Transmembrane electrical and pH gradients across human erythrocytes and human peripheral lymphocytes. Transmembrane electrical and pH gradients have been measured across human erythrocytes and peripheral blood lymphocytes using equilibrium distributions of radioactively labelled lipophilic ions, and of weak acids and weak bases, respectively. The distributions of methylamine, trimethylamine, acetic acid and trimethylacetic acid give calculated transmembrane pH gradients (pHe-pHi) for erythrocytes of between 0.14-0.21 for extracellular pH values of 7.28-7.16. The distributions of trimethylacetic acid. DMO and trimethylamine were determined for lymphocytes, establishing upper and lower limits of the calculated pH gradient over the external pH range of 6.7 to 7.7. Tritiated triphenylmethyl phosphonium ion (TPMP) and 14C-thiocyanate ion (SCN) equilibrium distributions were measured in order to calculate transmembrane electrical potentials, using tetraphenylboron as a catalyst to facilitate TPMP equilibrium. Transmembrane potentials of -7 to -10 mV were calculated from SCN and TPMP, respectively for red cells, and -35 to -52 mV respectively, in the case of lymphocytes. Distributions of TPMP and potassium ions were determined in the presence of valinomycin over a wide range of extracellular potassium concentrations for red cells and the calculated Nernst potentials for TPMP compared to the calculated potential using the Goldman equation for chloride and potassium ions. Distributions of TPMP, SCN and potassium ions were also determined for lymphocyte suspensions as a function of extracellular potassium and the calculated Nernst potentials for TPMP and SCN compared to the calculated potassium diffusion potential.


Functional characterization of an adhesive component from the embryonic chick neural retina. We have developed a quantitative assay for tissue-specific adhesive components which is based on the agglutination of glutaraldehyde-fixed cells. At least 2 components are required for fixed-cell agglutination: a cell-surface ligand which is obtained from tissue culture-conditioned medium, and a soluble 'agglutinin' which accumulates in conditioned medium from monolayer cultures. Our results suggest that the surface-binding ligand and the agglutinin interact directly, resulting in tissue-specific agglutination of cells. The agglutination reaction exhibits divalent cation, temperature, and pH dependence. Several models of cell adhesion are described; the simplest of these which can account for the data is a multicomponent model in which the 2 adhesive components have structural roles.


Gap and septate junctions in the excitable endoderm of Polyorchis penicillatus (Hydrozoa, Anthomedusae). The morphological basis of impulse conduction in a jellyfish epithelium was investigated. Lanthanum impregnation of endodermal canal and endodermal lamella verified the existence of true gap junctions in Polyorchis. In both transverse and en face sections of gap junctions, electron-lucent globules, with a width of 7--8 nm and a spacing of about 11 nm, are evident. Gap-junctions are concentrated at the peripheral canal margin and septate junctions are localized around the canal lumen. Epithelial cells of the endodermal canals are capable of conducting a non-decrementing action potential. It is suggested that endodermal spike propagation, which can mediate 'crumpling' behaviour, is dependent upon low-resistence ionic pathways provided by gap-junctions and upon sealing of the intercellular space from saline extracellular fluids by septate junctions.


The alpha-adrenoceptor control of adrenocorticotropin secretion in man. Oral administration to six normal male volunteers of an alpha-adrenoceptor agonist, guanfacine (4 mg daily for 4 days) had no significant effect on ACTH release induced by metyrapone (a single oral 1-g dose). The same treatment with guanifacine significantly reduced ACTH secretion stimulated by insulin-induced hypoglycemia in another group of six male volunteers. These results indicate that, in man, the adrenergic system has an inhibitory input on stress-induced ACTY secretion via alpha-adrenoceptors. The concept of alpha-adrenergic control of ACTH secretion in man is in agreement with some experimental in vivo and in vitro data recorded in animals.


Role of renal prostaglandins in sympathetically mediated renin relase in the rat. Renal prostaglandins (PG) appear to mediate renin release due to stimulation of the intrarenal baroreceptor, but not that due to activation of the macula densa. However, as the role of PG in sympathetically mediated renin release remains unclear, a possible interrelationship between these factors was examined in conscious rats. Hydralazine increased the serum renin levels from 3.1+/-0.8 to 16.7+/-3.0 ng/ml per h at a dose of 1 mg/kg. Indomethacin (5 mg/kg) suppressed urinary PGE(2) and PGF(2alpha) excretion by 89 and 74%, respectively, arachidonate hypotension by 82%, and inhibited the elevated renin levels from hydralazine by 100% without altering the hypotensive effect of the drug. Another PG synthetase inhibitor, meclofenamate, was also effective in attenuating hydralazine-induced renin release, urinary PGE(2) and PGF(2alpha) excretion, and arachidonate hypotension. Isoproterenol, a nonselective beta-adrenergic agonist, increased heart rate, lowered blood pressure, and also stimulated the release of renin when administered intraperitoneally. However, intrarenal infusion of the drug only resulted in increased renin release. Indomethacin inhibited isoproterenol-induced renin release by 66 and 67%, respectively, without altering the hemodynamic effects associated with the intraperitoneal administration of the drug. The selective beta(1) agonist, H133/22, increased the release of renin and heart rate in a dose-related manner without altering blood pressure. H133/22-induced renin release was inhibited by 80% by indomethacin pretreatment. Finally, intrarenal infusions of dibutyryl cyclic AMP (3 mg/kg per min) increased the serum activity from 4.1+/-0.2 to 20.4+/-3.9 ng/ml per h without altering mean arterial pressure. Indomethacin inhibited this renin response to dibutyryl cyclic AMP by 96%. Thus, renal PG appear to be important mediators of sympathetically stimulated renin release acting as a site distal to the beta-adrenergic receptor.


Anaphylactic release of a basophil kallikrein-like activity. I. Purification and characterization. These studies describe the IgE-mediated relase of a basophil kallikrein-like enzyme that is an arginine esterase and is inhibited by plasma, diisopropylphosphofluoridate, and Trasylol. The substrate specificity for the synthetic amino acid ester substrates p-toluenesulfonyl-L-arginien methyl ester, benzoyl-arginine methyl ester, and acetyl-tyrosine methyl ester is similar for the basophil enzyme and plasma kallikrein. The interaction of arginine esterase-active fractions from ion-exchange (DEAE-Sephacel) and gel filtration (Sepharose 6B) chromatography, with human plasma kininogen, generates immunoreactive kinin. The basophil arginine esterase and kinin-generating activities co-chromatograph on Sepharose 6B and the quantity of kinin generated is, in general, proportional to the arginine esterase activity of the column fractions, suggesting that these two activities are subserved by the same protease. The ability of this protease to generate kinin equally well from heat- and acid-treated plasma, as from fresh human plasma, suggests that this protease has kallikrein-like activity. These data suggest that kallikrein-like activity can be generated from human basophils as a direct result of a primary IgE-mediated immune reaction, thus providing a potential link between reactions of immediate hypersensitivity and the plasma and(or) tissue kinin-generating systems.


Micropuncture determination of pH, PCO2, and total CO2 concentration in accessible structures of the rat renal cortex. Previous studies evaluating the mechanism of renal HCO-3 reabsorption have assumed equilibrium between systemic arterial blood and tubular fluid PCO2. We have recently reported that the PCO2 in proximal and distal tubular fluid as well as the stellate vessel significantly exceeded arterial PCO2 by 25.9 +/- 0.92 mm Hg. The purpose of this study was to determine directly, for the first time, pH, PCO1, and total CO2 concentration in the accessible structures of the rat renal cortex with both microelectrodes and microcalorimetry. In addition, the concentrations of chloride and total CO2 were compared in the stellate vessel. The data demonstrate that: (a) values for total [CO2] in both the proximal tubule and stellate vessel calculated from in situ determination of pH and PCO2 closely agree with the measured values for total [CO2]: (b) values for chloride concentration in the stellate vessel are significantly less than the corresponding values in systemic plasma (delta[Cl-] = 5.6 meq/liter); and (c) the rise in [HCO-3] from systemic to stellate vessel plasma closely approximates the observed reciprocal fall in [Cl-] in this structure.


A comparison of self-delivered consequences and desensitization in the treatment of fear of rats. Exposed 52 rat phobic Ss to either group desensitization, self-delivered consequences imagined exposure, self-delivered consequences in-vivo exposure, or no treatment. Self-delivered consequences Ss conducted the treatment on their own and self-delivered preselected reinforcers contingent upon performance of the treatment exercises. All treatment groups improved significantly more than the no-treatment control group. The self-delivered consequences imagined exposure and the group desensitization treatments were equally effective. The self-delivered consequences in-vivo exposure treatment was significantly more effective than the self-delivered consequences imagined exposure and group desensitization treatments. The applicability of self-management techniques to the treatment of fear responses to specific stimuli and an extinction explanation of the effectiveness of systematic desensitization are discussed.


gamma-Glutamyl transpeptidase of bovine milk membranes: distribution and characterization. The distribution and characterization of gamma-glutamyl transpeptidase from bovine milk was examined. The enzyme was associated mainly with components of milk membrane. Skim milk membrane had 41% of the total activity in whole milk whereas milk fat globule membrane showed 7%. Enzyme kinetic characterization of these two membrane fractions showed they had identical amino acid specificities, pH, and sodium chloride effects, and similar apparent Michaelis constants. The main enzymatic difference between the membranes was a 2 to 3 times higher specific activity of the skim milk membranes. Skim milk membrane from milk would be a good source of this enzyme for continued studies of the function of gamma-glutamyl transpeptidase in amino acid transport during lactation.


[Sipple disease (author's transl)].

[Sipple disease (author's transl)]. The authors report a case of ocular manifestation of a Sipple disease. They discuss, the association with endocrine poly-adenomatosis and the relationship with the APUD system.


[The evolution of the thickness of rabbit corneas in hydratation, the influence of pH and composition of the solution (author's transl)]. The swelling of excised, de epitheliated, rabbit corneas has been measured every five minutes during their immersion in a hydrating medium. The following media have been used: distilled H2O, Krebs-bicarbonate Ringer solution, HCl 0,01 N and NaCl 1 M/l. The swelling is very moderate with Krebs and NaCl, much higher and practically proportional to the duration of immersion with HCl, still faster with H2O. On the other hand, the influence of pH has been studied using 13 different solutions buffered from pH 1 to pH 13. A pronounced minimum of the swelling was found for pH 4, along with 3 relative maxima: the first around pH 2, the second around pH 8 and the third around pH 12. The interpretation of those results on a biochemical basis is discussed. For all these media, the solvent was distilled H2O. At last, two statistical distributions, based on 131 corneas, have been determined: one concerning the initial thickness and the other concerning the difference between the initial thickness of the two corneas of the same rabbit.


Nature of the stimulus leading to lymphocyte-induced angiogenesis. Experiments are described that characterize the nature of the stimulus leading to lymphocyte-induced angiogenesis (LIA), a reaction previously shown to reflect a local in vivo graft-vs-host reaction. The studies demonstrate that circulating cells of the host animal provide the stimulation essential for activation of donor lymphocytes and that the major allogeneic stimulus in congenic lines of mice is correlated with I-region disparity, primarily associated with IA-controlled determinants. The results are readily compatible with the hypothesis that is proposed that LIA is in large part of the consequence of the release of soluble mediators or lymphokines that may act either directly on endothelial cells or indirectly by activating macrophages, which in turn generate the vascular reaction.


The elution of antibodies from viable murine tumor cells. Several low pH buffers were used in order to dissociate radioiodinated antibodies from sensitized living tumor cells. Three buffers were further tested for their dissociation abilities under different conditions of time and temperature, and for their influence on the eluted antibodies. The cytotoxicity mediated by these low pH buffers was also determined by viability assays. Optimal results were obtained with 0.1 M citrate buffer at pH 3.5.


A two-site immunoradiometric assay for the determination of alpha-albumin. A two-site immunoradiometric assay for a brain specific protein (alpha-albumin or glial fibrillary acidic protein) is described which may be applied to other proteins. The assay variables studied are immunoadsorbent dilution, temperature, incubation times, reactivity of the labelled antibodies and effect of the washing. Each of these factors is optimalised, resulting in a sensitive, specific, reliable assay. The working range is 5--5000 ng/ml, the within-assay variance is 5%. No high dose hook effect is seen in this range. The method is applied for the measurement of alpha-albumin present in cerebrospinal fluid, nervous tissue extracts and cell cultures.


Divergent results in radial immunodiffusion. III. Isolation and specificity test of class-specific antibodies. A method is described for the isolation of antibodies specific for immunoglobulin class determinants from antisera containing antibodies both for the immunoglobulin class and for its subclasses, using affinity chromatography. The model system used is bovine IgG with its subclasses IgG1 and IgG2, together with antisera raised in goats and sheep. The specificity of the isolated class-specific antibodies was demonstrated by double diffusion (DI) and radial immunodiffusion (RID). The levels of total IgG in normal bovine sera measured with the class-specific antibodies were the same as the sum of the IgG1 and IgG2 levels obtained with subclass-specific antisera. However, sera from cattle infected with Fasciola hepatica contain IgG1 fragments without class-specific determinants. In these sera, contrary to expectation, the class-specific antibodies gave higher total IgG levels than the subclass-specific antisera. The yield of class-specific antibodies varied with different batches of antisera. The minimum amount of each class-specific antibody preparation needed for a RID plate also varied. Class-specific antibodies isolated from antisera raised against IgG1 gave more intense precipitation reactions in RID against IgG1 than IgG2 and vice versa. Possible reasons for these differences are discussed.


The subcellular localization of neutral sphingomyelinase in rat liver. The subcellular distribution of neutral sphingomyelinase activity has been determined in rat liver. Neutral sphingomyelinase is present in the plasma membrane. This enzyme requires either Mg2+ or Mn2+ for full activity; these cations cannot be replaced by Co2+ or Ca2+. The plasma membrane sphingomyelinase is strongly inhibited by Hg2+. A small amount of neutral spingomyelinase activity appears to be present in microsomes. No neutral sphingomyelinase activity is present in liver mitochondria or bytosol. Lysosomal sphingomyelinase is fully active at pH 4.4--4.8 without added divalent cations. However, between pH 5.0 and 7.5 lysosomal sphingomyelinase activity is stimulated by Mg2+, Mn2+, Co2+, and Ca2+. Below pH 4.8, Mg2+ inhibits the reaction. In contrast to the results obtained with the neutral sphingomyelinase activity of plasma membranes and microsomes, lysosomal sphingomyelinase is unaffected by sulfhydryl inhibitors.


Lipoprotein lipase and acid lipase activity in rabbit brain microvessels. A preparation of cerebral microvessels was used to demonstrate the presence of lipoprotein lipase and acid lipase activity in the microvasculature of rabbit brain. Microvessels, consisting predominantly of capillaries, small arterioles, and venules, were islated from rabbit brain. Homogenates were assayed for lipolytic activity using a glycerol-stabilized trioleoylglycerol-phospholipid emulsion as substrate. Lipoprotein lipase activity was characterized with this substrate by previously established criteria including an alkaline pH optimum, increased activity in the presence of heparin and heat-inactivated plasma, and reduced activity in the presence of NaCl and protamine sulfate. A different substrate, containing trioleoylglycerol incorporated into phospholipid vesicles, was used to reveal acid lipase activity that was not affected by heparin, plasma, NaCl, or protamine sulfate. Lipoprotein lipase did not show activity with the vesicle preparation as substrate. Intact microvessels, when incubated in the presence of heparin, release lipoprotein lipase into the incubation solution. In contrast, release of acid lipase activity from intact microvessels was not dependent on heparin. The data show the presence of both lipoprotein lipase and acid lipase in brain microvessels and suggest that lipoproteins are metabolized within the cerebral vasculature.


Continuous monitoring of free fatty acid release from adipocytes by pH-stat titration. A methods for direct and continuous monitoring of free fatty acid release in adipocyte suspensions is described. Using a pH-stat apparatus the protons from the released free fatty acids are continuously titrated and the accumulated amount of OH- added is monitored on a recorder against time, the slope thus indicating the rate of free fatty acid release. Sinc pH is kept constant, an incubation medium with a low buffering capacity can be used, which gives the method a high sensitivity. Under the conditions described, free fatty acid release from 5% of maximal norepinephrine stumulation of rat adipocytes can be accurately measured and the kinetics can be followed over extended periods of time.


Adherence of Mycoplasma gallisepticum to glass. Attachment of washed Mycoplasma gallisepticum cells to glass was quantified with organisms in which membrane lipids were labelled with 3H. Siliconization of the test tubes decreased attachment, while centrifugation increased it. Attachment increased with temperature, decreased with increasing pH and ionic strength of the attachment mixture, but was unaffected by Ca2+, Mg2+ and EDTA. This suggests that ionic bonds, but not salt bridges, participate in the attachment process. Glycophorin, the major receptor responsible for M. gallisepticum attachment to erythrocytes, partially inhibited the attachment of the organisms to glass. However, bovine serum albumin also decreased attachment. Extensive pretreatment of the organisms with trypsin decreased their ability to attach to glass by about 35 to 40%. Trypsin and pronase failed to detach the organisms already bound to glass, suggesting that external mycoplasma cell components, other than membrane proteins, also participate in attachment of the organisms to glass.


Intracellular polysaccharide of Bacteroides fragilis. Formation of iodophilic polysaccharide (IPS) from glucose was demonstrated in 27 strains of Bacteroides fragilis. Synthesis was dependent on the glucose concentration of the medium, the pH and the growth phase. When glucose was in short supply the cellular polysaccharide was degraded rapidly at pH 4.5 to 6.5 and fatty acids accumulated in the medium. Storage of IPS was not responsible for the low carbon recoveries observed in fermentation balance studies. In electron micrographs of thin sections, the IPS was observed as cytoplasmic granules dispersed throughout the whole cell. After extraction and purification the IPS was characterized as a glycogen.


Interactions between Bifidobacterium bifidum N4 and Escherichia coli K-12 in their mixed cultures. The interactions between Bifidobacterium bifidum N4 (B. bifidum) and Escherichia coli K-12 (E. coli) were investigated in their mixed cultures. Under conditions in which both bacteria grew well in their pure culture, B. bifidum inhibited the growth of E. coli even when the latter was inoculated at 10(4)-fold and preincubated for 41 hr. The inhibition in the mixed cultures appeared when the pH values were reduced below 4.6. When the lowering of pH was prevented by the addition of NaOH, no inhibition was observed. At the same initial pH of 6.5, lactic acid and acetic acid, metabolites of B. bifidum, had more inhibitory effect on the growth of E. coli than other aliphatic fatty acids. On the other hand, in the mixed cultures with E. coli, B. bifidum grew in the absence of its essential vitamins, riboflavin and pantetheine and, furthermore, aerobically.


Persistent Müllerian duct structures in cryptorchid male infants: surgical dilemmas. Persistent Müllerian duct structures were found in 3 male cryptorchid infants aged 10--12 mo, during correction of a unilateral inguinal hernia. Division of the vas degerens, hysterectomy and scrotal orchidopexy were carried out. The authors believe that in subjects with a persistent müllerian duct syndrome, surgical placement of the testes into the scrotum should be performed. This is, as a rule, not possible without damage to the vas deferens which runs parallel and adheres closely to the surface of the uterus.


Plasticization of cellulose ethers used in the film coating of tablets. Plasticizer/polymer interactions have been studied by measuring the intrinsic viscosities of both ethyl cellulose and hydroxypropyl methylcellulose in a series of dialkyl phthalates and in a series of liquid glycols respectively. A correlation was found between the intrinsic viscosity of the polymer/plasticizer solutions and the tensile strength, elongation at rupture and work done in stressing to failure of cast films--the mechanical properties being at a minimum when the intrinsic viscosity was at a maximum. This correlation held only within a homologous series of plasticizers and none was found for plasticizers of different structures. A relationship was found between the lowering of a calculated glass transition temperature of hydroxypropyl methylcellulose in the presence of the plasticizers propylene glycol, polyethylene glycol 200 and glycerol and the intrinsic viscosity of the corresponding solutions--the higher the viscosity the greater the lowering of the transition temperature.


Powder mixing in direct compression formulation by ordered and random processes. The mixing processes taking place in a two component system involving a cohesive drug, tetracycline and a direct compression vehicle, spray dried lactose (SDL), have been studied by chemical analysis of powder samples and fluorescence microscopy. At a drug concentration level of 0.25% w/w, both random and ordered mixing is taking place. Mixture quality is better (Cv = 1%) using a fine grade of crystalline lactose (CL) than with SDL (Cv = 4%). Using fractionated material, it was found that SDL between 106 and 300 micron gave Cv values up to 12%, whereas with SDL below 106 micron values of 2% were obtained. The poor quality of the SDL mixtures is attributed to ordered unit segregation.


Relative effects of different surfactants on intestinal absorption and the release of proteins and phospholipids from the tissue. The actions of anionic, cationic and non-ionic surfactants on the absorptive capability of rat jejunal tissue in vivo were compared with their effects on the amounts of protein and phospholipid released from the mucosal surface under the same conditions. Release of a comparatively small amount of protein was accompanied by large increases in the absorption rates of both L-valine and salicylate, whereas much larger quantities of phospholipid were released before any increase in absorption were observed. Much of the released material appeared to be derived from mucus which was partly degraded after exposure to the higher concentrations of surfactants. The liberation of cholesterol by high concentrations of anionic surfactants suggested that some disruption of the mucosal membrane occurred under those conditions. The relative potency of the surfactants in stimulating both absorption of the solutes and the release of polypeptides and lipids followed the order: anionic greater than non-ionic greater than cationic. The possible pharmaceutical relevance of these findings is discussed.


Uptake of 5-hydroxytryptamine in blood platelets and its inhibition by drugs: role of plasma membrane and granular storage. The initial uptake of 3H-5-hydroxytryptamine (3H-5-HT) showed linearity for short time intervals in normal and reserpinized blood platelets of guinea-pigs, but was lower in reserpinized platelets. Teh Km values for the 3H-5-HT uptake were virtually identical in normal and reserpinized platelets, whereas Vmax was lower in the latter. Imipramine and chlorpromazine caused the same percentage inhibition of 3H-5-HT uptake in normal and reserpinized platelets; the reserpine-like compound Ro 4-1284 inhibited the uptake of 3H-5-HT in the normal, but not markedly in the reserpinized platelets. Haloperidol, prenylamine and Ro 4-9040 were more potent inhibitors in normal than in reserpinized platelets. It is concluded that (a) the Km of the initial uptake of 5-HT by platelets is probably determined by the mechanism at the plasma membrane, whereas Vmax may be codetermined by the intracellular storage capacity, (b) platelets are models for differentiating the site of action (plasma membrane or storage organelles) of drugs interfering with 5-HT uptake, and (c) neuroleptics- and reserpine-like compounds may either act selectively on the plasma membrane or on the intracellular storage organelles, or affect both of these subcellular sites.


The reversal by pyridostigmine of neuromuscular block produced by soman. The effect of pyridostigmine on neuromuscular block produced by soman was studied in the isolated phrenic nerve-diaphragm preparation. In the rat, soman produced an irreversible reduction in tetanic tension and functional acetylcholinesterase (AChE) activity. Pretreatment with pyridostigmine before exposure of the diaphragm to soman, followed by removal of the anticholinesterase from the organ bath, produced a return of tetanic tension and an increase of 5% in functional AChE activity. Similar results were obtained in the guinea-pig. The changes in synaptic AChE activity were verified pharmacologically by showing a decrease in the blocking activity of acetylcholine in preparations pretreated with pyridostigmine in comparison to those given soman alone following removal of the anti-cholinesterase. The blocking dose of carbachol did not change in these two groups indicating that desensitization was not a component of the protective action. A comparison was also made of the results obtained by measuring inhibition of AChE in situ with those obtained from muscle homogenates. The implications of these results are discussed.


The protection of primates against soman poisoning by pretreatment with pyridostigmine. The effectiveness of pyridostigmine pretreatment against soman poisoning has been determined in rhesus monkeys and marmosets receiving atropine therapy. Pretreatment with the maximum sign-free dose (200 microgram kg-1, i.v.) raised the subcutaneous LD50 of soman by a factor of 28 in rhesus monkeys and 15 in marmosets. The protection afforded by a quarter of the sign-free dose of pyridostigmine was not significantly less. These levels of protection are higher than any reported in non-primate species.


Corticosterone -- an anxiogenic or an anxiolytic agent? Corticosterone (3--12 mg kg-1, i.p., giving rise to plasma corticosterone concentrations from 26.7 to 89.0 micrograms/100 ml) failed to have a significant anxiogenic action. Instead, corticosterone (3 mg kg-1) had a significant anxiolytic effect in the social interaction test of anxiety. Adrenalectomized rats had very low levels of social interaction; but adrenalectomized rats that had been given replacement corticosterone therapy did not differ from the sham-operated controls. Thus, corticosterone appears to have the opposite effect to that previously reported for ACTH. Possible mechanisms for the observed results are discussed.


Muscimol and related GABA receptor agonists: the potency of GABAergic drugs in vivo determined after intranigral injection. Contralateral turning behaviour following unilateral intranigral injection of a large series of GABA analogues was investigated. The results indicated that the turning behaviour was induced stereospecifically and was selectively antagonized by the GABA antagonist bicuculline methochloride. The comparative potencies of a series of GABA agonists related to muscimol in general corresponded well to the affinity for 3H-GABA receptor sites and to the depressant action on single neurons using microelectrophoretic administration. However, the GABA agonists trans-aminocrotonic acid and 3-aminopropanesulphonic acid were much weaker than expected from in vitro studies. The GABA-uptake inhibitors nipecotic acid and guvacine showed only weak and short-lasting effects. The GABA-transaminase  inhibitor gamma-acetylenic GABA showed delayed effects compared with the agonists which acted immediately. It is proposed that this behavioural effect may be a sensitive and quantitative method for evaluation of GABA agonists in vivo.


Comparative metabolism of codeine in man, rat, dog, guinea-pig and rabbit: identification of four new metabolites. The metabolism and excretion of codeine and its metabolites in untreated urine of man, rat, dog, guinea-pig and rabbit have been examined. Metabolites were identified by gas chromatography mass spectrometry operated in the chemical ionization mode (methane). Concentrations of codeine and metabolites were measured by selected ion monitoring. Both codeine and norcodeine were detected in the urine of all species but a new metabolite, hydrocodone, was found only in the urine from man, guinea-pig and dog. Additional metabolites (presumably resulting from the metabolism of hydrocodone) were also detected in man and guinea-pig. Overall recoveries of drug and metabolites from untreated urine were low for all species.


Hypothermic effects of apomorphine homologues in mice. A single intraperitoneal (i.p.) injection in mice of apomorphine (I) and its analogues norapomorphine (II), N-ethylnorapomorphine (III), N-n-propylnorapomorphine (IV) and apocodeine (V), caused dose-related decreases in deep-core body temperature. The neuroleptic agent haloperidol blocked the hypothermia produced by these apomorphines but alpha-methyl-p-tyrosine failed to do so. This indicated a direct post-synaptic stimulation of dopamine receptors. Methysergide potentiated the hypothermic effect of the apomorphine analogues. Taking the amount of apomorphine to produce a 3 degree C fall in temperature at 30 min as unity, the approximate relative potencies were: I 1.00, II 0.06, III 47.50, IV 85.00, V 0.340. The doses of the apomorphines needed to produce hypothermia were much less than those needed to cause stereotypy. The ratios of the minimal doses required to produce hypothermia, to those producing stereotypy were: I 8.82, II 4.00, III 125.00, IV 28.50, V 1.43.


An in vitro study of drug displacement interactions: warfarin-salicylate and warfarin-phenylbutazone. The binding interactions between warfarin-salicylate and warfarin-phenylbutazone in the presence of 4 g percent bovine serum albumin at 37 degrees C were studied using equilibrium dialysis. Methods of representing and analysing drug binding interactions are discussed. Scatchard plots, double reciprocal plots and the like are shown to be of no use in representing drug displacement interactions since they display only one drug and they can be potentially misleading. It is argued that a preferable method of analysing drug displacement interaction data is in terms of a stepwise multiple equilibria model. The numerical problems associated with fitting this kind of model to the data are discussed. A three-dimensional representation of the binding surface is proposed as a superior means of visualizing drug displacement interactions.


Cobaltous chloride-induced hypothermia. II: Pretreatment with sympathoplegics, antihistamines, and narcotic antagonists. Body temperature depression was noted in rats, mice, and hamsters following intraperitoneal cobaltous chloride administration (25 mg/kg). Intracerebral cobalt injection elicited hypotermia in rats and mice but not in hamsters. Body temperature depression appeared to be centrally mediated in rats and mice and peripherally mediated in hamsters. The effect of intraperitoneal and intracerebral pretreatment with phentolamine, diphenhydramine, propranolol, cimetidine, and naloxone on the mouse rectal temperature response to cobalt (25 mg/kg ip) was noted. Systemic phentolamine injection (intraperitoneal) did not alter the cobalt response, whereas intracerebral administration partially antagonized cobalt-induced hypothermia, indicating that antagonism was mediated centrally. Pretreatment with propranolol and cimetidine  failed to modify the temperature response. Intracerebral diphenhydramine did not influence cobalt hypothermia. However, this agent reduced the cobalt response when given intraperitoneally, presumably through a peripheral inhibitory mechanism. The intracerebral injection of naloxone 30 min prior to cobalt slightly enhanced hypothermia, apparently through a central action. Intracerebral 6-hydroxydopamine injection depleted brain norepinephrine and dopamine but exhibited no apparent influence on cobalt-induced hypothermia.


Dissolution systems for chloramphenicol tablet bioavailability. The relationship between chloramphenicol (I) tablet bioavailability and in vitro dissolution rates was examined. The effect of solid food on the I tablet and powder bioavailability was also studied. Five tablets of I were selected for bioavailability testing on the basis of the dissolution rates of 18 I tablets (250 mg) determined by several methods. Compound I, 500 mg, was administered orally to five subjects, following overnight fasting, according to a crossover design. The bioavailability parameters were obtained from urinary I excretion. Among the five formulations studied, only one tablet (F) showed significantly poorer bioavailability. The dissolution rates at pH 1.2 did not give the same rank order as the bioavailability. The dissolution rate of Tablet F showed remarkable pH dependency. The dissolution rates at pH 4 showed good correlation with in vivo bioavailability data. The bioavailability of I powder was not affected by solid food. Tablet F, which had poor bioavailability in the fasting state, showed good bioavailability when administered just after the standard breakfast.


New biphenyl derivatives II: 1-(4-Biphenylyl)-1-hydroxy-2-aminoethanes and 1-(4-biphenylyl)-1-chloro-2-aminoethanes as potential beta-adrenoceptor blocking agents. Series of 1-(4-biphenylyl)-1-hydroxy-2-aminoethanes and 1-(4-biphenylyl)-1-chloro-2-aminoethanes were synthesized. Newly developed reaction conditions for aryl aminomethyl ketone reduction and reductive alkylation, using sodium borohydride, are described. The prepared compounds were examined for adrenergic blocking activity on an anesthetized dog blood pressure preparation and on isolated toad hearts. beta-Adrenergic blockade was investigated using isoproterenol as the agonist. The benzylamino and cyclohexylamino analogs exhibited marked beta-adrenoceptor blocking activity, for which the latter derivatives were more potent.


GI absorption of beta-lactam antibiotics. III: Kinetic evidence for in situ absorption of ionized species of monobasic penicillins and cefazolin from the rat small intestine and structure-absorption rate relationships. Absorption rates of monobasic beta-lactam antibiotics were measured as a function of lumen solution pH between 4 and 9 by utilizing the rat intestinal recirculating method in situ. Between pH 6.5 and 9, the absorption rate constants of ionized antibiotics were almost identical; but, at pH 4, the unionized species were highly absorbed, depending on their lipophilicity through the GI membrane lipoidal barrier. The structure-absorption rate relationship was established with the unstirred layer model.


Metabolic conversion of fluorenone oxime to phenanthridinone by hepatic enzymes. Fluorenone oxime is converted to phenanthridinone by enzymes present in rat liver homogenates. The reaction is analogous to the chemical Beckman rearrangement. The oxime-amide rearrangement enzyme is localized primarily in the microsomes, with some activity in the cytosol. The reaction requires reduced nicotinamide adenine dinucleotide phosphate and observes Michaelis-Menten kinetics. The reaction is relatively slow (Vmax = 7.75 +/- 2.01 nmoles of phenanthridinone formed/100 mg of liver/15 min), but the enzyme reaches maximum velocity at relatively low substrate concentrations (Km = 3.90 +/- 1.85 x 10(-5) M). The reaction is strongly competitively inhibited by 1-decylimidazole (KI = 3.75 +/- 1.77 X 10(-7) M) and inhibited to a lesser extent by the chelating agents bipyridyl (KI = 1.33 +/- 0.21 X 10(-3) M) and ethylenediamine tetraacetate (KI = 1.00 +/- 0.28 X 10(-3) M) and the sulfhydryl binding agent p-chloromercuribenzoate (KI = 2.71 +/- 0.07 X 10(-4) M). Studies also suggest that the reaction mechanism does not involve initial enzymatic substrate esterification through acetylation, glucuronidation, phosphorylation, or sulfation.


Interaction of streptonigrin with metals and with DNA. The antitumor antibiotic, streptonigrin, interacted with zinc, copper, and manganese but not with calcium or magnesium, as indicated by spectral shifts and difference spectra. The titration data showed the formation of 1:1 complexes, and further titration continued to show spectral shifts until a molar ratio for zinc to streptonigrin of 5-10 to 1 was reached. Streptonigrin interacted with DNA only in the presence of a metal ion such as zinc. Streptonigrin titration with DNA at varying zinc molar equivalents revealed that one antibiotic molecule required 5-7 moles of zinc and 20-25 moles of DNA-phosphorus for complexation. Similar values were obtained from gel permeation chromatography.


3-Quinuclidinyl benzilate hydrolysis in dilute aqueous solution. The hydrolysis kinetics of 3-quinuclidinyl benzilate were determined over the pH 0-14 range at different temperatures in solutions buffered to a constant pH. Analysis of data extrapolated to zero buffer concentrations permitted construction of an overall rate expression for pH 0-14 and 0-100 degrees. Reaction mechanisms are discussed.


13C-NMR spectra of alpha-adrenergic blocking agents. The natural abundance 13C-NMR spectra of five alpha-adrenergic blocking agents, tolazoline, dibenamine, azapetine, phenoxybenzamine, and phentolamine, are reported. The chemical shifts of various carbon resonances were assigned on the basis of chemical shift theory, multiplicities observed in single-frequency off-resonance-decoupled spectra, relaxation times, and comparisons with the chemical shifts of model compounds.


High-pressure liquid chromatographic evaluation of aqueous vehicles for preparation of prednisolone and prednisone liquid dosage forms. A high-pressure liquid chromatographic method was developed that separates prednisolone from prednisone, prednisone from methylprednisolone succinate sodium, and hydrocortisone from hydrocortisone acetate or cortisone acetate. The common liquid dosage preservatives methylparaben, propylparaben, and sodium benzoate do not interfere with quantitative prednisolone, prednisone, and hydrocortisone determinations. The method was used to study prednisolone and prednisone stability in five aqueous vehicles (water, citrate buffer USP, 50% glycerin, 50% sorbitol, and 50% sucrose) containing 10% (v/v) ethanol. Prednisone crystallized out in all vehicles except glycerin, in which it appeared to be stable for at least 92 days. Prednisolone did not crystallize in any vehicle but decomposed quickly in citrate buffer. Sorbitol and glycerin appeared to be the best vehicles for prednisolone. The developed method was applied successfully to the quantitative determinations of prednisolone, prednisone, and hydrocortisone in commercial tablets.


Modified fluorometric quantitation of pancuronium bromide and metabolites in human maternal and umbilical serums. The procedure for pancuronium bromid ion-pair extraction into chloroform using rose bengal and subsequent fluorometric measurement was modified by changing the extraction pH and eliminating phenol, ethanol, and acetone to give easier operation and enhanced fluorescence stability. Precision, accuracy, and sensitivty were evaluated over 0.14-0.82 microgram/ml (CV = 14; relative error = 9%) and 0.05-0.17 microgram/ml (CV = 19; relative error = 21%). Following a dose of 0.1 ml/kg for cesarean section in humans, the mean maternal arterial and umbilical venous serum concentrations of pancuronium bromide and metabolites were 0.52 and 0.12 microgram/ml, respectively, at delivery (mean of 13 min after injection).


Controlled drug release by polymer dissolution. II: Enzyme-mediated delivery device. A novel, closed-loop drug delivery system was developed where the presence or absence of an external compound controls drug delivery from a bioerodible polymer. In the described delivery system, hydrocortisone was incorporated into a n-hexyl half-ester of a methyl vinyl ehter-maleic anhydride copolymer, and the polymer-drug mixture was fabricated into disks. These disks were then coated with a hydrogel containing immobilized urease. In a medium of constant pH and in the absence of external urea, the hydrocortisone release was that normally expected for that polymer at the given pH. With external urea, ammonium bicarbonate and ammonium hydroxide were generated within the hydrogel, which accelerated polymer erosion and drug release. The drug delivery rate increase was proportional to the amount of external urea and was reversible; that is, when external urea was removed, the drug release rate gradually returned to its original value.


The effects of amiloride and ouabain on urinary acidification by turtle bladder. To investigate the mechanism by which amiloride inhibits urinary acidification, its effects on H+ secretion were examined in the isolated urinary bladder of the fresh water turtle. In short-circuited turtle bladders amiloride inhibited H+ secretion by 30% and Na+ transport by 100%. Maximal inhibition was reached at 10(-4) M amiloride for both transport systems. In contrast to amiloride, ouabain did not affect H+ secretion despite complete inhibition of Na+ transport. In bladders first treated with ouabain amiloride failed to inhibit H+ secretion and in bladders first treated with amiloride, the inhibition of H+ secretion was partially reversed by ouabain. The inhibition of H+ secretion by amiloride is attributed to hyperpolarization of the luminal cell membrane and the imposition of a voltage opposing the movement of protons in the active transport pathway.


Technique for minimizing dimensional changes in large-span ceramic-metal fixed restorations. In the technique described in this article, the long-span and full-arch fixed restoration can be soldered by isolating the restoration from the heatrobbing mass of investment and perching it on stilts of high-temperature-resistant rods. The porcelain is fired and glazed with a minimum dimensional change.


Distortions in indexing methods and investing media for soldering and remount procedures. A three-dimensional distortion analysis was made of seven indexing-investment systems and six indexing-remount systems. Measurements were made to within +/- 0.005 mm with a Nikon Profile Projector and a linear variable differential transformer (LVDT); distortions (linear and rotational) were calculated by means of a PDP 11/40 computer system. Mean vector displacements, square root deltaX2 + deltaY2 + deltaZ2, were calculated, and a statistical evaluation of the data was completed. The results of the study indicate: 1. The zinc oxide-eugenol (ZOE) indexing-investment system produced a narrower range and a significantly smaller mean distortion than the other six indexing-investment systems. 2. The ZOE-stone remount technique showed significantly less distortion than the ZOE-low-fusing metal or the ZOE-acrylic resin techniques. 3. The polyether-stone remount technique demonstrated significantly less distortion than either the polyether-low-fusing metal or the polyether-acrylic resin system. 4. The polyether-stone remount system was not significantly different from the ZOE-low-fusing metal system. 5. The ZOE-stone remount technique demonstrated a smaller range of distortions, but those distortions were not significantly different from those of the polyether-stone remount technique.


Syntheses, analgetic activity, and physical dependence capacity of 5-phenyl-6,7-benzomorphan derivatives. The synthesis, analgetic activity, and physical dependence capacity of a large number of 5-phenyl-6,7-benzomorphan derivatives are described. Observations made during the Stevens' rearrangement of 1-benzyl-1-methyl-delta 3-piperidinium salt derivatives (V) under various conditions are discussed. The absolute configuration of the 9-demethyl series and the 2'-deoxy series is established by comparison of their ORD and CD spectra with those of 49, whose absolute configuration was previously established by X-ray crystallography. A convenient synthesis of 3H-labeled phenols using 3H3PO4 is described, as well as the preparation of 14C-labeled compounds by conventional methods.


Synthesis of 2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole derivatives and their central nervous system activities. The synthesis and some pharmacological effects of cis- and trans-2-substituted 2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole derivatives are described. In these derivatives, the substituents of the 2, 5 and 8 position, together with the relative configuration of the 4a and 9b position, influenced the potency of the central nervous system activities. A cis-2-[3-(p-fluorobenzoyl)propyl] analogue (5k) of carbidine (1) possessed not only thymoleptic-like biological activity but had more potent neuroleptic activity than the parent drug.


beta-Adrenergic blocking agents with acute antihypertensive activity. Modification of the pharmacological profile of the vasodilating/beta-adrenergic blocking agent 2-[4-[3-(tert-butylamino)-2-hydroxypropoxy]phenyl]-4-(trifluoromethyl)imidazole (1) has been investigated. Introduction of selected substitutents onto the imidazole ring, in place of the trifluoromethyl group, has yielded highly cardioselective beta-adrenergic blocking agents such as 7, 17, and 18. The placement of alkyl or chloro groups onto the aryl ring of 1, as illustrated by 33, has produced a class of compounds characterized as antihypertensive beta-adrenergic blocking agents. In these examples, the acute antihypertensive activity does not appear to be due to either vasodilating or beta 2-agonist properties.


10-(Alkylamino)-4H-thieno[3,4-b][1,5]benzodiazepines. A novel class of potential neuroleptic agents. An investigation of the structural requirements for CNS activity of the title compounds was undertaken. A synthesis of the precursor dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-ones was achieved and three routes for their conversion to the title compounds were developed. The compounds were tested for neuroleptic activity by means of the blockade or d-amphetamine lethality in aggregated mice and/or effects on locomotor activity in rats. Antidepressant activity was examined using inhibition of tetrabenazine-induced depression in mice. Most of the compounds were found to be potent neuroleptic agents with several exhibiting additional antidepressant activity.


Cardioselectivity of beta-adrenoceptor blocking agents 1. 1-[(4-Hydroxyphenethyl)amino]-3-(aryloxy)propan-2-ols. A series of 1-[(4-hydroxyphenethyl)amino]-3-(aryloxy)propan-2-ols was synthesized together with several 1-[(3,4-dimethoxyphenethyl)amino]-3-(aryloxy)propan-2-ols. Their affinity to beta 1- and beta-2-adrenoceptors was determined and compared with the affinity of known beta-blockers. We were able to confirm the substantial cardioselectivity of 1-(3,4-dimethoxyphenethyl)-3-[(4-substituted aryl)oxy]propan-2-ols when compared to those with a 1-(4-hydroxyphenethyl) group. An increase in the size of the 4 substitutent of the 3-(aryloxy) moiety to caproamido leads to a substantially higher affinity for the beta 1--adrenoceptor of rat ventricular muscle in the presence of the 3,4-dimethoxyphenethyl than in the presence of the 4-hydroxyphenethyl or isopropyl group; this combination also gave the highest cardioselectivity.


Conformational effects on the activity of drugs. 7. Synthesis and pharmacological properties of 2-(p-nitrophenyl)-substituted morpholines. A series of 1-(p-nitrophenyl)-2-aminoethanol derivatives and their morpholine analogues have been synthesized and pharmacologically investigated in order to confirm some pharmacological observations made with the N-isopropyl-substituted compounds. In agreement with the previously obtained results, the weak alpha-adrenergic-stimulating activity and the potentiating effect on the responses to norepinephrine found in the open-chain compounds persist in their corresponding semirigid cyclic analogues. The results are discussed in the light of common knowledge of the structure-activity relationships of alpha-adrenergic drugs.


Coupled transport of protons and anions through lipid bilayer membranes containing a long-chain secondary amine. Transport of protons and halide ions through planar lipid bilayers made from egg lecithin and a long-chain secondary amine (n-lauryl [trialkylmethyl] amine) in n-decane was studied. Net proton fluxes were measured with a pH electrode, and halide fluxes were measured with 82Br- and 36Cl-. In membranes containing the secondary amine, a large net proton flux was produced either by a Br- gradient with symmetrical pH or by a pH gradient with symmetrical Br-, but not by a pH gradient in Br--free solutions. This H+ flux was electrically silent (nonconductive), and the H+ permeability coefficient was greater than 10(-3) cm sec-1 in 0.1 M NaBr. In Br--free solutions, H+ selectivity was observed electrically by measuring conductances and zero-current potentials generated by H+ activity gradients. The permeability coefficient for this ionic (conductive) H+ flux was about 10(-5) cm sec-1, several orders of magnitude smaller than the H+ permeability of the electroneutral pathway. Large electroneutral Br- exchange fluxes occurred under symmetrical conditions, and the permeability coefficient for Br- exchange was about 10(-3) cm sec-1 at pH 5. The one-way Br- flux was inhibited by substituting SO4= for Br- on the "trans" side of the membrane. These results support a "titratable carrier" model in which the secondary amine exists in three forms (C, CH+ and CHBr). Protons can cross the membrane either as CHBr (nonconductive) or as CH+ (conductive), whereas Br- crosses the membrane primarily as CHBr (nonconductive). In addition to these three types of transport, there is also a pH-dependent conductive flux of Br- which has a permeability coefficient of about 10(-7) cm sec-1 at pH 5. Experiments with lipid monolayers suggest that the pH dependence of this conductive flux is caused by a change in surface potential of about +100 mV between pH 9.5 and 5.0.


Operative versus non-operative management of patients with staghorn calculi and neurogenic bladder. During the last 5 years 22 patients have been treated at our hospital for staghorn calculi and neurogenic bladder. In 17 patients an operation was done soon after discovery of the calculi, while 5 patients were followed non-operatively. The latter 5 patients had a rapid downhill course marked by sepsis and renal function deterioration and an operation was necessary in 4 of the 5 cases. Injudicious non-operative therapy only prolongs the relentless effects of staghorn calculi in patients with spinal cord pathology.


Clinical implications of gonadal venography in the management of the non-palpable undescended testis. Selective gonadal venography was used on 28 patients with a total of 34 non-palpable undescended testes. The data obtained in this study suggest that 1) an internal spermatic vein with a pampiniform-like plexus indicates the presence of a testis, 2) a blind-ending vein on venography suggests the absence of a testis, 3) an internal spermatic vein or vas deferens may be present without a testis, 4) a testis probably cannot be present without a gonadal vein, 5) a testis may be present without a vas, 6) a blind-ending vas deferens does not necessarily indicate the absence of a testis and 7) a blind-ending vas deferens in a patient in whom a blind-ending gonadal vein is localized to the same region probably indicates the absence of a testis. Gonadal venography may localize a non-palpable undescended testis or suggest testicular agenesis. In addition, gonadal venography has aided in the selection of the operative approach and, in the future, may provide criteria under specific circumstances for determining whether an operation is necessary and, if so, the extent of surgical exploration.


Pressor response during cystomanometry in spinal injury patients complicated with detrusor-sphincter dyssynergia. Herein attention is focused on the documentation of high blood pressure response with detrusor-sphincter dyssynergia in spinal cord injury patients and with its amelioration after extended sphincterotomy. During cystomanometric evaluation of the bladder the monitored blood pressure response in 53 spinal injury patients, 27 non-dyssynergic spinal injury patients and 18 non-spinal injury patients was compared. A high correlation was observed among the magnitudes of blood pressure increase, level of injury and the severity of detrusor-sphincter dyssynergia in spinal injury patients. During cystomanometry blood pressure increases of greater than 20 mm. Hg systolic and 10 mm. Hg diastolic in normotensive paraplegics (below T5) and also in non-spinal injury patients were significant to suspect detrusor-sphincter dyssynergia. In normotensive tetraplegic patients blood pressure increases of greater than 40 mm. Hg systolic and 20 mm. Hg diastolic were significant to suspect detrusor-sphincter dyssynergia. The mechanism of blood pressure increase is elucidated. The management of this high blood pressure response in patients with detrusor-sphincter dyssynergia by drug therapy and extended sphincterotomy is discussed. Based on our experience the use of carbon dioxide for cystomanometry seems preferable in patients with spinal lesions above T5 since expedient deflation of the bladder can prevent an inordinate blood pressure increase.


Hemorrhagic cystitis and ureteritis, and interstitial nephritis associated with administration of penicillin G. Hemorrhagic cystitis and ureteritis, and interstitial nephritis developed in a patient receiving penicillin G and streptomycin as therapy for bacterial endocarditis. After therapy was changed to vancomycin there was prompt resolution of these abnormalities.


Association of diethylstilbestrol exposure in utero with cryptorchidism, testicular hypoplasia and semen abnormalities. Epididymal cysts and/or hypoplastic testes have been found in 31.5 per cent of 308 men exposed to diethylstilbestrol in utero, compared to 7.8 per cent of 307 placebo-exposed controls. Analyses of the spermatozoa have revealed severe pathological changes (Eliasson score greater than 10) in 134 diethylstilbestrol-exposed men (18 per cent) and 87 placebo-exposed men (8 per cent). Further investigation of the 26 diethylstilbestrol-exposed men with testicular hypoplasia has revealed that 65 per cent had a history of cryptorchidism. Only 1 of the 6 placebo-exposed controls with testicular hypoplasia had a history of testicular maldescent. Although none of our Diekmann's lying-in study group has had carcinoma to date one must keep in mind the reported increased risk of testicular carcinoma in testes that are or were cryptorchid. A 25-year-old man who was not part of the study group was treated recently by us for a testicular carcinoma ( mixed anaplastic seminoma plus embryonal cell carcinoma) and he had a history of diethylstilbestrol exposure in utero and cryptorchidism.


Unilateral abdominal cryptorchidism.

Unilateral abdominal cryptorchidism. The unilateral non-palpable undescended testis is considered separately from other forms of cryptorchidism. It is less likely to be fertile, it is more prone to malignancy and it is more difficult to place. Removal rather than orchiopexy often is in the best interests of the child.


Management of the abdominal undescended testicle. Of the orchiopexies performed for abdominal undescended testicles 85 per cent have resulted in satisfactory testicular growth and position. Three-fourths of these cases were in boys with the prune belly syndrome. We are satisfied with our recent experience using the Fowler-Stephens procedure to salvage intra-abdominal undescended testicles. An analysis of the failures in 5 testes early in this series, resulting in partial atrophy, has helped us to avoid technical errors through attention to the following details: 1) preservation of a broad pedicle of peritoneum overlying the mobilized vas, 2) avoidance of any dissection of the spermatic cord and 3) high ligation of the spermatic vessels well above the point of confluence of the vas and spermatic vessels. Although the Fowler-Stephens procedure has some risk of testicular ischemia and atrophy we believe it to be the preferred way to gain mobility on a short tethering gonadal vascular pedicle.


Urethral pressure profiles before and after Ornade administration in patients with stress urinary incontinence. Urethral pressure profilometry was done on 12 women with stress urinary incontinence and in 6 women with no history of incontinence, before and 1 to 2 hours after the administration of Ornade. Eleven of the 12 women with stress urinary incontinence had increases in the maximal urethral pressure of 20 per cent or more over the control value. Only 1 of the 6 control women exhibited an increase in the maximal urethral pressure of greater than 20 per cent after the administration of Ornade. It is believed that the phenylpropanolamine component of Ornade stimulates alpha-adrenergic receptors at the vesical neck and in the proximal urethra to achieve the therapeutic effect of reducing or eliminating stress urinary incontinence. This drug is preferred over ephedrine primarily because of its sustained release, allowing dosage twice a day, and because of its relative freedom from side effects.


Histamine-induced ACTH secretion and inhibitory effect of antihistaminic drugs. Concentration of adrenocorticotropic hormone (ACTH) in the serum increased and reached the maximum level 10 min after the injection of histamine (dihydrochloride, 0.5 or 1 mg/100 g) i.p. into rats. The maximum concentration of ACTH in the serum was dependent on the dose of histamine. The ACTH concentration then decreased and was close to the normal level 30 to 60 min after the injection. The ACTH secretion induced by histamine (0.5 mg/100 g) was inhibited completely by the pretreatment with the antagonists of H1-receptor, diphenyhydramine (hydrochloride, 0.2--0.5 mg/100 g), promethazine (hydrochloride, 0.1--0.2 mg/100 g) and d-chlorpheniramine (maleate, 0.02--0.05 mg/100 g). The antagonist of H2-receptor, metiamide (2--4 mg/100 g) inhibited the ACTH secretion significantly but not completely. These results suggest that H1-receptor plays a major role in the histamine-induced ACTH secretion, although H2-receptor is also involved in this ACTH secretion.


[Clinical use of arfonad and hygronium aerosols in emergency hypotensive therapy]. During clinical testing of the administration of ganglion-blocking agents by inhalation (175 persons) it was established that drug aerosols of arfonad and hygronium possess high effectiveness, act rapidly, and are relatively safe. The inhalation method of the management of hypertensive crises may find wide use in out-patient practice, under conditions of the admission room, cardiological and resuscitation departments, as well as in obstetrics when controlled hypotension is necessary.


Microelectrode determination of pH and PCO2 in rat proximal tubule after benzolamide: evidence for hydrogen ion secretion. Previous micropuncture studies supporting hydrogen secretion as the mechanism of bicarbonate reabsorption have relied on the demonstration of an acid disequilibrium pH in the proximal tubule after systemic administration of a carbonic anhydrase inhibitor. Previous calculations of disequilibrium pH, however, have involved the necessary assumption that PCO2 in the proximal convoluted tubule was equal to arterial blood PCO2. This assumption can no longer be supported in view of the recent demonstration that the PCO2 in proximal and distal tubular fluid exceeded arterial blood by approximately 25 mm Hg. The purpose of the present study was to determine directly pH and PCO2 with microelectrodes in both the early and late segments of the accessible proximal tubule of nine Sprague-Dawley rats before and after administration of benzolamide (2.0 mg/kg/hr, i.v.). In the early proximal tubule, pH decreased significantly after benzolamide administration from 6.98 +/- 0.03 to 6.62 +/- 0.03 pH U (P less than 0.001), and PCO2 also decreased from 65.1 +/- 1.2 to 59.3 +/- 1.4 mm Hg (P less than 0.005). In the late proximal convoluted tubule, pH did not change after benzolamide (6.75 +/- 0.02 to 6.77 +/- 0.02), but PCO2 decreased significantly (64.3 +/- 1.5 to 57.7 +/- 1.6) (P less than 0.01). We conclude: (1) the fall in both pH and PCO2 in the early proximal tubule indicates that carbonic acid, not carbon dioxide accumulates after inhibition of luminal carbonic anhydrase; (2) although PCO2 also decreased in the late proximal tubule, unlike the early segment, pH was unchanged after benzolamide administration, perhaps as a result of increased bicarbonate delivery; and (3) PCO2 in vivo was significantly greater than was systemic arterial PCO2 before and after benzolamide administration in both the early and late proximal convoluted tubule. These findings lend support to the view that bicarbonate reabsorption in the proximal convoluted tubule occurs, in part, by hydrogen secretion.


Microvascular and clinical effects of altered peritoneal dialysis solutions. Blood flow in the peritoneum is one of the more important factors governing the efficiency of peritoneal dialysis. Yet there have been no previous studies which relate alterations and control of the peritoneal microcirculation to dialysis efficiency. Thus, we used closed-circuit television microscopy to quantitative the in vivo response (changes in diameter) to dialysis solutions of the small arteries on the mesothelial surface of the rat cecum and arterioles of the rat cremaster muscle. These responses were correlated wiht solute clearances from multiple peritoneal dialysis performed in humans. In the cremaster, a transient constriction was followed by a prolonged dilation. pH adjustments of the dialysis solution from 5.6 to 7.4 had no effect on the microvascular response and no effect on solute clearances during human peritoneal dialysis. In the cecum, dialysis solution caused a prolonged dilation which reached a maximum in about 10 min. Since dilation appears to be an important determinant of solute clearances during human peritoneal dialysis, the effects of a vasodilator, sodium nitroprusside, were determined. Sodium nitroprusside decreased the time to maximal dilation, which correlated clinically with an increased solute clearance during exchanges with this drug. Since nitroprusside increased clearances of the larger molecular weight solutes proportionally more than the smaller molecular weight solutes did, we hypothesize that nitroprusside increases solute clearances by both a vasodilatory effect and by an effect on vascular membrane permeability and area for solute exchange.


The involvement of the sympathetic nervous system in tetanus. Besides the characteristic disturbances of the motor nervous system symptoms indicating an overactivity of the sympathetic nervous system can complicate the course of severe cases of tetanus. These symptoms include fluctuating tachycardia and hypertension, electrocardiographic changes, sweating, constipation with development of paralytic ileus and metabolic disorders. These symptoms are comparable to these developing in patients with phaeochromocytoma. Elevated catecholamine levels in plasma and urine have been found in several patients with tetanus who developed these symptoms. The prolonged over-activity of the sympathetic nervous system is thought to contribute to the still considerably high mortality rate. Myocardial lesions observed at necropsy are comparable to those found in patients dying of phaeochromocytoma. These lesions are suggested to be associated with sudden death from arrhythmias or cardiac failure in patients with tetanus. For the protection of the organism against the overactivity of the sympathetic nervous system a treatment using the combination of beta-adrenergic receptor blocking agents and adrenergic neuron blocking agents has been introduced. A reduction of the mortality rate was achievable by this treatment. Experimental evidence is accumulating that the tetanus toxin affects not only the motor, but also the sympathetic and sensory neurons.


[Effect of factors imitating space flight conditions on human lipid metabolism]. Studies of the effects of space flight simulation factors on lipid metabolism showed that space diets developed for space flights of different duration (dehydrated foodstuffs alone or in combination with foods preserved by other methods) did not produce noticeable changes in lipid metabolism. Nevertheless, other factors, i.e. hypokinesia, intake of nerobol during hypokinesia, an altered work-rest cycle, an increased carbon monoxide concentration (up to 15 mg/m3) influenced lipid metabolism.


[Effect of sealed chamber conditions on the functional state of the human adrenal cortex (based on data from a study of the 11-hydroxycortico-steroid content in the blood plasma)]. The effect of a changed atmosphere, hypoxia, hypercapnia, their combinations and different motor activities on the adrenocortical function was studied in 36 test subjects kept in an 8 m3 altitude chamber. Human adaptation to the environmental changes developed with an active involvement of the adrenal cortex. The level and direction of the changes depended on both the force of the influences and on the initial state of the test subjects.


Proliferative capacity of erythropoietic stem cell lines and aging: an overview. The earliest bone marrow precursor cell types, often called stem CELLS, have a very large capacity for self renewal. This makes them a useful model system in which to test the hypothesis that normal somatic cells have a limited proliferative capacity. Marrow precursor cells differentiate and multiply to replenish the supply of various blood cell types that constantly turn over. Especially with erythrocyte production, this function is well difined and can be tested rigorously to determine whether a significant amount of the stem cell proliferative capacity is exhausted. Functional tests generally show that marrow stem cell lines are exhausted after three to six serial transplantations into successive recipients; the few exceptions are cases in which functioning by cells from the irradiated recipients has not been ruled out. Genetic markers unambiguously identifying marrow stem cell lines from the original donor are necessary for clear cut interpretations of transplantation experiments. No significant differences are found when comparing erythrocyte production by marrow stem cell lines from old and young adult donors. This suggests that little or none of the erythropoietic stem cell's proliferative capacity is exhausted by a lifespan of normal functioning.


Mouse erythropoietic stem cell lines function normally 100 months: loss related to number of transplantations. Marrow stem cell lines from old and young donors in parallel experiments were transplanted into genetically anemic W/WV recipients. These recipients were populated and their anemias were cured by stem cell lines from WCB6F1 or C57BL/6 dorons that had been repeatedly transplanted up to five times at annual intervals into successive W/WV recipients. Old marrow cell lines produced erythrocytes normally for as long as 2600 to 3000 days. However, after three to four serial transplantations many stem cell lines failed to cure at least two-thirds of the recipients, and all failed by transplantation six. This decline occurred in a similar pattern whether the original stem line donor was old or young. Two experiments suggested that the decline was caused by the transplantation procedure: (1) chromosomally marked donor cells from old and young donors permanently populated lymph nodes in lethally irradiated recipients after the first transplantation, but under the same conditions cell lines from the same donors transplanted a second time were substantially infiltrated by regenerating recipient cells; (2) the ability to compete with the same chromosomally marked cell line in populating irradiated recipients declined markedly in both old and young marrow stem cell lines that had been previoulsy transplanted.


Reproducibility of clinical data and decisions in the management of upper respiratory illnesses: a comparison of physicians and non-physician providers. The ability of non-physician providers to collect the data required by an algorithm for upper respiratory illness management, and the appropriateness of resulting key management decisions, were studied by comparing non-physician data and management decisions on 426 patients with those of internists. The internists, blinded to Amosists' findings and plans, evaluated the same patients and indicated management without using the algorithm (AM-MD) study). To control for variability of internists' data collecting and illness management, 171 additional patients were evaluated and managed consecutively by two internists, each also kept unaware of the other's findings and plans (MD-MD study). Overall AM-MD agreement on history and physical findings (90 per cent and 81 per cent) and on the need for tests (84 per cent) and treatment (87 per cent) was as high as MD-MD aggrement (91 per cent, 80 per cent, 88 per cent, and 75 per cent, respectively). In both studies, there was significantly more agreement on history data than on physical findings, evaluation, and therapy.


[Granulomatous and allergic angiitis (Churg and Strauss). A case report (author's transl)]. The autopsy findings in a case of granulomatous and allergic angiitis, or Chung and Strauss' disease, are reported. Certain uncommon peculiarities were seen during the course of the disease, such as the presence of multiple lymph nodes presumed from a clinical standpoint to be lymphomas. Its differential diagnosis from other forms of granulomatous vasculitis, especially from those which affect the lungs preferentially or exclusively, is discussed. Special consideration is given to the limited forms of Wegener's disease, which is surprisingly similar morphologically; its more significant differences lie in the clinical and topographic areas, rather than in morphology. The lymph nodes, presumed to be lymphomas from a clinical view-point, are a truly exceptional circumstances in this disease. In the author's opinion the histologic pattern clearly indicates that the etiopathogenesis lies in a congenital or acquired immune disturbance. The recent literature is review, while the present knowledge about the broad and confusing spectrum of these conditions --arteritis, and pulmonary granulomatosis-- is discussed.


[On the value of drill biopsy in diagnosis of breast lesions (author's transl)]. During a period of 30 months 216 drill biopsies of palpable breast lesions were carried out. By using this method sufficient tissue material for a histological examination could be acquired in all cases. Out of 106 cases, in which the histological results could exactly be proved by following excision biopsy or mastectomy, 87% were correctly diagnosed by drill biopsy. The reason for failure in all of the 14 false drill biopsy diagnoses was due to sampling error. Comparing the diagnostic results of the first 15 month after establishing the method, with the second half of the investigation period, a considerable improvement from 80% to 94% of correct diagnoses could be established. This improvement was based on increasing experience and routine. By means of drill biopsy, cosmetically and diagnostically disturbing scar formation could be avoided. Drill biopsy can be carried out in local anaesthesia and on outpatient basis as well. It is also suitable for frozen-section technique.


Hemolytic activity of a togavirus, Getah. A purified toga-alphavirus, Getah (GET), showed optimal hemolytic activity for one-day-old chick red blood cells when incubated at 37 C for 120 min at pH 6.2. Experimental data obtained from various angles, such as pH dependency, inhibition by virus-specific antiserum and by concanavalin A, indicated that the hemolysis was a property of the virus particle itself. Although the mechanism of hemolysis by togaviruses has not been known, our results indicated that viral lipids may participate in this activity since the hemolytic activity was impaired by delipidation procedures.


On the mechanism of film neoplastogenesis. Since the inception of experimental cancer research, all theories concerning the mechanism of transformation of normal cells into neoplastic cells were constructed on the basis of the postulate that interaction of an agent and cell constituents is a condition indispensable for the occurrence of the neoplastic transformation. In the course of the past three decades, however, all attempts to uncover agents responsible for the transformations induced by chemically inert films implanted in living tissues or for the "spontaneous" transformations in vitro in cell cultures devoid of added neoplastogens, yielded consistently negative results. In regard to the neoplastogenic effect of imbedded inert films, the present article takes into consideration that films implanted in living tissues hinder the circulation of interstitial fluid in their vicinity and as a result elicit anoxia and protracted low pH gradients in the environment of the cells adjacent to the films. The effects of such protracted low pH on the metabolic activities of the surviving cells are examined and a working hypothesis is offered concerning the role of protracted environmental low pH in the mechanism of film neoplastogenesis.


The pineal gland as an APUD organ: supporting evidence and implications. It is only in recent years that the pineal gland has emerged from being thought of as non-functional and unimportant. The rise from obscurity has been the result of the interest of investigators of multidisplinary origins; such approaches, whilst clearly advancing understanding, also tend to leave knowledge fragmentary. In the last decade, a new neuroendocrine axis known as the APUD system has been delineated and scientifically accepted. The essence of the concept has been to link a physically widely dispersed and apparently unconnected series of glandular structures by a common embryological derivation and their secretion of closely similar functional products. The present proposal collates evidence for the inclusion of the pineal gland within the APUD system. In addition, because of the proven connections and response of the pineal gland to environmental changes, it is hypothesised that pineal products may provide the link between the environment and other members of the widely dispersed APUD system and thereby temper body homeostasis.


[Metabolic effects of a fixed combination (betablocker plus saluretic) in long-term treatment of arterial hypertension (author's transl)]. In 23 patients with essential hypertension of stage I and II according to the WHO, the effects of a fixed combination of a beta-receptor-blocker plus saluretic composed of 20 mg of metipranolol (Disorat 20) and 2.5 mg of butizid (Saltucin) = Torrat on blood pressure and important metabolic parameters (glucose, glucose tolerance, cholesterol, triglyceride, uric acid, plasma potassium and whole body potassium) were tested over a 6-month treatment period. blood pressure and pulse rate were significantly reduced; bradycardia (pulse rate less than 60/min) was not observed. The metabolic parameters showed no significant changes during the 6-month treatment period. In no case did the therapy have to be discontinued because of undesirable effects. The investigations show that the combination has a good antihypertensive effect with few side-effects and that it has no influence on important metabolic parameters during long-term therapy.


A new assay of X-prolyl dipeptidyl-aminopeptidase activity in human serum with glycylproline p-phenylazoanilide as substrate. A new assay procedure for X-prolyl dipeptidyl-aminopeptidase activity in human serum was developed with glycylproline p-phenylazoanilide tosylate as substrate. p-Phenylazoaniline liberated by the enzyme reaction was measured photometrically at 493 nm after stopping the reaction with acid. This assay was simple and sensitive, and less than 50 microliter of human serum was required for the assay. Km value was 2.5 mM and the optimum pH was 8.7. After disc gel electrophoresis of human serum, the enzyme activity could be distinctly observed as a reddish band on the gel when the gel was incubated with this substrate.


L-Tryptophan action on hepatic RNA synthesis and enzyme induction. L-Tryptophan increases the activity of hepatic amino acid metabolizing enzymes, affects gluconeogenesis and displays a modulatory effect on several enzymes connected with RNA synthesis. The underlying mechanism differ in individual cases and result in both an increase of enzyme synthesis de novo and a decrease of enzyme degradation. Tryptophan displays a unique effect causing aggregation of hepatic polyribosomes connected with enhanced protein synthesis and preceded by a higher transport of poly (A) messenger RNA from the nucleus to the cytoplasm. The variety of rather specific effects mediated by tryptophan brings to mind hormonal action and the existence of specific tryptophan receptors is predicted.


[NMR spin-echo study of behaviour dynamics of serum albumin macromolecules in aqueous solutions as a function of pH and ionic strength]. Alteration of the intermolecular interaction in aqueous solution of human serum albumin (SA) as a result of the increase of ionic strength and pH values brings about the slowing-down of the spin-echo decay curve for protein protons (several times at high SA concentrations). A specific effect of alkaline pH was observed, i.e. the slowing-down of quick component of the spin-echo decay curve. This result taken together with the data on complex spin-echo decay curve, correlation times of protons of different regions is SA and compared with SA isotope exchange data can be explained as a result of the polypeptide chain conformation mobility with frequencies more 10(4) c.p.s. This effect is observed in regions occupying about one half of the SA macromolecule volume.


[Isoelectric focusing of rhodopsin].

[Isoelectric focusing of rhodopsin]. By method of isoelectric focusing in polyacrylamide gel and sucrose density gradient it has been shown that rhodopsin preparation, obtained by different methods (including the rhodopsin with low content of lipids) are divided into a number of fractions with isoelectric points at the pH-range 5.4-6.0. The corresponding preparations of opsin show heterogeneity in pI, too. Heterogeneity in pI remains at denaturation conditions (8 M urea, 0.01% beta-mercaptoethanol, 1 mM EDTA). If separated in this system at least two protein components are detected. The nature of heterogeneity in pI found and its possible connection with complicated kinetics of the decay of early intermediate products of visual pigment are discussed.


[pH-dependence of the structural and functional properties of lactate dehydrogenase (M4). Indirect cooperativity in lactate dehydrogenase]. The dependence of structural and functional properties of LDH on pH in the 6.0--9.0 region was investigated. There were no marked deviations of pyruvate reduction initial velocity curves from the Michaelis--Menten equation in a wide range of pyruvate concentrations. It was shown that Vmax changes negligibly in the 6.0--9.0 pH regions, but Km increased markedly with pH elevation. The pK value of 7.8+/-0.1 was obtained for 50% changes of pyruvate binding. The dependence of enzyme inhibition from pH at a high pyruvate concentration (20 mM) was investigated. At pH values above 8.0 pyruvate inhibition disappeared. The dependence of the inhibition degree from pH was estimated as pK 7.8+/-0.1. Hill coefficient (n) calculated from the curves of Km and the degree of substrate inhibition depending on pH was 1.6; n for pyruvate inhibition at pH 7.5 was 2 greater than n greater than 1 for moderate substrate concentrations (1--5 mM) and n approximately 1 for higher concentrations (5--40 mM). The value of n approximately 1 at pH 7.8 was obtained. The model suiting all available data concerning the cooperativity phenomena in LDH during protonation and inhibition by pyruvate is outlined. The model is based on the results indicating the slow isomerisation of LDH in ternary complexes with NADH and pyruvate and the absence of equilibrium on the intermediate stage of reaction.


[DNA complexes with lysozyme].

[DNA complexes with lysozyme]. Sedimentation method has been used to study hen egg-white lysozyme binding to glucosylated (from T2 phage) and non-glucosylated (from calf thymus) DNA under conditions similar to physiological ones (pH 7,3--7,4, ionic strength 0.07--0.24). The results indicate that lysozyme binds cooperatively to both DNA's. Binding parameters have been obtained by applying the theory of one-dimensional adsorption of small molecules on a linear homopolymer. X-ray patterns of complexes with different protein content have been obtained.


[Electron transfer to hemoproteins. II. pH-dependence of the reduction rate of ferricytochrome c by oxymyoglobin]. The pH-dependence of the reduction rate of ferricytochrome C by intact and chemically modified oxymyoglobins has been studied. The modification was performed with respect to histidine residues and alpha-aminogroup of N-terminal valine. Two histidine residues of myoglobin, His A10 and His GH1, are shown to take part in the realization of the "active" contact between the molecules in the course of the reaction. The deprotonation of the first residue contributes to the acceleration and that of the second to the reduction of the reaction. The found orientation of the Mb molecules in the "active complex" implies that at any orientation of cytochrome C the distance between the haemes of the both molecules should be more than 30 A. This makes highly probable that a structure-dependent mechanism of electron transfer in the system under study can be proposed.


[Cooperative interaction of serum albumin with quaternized poly-4-vinyl pyridine and structure of the complexes]. Interaction of bovine serum albumin (BSA) with quaternized poly-4-vinyl pyridine (PE) in aqueous solutions at pH 7 was studied. It was shown that in a wide range of the ratios of the components (nBSA/nPE) soluble stable cooperative complexes were formed. At the same time a certain critical content of the protein exists at which the system loses its homogeneity. Complex formation is not accompanied by protein denaturation. At smaller nBSA/nPE ratios non-homogeneous distribution of protein globulas among polyelectrolite macromolecules was found; this corresponded to the "all or none" principle. Using ultracentrifugation technique viscosimetric measurements and electron microscopy it was shown that the soluble complexes exist in the form of rode-like particles consisting of protein globules stabilized by polycation chains. Such particle can be considered as a model of nucleoprotein complex. At certain crytical nBSA/nPE rations the rod-like particles aggregate with additional number of BSA-molecules and form more complicate soluble and insoluble cooperative complexes. Possible structural models of the complexes described were suggested and the thermodinamic and kinetic cryteria of their self-assembly were discussed.


[Cryptorchidism (author's transl)].

[Cryptorchidism (author's transl)]. The treatment of cryptorchidism should start at the age of two years because of pathological and anatomical studies. Ectopic testicles, inguinal hernias and postoperative situations associated with a wrong position of the testicle are primary indications for surgical corrections. Fixed inguinal, retractile or abdominal testicles may be primarily treated with human chorionic gonadotropin (HCG). The success rate after medical treatment averages 50%. The intranasal application of the releasing hormone of luteotropic hormone (LH-RH) may represent an alternative approach to the treatment of cryptorchidism. If treatment with LH-RH is to obtain the same success rate as HCG in larger series it may combine the advantage of painlessness with no androgenic side effects.


[Temperature dependence of conductance of isoionic DNA solutions. Determination of dissociation constants of primary phosphoryl groups]. Concentration dependence of the equivalent conductance of isoionic DNA solutions has been studied at different temperatures. The limiting equivalent conductance (lambda infinity) at every temperature investigated has been obtained by extrapolation to the infinite dilution in Kohlraush's plots. At the same time in plots c lambda c versus 1/lambda c (lambda c is equivalent to conductance at the concentration c), corresponding to the linear form of Ostwald's dilution law, the straight lines were obtained. Both lambda infinity and acidity constants (K) have been determined from these plots. The values of lambda infinity by two methods are in well agreement. The average values of lambda infinity were used for energy activation of conductivity calculation, equal to 2,40 +/- 0,05 kcal/mole. The acidity constant of primary phosphoryl groups passes through a maximum near 33 degrees. Equivalent conductance of hydrogen ions calculated by neglecting of macroion's mobility and by using of potentiometric determined concentration (cH+) has been shown to increase with cH+. Unusual behavior of DNA in isoionic solutions is discussed.


The role of thiamine in nervous tissue.

The role of thiamine in nervous tissue. The possibility that thiamine (vitamin B1) has a role in nervous tissue that is independent of its well-documented coenzyme function is discussed. After reviewing the localization and metabolism of the vitamin and its phosphate esters, the effects of either thiamine deprivation or antimetabolites of thiamine on conduction and transmission, and the relationship between thiamine triphosphate and the genetic, neurological disease, subacute necrotizing encephalomyelopathy (Leigh's disease), it is suggested that despite the lack of hard evidence, it is likely that the vitamin possesses this alternate function.


In vitro regulation of ACTH release from neurointermediate lobe of rat hypophysis. II. Effect of neurotransmitters. The effect of various neurotransmitters on adrenocorticitropic hormone (ACTH) release from superfused neurointermediate lobes of rat hypophysis (NIL) was investigated. Acetylcholine, serotonin, and histamine were shown to have no significant effect on the spontaneous release of ACTH. In contrast, dopamine (DA) and noradrenaline (NA) stimulated NIL ACTH release in a dose-dependent manner. The stimulating effect of DA was mimicked by apomorphine and inhibited by haloperidol, whereas that of NA was abolished by phentolamine. In a comparative study, none of these neurotransmitters is shown to have any significant stimulating effect on ACTH release from superfused anterior lobes. It is concluded that the ACTH release from NIL might be controlled, at least in part, by catecholaminergic innervation.


Action of androgenic steroids on brain neurotransmitters in rats. The effects of androgenic steroids on the dopamine (DA), noradrenaline (NA) and 5-hydroxytryptamine (5-HT) contents of different brain regions have been studied in order to elucidate the possible involvement of neurotransmitters in the negative feedback action of androgens. Administration of testosterone propionate (TP); (100 micrograms/kg or 5 mg/kg, i.p.) increased plasma testosterones, which reached a maximum at about 30 min following injections. TP (100 micrograms/kg) decreased the DA level in the hypothalamus to a minimum after 30 min and returned to normal level after 120 min. There was no effect in the amygdala, striatum and mesencephalon. Subsequent to 5 mg/kg i.p. TP administration, the minimum in the DA level was observed between 90 and 120 min in the hypothalamus, and after 120 min in the amygdala, but the treatment was without effect in the striatum and mesencephalon. Both doses of TP were ineffective as regards for in altering NA and 5-HT levels in the brain areas studied. In a dose of 5 mg/kg, androgens of different activities, such as norandrostenolone, dihydrostestosterone and androstenedione, decreased the DA contents of the hypothalamus and amygdala regions, but pregnenolone was ineffective. None of the androgens affected the NA and 5-HT levels in the brain areas studied. The data suggest that some of the actions of androgens are mediated via a dopaminergic mechanism in which not only the hypothalamus but also the amygdala is involved.


The stimulatory effect of 5HT and the role of the paraventricular nucleus on PMS induced ovulation in the immature rat. Immature rats can be induced to ovulate with pregnant mare serum (PMS) as long as they weigh over 60 g. In the rats weighing less than 60 g 5-hydroxytryptamine (5HT)-60 micrograms/rat intraventricularly or 2 micrograms/rat in the paraventricular nucleus (PVN)-stimulated ovulation. Injections into several other hypothalamic nuclei were ineffective. In rats weighing greater than 60 g, lesions of the PVN or injection of 10 micrograms/rat p-chlorophenylalanine into the PVN inhibited ovulation. The hypothalamic levels of 5HT and 5-hydroxy indole acetic acid (5HIAA) were generally lower in the afternoon and evening in the less than 60 g when compared with the greater than 60 g rats. It is possible that increased 5HT activity is required to stimulate ovulation and that its site of action is the PVN.


Monoamine metabolites in the CSF of epileptic patients. To assess the possible role of amine neurotransmitters in human epilepsy, we measured metabolites of serotonin (5-hydroxyindoleacetic acid [5-HIAA]), dopamine (homovanillic acid [HVA]), and norepinephrine (3-methoxy-4-hydroxyphenylethylene glycol [MHPG]) in the lumbar cerebrospinal fluid (CSF) of patients with partial complex seizures and in neurologic controls. Untreated epileptic patients had lower concentrations of 5-HIAA and HVA in the lumbar CSF than the controls, but the differences were not statistically significant. Among epileptic patients receiving effective antiepileptic drug treatment, the HVA concentration was within the control range. Mean MHPG concentrations were similar in patients and controls. From the epileptic patients whose CSF was obtained at pneumoencephalography we obtained a second sample of CSF that was originally in the basal cisterns. No significant differences between treated and untreated patients were found for any of the three metabolites. The concentrations of HVA and 5-HIAA were higher in cisternal than in lumbar CSF, but there was no such gradient for MHPG.


[Surgery of tumors of the endocrine pancreas. Result of a survey made in the Federal Republic of Germany]. Within a ten-year scan (1967-1976) 207 insulinomas, 50 gastrinomas, 8 Verner-Morrison tumours, 5 glucagonomas and 12 endocrine pancreatic tumours with associated MEA syndrome (multiple endocrine adenomatosis) were treated surgically at various university hospitals (information obtained by questionnaire). Half of the insulinomas were treated by enucleation, one third by resection of the tail of the pancreas. Total gastrectomy was the procedure of choice in 80% of patients with gastrinoma, but sometimes pancreatic resection to remove the tumour was added. An new therapeutic concept of using histamine-H2 receptor antagonists for treating patients with Zollinger-Ellison syndrome is discussed. In the eight patients with a Verner-Morrison syndrome removal of the tumour or distal pancreatic resection was the procedure of choice.


Three types of membrane modulations during transmitter release in rat spinal cord synapses. Protoplasmic fracture faces of vesicle attachment sites (VSA) in the presynaptic active zone of rat spinal motoneurons were classified morphologically on the basis of particle-to-membrane relationships. Intramembranous particles are absent in type 1, located around the edges of type 2 and covering the center of type 3. Application of 4-aminopyridine (4-AP), which is known to enhance transmitter release, affected strikingly the total number of VAS (P less than 0.001) but not the percentage of the three types. It is postulated that the particle-free VAS (types 1 and 2) sharing 80--85% of VAS within the active zone, are related to exocytosis. The predominance of type 3 outside the active zone and its similarity to particle-loaded indentations possibly corresponding to coated vesicle formation, suggested that type 3 may represent endocytosis.


Unexpectedly low incorporation of isotopic acetate into lipids of Ehrlich ascites tumor cells cultured in lipid-poor medium. The present communication reports data on the lipid biosynthesis of Ehrlich ascites tumor cells grown in culture media supplemented with modified sera. Whereas the metabolisms of [14C]pyruvate and [14C]mevalonate are identical in all media tested, the incorporation of [14C] acetate is higher in medium with dialyzed serum than in medium with delipidized serum; it is suppressed in the absence of all lipids in culture medium. Cellular integrity is not impaired in modified media. The results indicate that acetyl-CoA synthetase of Ehrlich ascites tumor cells is not regulated by exogenous lipids as is known to be the case in nonmalignant cells.


Sickled erythrocytes, hyphema, and secondary glaucoma: VI. The relationship between intracameral blood cells and aqueous humor pH, PO2, and PCO2. Injection of Hgb SC blood into rabbit anterior chambers resulted in lowering of aqueous humor pH and PO2 and elevation of aqueous humor PCO2. These effects appear to contribute to the sickling of erythrocytes that occurs in aqueous humor.


[Spontaneous perirenal haematoma occurring during 1 familial mediterranean fever. 3 cases (author's transl)]. A perirenal haematoma, associated with the presence of renal micro-aneurysms, developed in three patients with periodic syndrome. In one of the cases, the histology of a subcutaneous nodule confirmed the diagnosis of periarteritis nodosa. This emphasies the importance of vascular lesions in familial mediterranean fever.


[Reno-vascular hypertension: prognosis variations according to the method; surgery, or medical treatment. Retrospective study of 114 cases (author's transl)]. A retrospective study made of 114 cases of renovascular hypertension was undertaken to compare the effectiveness of different types of treatment. In this series, with a follow-up of 18 months to 9 years, a favourable result with regard to blood pressure was obtained in 45% of cases with surgery, in 63% of cases with medical treatment and in 88% of cases if treatment included beta-blockers. Medical treatment represents a valid alternative to surgery in hypertension of this type, regardless of the amount of renin secretion and whatever the criteria of ischaemia. The choice of surgery as a method of treatment thus depends above all upon the age of patient, the type of stenosis and the anatomical risk represented by the vascular malformation. Despite the very spectacular results of medical treatment, it remains essential to seek a renal cause for hypertension, since many renal conditions which require specific treatment present with hypertension alone.


[The prognosis and treatment of pneumococcal meningitis in Africa. 402 cases (author's transl)]. Over a period of 5 years (1973--1977), 1083 patients were hospitalised in the Infectious Disease Clinic of the Dakar University Hospital Centre with bacteriologically confirmed purulent meningitis. The pneumococcus was responsible in 462 cases (42.6%). Analysis of 402 records showed that 234 patients (58.2% of cases) died, 123 were completely cured (30.6%) whilst there were neurological sequelae in 45 cases (28% of the survivors). The chief factors in poor prognosis were the existence and depth of changes in conscious level, age over 20 years, a CSF cell count of less than 500 per mm3, a CSF protein level greater than 2 g per 1 and I CSF antigen level over 8 microgram per ml. From a therapeutic standpoint, the percentage mortality was similar with chloramphenicol and with penicillin G, but complete cures were statistically more frequent in the patients treated initially with chloramphenicol.