Kinetics and mechanism of degradation of some 2-sulfanilamidopyrimidine derivatives. Part 2. Log k--pH profile for sulfadimidine autoxidation. The overall first order rate constants for the reaction of degradation of sulfadimidine (kobs. = kOX+kh) in the presence of the air oxygen were determined from the measurements of absorbance in 0-1 M HCl at 243 nm, using "the feathering technique". The apparent first order rate constants for autoxidation of sulfadimidine at 403, 411 and 418 K, in the pH range 2-0--9-2 were calculated from the equation kOX = kobs. -- kh, where kh are the rate constants for hydrolysis carried out under nitrogen. The rate of sulfadimidine autoxidation is a function of concentration of the undissociated form (kOX = kOX-fHA). The thermodynamic parameters of the reaction: Ha, deltaHNo., deltaSNo. and logA were determined for the specific rate constant of autoxdiation (kOX).


Drug-drug interactions among residents in homes for the elderly: a pilot study. This pilot study investigated epidemiologically the potential for clinically significant drug-drug interactions, a subclass of adverse drug responses, in two homes for the elderly. The agent (drugs), host (residents), and environment (rural and urban nursing homes) in the illness known as drug-drug interaction were studied. Drug profiles on 188 subjects were compiled and screened by computer. Of these, 100 (80 in the rural home and 20 in the urban home) had the potential for clinically significant drug-drug interactions. Laboratory diagnostic procedures essential to confirm the unintentional interaction of two or more drugs were beyond the scope of the study; therefore, physicians independently reviewed the records of 66 residents who could be interviewed, agreeing that 27 residents were potential drug-drug interactors. These subjects had twice as many drug products and three times as many pro re nata products prescribed for them as did subjects without the potential for drug-drug interaction. The possible cause of interaction found most frequently was digitalis combined with thiazide or furosemide. The results of this pilot study suggest several implications for practice within the research setting.


Esophageal reflux. Diagnosis and therapy. Diagnosis of esophageal reflux often can be made on the basis of the characteristic symptoms of heartburn and regurgitation. When the picture is not so typical, acid reflux testing and esophageal biopsy appear to be the best indicators of esophageal reflux. Medical management is directed toward preventing reflux, neutralizing refluxed gastric contents, and enhancing clearance of refluxed material. Antacids are a mainstay of therapy, along with restrictions on diet and certain types of activity. If conservative therapy fails to control symptoms and stricture is likely to develop, surgery may be indicated.


The effect of beta-adrenoreceptive antagonists on the morbidity and mortality in cardiovascular disease. The effect is critically reviewed of chronic administration of beta-adrenoreceptor antagonists on morbidity and mortality in angina pectoris and myocardial infarction. There is inconclusive evidence that the abrupt cessation of therapy with these agents may increase morbidity and mortality in angina pectoris. The type of anginal patient in which this may occur is not yet defined and neither is the mechanism. There is no evidence that beta-antagonists prolong the life of anginal patients. In the acute phase of experimental myocardial infarction, these drugs reduce mortality but do not do so in man. There is increasing evidence that they prolong life if administered to patients surviving the acute phase of myocardial infarction. The need for further studies is discussed.


Recommending coronary artery surgery: refining judgement through application of new knowledge. An analysis is made to help decide on the best form of treatment for atherosclerotic coronary disease. Available data on surgical treatment are reviewed with emphasis on prognosis and management of the patient with stable angina.


Correlations between hydrophobicity and non-specific pharmacological effects of beta-adrenoceptor blocking agents. It was the aim of this study to test whether the non-specific pharmacological activities of the beta-adrenergic blocking drugs can be predicted by estimation of the hydrophobicity of the compounds. Srong correlations were obtained between the octanol buffer partition coefficients and the ability of the drugs to decrease conduction velocity of the isolated frog heart, to raise the electrically induced ventricular fibrillation threshold in guinea pigs, and to depress ventricular contractility in the cat. The strong correlations between the partition coefficients and the pharmacological actions suggest that estimation of the hydrophobicity of the beta-adrenergic blocking drugs is suitable to predict the non-specific pharmacological properties.


Rhodopsin in model membranes: charge displacements in interfacial layers. A model membrane was developed in which interfacial layers of rhodopsin were reoriented onto one side of a thin Teflon film separating two aqueous compartments. Flashes evoked fast photoelectric signals (1 ms) that originated from capacitative charge displacements of oriented rhodopsin upon bleaching. The photoelectric responses of rhodopsin in the model membrane are compared with the early receptor potential of photoreceptor cells; it is concluded that the signals in both systems originate from the same mechanism.


[Polyarteritis nodosa with renal agenesis and immunosuppressive treatment]. A case of a 44 years old man with the unique combination of polyarteritis nodosa (PAN) and the congenital absence of a kidney is presented. The clinical picture consisted of fever, general symptoms, hypertermia, peripheric neuropathy, subcutaneous nodules and renal damage. Laboratory findings included increased WBC, telescoped urinary sediment, renal insufficiency, positive rheumatoid factor, policlonal gammopathy and positive Australia antigen. A review of the pertinent literature and the etiopathogenic role of Australia antigen in PAN is discussed. Efficacy of immunosuppressive therapy was evident in this case.


Intramolecular general base-catalyzed ester hydrolyses by the imidazolyl group. Intramolecular general base catalysis by the imidazolyl group was found in the hydrolyses of endo-5-[4;(5')-imidazolyl]-bicyclo[2.2.1]hept-endo-2-yl trans-cinnamate and endo-5-[4'(5')-imidazolyl]bicyclo[2.2.2]oct-endo-2-yl trans-cinnamate in which the imidazolyl and trans-cinnamoyl groups are bound in close proximity to each other by rigid bicyclic rings. The rate constants for the intramolecular general base-catalyzed hydrolyses at 60 degrees are 6.4 X 10(-7) sec-1 for the former and 1.8 X 10(-7) sec-1 for the latter and the deuterium oxide solvent isotope effects are 3.0 for both. On the other hand, no intramolecular catalytic participation of the imidazolyl group was observed in the hydrolyses of the endo-exo isomers, exo- 5-[4'(5')-imidazolyl]bicyclo[2.2.1]hept-endo-2-yl trans-cinnamate and endo-5[4'(5')-imidazolyl]bicyclo[2.2.2]oct-exo-2-yl trans-cinnamate, in which the imidazolyl groups are located far from the trans-cinnamoyl groups. Intramolecular general base-catalyzed hydrolyses by the imidazolyl groups in endo-5[4'(5')-imidazolyl]bicyclo[2.2.1]hept-endo-2-yl trans-cinnamate and endo-5-[4'(5')-imidazolyl]bicyclo[2.2.2]oct-endo-2-yl trans-cinnamate can serve as models of serine esterase-catalyzed hydrolyses.


3':5'-cyclic AMP: independent induction of amino acid transport by epinephrine in primary cultures of adult rat liver cells. Liver cells were obtained from adult rats by a collagenase perfusion technique and cultured as monolayers in serum-free media. Epinephrine and isoproterenol both induced large increases in intracellular adenosine 3':5'-monophosphate (cAMP) within 1-2 min whereas epinephrine (but not isoproterenol) induced 2- to 3-fold increases in the rate of alpha-aminoisobutyric acid transport within 2-4 hr after a 1 hr lag. Propranolol abolished the increase in cAMP elicited by epinephrine and isoproterenol, but did not block the induction of alpha-aminoisobutyric acid transport by epinephrine. In contrast, dihydroergotamine abolished and phentolamine diminished the induction of alpha-aminoisobutyric acid transport by epinephrine but did not decrease the stimulation of cAMP levels by epinephrine. Epinephrine dose response curves for cAMP and alpha-aminoisobutyric acid transport were similar. Once exposed to epinephrine, cells became refractory to further stimulation of cAMP levels by epinephrine.


Antigen-specific nonimmunoglobulin factor that neutralizes xenotropic virus is associated with mouse serum lipoproteins. A soluble nonimmunoglobulin factor that specifically neutralizes mouse xenotropic C-type virus is found in normal mouse sera. It is stable from pH 2 to neutrality and resists ether extraction, freezing, or brief heating to 100 degrees. It can be separated from immunoglobulins by ultracentrifugation at a density of 1.21 g/cm3. Neutralizing activity is only found with the serum lipoproteins in the fraction with density less than 1.21 g/cm3.


Inhibitors of genetic recombination in pneumococci. Treatment of transformable pneumococci with DNA-intercalating agents shortly after the uptake of DNA molecules inhibited the appearance of genetic transformants. The same drug treatments applied 20 min after DNA uptake were ineffective. Ethidium bromide, proflavin, daunomycin, actinomycin D, and platinum red were found to be effective inhibitors. Donor DNA molecules reisolated from the drug-treated bacteria appeared to be associated with the resident DNA in an abnormal manner, and they had only poor transforming activity.


Carcass components at first estrus of rats on high-fat and low-fat diets: body water, protein, and fat. Carcass analysis data show that weanling rats fed high-fat (HF) and low-fat (LF) diets until the day of first estrus had similar body compositions at estrus, although the HF rats had estrus significantly earlier and at a lighter body weight (P less than 0.01) than the LF-diet rats. Total water as percent of wet weight, protein as percent of wet weight, and the water/protein ratios of the HF- and LF-diet rats did not differ significantly, whereas the absolute amounts of body water and protein of the two diet groups differed significantly (P less than 0.01), in accord with means (+/- SEM) of total body water as percent of wet weight were 66.2 +/- 0.3% for the HF rats and 66.4 +/- 0.3% for the LF-diet rats, whereas the mean absolute total body water for the two diet groups was 69.7 +/- 2.2 g and 81.1 +/- 2.4 g, respectively (P less than 0.01). Carcass fat of the HF rats, 15.6 +/- 1.0 g, was identical with that of the LF-diet rats, 15.6 +/- 0.9 g. The HF rats were therefore relatively fatter, 14.6 +/- 0.6 wet weight %, than the LF-diet rats, 12.6 +/- 0.4 wet weight % (0.05 greater than P greater than 0.01). The percentage of water in the fat-free wet weight of the HF rats, 77.5 +/- 0.3%, was significantly (P less than 0.01) greater than that of the LF-diet rats, 76.1 +/- 0.3%. These data and the high percentages of total water of body weight show that at first estrus the HF- and LF-diet rats had not as yet attained an adult body composition, similar to the human female at menarche. Within each diet group, the percentages of total water/body weight, protein/wet weight and fat/wet weight, or fat/dry weight, did not change significantly with increasing age of estrus, whereas each absolute carcass component--body water, protein, and fat--increased significantly with increasing age of estrus. The carcass data support G.C. Kennedy's hypothesis that a metabolic signal, related to fat stores, is a signal for puberty in the rat and are in accord with the hypothesis that a critical body composition of fatness is necessary for estrus in the rat, as in the human female. The greater relative fatness of the HF-diet rats may be associated with higher levels of estrogen in the HF rats than in the LF-diet rats.


Extension of longevity in Drosophila mojavensis by environmental ethanol: differences between subraces. Drosophila mojavensis adults, which breed and feed on necrotic cacti, show an increase in longevity when exposed to atmospheric ethanol. The increase in longevity is accompanied by retention of mature ovarioles and is independent of diet. Differences in longevity among strains from different localities were detected for females. Strains from Arizona and Sonora, Mexico, showed the greatest increase in longevity, while strains from Baja California, Mexico, showed the least increase. These differences may be controlled by the alcohol dehydrogenase locus, the octanol dehydrogenase locus, and modifier genes, because the aduld response is correlated with the frequency of alcohol dehydrogenase alleles, as well as second chromosomal inversions containing the octanol dehydrogenase locus. The longevity response is also consistent with the more uneven distribution and availability of the host plant in Arizona and Sonora, Mexico. Strains from Arizona and Sonora, Mexico, have a high frequency of Adh-S, the allele whose product is heat and pH tolerant. The host plant, organpipe cactus, exhibits extremes in temperature and pH in the same geographic region. Strains from Baja California, Mexico, possess a high frequency of Adh-F, whose product is heat and pH sensitive. The substrate in this region, agria cactus, has moderate temperature and pH extremes and contains relatively high concentrations of isopropanol. Isopropanol is presumable a selective agen favorable to Adh-F. The environmental heterogeneity that is proposed for maintaining the alleles at the alcohol dehydrogenase locus is the interaction of substrate alcohol content with temperature and pH. Substrates that do not contain appreciable amounts of isopropanol and are exposed to high temperatures and exhibit variable pH favor Adh-S, while substrates containing isopropanol and having moderate temperatures and pH favor Adh-F.


Reconstitution of native human hemoglobin from separated globin chains and alloplex intermediates. A complete experimental format is given for the reconstitution of human hemoglobin from the separated heme-free alpha- and beta-globin chains (alpha degrees, beta degrees) and hemin, by two alternative routes. Based on their oxygen binding properties, the reaction of the ferri-forms with reducing agent, and the response of the oxygen binding curves to pH variation and to the addition of the allosteric effector 2,3-diphosphoglycerate, the molecules are native. One reconstitution route uses direct addition of hemin to the separated globin chains with production of the separated subunits, which can then be recombined and reduced. This procedure occasions losses by precipitation in the heme-addition step except at high dilutions, and the yields are low. In the second pathway, either globin chain is mixed with the complementary untreated subunit to form the half-filled (with heme) intermediates, which combine stoichiometrically with hemin. No precipitation accompanies these reactions. For alpha-globin, the yield is about 50% because of incomplete combination with the heme-containing beta chain. For beta-globin, the yield is better than 70%. It is suggested that experiments intended to test either globin chain should use the second route in preparation for structural or functional comparisons with native hemoglobin.


Effect of gangliosides and substrate analogues on the hydrolysis of nicotinamide adenine dinucleotide by choleragen. Choleragen and its A protomer catalyzed the hydrolysis of NAD to ADP-ribose and nicotinamide. NADase activity was inhibited by gangliosides GM1 (galactosyl-N-acetylgalactosaminyl-[N-acetylneuraminyl]-galactosylglucosylceramide), GM2 (N-acetylgalactosaminyl-[N-acetylneuraminyl]-galactosylglucosylceramide), GM3 (N-acetylneuraminyl-galactosylglucosylceramide), and GD1a (N-acetylneuraminylgalactosyl-N-acetylgalactosaminyl-E1N-acetylneuraminyl]-galactosylglucosylceramide). These gangliosides also increased the intensity of the tryptophanyl fluorescence of the isolated A protomer (lambda max = 328 nm). GM1 but not GM2, GM3, and GD1a caused a "blue shift" in the fluorescence spectrum of the B protomer. These results are consistent with other evidence that the specificity of GM1 as the choleragen receptor resides in its carbohydrate moiety. The NADase activity of choleragen was similar to that of diphtheria toxin previously described [J. Kandel, R. J. Collier & D. W. Chung (1974) J. Biol. Chem. 249, 2088-2097]. As with diphtheria toxin, analogues of NAD were inhibitory, adenine being the most effective. Significant inhibition was also noted with adenosine, AMP, ADP-ribose, nicotinamide, nicotinamide mononucleotide, and NADP. NADP was hydrolyzed only slowly by choleragen. In the NADase reaction catalyzed by diphtheria toxin, water serves as an acceptor for the ADP-ribose moiety of NAD in lieu of the natural acceptor molecule, which is elongation factor II (Kandel et al., 1974). It seems probable that the natural protein acceptor for ADP-ribose in the reaction catalyzed by choleragen is adenylate cyclase or a protein component of a cyclase complex that regulates enzymatic activity.


31P nuclear magnetic resonance studies of Ehrlich ascites tumor cells. High-resolution 31P nuclear magnetic resonance spectra at 145.7 MHz are reported for intact Ehrlich ascites tumor cells and their perchloric acid extracts. In the extracts it was possible to assign resonances to fructose 1,6-bisphosphates, dihydroxyacetone phosphate, ATP, ADP, AMP, Pi, NAD+, phosphorylcholine, glycero-3-phosphorylcholine, glycero-3-phosphorylethanolamine, and glyceraldehyde 3-phosphate from their chemical shifts, pH behavior, and spin couplings. All but glyceraldehyde 3-phosphate were observed and assigned in the intact cells. It was possible to show that the hydrolysis of fructose 1,6-bisphosphate to dihydroxyacetone phosphate and glyceraldehyde 3-phosphate is in equilibrium, that the dihydroxyacetone phosphate leads to glyceraldehyde 3-phosphate reaction is not, and that in the intact cell without added oxygen or glucose the reaction 2ADP in equilibrium ATP + AMP is in equilibrium. From the known pH dependence of the Pi resonance it was possible to show that during aerobic or anerobic glycolysis the difference between intracellular and extracellular pH values was less than 0.2 pH units. Upon oxygenation the ATP concentration increased while the ADP concentration fell. Introducing deoxyglucose depleted the ATP and resulted in an AMP signal and one from deoxyglucose 6-phosphate, which is transported and phosphorylated but not catabolized.


Influence of three short-chain peptides (alpha-MSH, MSH/ACTH 4-10, MIF-I on) dimensional attention. Male, albino rats were treated with alpha-MSH, MSH/ACTH 4-10, MIF-I or a diluent control solution and then tested on a visual discrimination problem. Immediately after acquistion of the visual task the animals were tested with a spatial extradimensional shift problem. The animals treated with the MSH/ACTH 4-10 and MIF-I acquired the discrimination nonsignificantly faster than animals treated with alpha-MSH or a placebo. A subproblem analysis of the EDS behavior indicated that the peptides significantly improved performance probably by affecting attention.


Investigations on alpha-MSH and MIF-1 effects on cyclic AMP levels in rat brain. It has been suggested that the peptides alpha-metanocyte stimulating hormone (alpha-MSH) and MSH-release inhibitory factor (MIF-1) may alter adenosine-3', 5'-cyclic monophosphate (cAMP) metabolism [13,26]. Normal and hypophysectomized (hypoxed) rats were administered saline (controls IP daily X 3), alpha-MSH (80 mug/kg IP daily X 3) or MIF-1 (1 or 10 mg/kg IP daily X 3) and sacrificed 30 min after the third injection in a focused microwave oven (1.5 KW; 2-3 sec). Various brain areas were then assayed for cAMP levels after each treatment. The occipital cortex area was the only area to show consistent changes in both normal and hypoxed rats after alpha-MSH treatment. These findings were replicated for the occipital cortex in a second group of normal and hypoxed rats which were similarly treated. The results suggest a correlation between the rise in cAMP found and reported changes in visual acuity and attention in rats and human after treatment with alpha-MSH [8,14, 23].


Possible association of increased rat behavioral effects and increased striatal dopamine and norepinephrine levels during the DOPA-potentiation test. Previous reports have indicated that alpha-MSH release inhibiting hormone (MIF-1) increased the behavior occurring as a result of the dihydroxyphenylalanine (DOPA) potentiation test [3,7]. This study was undertaken to see whether dopamine (DA) or norepinephrine (NE) levels likewise increased in the test animals. The DOPA potentiation test was performed as follows: 2-4 hr before behavior measurement, 40 mg/kg of the monoamine oxidase inhibitor pargyline HCl was given orally. Two hr later this was followed by the intraperitoneal (IP) injection of MIF-1 at doses of 0.1, 0.3 or 1.0 mg/kg. Behavioral measurement was begun after the IP injection of 200 mg/kg of dl-DOPA 1-2 hr after the MIF-1. The parameters included social interaction, aggressiveness, fighting, ataxia, jumping, defecation, urination and salivation. The animals were beheaded while the behavior was still increased and the striatal area removed, placed in aluminum foil, and kept at -50 degrees C until assayed. In general, especially among the younger animals, a significant correlation (p=0.05 to p=0.01) was found between the increased behavioral responses to MIF-I and the rise in DA. Because of a few exceptions to this correlation the possibility is suggested that MIF-I might also affect behavior by acting directly on the postsynaptic membrane thus bypassing any change in NE or DA which is known to increase cycli AMP in the striatum.


Effects of L-prolyl-L-leucyl-glycine amide (MIF-I) on dopaminergic neurons. In an attempt to determine the mechanism of action of L-proly-L-leucyl-glycine amide (MIF-I) in the treatment of Parkinson's disease, various parameters of dopaminergic neuronal function were studied in rats. It was found that the active uptake of 3H-dopamine (3H-DA) by synaptosome-rich homogenates of the striatum of rats treated with MIF-I (1 mg/kg IP X 3, 24 hr intervals) was unaltered 1 hr after final treatment with MIF-I. Also, neither tyrosine hydroxylase nor dopa decarboxylase activity was altered in the striatum and substantia nigra of rats treated with MIF-I (20 mg/kg IP X 3, 24 hr intervals). Thus, vital functional processes associated with dopaminergic neurons apparently are not altered by MIF-I under the conditions studied. These findings illustrate the importance of concurrent DOPA administration in observing an effect of MIF-I on dopaminergic neuronal function.


Neurochemical responses of mice to ACTH and lysine vasopressin. Subcutaneous administration of ACTH 1-24 to mice increased the incorporation of [3H]lysine into brain and liver proteins, an effect which resembled that due to footshock. Corticosterone administration did not mimic these effects. ACTH 4-10 increased the [3H]lysine incorporation into brain or liver. These results are consistent with ACTH mediating the effects of footshock. However, dexamethasone decreased the brain responses to both footshock and ACTH, but while the liver response to ACTH was blocked, the footshock response was only diminished. This suggests a neural component in the response of the liver and possibly the brain. Intraventricular administration of ACTH 1-24 or ACTH 4-10 (D-phe), but not ACTH 4-10, increased [3H]lysine incorporation into brain protein. These neurochemical responses parallelled a distinctive pattern of behavior characterized by stretching, yawning and excessive grooming. Treatment for 3 days with long-acting preparations of ACTH 4-10, ACTH 4-10 (D-phe) or ACTH 1-24 increased the conversion of [3H]tyrosine into dopamine but not norepinephrine, alpha-MSH, beta-MSH or LVP had no such effect. Similar treatment with ACTH 4-10 or ACTH 1-24 increased striatal tyrosine hydroxylase activity measured in vitro, but did not significantly alter the enzyme activity from other brain regions. We conclude that ACTH peptides can stimulate protein and dopamine metabolism in mouse brain and that LVP has no such effects.


Peptides readily penetrate the blood-brain barrier: uptake of peptides by synaptosomes is passive. The intracarotid artery quick injection technique of Oldendorf was utilized to determine the Brain Uptake Index (BUI) of radio-labeled peptides in comparison with 3H2O or 14C-antipyrine as counterlabels. The normalized BUI values for 3H-MIF-I, 3H-alpha-MSH and 14C-AVP were 13.7, 9.6 and 13.0 respectively at 15 sec after injection consistent with their having readily penetrated the blood-brain barrier. The BUI values were similar, though somewhat increased, at 10 min postinjection consistent with their ready exit across the blood-brain barrier. At 15 sec after injection 0.5+/-0.1%/g brain of the originally injected peptide label was recovered; and 0.1+/-0.2%/g brain was recovered after 10 min. The label was distributed uniformly in the major brain regions at both times. However, the percentage of the originally injected label/g of pineal and pituitary gland tissue was 10-20 X increased as compared with the major brain regions as would be expected by their location outside the blood-brain barrier. The in vitro uptake of the radio-labeled peptides by synaptosomes prepared from the whole brain and the major brain regions was passive; it was not temperature dependent, nor was it Na+ dependent. However, the binding of the three peptides by the synaptosomes varied considerably: AVP greater than MSH greater MIF: 50 greater than 5 greater 1. The penetratin of the blood-brain barrier by the three peptides is consistent with their having CNS effects.


Neurologically active peptides.

Neurologically active peptides. This paper reviews recent evidence that a number of small peptides found in the brain are active in the central nervous system and behaviorally. Attention is focused on MSH/ACTH 4-10, alpha- and beta-MSH, and the prohormone beta-LPH, as they produce a syndrome of yawning and stretching. Studies with substance P and mainly with MIF-I are also reviewed. It is shown that substance P is an excitatory transmitter or modulator in the dorsal spinal cord with that MIF-I has antiparkinson properties. It is concluded that many polypeptides have direct actions on the central nervous system independent of their neuroendocrine properties.


Hypothalamic releasing factors: physiological evidence for a regulatory action on central neurons and pathways for their distribution in brain. Recent observations based on single cell recordings obtained in various areas of the brain indicate that TRH, LH-RH and somatostatin have potent effects on the activity of central neurons. There is also electrophysiological evidence for the existence of a system of hypothalamic tuberoinfundibular neurons with widespread extrahypothalamic connections. These connections may indicate possible pathways for the observed widespread distribution of these peptides in the brain. These findings, coupled with behavioral studies and subcellular localization data support the postulate that hypothalamic peptides may have an important role inthe modulation of central neuronal activity.


MIF, TRH, and simian social and motor behavior. MSH-release-inhibiting factor (MIF) and thyrotropin-releasing hormone (TRH) both have been reported to modify mood and activity in man. These two hypothalamic peptides were given intramuscularly across a 1000-fold dose range to 5 juvenile male M. nemestrina monkeys living in a social group. Motor activity was recorded automatically, and an observer counted various social behaviors. MIF increased motor activity for up to 11 hr. It decreased quiet foraging behavior, but did not change behaviors of social interaction. TRH did not stimulate motor behavior; high doses strongly suppressed it and produced apparent somatic distress. TRH increased behaviors of quiet rest and association and decreased environment exploration and low-intensity dominance behaviors. The lowest dose of TRH increased social play. Two monkeys showed repetitive, stereotyped behaviors even in baseline observations, and certain doses of TRH and MIF may have increased the frequency of these behaviors.


Clinical investigations for emotional effects of neuropeptide hormones. After the demonstration that hypothalamic peptides can have a direct effect on the central nervous system, a series of studies was initiated to investigate the hypothesis that hypothalamic peptides could have an effect on emotions and affect. TRH was administered to 6 patients with endogenous depressions in a double-blind, cross-over design with transient improvements in the mental depression of 4 of the 6 patients. In a second study involving 8 seriously depressed patients given 1000 mug of TRH for 10 days, no significant antidepressant effect of TRH was observed. In a pilot, double-blind study of 18 women with endogenous depressions, the group receiving MIF-1 60 mg per day in a single daily dose for 6 days responded better than the placebo group, which in turn responded better than the group receiving MIF-1 150 mg per day. In a second, double-blind study testing MIF-1 in endogenous depressions, 5 patients met the criteria for substantial improvement out of a total of 8 receiving MIF-1 75 mg per day. In contrast, only one patient met these criteria in each of the remaining 2 groups, consisting of 10 patients receiving MIF-1 750 mg per day and 5 patients receiving placebo. Finally, 6 men complaining of decreased libido and/or potency were given intravenous injections of LHRH 700 mug or saline once daily for 3 consecutive days per week in a double-blind, cross-over design. In addition, 3 men were given much higher doses of LHRH in a single-blinded study. No substantial effect on libido or sexual performance was observed.


The structure of a spherical plant virus (bromegrass mosaic virus) established by neutron diffraction. The localization of the RNA in a spherical plant virus is established by neutron diffraction. For BMV, this localization is different at low pH than it is at high pH (swollen virus).


Assembly of a spherical plant virus.

Assembly of a spherical plant virus. The conditions previously reported as necessary for the reassembly of spherical viruses have been distinctly unphysiological and such reassembly cannot be related directly to the in vivo reaction. Mild conditions for the in vitro reassembly of cowpea chlorotic mottle virus (CCMV) from its isolated components have now been described (Adolph & Butler 1975) and the reassembled virus characterized. This reassembly involved the co-aggregation of the RNA and protein around neutrality and at ionic strength 0.2, giving yields of 70% encapsidation at pH 6.0. The reaction was independent of temperature over the range 5-25 degrees C and did not require the presence of Mg2+ ions. The reassembled virus shows a stability similar to that of native CCMV, with the same change in sedimentation coefficient around pH 6.5. The molecular mass and buoyant density in CsCl are also the same as those of native CCMV, while the electron microscope reveals a surface morphology on the reassembled particles like that on native CCMV. Analysis of the number-average, mass-average, and Z-average molecular masses of the purified protein at both pH 6.0 and pH 7.5 suggests that the active unit for reassembly is a dimer of the protein subunit.


Nature and specificity of the RNA-protein interaction in the case of the tymoviruses. Dissociation-reassociation experiments performed with turnip yellow mosaic virus in the presence of various RNAs and polynucleotides were used to investigate the degree of specificity and the contribution of the associated RNA moiety to the stability of TYMV. The results emphasize the importance of strategic cytosine residues spread along the RNA chain. Some insight into the contribution of the protein could be gained from comparison of TYMV and eggplant mosaic virus (EMV), a virus similar to TYMV although its top component contains low molecular mass RNA's able to bind various amino acids. Hydrophobic interactions between protein subunits are less important in EMV than in TYMV, and artificial capsids could be obtained from dissociated EMV coat protein. Whether the capsid is or is not the precursor of the virion in tymovirus morphogenesis is discussed.


A study of the states of aggregation of alfalfa mosaic virus protein. The states of aggregation of alfalfa mosaic virus (AMV) protein have been characterized by sedimentation velocity experiments and electron microscopy. The main association product is a spherical particle with an s value of about 30S. It is highly likely that the assembly of this particle starts with dimers of the 25000 molecular mass unit resulting in an icosahedral particle made of 30 dimers. No intermediate aggregation products have been detected. The clustering pattern of the protein in the cylindrical part of the AMV capsid favours the concept of dimers as the active assembling units.


Packaging of genomes in bacteriophages: a comparison of ssRNA bacteriophages and dsDNA bacteriophages. In complex DNA bacteriophages like lambda, T4, T7, P22, P2, the DNA is packaged into a preformed precursor particle which sometimes has a smaller size and often a shape different from that of the phage head. This packaging mechanism is different from the one suggested for the RNA phages, according to which RNA nucleates the shell formation. The different mechanisms could be understood by comparing the genomes to be packaged: single stranded fII RNA has a very compact structure with high helix content. It might easily form quasispherical structures in solution (as seen in the electron microscope by Thach & Thach (1973)) around which the capsid could assemble. Double stranded phage DNA, on the other hand, is a rigid molecule which occupies a large volume in solution and has to be concentrated 15-fold during packaging into the preformed capsid, and the change in the capsid structure observed hereby might provide the necessary DNA condensation energy.


Studies on the maturation of the head of bacteriophage T4. The presentation focuses on the structural rearrangements of the subunits and the processing of the various protein constituents which accompany the maturation events of the head of bacteriophage T4. The major features of the maturation steps of the head are the following: (a) the viral DNA is pulled into an empty head in a series of events; (b) cleavage of two core proteins, P22 (mol. mass = 31000), to small fragments and the internal protein IPIII (mol. mass = 23000) to IPIII (mol. mass = 21000) appears to be intimately linked to the DNA packaging event, whereas the cleavage of the major head protein of the viral coat, P23 (mol. mass = 55000), to P23 (mol. mass = 45000) precedes the DNA packaging event. Recently, we have obtained information about the mechanism by which the viral DNA is pulled into a preformed empty head. Our evidence suggests that the DNA becomes attached to the inside of the empty head and is subsequently collapsed in the interior by the so-called internal peptides. These are highly acidic and derived from a large precursor protein by cleavage.


Assembly of tobacco mosaic virus.

Assembly of tobacco mosaic virus. The assembly of tobacco mosaic virus requires the presence of a particular protein aggregate, the disk. During the nucleation, a specific region of the RNA interacts with a single disk, to bring about a necessarily cooperative transition from the paired two-layer structure to a short segment of nucleo-protein helix. There is a high selectivity for this region of the TMV RNA, because of the many nucleotides bound at once, and other nucleotide sequences appear only to bind by a different mechanism. Elongation of the nucleated rods can continue with either further disks or the less aggregated 'A-protein' as the protein source, but the continued cooperativity inherent with disks would have some advantages. The rates of the two processes have been separately determined and growth is faster when disks are still present. New experiments show that the breakdown of disks to yield A-protein is relatively slow and it is concluded that virus growth from disks could not proceed through a prior breakdown in solution, but must involve the direct interaction of the disk with the growing nucleoprotein rod. The detailed mechanism of disk addition is not understood but it may involve a directed breakdown, since there is also evidence for the existence of a non-equilibrium form of A-protein which has aggregation kinetics distinct from those of equilibrium A-protein. Some implications for the general assembly pathways of viruses both of the specificity and of the assembly/disassembly cycle during the viral infection are considered.


Tobacco rattle virus RNA-protein interactions. For the purpose of attempting to generalize the rules concerning morphogenesis of helical viruses, the in vitro reconstitution of the CAM strain of TRV was studied. The conditions for reconstitution and the importance of the aggregation state of the protein for initiation and elongation are compared with those of TMV. The initiation step consisting of the binding of RNA with the 36S disk of protein was easily accomplished. The polarity and the specificity of encapsidation of TRV RNA by homologous and heterologous viral protein is discussed.


Assembly of flexuous plant viruses and their proteins. Recent experiments on the disassembly and assembly of some flexuous plant viruses and their proteins are described. The properties of reconstituted potato virus X and those of assembled potato virus Y protein are considered as well as the suitability of other flexuous viruses for reconstitution studies.


Specific encapsidation of fragments of TMV RNA. The in vitro reconstitution of tobacco mosaic virus (TMV) is initiated by the binding of a disk of TMV protein to the 'disk recognition site', a region of the RNA chain at or near the 5'-terminus for which the disk has special affinity. In order to gain insight into the recognition process, we have studied the ability of disks to encapsidate short RNA fragments produced by partial pancreatic or T1 RNase digestion of TMV RNA. The disk is capable of dicriminating among such fragments, encapsidating only a few of the many present in the digest. The products of encapsidation are short nucleoprotein rods of the same diameter as TMV and of length proportional to that of the encapsidated RNA fragment. The particles differ from TMV, however, in one significant aspect (apart from their length): they possess rings of RNA-free protein at one or both extremities of the rod. In the case of T1 RNase digestion the principal encapsidated fragments were fragments T1 (105 nucleotides) and a family of smaller fragments containing elements of the same sequence. Partial digestion with pancreatic RNase generated only one major fragment (fragment P1; 150 nucleotides) with affinity for the disk. Fragment T1 has been sequenced and shown to represent a portion of the coat protein cistron. Fragment P1 has been partially sequenced but its function is not yet known. Several lines of evidence indicate that fragment T1 is not the disk recognition site. The portion of the TMV RNA chain from which fragment P1 is derived, on the other hand, is encapsidated early in the reconstitution process; thus fragment P1 may contain the disk recognition site. Fragment T1 and fragment P1 both have purine-rich and cytosine-poor sequences near their termini. In addition, fragment T1, and possibly fragment P1, possess a periodicity of order three in purine residues. It seems likely that one or both of the aforesaid properties are largely responsible for the affinity of these fragments for the disk.


The region of tobacco mosaic virus RNA involved in the nucleation of assembly. The interaction of TMV RNA with the disk aggregate of TMV protein at the initiation of assembly has been studied by using the techniques of RNA sequencing. The 5' end group has been identified, and shown not to be protected in the early stages of assembly from accessibility to nuclease digestion. A population of RNA fragments of average length 250 nucleotides, originating from a unique region of TMV RNA, is encapsidated by limited assembly, and sufficient sequence information is available to identify certain unusual features. The protected region does not contain highly reiterated simple repeating sequences, but may contain more complicated repeats. The length and complexity of the nucleation region may reflect adaptation to the efficient mediation of the conformational change from disk to helix of TMV protein, besides a requirement for binding to the disk, and this may be an important part of the mechanism of specificity in the nucleation of assembly.


Structure and assembly of phage phi29.

Structure and assembly of phage phi29. Bacteriophage phi29 is a small, morphologically complex, virus with a DNA of molecular mass 12 X 10(6). The most likely structure of the head of phi29 consists of two fivefold symmetric end-caps based on T = 1 icosahedral symmetry, separated by an equatorial row of 5 hexamers. The eighteen genes identified in phi29 genome have been mapped and, in some cases, the gene products have been identified. Five linked genes, four coding for structural proteins (G, A, E, H) and one coding for a non-structural protein (J), are essential to determine the normal shape of the capsid. Protein pJ may be a scaffolding protein. An account of the effects of mutations in phi29 genes is given.


DNA viruses: cooperativity and regulation through conformational changes as features of phage assembly. The assembly of bacteriophages provides experimental model systems for the study of regulation at the level of gene products. We discuss the hypothesis of regulation through sequentially induced conformational changes by which precursor-assemblies become ready at a specific stage of maturation to interact with an additional gene product or nucleic acids. Phage mutants provide excellent experimental model systems for studying, for example, the role and fate of the core in the prehead assembly. The conservative maturation of the prehead to the final, stable head consists of several steps whose complexity reflect that of the virus. It includes packaging of DNA. The surface lattice of maturing preheads apparently undergoes several steps characterized by different conformational states as suggested by in vitro studies on a morphological variant of the prehead, the polyhead of phage T4 (Steven, Couture, Aebi & Showe 1976; Laemmli, Amos & Klug 1976). Addition of a partly purified, enriched proteolytic fraction--which is gene 21-dependent--to empty purified polyheads leads to different conformational states. These seem to go in a direction approaching the structure of the surface of finished capsids as studied by Aebi et al. on gene 24 related (Bijlenga, Aebi & Kellenberger 1976) and other genetically defined giant-variants of T4 phage (Doermann, Eiserling & Boehner 1973). We show some experiments which suggest that high cooperativity is responsible for the stabilization of capsids. The activation energy necessary for dissociation of capsids is very high, 247 kJ for T4 capsids, and 10% smaller for T2. Once the energy barrier has been overcome, the capsids are first structurally modified before they undergo partial and finally complete dissociation.


Structure and assembly of the capsid of bacteriophage P22. Identification of the genes and proteins involved in phage P22 formation has permitted a detailed analysis of particle assembly, revealing some unexpected aspects. The polymerization of the major coat protein (gene 5 product) into an organized capsid is directed by a scaffolding protein (gene 8 product) which is absent from mature phage. The resulting capsid structure (prohead) is the precursor for DNA encapsidation. All of the scaffolding protein exits from the prohead in association with DNA packaging. These molecules then recycle, directing further rounds of prohead assembly. The structure of the prohead has been studied by electron microscopy of thin sections of phage infected cells, and by low angle X-ray scattering of concentrated particles. The results show that the prohead is a double shell structure, or a ball within a shell. The inner ball or shell is composed of the scaffolding protein while the outer shell is composed of coat protein. The conversion from prohead to mature capsid is associated with an expansion of the coat protein shell. It is possible that the scaffolding protein molecules exit through the capsid lattice. When DNA encapsidation within infected cells is blocked by mutation, scaffolding protein is trapped in proheads and cannot recycle. Under these conditions, the rate of synthesis of gp8 increases, so that normal proheads continue to form. These results suggest that free scaffolding protein negatively regulates its own further synthesis, providing a coupling between protein synthesis and protein assembly.


Capsid transformation during packaging of bacteriophage lambdaDNA. Assembly pathways of complex viruses might not be simple additions of one protein after another with rigid tertiary structure. It might in fact involve shifts in subunit structure, movement of subunits relative to each other to form new arrangements, transient action of proteins and protein segments, involvement of structure forming 'microenvironments' of the host. Thus morphogenesis of the bacteriophage lambda head starts with the formation of a core-containing DNA-free petit lambda particle. In a first transition, and dependent on a host function, the core is released, minor protein components of the capsid are processed and the particle's structure is altered, as shown by a change of its hydrodynamic properties. The resulting 'prehead' undergoes a second transition triggered by a complex of DNA and recognition protein (A-protein). This transition is more drastic than the first one. The particle doubles its volume without increasing in protein mass, the shell becomes thinner, and the surface structure is changed. Concomitantly with this process, the DNA becomes packaged and the particle becomes able to bind the small 'D-protein' in amounts equimolar to the capsid protein, which it could not do before. The D-protein addition probably causes another shift of the capsid structure. DNA packaging is completed, and the DNA is cut from concatemeric precursors to unit length molecules. Binding sites are created for the tail connector molecules which in turn allow the independently assembled tail to attach. Research on these processes proceeds along several lines: comparison of physical and chemical properties of particles accumulating in mutants; pulse-chase experiments on assembly precursors; morphogenesis in vitro; and model transitions of aberrant lambda polyheads.


Structure and assembly of lipid-containing viruses, with special reference to bacteriophage PM2 as one type of model system. The simpler lipid-containing viruses (influenza, Semliki Forest, PM2) may have a phospholipid bilayer sandwiched between an outer shell of protein and an internal nucleocapsid possessing helical or icosahedral symmetry. Extensive physical and chemical studies have enabled us to form a more detailed picture of the structure of bacteriophage PM2 and controlled stepwise degradation of the virion has helped us to localize the four viral proteins. The surface protein (II) of PM2 is basic and interacts with the acidic phosphatidylglycerol of the bilayer to stabilize the membrane. The nucleocapsid protein (III) has proteolipid characteristics and may interact with the phospholipids in a hydrophobic fashion. The spikes are formed from protein I and the fourth protein (IV) is closely associated with the DNA. It is possible to reassemble the virus by reversing the degradation steps. Assembly has been especially useful in revealing the processes whereby the proteins and lipids interact to form the bilayer. Furthermore, results of in vivo studies of phospholipid synthesis and both in vivo and in vitro studies of viral protein synthesis have enabled us to form a reasonably complete picture of the biosynthesis of PM2.


Structure and assembly of filamentous bacterial viruses. Filamentous bacterial viruses are flexible nucleoprotein rods, about 6 nm in diameter by 1000-2000 nm in length (depending on the virus strain). A protein shell encloses a central core of single-stranded circular DNA. The coat protein subunits forming the shell are largely alpha-helix, elongated in an axial direction, and also sloping radially, so as to overlap each other and give an arrangement of subunits reminiscent of scales on a fish. This arrangement of alpha-helices is rather like some models of myosin filaments. An early step in assembly of the virion is the formation of a complex between the viral DNA and an intracellular packaging protein that is not found in completed virions. Newly synthesized coat protein becomes associated with the plasma membrane of the cell. During the final steps of assembly, the packaging protein is displaced from the DNA and replaced by coat protein as the virion passes out through the plasma membrane of the host cell.


RNA viruses: stabilization of brome mosaic virus. The relative importances of protein-protein and RNA-protein interactions in stabilizing the architecture of brome mosaic virus particles are discussed in the light of the following experimental evidence: (a) disassembly pathways of the virus particles, (b) reassembly of the virus and self-association capacity of the protein moiety, and (c) the role of divalent cations in virus stabilization, and their relevance to localization of the RNA in the virus particles. Evidence is given that the capsid of BMV is primarily stabilized by hydrophobic bonds at low pH, but not around and above neutrality where RNA-protein electrostatic interactions are essential to the integrity of the virus particles. A model is proposed for the structure of BMV in the different configurational states.


Fluorescent probe studies of haptoglobin type 2-1. Haptoglobin is an alpha2 serum protein that forms an irreversible complex with hemoglobin. The combination between these two macromolecules resembles the binding of an antigen to its antibody except that the complex remains soluble. This investigation was undertaken to determine the nature of the hydrophobic sites on haptoglobin type 2-1. The interaction of 1-anilinonphthalene-8-sulfonate (ANS) with haptoglobin type 2-1 is characterized by a flourescence intensity in solutions containing ANS and haptoglobin as the pH is decreased from 9 to 4. The dissociation constant for the ANS interaction with haptoglobin 2-1 is 5.8 x 10--5 M at pH 7.0, 5.2 X 10--5 M at pH 5.0 AND 30.3 X 10--5 M at pH 4.0. Fmax shows no change in the pH range 6-9 but does show an increase at pH 4.0 when compared to the neutral region.


Models for biological ion exchangers. I. Proton magnetic resonance studies of water structure in Bio-Rex 70. Bio-Rex 70, a carboxylic acid cation exchanger, is studied as a biological ion-exchanger resin model for cellular cytoplasm. High-resolution proton magnetic resonance spectra of 1l ionic forms of Bio-Rex 70 are determined. From measured cation exchange capacities, water contents, and chemical shifts for the resin-phase water protons, the dependence of the chemical shift on the counter ion is calculated. The observed chemical shifts (Hz/geq/kg internal water, referred to the Ba2+ form) for each ionic form are: H+, --0.5; Li+, --0.2; Na+, 1.2; K+, 2; Rb+, 2.1; Ag+, --0.4; NH4+, --2.0; NMe4+, 1.2; NEt4+, 1.8; Mg2+, --2.0; Ca2+, --1.5; Sr2+, --0.6; Ba2+, 0.0 Zn2+, --2.3; Cd2+, --4.7; and La3+, --3.3. The results are in good agreement with earlier studies on Dowex 50, indicating that the carboxylate ion exchanger behaves like a concentrated polyelectrolyte. The widths at half-height for the internal water peaks of the polyvalent forms are quite large, ranging from 40 to 100 Hz.


[Effects of antianxiety drugs on the water intake in trained and untrained rats and mice (author's transl)]. In water-deprived rats and mice, animals trained to the test situation spent more time in drinking than naive animals (first exposure to the test situation). The time spent in drinking, either during 5 min or during 10 min was recorded. As compared to controls, benzodiazepines, phenobarbital, meprobamate, and mecloqualone increased drinking time whether the experiments were run on naive or on experienced animals [5 or 10 (in mice) and 9 (in rats) exposures in the test situation]. All drugs were injected i.p. 30 min before testing. This release of the drinking behavior was more pronounced during the last 5 min than during the first 5 min of the 10 min test session. These results suggest that: 1. The inhibition of water intake of naive animals as compared to trained rats and mice, could be related to some emotional factors elicited by the first exposure to an unknown situation. 2. The increase in drinking time induced by the antianxiety drugs in a novel and in a familiar situation seems difficult to correlate only with the antianxiety action of these compounds. 3. Antianxiety drugs could interfere with the regulatory mechanism of thirst.


Operant behavioural and neurochemical effects after neonatal 6-hydroxydopamine treatment. Newborn rats were treated at 1 and 2 days after birth with 100 mg/kg 6-hydroxydopamine (60HDA), s.c. Testing on several operant behavioural tasks was begun at 6 months of age. On a fixed ratio 30 (FR 30) schedule of food reinforcement, the neonatal 60HDA treated rats responded at a significantly higher rate. Further analysis of the FR 30 response pattern indicated that the higher rate was due to a decrease in the amount of time spent pausing after the receipt of each reinforcer. The 60HDA treatment failed to alter the rat's behaviour during the extinction of the FR 30 response and on the progressive ratio or variable interval schedules of food reinforcement. Biochemical analysis of several brain areas at 9 months of age showed a decrease in noradrenaline (NA) levels in the cerebral cortex and hippocampus, while in the pons-medulla NA content was doubled. The tyrosine hydroxylase activity in these same brain areas was not significantly altered, but there appeared to be some decrease in the activity of this enzyme in the hippocampus. Comparison of the operant behavioural effects seen after various lesioning procedures in this and other studies, suggest the effects on FR performance are a result of destruction of NA neurons in the hippocampus and/or the apparent regeneration of neurons in the pons-medulla.


Anticholinergic properties of antipsychotic drugs and their relation to extrapyramidal side-effects. The effects of haloperidol, alone and in combination with atropine, were compared with the effects of clozapine, alone and in combination with physostigmine, in a variety of tests commonly used to characterize neuroleptic compounds. It was found that clozapine in combination with physostigmine did not present the profile of activity of a classical neuroleptic agent; neither did haloperidol in combination with atropine present that of clozapine. In fact, some effects of haloperidol (catalepsy) were antagonized by atropine, while others (induction of striatal DA-receptor hypersensitivity) were enhanced. It is concluded that the interaction between dopaminergic and cholinergic systems in the striatum is highly complex, and that a neuroleptic possessing both potent DA-receptor blocking and muscarinic anticholinergic activity, while being less likely to cause parkinsonism in patients, would be more likely to induce tardive dyskinesias.


Alterations of mouse adrenal medullary catecholamines and enzymes in response to attack: effect of pre- and post-treatment with phenobarbital. Group-housed male C57BR/cdJ mice (victims) were exposed to attack for 10 min daily for up to 14 days by male Swiss-Webster mice, made aggressive by prolonged isolation. Their adrenal glands were analyzed for tyrosine hydroxylase (TH) and phenylethanolamine-N-methyltransferase (PNMT) activities and for norepinephrine (NE) and epinephrine (EPI) concentrations. TH was increased to 41 per cent above control after two exposures and remained elevated through 14 exposures to attack. PNMT was increased to 29 per cent above control after 2 days and increased further to 50 per cent above control after 14 days of attack. Both NE and EPI increased to 88 per cent and 51 per cent above control, respectively, after 7 days. In victim mice recuperating after 1 week of daily stress, EPI levels and PNMT activities were back to normal after 4 days whereas NE levels and TH activities returned to normal only after 1 week. Phenobarbital (40 mg/kg, i.m.) was effective in preventing the biochemical changes when given 2 h prior to each daily attack but was ineffective when given immediately after each daily stress.


Cyclic GMP in the CSF of patients with schizophrenia before and after neuroleptic treatment. Cerebrospinal fluid (CSF) cyclic GMP may derive from central cholinergic neurotransmission. Measurement of CSF cyclic GMP may allow evaluation of possible implications of the dopaminergic hyperactivity in schizophrenia proposed by the dopamine hypothesis. The CSF cyclic GMP levels in 27 drug-free schizophrenic patients was measured and compared to that in 9 psychiatrically-healthy individuals. The mean CSF cyclic GMP level of the schizophrenic patients was 23 per cent lower than that of the control group, but this difference did not attain statistical significance. In addition the CSF cyclic GMP levels in a group of 10 schizophrenic patients were compared before and after 2 months of neuroleptic treatment. The mean level of cyclic GMP rose 50 per cent after treatment with phenothiazines (P less than 0.05). These results could indicate some tendency for decreased activity of central cholinergic neurons in schizophrenia as well as a restored dopaminergic-cholinergic balance after neuroleptic treatment.


Pulmonary function in premature lambs during the first few hours of life. This study establishes the mean values, variations, and trend of pulmonary function during the first few hours of life in premature lambs. Measurements of intraesophaheal and tracheal pressure, air flow, tidal volume, and functional residual capacity enabled calculations of lung compliance, specific lung compliance, and inspiratory and expiratory resistance of the lungs. Arterial carbon dioxide tension and pH were maintained within a physiologic range. Mean arterial oxygen tension (PO2) at elevated inspired oxygen tension, varied in the individual animals from 51 to 185 mm Hg at an inspired oxygen concentration of 46 to 71%. It was found that the lungs of premature lambs delivered by cesarean section were mechanically unstable; the lambs were all ineffectual at breathing and required some form of mechanical ventilation. During the first 6 hours of postnatal life the lungs of premature lambs are characterized by a wide range of mechanical values and blood gas tensions.


Calculations for pH during CO2 and O2 exchange with blood. New mathematical formulas are presented to calculate directly the change in blood pH during CO2, and O2 exchange with blood. pH changes are calculated from changes in blood PCO2 and saturation values or from changes in blood PCO2 and blood PO2 values. Computational results agree well with information obtained from a Dill nomogram. These new formulas have applicability to the modelling of gas exchange in blood oxygenators as well as to estimating blood acid-base parameters following the mixing of blood samples.


[Biochemistry of collagen and the locomoter apparatus (Hereditary connective tissue diseases and rheumatic diseases. Part I]. The elementary collagen molecule consists of three chains rolled into a spiral and ending in nonhelical telopeptides. In cutaneous collagen, there are two types of chains, in cartilaginous collagen there is only one. In the synthesis, several enzymes play successive parts: proline hydroxylase, lysine hydroxylase, then pro-collagen peptidase and finally, lysine oxidase and hydroxylysine oxidase; their coordinated actions ultimately allow the chains to establish the transverse intra and intermolecular links which give the collagen fiber its cohesion. The type and number of these transverse links vary from one tissue to another. Specific collagenases make collagen degradation possible.


The van Slyke equation.

The van Slyke equation. The Henderson-Hasselbalch equation has always occupied a central place in the description of the acid-base status of the blood. An equation of similar importance is the equation for the CO2 equilibration curve of blood in vitro. It is proposed to name this the Van Slyke equation: a - 24.4 = - (2.3 X b + 7.7) X (c - 7.40) + d/(1 - 0.023 X b), where a = bicarbonate concentration in plasma/(mmol/l), b = hemoglobin concentration in blood/(mmol/l), c = pH of plasma at 37 degrees C, d = base excess concentration in blood/(mmol/l). These two equations provide an arithmetic algorithm for calculation of the various acid-base variables of the blood after measuring the pH, the pCO2, and the hemoglobin concentration.


Physiological viewpoints on clinical acid-base diagnostics. Acid-base physiology is concerned with sources, extent, and control of hydrogen ion donation in the body, at the organ-physiological as well as the molecular level of study. With the introduction of Van Slyke's methods for quantitative carbon dioxide measurements in biological fluids, one important source of hydrogen ion donation became identifiable; and these and derived methods have permitted of fairly precise quantitative descriptions of transport and pulmonary elimination of carbon dioxide. However, the inevitable operational concept of non-carbonic (non-volatile) contributions to the titratable acidity of the body fluids has been a cause of considerable methodological and conceptual difficulties; and whereas it is now possible by means of the micro-equilibration technique to make accurate assessments of the concentration of non-volatile titratable acid (base) in blood, the question of the physiological relevance of the concept of 'base excess' remains open. In particular, the concept of non-carbonic acid does not possess a specific relevance with respect to the acid-base physiology of kidney, bone, and gastro-intestinal tract comparable to the 'substrate-specificity of carbon dioxide with respect to the lung. Our studies indicate that a subdivision of the titratable non-carbonic acid of any biological medium in two subcomponents will provide an improvement of specificity, adequate for a system physiological approach at the organ level. Thus, a distinction should be made between (1) processes of hydrogen ion donation, reversible by endogenous metabolic means (quantitated in terms of the component MA = metabolizable non-carbonic acid) and (2) processes of hydrogen ion donation associated with gastro-intestinal, skeletal, and renal transport, storage, and control of non-metabolizable non-carbonic acid (NA). Some implications of this distinction for acid-base physiology and acid-base diagnostics are discussed.


Stoichiometric concentration and chemical potential. It has been recommended to use SI units in clinical chemistry. A consequence of this is that pH is reported as the excess chemical potential (or standard chemical potential) of hydrogen ions with the unit kJ/mol. On the basis of the excess chemical potential of H+ it is possible to calculate the hydrogen ion concentration in the system = the equilibrium concentration of H+ = the concentration of free H+. This quantity must be clearly distinguished from the stoichiometric concentration of H+ = the excess concentration of total H+, which indicates the amount of added or removed H+. The latter quantity with opposite sign has been called the excess concentration of base, but the designation "stoichiometric concentration of H+" seems to be more logical. The general principles for description of a component in a chemical system are based on (1) an extensive quantity (the stoichiometric amount of substance), and (2) an intensive quantity (the excess chemical potential); the product of these has the dimension of energy.


Gastrin, antral g cells, and gastric acid in secretagogue-induced and antihistamine-inhibited duodenal ulcers. In fasting control rats there was continuous basal gastric acid secretion, with a low plasma gastrin and antral G-cells full or immunofluroescent gastrin. After subcutaneous infusion of the gastric secretagogues, pentagastrin + carbachol, there was a six-hour period of gastric hypersecretion, but no change in plasma and G-cell gastrin. Pretreatment with the antihistamine derivative, Pfizer UK-9040, decreased both basal and stimulated acid secretion, whereas plasma gastrin levels increased and the antral G-cells were emptied of gastrin. These results suggest that this antihistamine derivative decreases gastric acid secretion by a direct action on the parietal cells and not by reducing gastrin release from the G-cells. The increased release of gastrin from the G-cells may be secondary to decreased gastric acid production, or more probably by a direct stimulation of the antral G-cells.


Effect of resection of antrum and duodenal bulb on sham-feeding-induced inhibition of canine gastric secretion. In dogs with Heidenhain pouches and oesophageal and gastric fistulae, sham feeding inhibited pentagastrin-stimulated Heidenhain pouch acid output. Resection of the antrum and the duodenalbulb reduced oin stomach was diverted through the gastric cannula. The present results are conid secretion at least partly by inducing a vagal release of an inhibitory hormone. The results suggest that this hormone is released from the antrum and the duodenal bulb.


[Exercise hemodynamics and renin before and after acute beta block in patients with essential hypertension]. Hemodynamic and renin studies at rest and during graded upright ergometry were performed in 21 patients with essential hypertension before and after propranolol. Beta-adrenergic receptor blockade reduced exercise-stimulated cardiac and renin responses significantly more when compared with the corresponding effects at rest. Propranolol increased peripheral resistance at rest but not during exercise. The degree of the individual hemodynamic changes after propranolol correlated better with the corresponding control values than with age or renin. A direct relationship between the percent reduction of heart rate and renin responses after acute beta-blockade indicates a parallel suppression of cardiac and renal receptor functions.


[The burden of a general medical clinic with patients after suicide attempts]. All 125 patients who entered the "suicide ward" of the Medical Department of a large public hospital during 1974 were analyzed according to age and sex distribution, duration of hospital stay, motivation and method of committing suicide and fate after recovering from the acute phase of intoxication. Motivation to commit suicide was mainly due to conflicting interpersonal relations. Suicide attempts were 3 times more frequent in women than in men. 49% of all suicide attempts were considered to be of the "cry for help" variety and 29% were classified as obviously ineffective but serious attempts of self-killing. The remaining 22% of patients wanted to mark a "caesura" in their lives. Since the early phase of recovery is of utmost importance for the patient's future, medical and nursing staff have to be trained and experienced in coping with the suicide patient's numerous problems. The permanent collaboration of an experienced psychiatrist within the staff of larger acute-phase hospitals is highly desirable in order to analyze the underlying social and medical problems, assess the danger of a renewed suicide attempt, start early and appropriate therapy and train hospital staff and nurses.


[Drug-induced lung diseases].

[Drug-induced lung diseases]. Adverse drug reactions involving different organs, including the lung, are numerous; much more numerous, however, are the offending drugs. According to the results of the Boston Collaborative Drug Surveillance Program, adverse reactions occur in about 6% of all drug exposures and 28% of all patients. Drug-induced lung diseases may present as bronchial reactions (e.g. bronchial asthma), diseases of the parenchyma (e.g. pulmonary infiltrates with eosinophilia, diffuse fibrosing alveolitis), of the pulmonary vasculature (vasculitis) and of the pleura (e.g. pleurisy or pleural fibrosis). Pathogenetically the two most pertinent types of reaction are hypersensitivity or toxic reactions, and less often biologic reactions such as opportunistic infections after cytotoxic and immunosuppressive therapy. Many drug-induced respiratory diseases are reversible upon withdrawal of the offending agent; others may be irreversibly or even progress.


Mode of action of beta blockers in angina pectoris. The therapeutic effect of beta adrenoceptor blockers in angina pectoris can be ascribed to an inhibition of beta1 receptor mediated stimulation of heart rate and myocardial contractility, resulting in an improved oxygen supply-demand balance in the myocardium. When given in equipotent beta1 blocking doses, the nonselective blocker propranolol and the beta1 selective blocker metoprolol differ markedly as regards inhibition of adrenaline induced beta2 mediated vasodilatation. Only propranolol will inhibit this effect. After propranolol, adrenaline therefore elicits a haemodynamic effect pattern characterized by high peripheral vascular resistance, high arterial blood pressure, low cardiac output and increased cardiac size. In view of these findings it is suggested that a beta1 selective blocker may be a more efficient antianginal agent than a nonselective blocker in those patients in which the anginal attack is associated with a significant release of adrenaline. The clinical relevance of this hypothesis has not been tested.


Haemodynamic effects of different beta blockers in angina pectoris. Beta-blocking agents with partial agonist activity seem to reduce heart rate at rest slightly less than those without this property. Cardio-selective drugs have no effect on stroke volume at rest contrary to the non-selective ones which will reduce it somewhat. This difference is abolished during exercise. The only difference seen during work between different beta-blockers is the effect on the peripheral vascular resistance. The selective drugs lower the arterial pressure with unchanged resistance.


Inorganic photoreduction of nicotinamide adenine dinucleotide phosphate. I. Photoreduction by certain oxide semiconductors in the near ultraviolet. The action of chloroplasts in the light reactions of photosynthesis is the reduction of NADP to NADPH and phosphorylation of ADP to ATP by light energy. According to the electron theory of catalysis of photosynthesis, these functions of chloroplasts can be mimicked by any inorganic semiconductors. This paper reports that with ZnO instead of chloroplasts NADP can be photoreduced to NADPH in the near ultraviolet.


Observations in man of hypoglycaemia during selective and non-selective beta-blockade. The acute hypoglycaemic reaction is accompanied by a rise in systolic and a slight fall in diastolic blood pressure and a tachycardia. In contrast, during beta-blockade with propranolol there is a rise of both systolic and diastolic blood pressures and bradycardia. Restoration of blood glucose to normal is delayed. With metoprolol there is a lesser increase in diastolic blood pressure and a slight tachycardia. Restoration of the blood glucose to normal is little delayed. When patients liable to hypoglycaemia require a beta-blocking agent, it is suggested that a selective blocker such as metoprolol should be used.


Dopamine-sensitive adenylate cyclase: location in substantia nigra. A dopamine-sensitive adenylate cyclase with characteristics similar to those measured in the striatum is present in the rat substantia nigra. Destruction of dopamine cell bodies by intranigral 6-hydroxydopamine application failed to abolish the response of nigral adenylate cyclase to dopamine. In contrast, brain hemitransection between the striatum and substantia nigra, or a more circumscribed lesion of striatonigral pathways, abolished the dopamine stimulation of adenylate cyclase in the substantia nigra. These results suggest that dopamine receptors within the substantia nigra are not located on dopamine cell bodies but are associated with a pathway, containing gamma-aminobutyric acid or substance P, which projects from forebrain structures to the substantia nigra.


Uterine and cardiovascular effects of beta2-selective sympathomimetic drugs administered as an intravenous infusion. The uterine and cardiovascular effects of fenoterol, hexoprenaline, ritodrine and salbutamol, given as intravenous infusions in equivalent and therapeutic dosages in oxytocin-induced labour, were studied and compared. All the drugs were effective in reducing the uterine activity to less than 30% of the original. The effect on the cardiovascular system was to produce a moderate tachycardia and a widening of the pulse pressure by raising the systolic and decreasing the diastolic blood pressures.


Studies of the pharmacology of a new antidepressant, S1694. A new antidepressive drug, S1694, produces increased locomotor activity (LA) in mice, but less so than d-amphetamine. This effect is decreased by pimozide, phenoxybenzamine, as well as by pretreatment of the animals with reserpine or alpha-methyl-p-tyrosine methyl ester (H44/68). S1694 inhibits active dopamine (DA) uptake into rat striatal synaptosomes, but not noradrenaline (NA) uptake into rat hypothalamic synaptosomes, or serotonin (5-HT) uptake into rat midbrain synaptosomes, in the concentrations used. The inhibition of DA uptake appears tp be competitive and the inhibition constant estimated is 1,3 X 10(-6) M. In addition, S1694 releases DA in the same concentrations, and NA as well as 5HT at higher concentrations. It is concluded that S1694 activates LA primarily by inhibitionof DA re-uptake and DA release. The central DA system activation may be important in the antidepressive effect.


Enzymatic and hemodynamic changes after short term hepatic outflow occlusion in the dog. In normal mongrel dogs, outflow occlusion of 15 or 30 minutes duration was produced by clamping both the suprahepatic and suprarenal portions of the vena cava. One dog died immediately after release of occlusion; two dogs died from recurrent hypotension between six and 24 hours postoperatively. The other five dogs survived for three days, at which time an autopsy was done. During outflow occlusion, the blood pressure fell in all dogs, as did the central venous pressure. The pulse rate decreased during, and after, occlusion but toward a tendency of gradual recovery. A significant drop in pH and base excess of arterial blood was seen after occlusion. Although a steady, but not substantial, increase in hemoglobin and hematocrit values was noted, there were no remarkable changes in the blood coagulation system. Significant increases in serum glutamic-oxalacetic transaminase, glutamic-pyruvic-transaminase, lactic dehydrogenase, acid phosphatase and beta-glucuronidase activities were observed from immediately after release of occlusion, but alkaline phosphatase values increased much later than did these. Thus, hepatic outflow occlusion, even if it is short, seems to be dangerous in the dog, since it produces hypotension, metabolic acidosis and diffuse damage as well as disruption of the parenchyma of the liver.


A review of recent advances in vascular smooth muscle pharmacology. An understanding of the physiology of vascular smooth muscle and knowledge of the reaction of such muscle to certain drugs are essential for the development of a means of treating cerebral arterial spasm. The role of cyclic nucleotides in vascular smooth muscle activity is reviewed and possible therapeutic approaches are listed. Probably the safest and most effective treatment would be 1) stimulation of the adenyl cyclase-cyclic adenosine monophosphate system by a beta(2)-adrenergic drug combined with 2) inhibition of the phosphodiesterase system.


Bioavailability and generic prescribing. Although oral drug bioinequivalence has been attributed to a number of causes (excipients, dosage form, variation in dissolution time, and aging) less is known about bioavailability problems of topical medications in ophthalmology. Factors that can alter drug absorption from solutions (pH, partition coefficient, container impurities, contact time, etc.) are noted, and cases in which bioavailability problems should be considered as causes of therapeutic failure are discussed. Various attitudes representing pharmaceutical companies, the federal government, pharmacists, consumers and physicians toward the related problems of bioinequivalence and generic prescribing are examined. Techniques for in vivo and in vitro drug testing and for establishing uniform conditions of drug manufacture and storage can contribute to identification and minimization of bioavailability problems. A rational program based on a combination of such techniques could, ultimately, lead to establishment of the terms "generic equivalency" and "therapeutic equivalency" as synonymous.


Total body potassium in cor pulmonale.

Total body potassium in cor pulmonale. Total body potassium was measured in 12 patients with cor pulmonale, by determination of potassium-40, a naturally occurring radioisotope. In all subjects the observed value of total body potassium showed no significant depletion when compared with that predicted from height and age. All previous studies in similar groups of patients have been confined to the estimation of exchangeable potassium by the technique of isotope dilution. Results using the latter technique have shown gross potassium depletion. It is suggested that the apparent disparity between total body potassium and exchangeable potassium could be explained by the requirement for a longer equilibration period when using isotope dilution techniques in patients who are in chronic hypoxaemic state.


Arterial blood gas tensions, hydrogen ion, and electroencephalogram during sleep in patients with chronic ventilatory failure. We have studied arterial PO2, PCO2, and hydrogen ion and electroencephalogram during sleep in 10 patients with stable severe chronic respiratory failure. As a group the patients slept badly. Sleep was associated with a worsening of hypoxia and no significant change in PCO2 and H+. Two patients were restudied, receiving oxygen therapy overnight. Both had improved sleep but one, who had an intact hypoxic drive to breathing, developed marked hypercapnia and acidosis when his PO2 was restored to normal during sleep; the other, who had no hypoxic drive to breathing, developed no more hypercapnia or acidosis during sleep when breathing oxygen than when breathing air. Oxygen therapy may improve sleep disturbance in these patients, but its effect on the drive to breathing during sleep should be considered if severe hypercapnia and acidosis are to be avoided.


Studies on the properties of the immunologically effective anti-tumor substance from spleen cells of tumor-resistant rats. The influence of physical and chemical treatments upon the immunologically effective subcellular fractions (5,000 X g supernatant and 105,000 X g sediment), which were prepared from the spleen cells of Yoshida sarcoma (YS)-resistant Donryu rats, was studied. The immunological activity of the 5,000 X g supernatant was stable to heating at 80 degrees C for 30 min. It was stable to alkali (pH 10) and less stable to acid (pH 2). It was labile to a ten-day storage at 4 degrees C, but relatively stable to a 30-day storage at -20 degrees C. When the 105,000 X g sediment was lyophilized and stored at -20 degrees C for 95 days, its immunological activity was well maintained. It was labile to 95% ethanol, 90% phenol and 2 M NaNO2, but relatively stable to 10% as well as 100% acetone, 10% phenol and 10% ethanol. It was labile to 0.1 M NaIO4 and relatively stable to 0.1 M K2Cr2O7 solution. It was labile to RNase but relatively stable to DNase.


Minor and trace sterols in marine invertebrates. 1. General methods of analysis. 3beta-Hydroxy sterols occurring at a concentration of at least 0.001% of the sterol mixtures of Pseudoplexaura porosa and Plexaura homomalla have been fractionated using a series of refined techniques and subsequently analyzed using combined gas chromatography-mass spectrometry (GC-MS) in the development of a procedure for examining the minor and trace components of marine sterol mixtures. A total of 49 sterols were found which spanned a molecular weight range of 274 to 440. In addition delta4-3-keto analogs of cholesterol, 24-methylcholesterol and gorgosterol were found in the extracts of P. homomalla. Initial separation of various natural sterol-containing conjugates and free sterols was found to have a number of advantages. Fractional digitonin precipitation and alumina column chromatography were found to possess greater sterol separation abilities than previously recognized. Many of the minor sterols were found to possess novel structures including a series of short side chain sterols, 19-nor sterols, 5beta-stanols and 4-monomethyl sterols for which structure elucidation work is continuing.


Detection of serum-blocking factors by inhibition of allorosette formation in rats with long-surviving renal allografts following short-term postoperative ALS treatment. Thirty-nine (LEW x BN)F1 kidneys were transplanted to LEW rats. Twenty-four untreated recipients survived for a mean time of 16.1 +/- 1.7 days (group 1). Fifteen recipients received 4 ml of antilymphocytic serum per rat (group 3). In the last group 10 recipients survived for more than 4 months. The spleen cells of these permanently surviving 10 rats were obtained by splenectomy and used in a graft-versus-host assay, and this assay showed that the reactivity of these cells was normal. Following splenectomy the animals were given an (LEW x BN)F1 skin allograft, followed 18 days by a second. After another 18 days (LEW x Buf)F1 "third party" skin allografts were transplanted to the same animals. Animals of group 2 rejected their first grafts with a mean survival time of 12.2 +/- 1.2 days, whereas the second grafts were rejected normally as were the third party grafts. Attempts were made to detect lymphocytotoxic antibodies and haemagglutinins before and after the transplantation of skin grafts and none could be found up to day 53. The sera of group 2 inhibited allorosette formation by 38%. This serum-blocking factor was donor specific. It is probable that the survival of the kidney transplants following antilymphocytic serum treatment was brought about by the development of blocking antibodies.


Cortical evoked potential and extracellular K+ and H+ at critical levels of brain ischemia. As shown previously, the electrical function of the brain is critically dependent on cerebral blood flow in the sense that reduction beyond an ischemic threshold of approximately 15 ml/100 gm per minute (approximately 35% of control) in the baboon leads to complete failure of the somatosensory evoked response. This study tests the hypothesis that electrical failure in ischemia may be directly associated with a massive release of intracellular K+ or with a critical degree of extracellular acidosis. By microelectrode techniques, measurements of blood flow, extracellular activity of K+ and H+ as well as evoked potential were made in the baboon neocortex. Reductions in blood flow were obtained by occlusion of the middle cerebral artery and depression beyond the ischemic threshold of electrical function achieved by a reduction of systemic blood pressure which, in the ischemic zones, changed local cerebral blood flow proportionally. Abolition of evoked response could not be explained by depolarization by release of intracellular K+, nor was it critically dependent on cortical pH. However, the massive release of intracellular K+ was by itself critically dependent on cortical blood flow and occurred at 18 greater than 6 greater than 2 ml/100 gm per minute (median with 5% confidence limits). Thus a dual threshold in ischemia for neuronal function is described, the threshold for release of K+ being clearly lower than the threshold for complete electrical failure. Further, the findings support the concept of an ischemic penumbra during which the neurons remain structurally intact but functionally inactive. That neurons can survive for some time in this state of lethargy is evidenced by the observations that an increase in rCBF, if sufficient, can restore evoked potential and normalize extracellular K+ activity as well as pH.


Deficiency in the thymus-dependent immunity in "lethargic" mutant mice. T cell function of "lethargic" mutant mice which exhibit spontaneous thymic involution was evaluated by skin transplantation and graft-versus-host reaction tests. At 15 to 30 days of age, the mutant mice did not reject skin allografts, but by 45 days of age their response was normal. Spleen cells from 24-day-old mutant donors demonstrated delayed appearance of graft-versus-host induced splenomegaly in F1 recipients. Implications of these results in understanding the immunological status of lethargic mice were considered.


Epidemiologic study of arboviruses in the Arba-Minch district of Ethiopia. A yellow fever outbreak occurred in 1966 in Arba-Minch District, east of Abaya Lake, in Ethiopia. The present study was undertaken to assess the southern limits of that epidemic and to contribute to the inventory of arboviruses and potential vectors in that area. In the highlands 90 sera were collected, in the lowlands 140. With regard to Group B the sera reacted only with yellow fever, Wesselsbron and Spondweni antigens. In the highlands 17.8%, in the lowlands 22.2%, were positive for group B. In two sera only the titers against yellow fever were high. The absence of reactivity to West Nile virus was striking. A wide variety of Culicidae was present and differentiated. Potential or proven vectors were collected. At the time of the survey yellow fever was not active in the region. Because of an only partly immune human population, and of the presence of non-immune monkeys and some potential vectors, the area should, however, be considered to be receptive.


[Experience with the use of viadril anesthesia]. Based on experimental and clinical findings the authors concluded that a combination of viadril with neuroleptanalgesics shows a number of advantages over purely viadril anesthesia or its combination with other drugs for inhalation and intravenous anesthesia. The technic of thalmonal-viadril anesthesia is reported.


[Adaptation to oxygen breathing].

[Adaptation to oxygen breathing]. Controlled, dosed, uninterrupted and continuous oxygen treatment was applied in 63 patients with global respiratory insufficiency, through a nasopharyngeal catheter in concentrations to 30 per cent. PaO2, is elevated with and average of 12 mm mercury column after 30 minutes 25% oxygen breathing and PaCO2--at an average of 8 mm mercury column. PaO2 level was kept after 24 hours whereas PaCO2 decreased at an average of 4 mm mercury column. Besides, respiration and pulse rate are decelerated, secondary polyglobulia decreases, cardiac and renal function is improved. Those changes are interpreted as patients' adaptation to oxygen breathing. The adaptation to oxygen breathing decreases the danger of critical intensification of the respiratory depression in the course of the treatment and conditions for a successful application of O2 treatment at home are created.


[Postural hypotension: pathophysiology and clinical features (author's transl)]. Circulatory regulation in response to postural changes follows mechanical rules, whereby the shifts in volume in the various organs of the body play an essential role. The change from the horizontal to the vertical position is accompanied by a decrease in pressure above the hydrostatic neutral point, i.e. in the cephalic vessels, whereas the capacious vessels in the caudal region are dilated and the venous return becomes sluggish. As a consequence of the different time courses followed by the various circulatory parameters in the wake of counter-regulatory measures, a distinction can be made between an early orthostatic instant regulatory response and a late orthostatic response. Prominent clinical features do not necessarily always consist of non-systemic dizziness, tinnitus, pallor cold sweat and, finally, orthostatic collapse, but general subjective symptoms such as deafness and tingling of the extremities, a chilly sensation and cardiac symptoms may frequently predominante. In the case of development of an autonomic neurotic symptom complex, psychoautonomic symptoms such as general sleep disturbance are observed. Apart from investigations carried out on a surgical tilting table in general practice, other procedures such as the Valsalva manoeuvre, the squatting test and, in most cases, the erect test are performed. Broadly speaking four different reaction types can be distinguished amongst cases of postural hypotension. Drugs with different therapeutic actions are selectively administered according to the pathophysiological characteristics of the individual patient and the sympathetic adrenal counter-regulatory response. Medico-mechanical measures and physical training should not be neglected.


[Early clinical symptoms and therapy of haemorrhages in old age (author's transl)]. There is hardly a bleeding, where the extrinsic-and/or the intrinsic-system of the coagulation does not take part in. Haemorrhages represent a symptom only, and it is always to clear, if they are come from a local process of illness or from a general tendency of haemorrhage. There is point to the clinical differences of great bleeding (coagulopathy) and bleedings like points (the causes lie in the thrombocytes or in a vascular damage). The early clinical symptoms and the therapy of haemorrhages by the old human without the primary disturbance of the coagulate-system are discussed.


[Duodenogastric reflux and anastomosis abscess. Experimental study]. Different types of duodenal by-pass operations with and without duodenogastric reflux were performed on 54 male Wistar rats. The results of our investigation show that following duodenal by-pass with reflux peptic anastomotic ulcer regularly occurs. The constant reflux of bile and pancreas juice is the most important aetiologic factor in the development of ulcer in the vicinity of the anastomosis between the stomach and small intestine. Stasis in the by-passed duodenum (afferent loop syndrome) promotes ulcerogenic action of reflux. In the absence of the pylorus the effects of reflux and stasis potentiate, resulting in a high frequency of ulcer (greater than 90%). With intact pylorus the incidence is low. Duodenogastric reflux prevents hydrochloric acid secretion significantly (p less than o,o1); hydrochloric acid thus plays a minor role in the development of experimental anastomotic ulcer of the rat. -- In considering the prophylaxis against anastomotic ulcer, these findings support the claim of avoiding surgical techniques involving duodenal by-pass and reflux (Billroth II with short loop GE). Gastric resection should, therefore, aim at the reconstruction of the orthograde peristalsis.


[Histopathological study of the mosquito-bite infiltrate in patients with various underlying diseases and different medications]. A histologic study was carried out on tissue-reactions after insect bits in 9 patients with various primary diseases. The clinical and cellular reactions to the bite in the epidermis varied, according to the length, intensity of toxity of the insect bit. The dermal infiltrate was similar in almost all cases and corresponded to a cellular immunologic reaction of the early or late type, as is also to be seen in trichophytin and tuberculin-reactions. Tere was clearly no relationship between the character of the dermal infiltrate and the basic disease. We also found no change in the dermal infiltrate due to special medicaments. Even corticosteroids did not suppress the dermal cellular reactions. There was also a striking absence of eosinophil leucocytes in the dermal infiltrate.


Non-equivalence and inverse allosteric response of the alpha and beta chains in haemoglobins. An electron spin resonance study of NO-ligated Hb Kansas. The electron spin resonance (ESR) spectra of 15NO- and 14NO-ligated Hb Kansas have been measured at 77 K in the range of pH 5 TO 10. At low pH the ESR spectrum is the composite of a type I and a type II spectrum which changes to another composite of type I and type II spectrum at high pH. For the definition of type I and type II spectra and the correlation of these types with two tertiary conformation states see Overkamp et al., Z. Naturforsch. 31 c, 524 [1976]. Both, the type I and the type II spectra observed at low and high pH respectively are different with regard to g-tensors and hyperfine-splitting constants. Therefore at intermediate pH values the ESR spectra of NO-Hb Kansas are the composites of four spectral components. The assignments of the four spectral components to the alpha and the beta chains are arrived at from the comparison of the ESR spectra of the alpha2Mmet beta2NO and of the alpha2MNObeta2NO species of Hb M Iwate. alpha and beta chains are both characterized by a pH-dependent spectral transition from a type I to a type II spectrum. The chains are non-equivalent with regard to both the type I and the type II spectra. The type I spectra assigned to the alpha and the beta chains are characterized by G*ZZ=2.0095 with a hyperfine splitting of alpha*ZZ(15NO)=2.36 mT and gZZ-2.0085 with a hyperfine splitting of aZZ(15NO)=2.41 mT respectively. The type II spectra assigned to the alpha and the beta chains are characterized by g*'ZZ-2.005 and a hyperfine splitting of alpha*'ZZ(15NO)-3.07 mT and g'ZZ-2.005 and a hyperfine splitting of alpha'ZZ(15NO)=3.31 mT. The change of the hyperfine splitting at gZZ during the transition from type I to type II corresponds to an increase of the spin density at the NO by about 25% in both types of chains. Comparison of type I spectra of the NO-ligated alpha and beta chains respectively demonstrates that the spin density at the NO is larger in the beta chains that in the alpha chains. The spectral types are correlated with functional states defined by the kinetics of N0-binding. Binding of inosital hexaphosphate has no influence on the ESR spectra in the whole range of pH as it is expected if NO-Hb Kandas is in the quaternary T structure.


Kinetic analysis of the catalytic properties of peptides in ester hydrolysis. The catalytic properties of peptides containing histidine, cysteine and aspartic acid in ester hydrolysis were studied. Saturation kinetics were found for the reaction of p-nitrophenyl acetate (NPA) with Z-His-Ala-Asp-Gly-Cys-NH2 and Z-His-Ala-Gly-Cly-Cys-NH2. The Brönsted equation for the hydrolysis of tert-butyloxcarbonyl-L-alanine-p-nitrophenylester (Bos-Ala-ONp) catalyzed by simple imidazole and SH-compounds was determined. The catalytic behaviour of the peptides in ester hydrolysis could not be described by the Brönsted equations for imidazole o thiole catalyzed hydrolysis of NPA and Boc-Ala-ONp. The pH dependence of the rate constants of the catalyzed ester hydrolysis gave no linear plots in 1/k versus H+ diagrrams.


Light-dependent interactions of phenazine methosulfate with 3-(3,4-dichlorophenyl)-1,1-dimethylurea-poisoned chloroplasts. The chlorophyll fluorescence of isolated chloroplasts in the presence of phenazine methosulfate (PMS) and 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU) can be quenched in a light-depentdent reaction. This phenomenan has been studied and the following observations were made: 1. Quenching occurs under non-phosphorylating conditions and is stimulated by Mg2+ ions. 2. Under the same conditions, a light-dependent, Mg2+ stimulated transient decrease of absorption at change and binding of PMS. Others, such as methylamine, ammonia, gramicidin and nigericin do not. It is suggested that fluorescence quenching, transient absorption change and binding of PMS are casually related. The concept, postulated by others, that a high-energy state of the chloroplast membrane is involved in the fluorescence lowering is questioned.


Kinetics and properties of L-glutaminase and L-asparaginase activities of Pseudomonas ovalis. Pseudomonas ovalis produces L-glutaminase and L-asparaginase activities simultaneously upon induction by L-glutamine or L-asparagin in the growth medium. Both activities are confined to the cell during active growth and are not released into the medium. The apparent Km values are 1.4 X 10(-2) M and 6 X 10(-3) M for L-glutamine and L-asparagine substrates, respectively. Induction of both activities is substantially favoured in media with initial pH values higher than 7. In buffered yeast extract L-asparagine medium, significant amounts of L-glutaminase and L-asparaginase activities appeared towards the end of the exponential phase and along the stationary phase. The process of enzyme formation showed a firm link to the cell active growth, as evidenced by the use of growth inhibitors.


[Comparison in vitro between farm-yard manure and liquid manure (author's transl)]. Spreading of liquid manure in a grassland ecosystem, stable since a long time when treated with farm-yard manure, brings out a great unbalance in the soil. In comparison of farm-yard manure, the liquid manure involves -- a decrease of C and N in the soil, -- a deterioration of the soil structure, -- a dangerous change in the CEC for K+ and Na+, -- an excessive stimulation of the microflora. In brief, through its composition the liquid manure involves a hyperactivity of the microglora. This heterotropic microflora is particularly mineralizing and breaks down the organic matter. The result is a temporary increase in fertility. But this stimulation of the soil life disbalances the eco-system in which -- the pool of organic matter decreases without replacement, -- the content in Ca++ and Mg++ decreases to the benefit of K+ and Na+.