reduced by antacid titration.


A manpower policy for primary health care. A National Academy of Sciences study of policy options for the supply of primary health-care manpower has produced a comprehensive set of recommendations. The study finds an adequate overall supply of physicians, but a shortage of primary health-care practitioners. It recommends maintaining current enrollment levels in medical schools and training programs for nurse practitioners and physician assistants and increasing the proportion of primary-care residents. To enhance the availability of primary care, the report advocates reimbursement for all physicians within a state at the same payment level for the same primary-care service, a reduction in payment differentials between primary-care services and nonprimary-care services, and reimbursement for educational and preventive services and for new health-practitioner services. The report supports a team approach in primary-care training and recommends that all medical students obtain clinical experience in a primary-care setting and some instruction in epidemiology and behavioral and social sciences.


The structure of the flavoenzyme glutathione reductase. The three-dimensional structure of the dimeric flavoenzyme glutathione reductase from human erythrocytes has been elucidated by an X-ray diffraction analysis at 0.3 nm resolution. The polypeptide chain has been traced, and the binding positions of FAD, NADP and glutathione have been determined. A mechanism for the electron transfer is discussed.


[Effect of antimediator preparations on the intercellular relations in early embryos of the sea urchin]. The dated treatment of the early embryos of an irregular (flat) sea urchin Scaphechinus mirabilis by neuropharmacological drugs (anti-neurotransmitters) during one of the first four cleavage divisions results in the impairment of intercellular connections and leads to the formation of twin embryos, dwarf embryos, embryos of the dumb-bell shape etc. In the experiments with some of the drugs under study such developmental abnormalities were not seen or were expressed much more weakly when serotonin or bufotenin (N,N-dimethylserotonin) were added to the medium. A suggestion is put forward that the early embryos possess an intracellular mechanism participating in the interaction between the cells and operating via endogenous monoamines, primarily serotonin.


[Effect of cortisol administration and stress actions in early ontogeny on hormonal induction in adult rats]. The influence of cortisole injections and stress ("handling") in the early ontogenesis (during the first 9 or 16 days of life) on the process of thyrosine aminotransferase induction by cortisol in the adult rats has been studied. It was shown that both the injection of the hormone in the young rats and "handling" led to the manifested trace effects: (1) stable increase of thyrosine aminotransferase activity in the liver of adult (5-6 months) rats and (2) appearance of peculiar tolerance to cortisol in the form of decrease in the ability of cells to induce thyrosine aminotransferase in response to the hormone injection. The data obtained suggest that the sensitive period of postnatal ontogenesis when cortisol or "handling" exert such a stable effect is limited by the 3rd and 9th days after birth. The causes of such "biochemical imprinting" are considered with respect to the increased sensitivity of the genetical system of cells-targets to the transcription inducers during the early postnatal development.


Cystic fibrosis: isolation and physical properties of a salivary cystic fibrosis factor. A ciliostatic factor has been isolated from cystic fibrosis (CF) saliva by dialyzing it from purified alpha-amylase prepared by a glycogen-complex method. This method of isolating the CF factor is an improvement over the previously employed heparin procedure. The activity of the isolated factor is proportional with concentration using the oyster gill ciliostatic assay and in its inhibition of mammalian glycogen debranching enzyme. The ciliostatic action of the factor can be reversed by heparin under certain conditions. The type of inhibition of the debranching enzyme by the isolated CF factor indicates that its chemical structure is similar to that observed with hydroxyalkylamines and polyamine metabolites. Physical properties of the isolated factor indicate that it is of low molecular weight and is labile as a function of pH and temperature. At neutral pH the conditions under which it is maintained have a direct effect on the length of time that it is stable.


Immunologic studies of arylsulfatase A in normal and metachromatic leukodystrophy liver. Purified human liver arylsulfatase A on polyacrylamide gel electrophoresis at pH 4.0 is separated into two protein forms with enzymatic activity and two distinct inactive subunits. All of these components were immunologically distinguishable using different antisera preparations. In late infantile metachromatic leukodystrophy, only one of the two inactive subunits was immunologically detected, whereas in the juvenile form of metachromatic leukodystrophy, both inactive subunits were antigenically present.


Hypophosphatemic vitamin D-resistant rickets: metabolic balance studies in a child receiving 1,25 dihydroxyvitamin D3, phosphate, and ascorbic acid. A child with hypophosphatemic vitamin D-resistant rickets was treated for three years with the conventional vitamin D-inorganic phosphate supplementation followed by a new therapeutic regimen consisting of 1,25 dihydroxyvitamin D3 (1,25 (OH)2D3) and half of the previous phosphate supplementation. The effectiveness of the two treatment regimens was compared by calcium, phosphate, and magnesium balance techniques and by serial radiological examinations as well as careful height measurements. In addition, the lowering of the urinary pH with ascorbic acid supplementation seems to be associated with improvement in the renal tubular reabsorption of phosphate, but its distinct effect, separate from the rest of the treatment modalities, was not tested in this study. The conventional treatment did not correct the hypophosphatemia and alkaline phosphatase elevation, whereas the 1,25 (OH)2 D3-inorganic phosphate regimen is well tolerated and effective in achieving a sustained normalization of these variables. In addition, the improved growth and healing of rickets further attest to the efficacy of the new treatment.


Arterial blood gases in Pranayama practice. Pranayama is a Yogic breathing practice which is known experientially to produce a profound calming effect on the mind. In an experiment designed to determine whether the mental effects of this practice were accompanied by changes in the arterial blood gases, arterial blood was drawn from 10 trained individuals prior to and immediately after Pranayama practice. No significance changes in arterial blood gases were noted after Pranayama. A neural mechanism for the mental effects of this practice is proposed.


[Giant cell arteritis and takayasu's disease: histopathological criteria (author's transl)]. Both of these arterial diseases may involve the aorta and the major arterial trunks. Two cases of subclavian involvement are used to contrast them from a histopathological standpoint. In giant cell arteritis, the lesions affect above all the internal elastic layer and the inner part of the media, destroyed by an inflammatory infiltrate with giant cells. In Takayasu's disease, the lesions involve the adventitia, the site of fibrosis and of inflammatory islets with the vasa vasorum at the centres. Involvement of the media is predominantly in its outer part, the internal elastic layer being intact. A histopathological definition of these arterial diseases may be envisaged on the basis of these facts.


Preparative separation of the complementary strands of DNA restriction fragments by alkaline RPC-5 chromatography. High pressure reversed phase chromatography (RPC-5) at pH 12 was used for preparative separation of the complementary strands of the smaller DNA fragments which are generated by the Hae III restriction endonuclease digestion of Col El DNA. A single high pressure RPC-5 chromatographic step at neutral pH served to purify duplex fragments 70, 172, 250 and 440 base pairs long; each of these yielded two elution peaks upon chromatography under alkaline denaturing conditions.


Turbidimetric and potentiometric studies of ribosomal subunits from an erythromycin resistant mutant of Escherichia coli. Turbidimetric and potentiometric techniques were applied to the analysis of an EryR mutant. Results show that in the mutant, the 30S subunits are drastically altered, as indicated by a higher Mg2+ requirement for subunit association and by an important difference in the titratable groups. Replacement of parental 50S by mutant 50S subunits does not decrease the association capacity with 30S parental subunits, but a structural difference is detected in the mutant 50S with potentiometric measurements. The mutation results in decreased ribosomal in vitro activities at 22 degrees C including lowered polyphenylalanine synthesis, drastic altered initiation step and the loss of erythromycin binding to the ribosomes. The results extend previous observation of a gene eryC part in the maturation of both subunits.


Affinity adsorbents consisting of nucleic acids immobilized via bisoxirane activated polysaccharides. An easy and efficient procedure for the immobilization of polynucleotide ligands to bisoxirane activated insoluble polysaccharides has been elaborated and is described in this paper. The resulting materials have been applied to the chromatography of DNA polymerase I, and RNA polymerase from E.coli. Because of their extraordinary stability to temperature, formamide, and alkaline conditions they seem to be particularly useful adsorbents for nucleic acid hybridization.


Sequence analysis of 5'[32P] labeled mRNA and tRNA using polyacrylamide gel electrophoresis. Sequence analysis of 5'-[32P] labeled tRNA and eukaryotic mRNA using an adaptation of a method recently described by Donis-Keller, Maxam and Gilbert for mapping guanines, adenines and pyrimidines from the 5'-end of an RNA is described. In addition, a technique utilizing two-dimensional polyacrylamide gel electrophoresis for identification of pyrimidines within a sequence is described. 5'-[32P] Labeled rabbit beta-globin mRNA and N. crassa mitochondrial initiator tRNA were partially digested with T1- RNase for cleavage at G residues, with U2-RNase for cleavage at A residues, with an extracellular RNase from B. cereus for cleavage at pyrimidine residues and with T2-RNase or with alkali for cleavage at all four residues. The 5'-[32P] labeled partial digestion products were separated according to their size, by electrophoresis in adjacent lanes of a polyacrylamide slab gel and the location of G's, A's and of pyrimidines extending 60-80 nucleotides from the 5'-end of the RNA determined. Two-dimensional polyacrylamide gel electrophoresis was used to separate the 5'-[32P] labeled fragments present in partial alkali digests of a 5'-[32P] labeled mRNA. The mobility shifts corresponding to the difference of a C residue were distinct from those corresponding to a U residue and this formed the basis of a method for distinguishing between the pyrimidines.


Poly(dG).poly(dC) at neutral and alkaline pH: the formation of triple stranded poly(dG).poly(dG).poly(dC). Alkaline titrations of different samples of poly(dG).poly(dC) and of the constituent homopolymers poly(dG) and poly(dC) have been performed in 0.15 M NaCl and their CD spectra followed. Sample I contained a slight excess of poly(dC) (52% C: 48% G) and showed a single reversible transition (pK = 11.9) due to the dissociation of double stranded poly(dG).poly(dC). Sample II, containing an excess of poly(dG) (43% C: 57% G), showed two transitions (pK1 = 11.4, PK2 = 11.9) the first one being only partially reversible. Examination of the CD spectra along the alkaline titrations indicated the presence of another hydrogen-bonded complex of higher G content. Mixing curves performed at pH 8 have confirmed the presence of a 2G: 1C complex, besides the double stranded complex. It can be formed in amounts up to 30% by mixing the two homopolymers, alkali treatment and heating. The CD spectra of the two complexes have been computed from the CD data of the mixing curves. This permitted the determination of the concentrations of both complexes and homopolymers in all samples. The ratio of triple to double stranded complex is not only dependent on the G/C ratio of the sample, but also a function of the previous physico-chemical conditions. These results explain the variability of many properties of different poly(dG).poly(dC) samples observed by other workers.


Base specific fractionation of double stranded DNA: affinity chromatography on a novel type of adsorbant. A material suitable for base-pair-specific "affinity chromatography" of double stranded DNA is described. The synthesis of this material involves two successive polymerization reactions yielding solid particles of cross-linked bisacrylamide to which base-pair-specific dyes are covalently attached by spacers of polyacrylamide chains of different length. Materials with immobilized A.T-specific malachite green or G.C-specific phenyl neutral red were used for base-pair-specific fractionation of sheared DNA from bacterial sources, as well as of higher molecular weight Calf thymus DNA or defined fragments of coliphage lambda DNA. The excellent resolving power of this method of "affinity chromatography" of nucleic acids is comparable only to DNA fractionation in buoyant density gradients in the presence of base-pair-specific ligands. A great advantage of this material is its simple handling and its chemical stability, which allows repeated re-use of the same column.


New observations concerning the chloroacetaldehyde reaction with some tRNA constituents. Stable intermediates, kinetics and selectivity of the reaction. The stable intermediates formed in the reaction of cytosine, cytidine and adenosine with chloracetaldehyde were isolated. The -CH2CH/OH/- bridge between the exo and endo nitrogen atoms of the parent base was found in these compounds by means of PMR spectroscopy. Their acid-induced dehydration resulted in formation of appropriate ethenoderivatives. The rate constants of the intermediate formation and its dehydration were found to be 38x10(-4) and 47x10(-4) /min-1/ for adenosine, and 33x10(-4) and 10x10(-4) /min-1/ for cytidine. The PH range of 4.5--5.0 was found to be optimum for both adenosine and cytidine reactions. The quantitative modification of these two nucleosides in the presence of guanosine may be achieved with high selectivity only at a low pH of 3.0--4.0 N6-methyladenosine and N4-methylcytidine react quantitatively with chloroacetaldehyde and the reaction rate is higher than in the case of the parent nucleosides. The structure of the reaction products was assigned on the basis of PMR spectroscopy.


Evidence that proteins S1, S11 and S21 directly participates in the binding of transfer RNA to the 30S ribosome. In a previous publication1 we reported that the tyrosine selective reagent, tetraitromethane, causes complete inactivation of E. coli 30S ribosomes for poly U directed non-enzymatic phe-tRNA binding. This inactivation was demonstrated to be due to the chemical modification of the protein moiety of the ribosome. We have no identified the proteins of the 30S particle inactivated by this modification. Using a method of ribosome reconstruction we have found that unmodified proteins S1, S11, and S21 are essential for the restoration of the phe-tRNA binding activity of tetranitromethane inactivated ribosomes. We propose that these three proteins are intimately involved in the 30S ribosome binding site for tRNA.


Physico-chemical investigation of AlPO4 for the manufacture of antacids. I. Effect of precipitation and processing conditions on physico-chemical properties of AlPO4. Aluminium phosphate was precipitated from AlCl3-H3PO4 and NaOH, NH3H2O and NaHCO3--Na2CO3 mixture up to different pH values. The precipitates were dried at room temperature, 40 degrees and 105 degrees and their neutralizing properties (rate of neutralization and acid-consuming capacity) against 0.l N HCl were investigated. It was found that these properties depend on the nature of the reagents used for the formation of AlPO4, the pH and also the temperature of drying. The best antacid properties shows the AlPO4 preperation obtained from AlCl3-H3PO4 and NaHCO3-Na2CO3. For comparison, the therapeutic preparate "Aluphos" was also investigated.


[Mendelson's syndrome].

[Mendelson's syndrome]. Mendelson's syndrome is discussed with a review of the literature and presentation of 27 personal cases studies. Accidental aspiration of gastric fluid occurs primarily during anesthesia, in cranial trauma victims, and in toxic coma patients. Tissue damage is proportional to the acidity and the quantity of aspirated fluid. The initial clinical manifestations are often serious, sometimes leading to acute respiratory distress syndrom with pulmonary edema. Frequent infectious complications, often with anaerobic microbes, are deciding factors in the prognosis. Artificial ventilation with positive pressure (sometimes continuous) is often necessary. Administration of corticosteroids at high doses is likely favorable. Prophylactic administration of antibiotics is initially directed against anaerobic agents. The prevention of this serious syndrome should be a primary concern of anesthesiologists and physicians treating comatous patients.


Choline acetyltransferase and acetylcholinesterase activities in mice brain during the antagonistic action of antidepressant drugs and Ro 4--1284. Choline acetyltransferase (Ach-T) and acetylcholinesterase (Ach-E) activities in mice brain during the reverse action by imipramine, pheniprazine and pargyline to the syndrome elicited by intraperitoneal administration of Ro 4--1284 were investigated. A single dose of imipramine did not reverse reserpine-like syndrome whereas inhibited Ach-E activity and increased Ach-T activity at the same time. The reversal of reserpine-like syndrome by administration of pargyline, pheniprazine or chronic administration of imipramine was accompanied by no changes in Ach-E and Ach-T activities.


Central action of narcotic analgesics. II. Locomotor activity and narcotic analgesics. The effect of morphine, codeine, fentanyl and pentazocine on locomotor activity of rats and mice and open-field performance of rats were tested. All the analgesics tested produced a depressive action in the rat. In mice a depressive action was produced by pentazocine and codeine. Fentanyl increased the exploratory and basal locomotor activity of mice. Morphine increased the exploratory activity, but, given at doses of 2.5 and 10 mg/kg decreased the basal locomotor activity. The increase of locomotor activity in mice by morphine and fentanyl is caused by an indirect stimulation of catecholamine receptors.


[Preventive action of catecholamine and serotonin synthesis inhibitors and of adrenergic blockaders on the occurrence of the anovular syndrome in neonatally androgenized rats. I]. Administration of catecholamine synthesis inhibitors (alpha-methl-p-tyrosine) or serotonin (parachlorphenylalanine) simultaneously with testosterone propionate prevented the anovular sterility in the majority of the neonatally androgenized rats. Preventive action of adrenoblockers (droperidol and propranolol) on the effects of early androgenization were weak. The data obtained pointed to the participation of catecholamines and serotonin in the realization of the masculinizing action of androgen on the neuroendocrine centres of the gonadotropin hormones secretion control.


Regulation of Ca2+ release from mitochondria by the oxidation-reduction state of pyridine nucleotides. Mitochondria from normal rat liver and heart, and also Ehrlich tumor cells, respiring on succinate as energy source in the presence of rotenone (to prevent net electron flow to oxygen from the endogenous pyridine nucleotides), rapidly take up Ca(2+) and retain it so long as the pyridine nucleotides are kept in the reduced state. When acetoacetate is added to bring the pyridine nucleotides into a more oxidized state, Ca(2+) is released to the medium. A subsequent addition of a reductant of the pyridine nucleotides such as beta-hydroxybutyrate, glutamate, or isocitrate causes reuptake of the released Ca(2+). Successive cycles of Ca(2+) release and uptake can be induced by shifting the redox state of the pyridine nucleotides to more oxidized and more reduced states, respectively. Similar observations were made when succinate oxidation was replaced as energy source by ascorbate oxidation or by the hydrolysis of ATP. These and other observations form the basis of a hypothesis for feedback regulation of Ca(2+)-dependent substrate- or energy-mobilizing enzymatic reactions by the uptake or release of mitochondrial Ca(2+), mediated by the cytosolic phosphate potential and the ATP-dependent reduction of mitochondrial pyridine nucleotides by reversal of electron transport.


Identification and properties of two methyltransferases in conversion of phosphatidylethanolamine to phosphatidylcholine. Two methyltransferases involved in the methylation of phosphatidylethanolamine to form phosphatidylcholine were demonstrated in a microsomal fraction of bovine adrenal medulla. The first methyltransferase catalyzes the methylation of phosphatidylethanolamine to form phosphatidyl-N-monomethylethanolamine. This enzyme has an optimum pH of 6.5, a low Km for S-adenosyl-L-methionine (1.4 micron), and an absolute requirement for Mg2+. The second methyltransferase catalyzes the two successive methylations of phodphatidyl-N-monomethylethanolamine to phosphatidyl-N,N-dimethylethanolamine and phosphatidylcholine. In contrast to the first methyltransferase, it has an optimum pH of 10 and a high Km for S-adenosyl-L-methionine (0.1 mM) and does not require Mg2+.


Differences in the isoelectric focusing patterns of gamma-glutamyl transpeptidase from normal and cancerous rat mammary tissue. Highly purified fractions of gamma-glutamyl transpeptidase [gamma-glutamyltrinsferase; (5-glutamyl)-peptide:amino-acid 5-glutamyltransferase, EC 2.3.2.2] from normal and malignant rat mammary tissue were prepared. Analyses by isoelectric focusing indicate the existence of at least 12 enzymatically active species. The gamma-glutamyl transpeptidase from the tumor tissue had a greater proportion of the activity concentrated in the more negative species than the enzyme from normal tissue. Treatment of the two enzyme preparations with neuraminidase (acylneuraminyl hydrolase, EC 3.2.1.18) greatly reduced this difference. When whole tissue homogenates were treated with papain to solubilize the enzyme and then focused, the same relationship held. The neuraminidase activities in the two homogenates were similar, but the sialytransferase activity (CMP-N-acetylneuraminate:D-galactosyl-glycoprotein N-acetylneuraminyltransferase, EC 2.4.99.1) of the tumor homogenate was 13 times that of the normal mammary homogenate. These observations suggest that the gamma-glutamyl transpeptidase of the tumor is more heavily sialylated than that from the normal tissue, possibly reflecting the greater sialyltransferase activity of the tumor.


High-resolution 31P nuclear magnetic resonance study of rat liver mitochondria. Intact mitochondria were studied by high-resolution 31P nuclear magnetic resonance. Observable internal phosphate compounds included inorganic phosphate (Pi), ADP, and ATP. The internal pH was determined by the chemical shift of the internal Pi, the pK2 (6.7) of which was measured in uncoupled mitochondria. The observed equilibrium relation between the internal and the external Pi was consistent with the exchange equilibrium through the H2PO4-/OH- carrier. The internal ATP and ADP were essentially Mg2+ bound and their resonances were distinguishable from those of the external ATP and ADP by the chemical shift differences due to the Mg2+ concentration gradient and deltapH. Oxidative phosphorylation was followed by the separate resonances of Pi and adenine nucleotides both internal and external to mitochondria. From these resonances the internal and external phosphate potentials could be estimated.


Differential desensitization of functional adrenergic receptors in normal and malignant myeloid cells: relationship to receptor-mediated hormone cytotoxicity. Malignant myeloid leukemic cells and normal macrophages and granulocytes have functional beta-adrenergic receptors, which have been quantitated by radioreceptor binding with the beta-adrenergic antagonist [(3)H]dihydroalprenolol and by induction of cyclic AMP by adrenergic hormones. Both the normal and leukemic cells have beta(2)-adrenergic receptors, and the [(3)H]dihydroalprenolol binding was saturable, reversible, and stereospecific. The leukemic cells consisted of clones that could be induced to differentiate (MGI(+)D(+)) and clones that could not be induced to differentiate to mature macrophages and granulocytes by the protein inducer MGI. The different types of leukemic clones all had 1100-2300 receptor sites per cell, whereas normal macrophages had 7000 receptors per cell. The differentiation of MGI(+)D(+) leukemic cells was associated with an increase in receptors to a number similar to that found with normal macrophages. MGI(+)D(+) leukemic cells and normal macrophages were able to densensitize to the beta-adrenergic agonist (-)isoproterenol, shown by termination of cyclic AMP induction within 10-15 min and the lack of a second induction. The leukemic cells that could not be induced to differentiate lacked this capacity for desensitization, possibly due to an alteration in the uncoupling system between the receptor and adenylate cyclase. The lack of desensitization in these leukemic cells was associated with a higher sensitivity to the receptor-mediated cytotoxic effects of adrenergic hormones. It is suggested that cells, like some leukemic cells, that are unable to desensitize to adrenergic and possibly other hormones may be appropriate targets for differential destruction by hormones under conditions that do not affect normally desensitizing cells.


Functional properties of beta-galactosidase from mutant strain 13 PO of Escherichia coli. The functional properties of CZP protein, a mutant deriving from wild-type beta-galactosidase (beta-D-galactoside galactohydrolase; EC 3.2.1.23) by a point mutation, were investigated. A large decrease of the specificity, as evaluated by the kcat/Km ratio, was observed, principally originated by a weaker binding of the substrates. The catalytic constants, whose values are strongly affected by the presence of divalent cations, were smaller or larger for mutant enzyme than for wild-type enzyme, depending upon the experimental conditions. Analysis of the kinetic pathway indicates, with some substrates, a change in the limiting step for the mutant enzyme compared to the wild type. Because the k'3 step is rate limiting for hydrolysis of p-nitrophenyl-beta-D-galactoside by the mutant enzyme in the absence of Mg2+ and its value is relatively small, it is possible to observe a burst of p-nitrophenol during hydrolysis. This provides conclusive evidence for the occurrence of a two-step mechanism, with a sequential release of the products.


Ontogenetic development of kainate neurotoxicity: correlates with glutamatergic innervation. Stereotaxic injection of kainic acid into the striatum of adult rats causes degeneration of neurons intrinsic to the striatum but spares axons of passage and of termination of extrinsic neurons. Neurochemical and histologic studies demonstrate that striatal neurons are almost insensitive to kainate at 7 days after birth and that their vulnerability increases with age; by 3 weeks after birth, striatal injection of kainate produces a lesion comparable to that of the adult. The intensity and duration of the acute behavioral response to kainate also increases with age. The maturational increase in striatal neuronal sensitivity to kainate correlates with the development of glutamatergic innervation to the striatum, as measured by [3H]glutamate uptake by synaptosomes, and with the development of a postsynaptic, high-affinity receptor site for kainate. These ontogenetic studies provide additional evidence that kainate's neurotoxicity is a receptor-mediated event related to glutamatergic innervation of vulnerable neurons.


Evaluation of psychotropic drugs with a modified open field test. The open field test used to study behavioral alterations induced by psychotropic drugs is based mainly in the defecation, ambulation, rearing and grooming presented by animals subjected to the test. Because of the criticisms raised against the defecation score as a measure of the central effects of drugs, in the present experiment a modification of the test is proposed for the rat. The main points that characterize the new procedure are: (1) defecation scores are not considered; (2) besides ambulation, rearing and grooming, immobility was also recorded; (3) the total time of observation was increased, and (4) the stimuli, usually presented simultaneously in the open field (light and noise), were presented separately. The results obtained suggest that it is possible to differentiate classes of psychotropic drugs, without taking the defecation and grooming scores into consideration. Besides stimulants that evoked a characteristic pattern of behavior, neuroleptics could be differentiated from anxiolytics. Similarities, according to the dose, between barbiturates and anxiolytics were detected. Under LSD a peculiar pattern of behavior characterized by a large reactivity to light was observed.


Bromocriptine, lergotrile: the antiparkinsonian efficacy and the interaction with monoaminergic receptors. The antiparkinsonian activity of bromocriptine and of lergotrile was investigated in monkeys with surgically induced tremor and in parkinsonian patients. Both drugs effectively relieve tremor in experimental monkeys and induce less pronounced abnormal involuntary movements than L-dopa or piribedil. Both drugs were shown to be of therapeutic value in a group of patients with advanced Parkinson's disease who were no longer responsive to levodopa combined with carbidopa. Adverse effects were similar to those observed with levodopa and carbidopa, except that in individual patients abnormal involuntary movements and diurnal oscillations in performance ("on-off" effect) were decreased, while mental changes were increased. The interactions of bromocriptine and of lergotrile with dopamine and alpha-adrenergic receptors were investigated. Both drugs have mixed agonist-antagonist activities with respect to the dopamine receptors; lergotrile has a higher affinity for the agonist site while bromocriptine has a higher affinity for the antagonist site of the receptors. Both drugs effectively displace the binding of the alpha-adrenergic antagonist WB-4101 to cerebral cortex membranes. The mechanisms underlying the antiparkinsonian efficacies of these two drugs were discussed.


Blood pressure response to bolus administration of vasoactive drugs in the rat. The time course of systemic blood pressure response in normotensive anaesthetized rats was studied after a bolus administration of standard doses (0.4 microgram/kg) of noradrenaline, adrenaline, isoprenaline, acetylcholine, serotonin, bradykinin, and histamine. The single stimulus of a vasoactive agent elicits a blood pressure deviation with typical phasing. The time dimension of the individual wave is less variable and less dose dependent than their amplitude. Under the given experimental conditions the blood pressure response is predominantly determined by the peripheral vasomotor reactions; the cardiac component is of minor importance. Though the overall responses to the individual drugs are quite characteristic, they seem to comprise several common components. Thus the peripheral vascular system is supposed to consist of different regulatory subsystems which take part in the systemic blood pressure control by typically timed responses. The pattern of the reaction is then given by their unequal combination and various intensity.


Skin rejection in graft-versus-host disease. Graft-versus-host disease is becoming a common clinical problem, one which can require the consultation of a plastic surgeon for restoration of skin coverage. An understanding of the immunological basis of the disease is essential to the clinical management of this condition. A case of GVHD is reported, and the principles of treatment are discussed.


The effect of chronic lithium administration on dopamine metabolism in rat striatum. Striatal dopamine and its metabolites were studied in rats given lithium chloride in the diet. Results showed an increase in homovanillic acid and 3,4-dihydroxyphenylacetic acid levels but no significant change in dopamine concentration after 3 weeks of lithium administration. There was no change in tyrosine hydroxylase activity after 1, 2, and 3 weeks treatment. The results indicate an increase in the release and turnover of dopamine in the lithium-treated animals.


Prolactin secretion during and after Noveril infusions to depressive patients. Dibenzapine (720 mg, Noveril) was infused intravenously to 16 depressed patients during a period of 3 h. Serum prolactin levels were determined by radioimmunoassay and changes in clinical condition were evaluated according to the Hamilton Equation. The two variables were correlated to each other. In most of the patients Noveril caused a dramatic but short-lived improvement in depressive symptoms. There was much variability in the prolactin response to the drug. Serum prolactin levels showed a great elevation in 9 patients. In all patients the hormonal levels returned to their former normal levels after termination of the infusions. The treatment was then continued with Noveril per os. There was no significant correlation between serum prolactin levels and clinical condition or its change. The elevation of serum prolactin levels as a reaction to Noveril treatment may be explained by the prominent serotonergic action of Noveril. A time lag between serotonergic and dopaminergic actions of the drug when given in higher doses may be an additional explanation. Other possible hypotheses are discussed.


The degradation of a nonapeptide, sleep inducing peptide, in rat brain: comparison with enkephalin breakdown. The degradation of delta sleep inducing peptide (DSIP) was studied and compared with that of Met-enkephalin in brain homogenates. After 7.5 minutes of incubation of 2.5% (w/v) homogenate, 30% of N-terminal tryptophan was released from DSIP, while 75% of N-terminal tyrosine was released from Metenkephalin. The optimal pH of degradation of both peptides was pH 7.35. A rapid increase of breakdown of the peptides was observed during the 10 days of postnatal growth, with breakdown expressed per unit weight of brain. Neither morphine nor deprivation of rapid eye movement (REM) sleep affected the degradation of peptides.


In vivo and in vitro alteration of nicotine metabolism by the major metabolite of phenytoin. The influence of hydroxyphentoin (HPPH), the major metabolite of phenytoin, on the in vitro and in vivo metabolism of nicotine was examined. In rat liver 9,000 g supernatant HPPH decreased the appearance of cotinine from nicotine by 65% while not influencing the disappearance of nicotine or the appearance of nicotine-l'-N-oxide. In vivo, HPPH inhibited both nicotine elimination and cotinine formation but did not affect nicotin-l'-N-oxide formation.


[The effect of mainly alpha-adrenergic drugs, indirect sympathomimetrics and dopamine on exocrine pancreatic function. Studies in the isolated cat pancreas (author's transl)]. The influence of mainly alpha-adrenergic drugs (noradrenaline, adrenaline, phenylephrine), indirect sympathomimetics (ephedrine, tyramin) and dopamine on the exocrine pancreatic function of the isolated perfused organ of cats was studied. The injection of noradrenaline and adrenaline induced simultaneously a rapid depression of flow rate and an increase of perfusion pressure. Phenylephrine, indirect sympathomimetic drugs and dopamine did not change the perfusion pressure and the hydrelatic function (flow rate, secretion of chloride and total calcium). The protein and enzyme secretion was enhanced both in normal animals and cats pretreated by reserpine or 6-hydroxydopamine. The pancreatic protein secretion was inhibited by alpha-adrenolytic as well as beta-adrenolytic substances, tetracain and atropine. It is concluded, that mainly alpha-adrenergic drugs stimulate the pancreatic enzyme secretion in a cholinergic manner.


A comparison of rimiterol and salbutamol by inhalation at high and low dose in asthmatic patients. Rimiterol hydrobromide (Pulmadil) has been shown to have a dose-related bronchodilator effect; the optimum dose by inhalation appears to lie between 200 and 1,000 microgram. When given to a group of asthmatic patients at 'recommended' and 5--10 times 'recommended' dose by aerosol, cardiovascular effects were minimal and of a magnitude similar to that of salbutamol given in the same dosages to the same patients. The very rapid bronchodilator effect of rimiterol would appear to make the drug particularly suitable for the treatment of patients with intermittent asthmatic attacks, before exercise in patients with exercise-induced asthma and for bronchodilatation before using inhaled sodium cromoglycate or corticosteroid aerosols.


A brief review of sympathomimetic bronchodilators and a description of a new selective agent, rimiterol hydrobromide. The development of beta2-specific sympathomimetic bronchodilators (rimiterol, salbutamol, terbutaline) has made the basic treatment of asthmatic patients more safe and effective. Despite that, the asthmatics should be under careful control and all patients should be taught the correct way to use their bronchodilator aerosols. If a sympathomimetic drug has lost its effectiveness, the patient should be able to have easy contact to the treating physician or outpatient department.


The effect of dibutyryl cyclic AMP and glucagon on the myocardial cell pH1. DBcAMP or crystalline glucagon was utilized to elevate the intracellular cyclic AMP concentration in isolated rat hearts. Butyric acid, a metabolite of DBcAMP, was also investigated. Their effect on the intracellular pH (pHi) as determined by the distribution of [14C]DMO was investigated. Rat hearts, perfused with a recirculated modified Krebs-Henseleit solution maintained at 30 degrees C, were exposed to respiratory acidosis by bubbling the perfusate with 20% CO2. alpha- and beta-receptor antagonists were used to block the effects of endogenous catecholamines. Hypercapnia decreased the pHi from 7.09 to 6.82. A similar degree of hypercapnia decreased the pHi to only 6.95 in the presence of DBcAMP and to only 6.96 in the presence of glucagon. The effective buffer values (delta[HCO-3]i/deltapHi) were: control, 19; butyric acid, 16; DBcAMP, 139; glucagon, 148. These data suggest that cAMP mediates the effect of norepinephrine, which has been shown to diminish the change in pHi accompanying respiratory acidosis.


Behavioral neurochemistry: neuroregulators and behavioral states. There is compelling evidence that behavioral events after neurochemical function and that altered neurochemical function can change behavior. Such processes have been related both to neurotransmitters and to neuromodulators, together termed neuroregulators. Available research tools and theoretical constructs have begun to permit studies of certain types of behavior, primarily those related to emotional states and drives. This work is changing long-held concepts about severe mental disorders and the treatment of them.


Medical treatment of mental illness.

Medical treatment of mental illness. Psychotherapeutic drugs have dramatically improved the prognosis for patients with severe mental illness. The drug treatments are not a panacea. The medications sometimes cause irreversible side effects, and they are not helpful for all patients. They allow large numbers of individuals to leave the hospital, but to return to communities that are often poorly prepared to provide continuing care. Despite their limitations, psychotherapeutic drugs relieve a great deal of human suffering. They also involve psychiatry in modern biological science. This has led to the continuing search for more effective medications based on the study of possible biochemical substrates of psychiatric disorders.


Somatostatin--paracrine and neuromodulator peptide in gut and nervous system. Somatostatin, a tetradecapeptide widely distributed in nervous tissue and gut, has inhibitory effects on secretion and neuromuscular activity. The actions of this peptide probably embrace three types of transmitter-receptor interaction, namely that of a neurotransmitter in the nervous system, that of a hormone in the hypophyseal portal circulation and that of a local (paracrine) effector in gut and pancreas.


Comparison of cardiovascular responses and left ventricular work during exercise before and after artificial heart implantation. Cardiovascular dynamics and left ventricular work were evaluated in 15 resting, standing, and treadmill-exercised calves before and at periodic intervals after their natural hearts (NH) were replaced with an artificial heart (AH). Standing produced increases in heart rate, cardiac output, oxygen uptake, and left ventricular work and decreases in mean aortic pressure and systemic vascular resistance in NH calves which were more marked with exercise. AH calves had higher aortic pressures, cardiac output, systemic vascular resistance, oxygen uptake, and left ventricular work during resting conditions in the first 2 postoperative weeks than did NH calves, which gradually returned to values similar to the latter by the fifth week after operation. Exercise was not tolerated early after AH implantation, but was after 5 to 6 weeks. Our results indicate that AH calves increase cardiac output with exercise by reducing systemic vascular resistance, whereas NH animals respond similarly, but also increase heart rate. The data suggest that a marked elevation in systemic vascular resistance early after AH implantation increases left ventricular work and prevents adequate rises in cardiac output to all but minor increases in metabolic requirements.


Endocrine-like cells in the terminal bronchioles and saccules of human fetal lung: an ultrastructural study. An ultrastructural study of Kulschitsky cells was made on lung tissue from five human fetuses of gestational ages between 18 and 25 weeks. The cells were found to occur with relative frequency throughout the bronchi and bronchioles, as well as in the developing saccules. This report describes in detail the cells of the terminal bronchioles and saccules, where their long cytoplasmic processes weave through the epithelium and come into contact with intercellular spaces and the lumen. The cytoplasmic organelles have an orderly arrangement comparable to secreting cells. Dense core vesicles characterise the cytoplasm but clear vesicles and some with less dense, diffuse cores are also present, and may be seen outside the plasma membrane and in the interstitial spaces. The K-cells are usually colsely associated with capillaries or smooth muscle cells across the basement membrane. In addition, the rare occurrence of a small unmyelinated nerve fibre in the vicinity of a K-cell in a terminal bronchiole raises the possibility that the cells fulfill a type of 'mini receptor' role in addition to their probable vasoactive one. Evidence is given that K-cells divide in human fetal lung.


Anchoring cells (Desmocytes) in the hydrozoan polyp Cordylophora. Desmocytes or anchoring cells are present on the upright stolons of the athecate hydroid Cordylophora caspia and function to support the soft coenosarc within the rigid tube of perisarc by linking the perisarc with the mesoglea. These cells are characterized by accumulations of 70 A filaments which aggregate into dense rods at the apical end and contact the perisarc. At the base of the desmocytes the filaments are distributed within large cytoplasmic processes which interdigitate with an extension of the mesoglea. Desmocytes in Cordylophora are temporally and spatially  formed in sequence as the upright elongates. Depending on their location and structure they can be categorized as forming, functional, or remnant desmocytes. The youngest, forming desmocytes are found in the distal end of the stolon 0.5-1.0 mm from the base of the hydranth. In this region coenosarc is just beginning to separate from the perisarc. Functional desmocytes are scattered 1-3 mm from the base of the hydranth and are associated with perpendicular extensions of the mesoglea. Remnants have lost their mesogleal connection and are located in more proximal, older regions of upright stolon. Support provided by the desmocytes to the upright stolon is limited by three factors that characterize the athecate hydroid: distribution of perisarc, pattern of growth, and extent of movement. The distal location of forming desmocytes is coincident with the hardening of new perisarc. The temporary nature of attachment sites is directly related to upright elongation. It is probable that the orientation of filaments within the cell and the mesogleal extension provide an addition feature of flexibility necessary to permit feeding, growth, and rhythmic pulsation movements characteristic of these hydroids.


Testicular descent. Normal and abnormal. The subject of testicular descent has been reviewed. An attempt has been made to present a basic understanding of the embryology and mechanisms of this event. The abnormalities of testicular descent have also been discussed, including the pathogenesis and complications of this disorder, which is the most common developmental abnormality in childhood. The aims and results of both the hormonal and surgical treatments of cryptorchidism have been summarized. From data gleaned from the literature, a plea is made for the earlier treatment of the undescended testis in patients under five years of age.


Storage of platelets prepared by discontinuous flow centrifugation. Platelet concentrates were prepared by plateletpheresis using discontinuous flow centrifugation. Platelet units were stored in PL-146 bags of 300 ml and 2,000 ml capacity, and in vitro measures helpful in predicting platelet viability were compared. Storage in bags of 300 ml capacity led to significant fall in pH, decreased recovery from osmotic stress, and deterioration of morphology in 24 hours. Storage lesions were significantly decreased by use of 2,000 ml capacity bags.


The influence of pH on antimicrobial substances in canine vaginal and urethral secretions. Trimethoprim and rosamicin (a new basic macrolide antibiotic) were administered to normal and oophorectomised female dogs by constant intravenous infusion before and after oestrogen and androgen administration. Their concentrations in plasma and in urethral and vaginal secretions were determined by bioassay and correlated with the pH values of vaginal and urethral secretions. Both compounds were concentrated in the vaginal and urethral secretions in reverse correlation with the pH of these fluids. Trimethoprim and rosamicin have antimicrobial spectra well suited for the treatment of bacterial urethritis and vaginitis and require further clinical investigation.


Milk fever prevention.

Milk fever prevention. Milk fever is a disease of increasing importance. In dairy herds its incidence has doubled since 1950; today about 8 per cent of parturitions in Swedish dairy cattle are complicated by milk fever. At the same time, the clinical picture has changed and the effectiveness of calcium therapy has been markedly reduced. Thirty to 40 per cent of cows with milk fever need more than one treatment. These trends are obvious in Sweden and Norway and have been reported from many other parts of the world. However, there are also geographical and breed differences so that these figures might not be applicable under British conditions.


Glutathione conjugation and mercapturic acid formation in the developing rat, in vivo and in vitro. 1. The levels of GSH-S-epoxidetransferase (GSH-S-transferase E, EC 2.5.1.18), gamma-glutamyl transpeptidase (EC 2.3.2.2) and S-substituted cysteine N-acetyltransferase have been measured in the liver and kidney of neonatal to adult rats. 2. GSH-S-epoxidetransferase and S-substituted cysteine N-acetyltransferase activities were less than 10% of the adult values in neonatal rats, rising gradually to reach adult values at about 40 days of age. Renal gamma-glutamyl transpeptidase activity was 27% of the adult value 2 days after birth and increased after 15 days reaching adult levels by 40 days. 3. The percentages of the doses of 1,2-epoxy-3-(p-nitrophenoxy)propane (ENPP) and of 1,2-epoxybutane, administered at the same dose level to rats aged 4 days to adult, excreted as the corresponding mercapturic acids in 24 h, were not significantly different. 4. Adult and 10 day old rats doses at the same dose level with ENPP excreted N-acetyl-S-[2-hydroxy-3-(p-nitrophenoxy)propyl]-L-cysteine (ENPP-MA) at the same rate. 5. In addition to ENPP-MA, dosed rats under 13 days of age excreted the corresponding substituted cysteine. 6. The correlation between results in vitro and in vivo is discussed.


[Characteristics of pancreatic basal secretion in the dog]. A method is described for the simultaneous evaluation of the pancreatic, the biliary and the gastric secretion in long-term experiments. Under these conditions, the pancreatic basal secretion is characterized. The pancreatic basal secretion is a very variable reference value that is influenced by endogenous stimuli. The upper threshold value for the secretion rate was 2.2 ml/15 min. Under the influence of spontaneous biliary secretion, the protein concentration amounts to a characteristic value of relatively unimportant variance. If the pancreatic basal secretion is used as a reference value, the spontaneous secretions of the biliary ducts (gastrin release from the duodenum?) and of the stomach (secretin release from the duodenum) and be taken into account. A further disturbing factor interfering with both the pancreatic and the gastric basal secretion is to be neglected.


[Animal experiment studies on the neurohumoral control of female puberty]. To study the mode of action of oestrogen in female sexual maturation, prepubertal female rats were treated in different ways with oestradiol benzoate (OB). Using an improved implantation method, former findings on a hypophysial site of oestrogen action in the positive feedback (Hohlweg effect) were confirmed. A single s.c. injection or intrahypophysial implantation of OB at 25 or 26 days of age induced precocious vaginal opening (VO) and one ovulation, but the subsequent ovarian cycle was significantly prolonged, so that the first spontaneous ovulation occurred only at the normal time of the onset of puberty. Further studies demonstrated that the sensitivity to the ovulation-inducing effect of oestrogen increases as the rats approach the age of puberty, and that the first pubertal ovulation can be suppressed by intrahypophysial, but not by intrahypothalamic implantation of progestereone. The conclusion is drawn that the precocious induction of one ovulation via the Hohlweg effect is not tantamount to an advancement of puberty. The results furthermore suggest that the positive oestrogen feedback forms the basis for the first pubertal ovulation as it does with regard to later cyclic ovulations. True acceleration of sexual maturation was achieved by daily injections of 0,05 microgram OB/100 g b.w. from 5 days of age to VO. In contrast to findings obtained by other authors in Sprague-Dawley rats, a shortened OB treatment from 26 days of age to VO was not effective in advancing the onset of puberty unless the rats had additionally been injected with OB from 5 to 10 days of age. A final experiment demonstrated that the first ovarian cycle was not prolonged after neonatal ovariectomy and implantation of ovaries at 24, 28 or 32 days of age. Thus, maturation of the neurohormonal mechanisms that are responsible for the cyclic ovarian function continues during the prepubertal development in the absence of ovarian steroids.


[Relationship between the pathogenesis of lumbosacral radiculitis and specific treatment]. On the basis of personal experience in treating 534 patients with sacro-lumbar radiculitis the authors believe it expedient to distinguish the following clinical syndromes: lumbago, radicle neuralgia, radicle neuritis, radicle neuritis with a paralysis of the foot and the caudal syndrome. In their opinion, the main pathogenetical mechanisms of the disease, which facilitates the selection of the methods of treatment should be taken into consideration. It is stressed that a differentiated clinical approach to patients with therapeutically resistent forms of sacro-lumbar radiculitis in the majority of the cases provides good results in medicational and surgical treatment.


[Diffuse x-ray wide-angle scattering of polyglutamic acid in solution]. The diffuse wide angle x-ray scattering (WAXS) of polyglutamic acid (PGA) in solution was studied using an x-ray diffractometer with small aperture of the primary beam. The scattering  curve was recorded at an angular interval from (article: see text). The experimental scattering intensity of PGA with alpha-helical CD spectrum showed a maximum at 14.4 nm-1. Unordered PGA in solution yielded no maximum at this scattering angle. The studies have proved that the scattering theory can be applied to globular proteins in solution as well as to chain molecules in solution in this angular interval. The differences between the calculated scattering curves and the experimental curves indicate minor movements of the side chains of PGA in solutions and slight structuring of the solvent at the surface of the polypeptide chain.


Substrate binding to solubilized cytochrome P-450 from rabbits at different temperatures. The binding affinities of selected type I- and type II-substrates to partially purified cytochrome p-450 from rabbit liver microsomes were studied and found to differ from those of rats. The temperature dependence of the apparent binding constants qualitatively exhibited the same characteristics compared with that of rats. For type I-substrates endothermic and for type II-substrates exothermic reaction characteristics were observed. Taking into account the partition coefficients of the substrates so far investigated it is obvious that type I substrates with increasing hydrophobicity are bound more strongly while type II-substrates show a more complicated behvaiour. This may due to the fact that other types of binding are included besides the hydrophobic interactions.


The influence of NADH on the ethylmorphine-N-demethylation in liver microsomes from control and phenobarbital-treated rats or different ages. The ethylmorphine-N-demethylation by liver microsomes from control and phenobarbital-treated rats of different ages was investigated by means of adding NADPH in combination  with NADH to the incubation medium. The rate of ethylmorphine-N-demethylation in the presence of NADPH without NADH is greater in adult than in young rats and greater in induced that in control rats. The higher the activity of ethylmorphine metabolism with NADPH alone the more it is abolsutely enhanced by NADH. The relative increase in ethylmorphine metabolism caused by NADH is equal in all groups of animals. It is concluded that there are no differences in the introduction of the second electron from NADH to the oxygenated cytochrome P-450 but there are differences in the concentration of cytochrome-substrate complex and, consequently, in the oxygenated cytochrome-substrate complex. The enhancing effect of NADH is higher at lower NADPH concentrations. In the presence of NADH, the NADPH concentrations necessary to obtain a msximum metabolic rate are lower than without NADH.


Role of neurotransmitters, prostaglandins and glucose on precursor incorporation into the RNA of thyroid slices. The present studies were performed in order to investigate the role of neurotransmitters, prostaglandins and glucose on [3H] uridine incorporation into total RNA in beef thyroid slices. Carbamylcholine strongly stimulated RNA labelling from [3H uridine; atropine abolished this effect. NaF, at 1 and 5 mM, progressively increased this parameter while norepinephrine caused a similar effect at 10(-3) but not at 10(-6) M. Phentolamine (1 mM) blocked the stimulatory action of TSH; propranolol and atropine did not. Glucose at concentrations between 4 and 24 mM caused a progressive increase in RNA labelling from [3H] uridine. This effect was inhibited by dinitrophenol. Prostaglandins (E1, A1, F1alpha and F2alpha) assayed in concentrations between 5 and 25 microgram/ml, with or without caffeine, had no effect on RNA labelling. Moreover, neither aspirin nor indomethacin inhibited TSH stimulation. Under similar experimental conditions, PGE1 did simulate PB125I formation.


Sympathetic amines, renin and blood pressure. The sympathetic nervous system and the renin-angiotensin mechanism each can influence blood pressure separately but the two systems also interact functionally in various ways. There is good evidence that central catecholaminergic neurons play an essential role in the regulation of blood pressure but it may be assumed that other putative neurotransmittors such as serotonin, GABA and various peptides also participate in the central regulation of blood pressure. The secretion of renin, which catalyzes the production of angiotensin(s), is stimulated by increased sympathetic activity and circulating sympathetic amines. Dopamine seems to have an opposite effect on renin release but it is not clear whether this is due to a direct effect on the renin producing cells or an influence on sympathetic activity, centrally or peripherally.


Cardiovascular actions of bromocriptine. Bromocriptine lowers blood pressure in animals and in man. Results obtained in experiments performed in the dog and cat suggest three possible mechanisms of action: a) relaxation of vascular smooth muscle, principally in splanchnic and renal vessels, (b) inhibition of transmitter release from noradrenergic nerve endings, (c) central inhibition of sympathetic nerve activity. The effect of bromocriptine at each putative site of action can be explained in terms of dopamine receptor stimulation.


Bone marrow transplantation between mixed leukocyte culture reactive siblings. Bone marrow transplantation from an HLA identical MLC reactive sibling has been performed in a patient with acute myelogenous leukemia resistant to drug treatment. Prompt engraftment was documented; however, the patient died of septicemia 34 days after transplant. Clinical manifestation of graft vs. host reaction was mild but was moderately strong expressed at autopsy tissue samples. Recurrence of persistence of leukemia was found at the time of death.


Salicylazosulphapyridine-induced Heinz body anemia. A 58-year-old patient suffered from severe malabsorption due to agammaglobulinemia. Treated empirically with salicylazosulfapyridine 2--6 g/day, the subjective and objective features of malabsorption regressed. About a year after this treatment she developed a generalized weakness without renewal of the diarrhea; the diagnosis of Heinz body hemolytic anemia was established. In our patient, hemolysis began many months after the commencement of treatment and no deficiency of G6PD or other erythrocyte enzyme or pathological hemoglobin were found.