Disodium cromoglycate in ragweed-allergic rhinitis. This study was designed to test the effectiveness of disodium cromoglycate when compared to placebo in a double-blind study in patients with ragweed allergic rhinitis. Patients were selected on the basis of a clinical history and a 4+ reaction to the intradermal injection of water-soluble ragweed, 0.02 c.c. of 500 PNU/c.c. Active agent/placebo groups were selected at random and were on the drug for approximately 8 wk, commencing 1 wk prior to the onset of the ragweed pollen season. Patient response was evaluated using patient diary cards, number of antihistamine tablets taken, and patient interviews. In the Toronto study, of 17 patients on the active drug, 15 were graded as improved, compared to only 6 of 21 placebo-treated patients who were improved. However, in the Hamilton study, results were less impressive. Nonetheless, it appears that intranasal insufflation of disodium cromoglycate was more effective in reducing ragweed hay fever symptoms than placebo.


Piperacetazine versus thioridazine in the treatment of organic brain disease: a controlled double-blind study. In a double-blind cross-over study, 50 geriatric patients with organic brain disease were divided into two groups. One group first received piperacetazine for 15 days and then thioridazine for 15 days. For the other group the sequence was reversed. Piperacetazine proved to be at least as effective as thioridazine and seemed to be more effective against certain target symptoms; side effects were less common and less severe.


Duodenal immunoglobulin deficiency in graft versus host disease (GVHD) mice. The small intestine is a well documented target organ in mouse and human GVHD, and diarrhea is a prominent part of the clinical GVHD syndrome. Although a plethora of systemic immune deficits has been documented in GVHD, the integrity of the small intestinal immune system has not been investigated. A correlation has not been demonstrated between systemic immune dysfuction and the incidence of lymphomas in mouse GVHD survivors. If gastrointestinal immune deficiency exists in mouse GVHD, its possible relationship to GVHD lymphomas, frequently abdominal. should be investigated. GVHD was produced in newborn BLA (C57 BL/Ka females x BALB-C males) mice house in a specific pathogen-free environment by the i.p. inoculation of 10(7) male BALB-C spleen cells. Control mice received syngeneic spleen cells. Twenty GVHD and 16 control mice were sacrificed at 3 weeks and specimens of duodenum were removed for routine histologic and immunofluorescent examination. All but one GVHD mouse (95%) had virtually absent duodenal IgA and IgM. Duodenal cellular fluorescence was demonstrated in all controls. A significant duodenal immunoglobulin deficit has been demonstrated in 3-week-old GVHD mice. The relationship of this finding to GVHD diarrhea, wasting, and neoplasia remains to be determined.


Partial regain of activity in heterologous recombinants of phosphorylcholine-binding M-components from different species. Recombination experiments were performed with heavy and light chains derived from a Waldenström's IgM with specificity against phosphorylcholine. The recombinant molecules had an association constant for phosphorylcholine in the same order of magnitude as the native IgM; the number of binding sites at saturation was only slightly decreased in the reconstituted molecules, indicating regain of binding activity after recombination of IgM heavy and light chains. Heterologous recombinants obtained with polypeptide chains of another monoclonal IgM without demonstrable binding activity recovered only 5 to 10% of the binding activity of homologous recombinants. Hybrid molecules prepared with heavy and light chains from the phosphorylcholine-binding mouse IgA myeloma protein TEPC-15, however, regained as much as 41% of the binding activity of the homologous recombinants; these data suggest a considerable degree of structural homology shared by the human IgM and the murine IgA proteins with phosphorylcholine-binding specifity.


Neonatal infection with mouse thymic virus. Differential effects on T cells mediating the graft-versus-host reaction. Neonatal infection with mouse thymic virus (TA), a murine herpes virus, produced extensive but temporary necrosis of the thymus which was maximal at 10 to 14 days of age. Studies of precursor and amplifier cells mediating graft-vs-host (GVH) reactivity of thymocytes, spleen cells (SC), and lymph node cells (LNC) of normal and TA-infected mice were made at 4 and 8 weeks of age. Infection with TA resulting in a profound reduction (70 to 80%) in the direct GVH reactivity of thymocytes at both ages; by comparison, the capacity of thymocytes to produce synergy when combined with normal LNC was normal at 8 weeks. Direct GVH reactivity of SC was depressed 90% 4 weeks after infection with TA but returned to near normal at 8 weeks. Direct GVH reactivity of LNC from TA-infected mice was normal at 4 and 8 weeks of age, but amplifier T cell activity in LNC was markedly depressed at 8 wekks. These results demonstrate that TA has highly selective effects upon subpopulations of T cells in thymus and lymph node.


[Voluntary choice of sex. The present state of our knowledge]. Whether we like it or not, the next demand that the modern couple will make after birth control will be voluntary selection of the sex of their babies. Furthermore, this selection does have an undoubted medical value in preventing certain sex-linked congenital or hereditary diseases. Many research workers have turned their attention to these problems over the past years, especially in the U.S.A., in England and in Germany. After a historical review of the progress that has taken place in this area a study has been undertaken into the actual state of research in the U.S.A. and in Germany, in which the country the Federal Government has created a special department for scientific research. Our present knowledge into the methods that are adopted to obtain a foetus of male of female sex up to the present is then briefly explained. The results obtained by the principle research workers have been summarised. These are between 80 and 90 per cent success. The steps that have marked these discoveries in this field that is ill understood by the majority of doctors and the French public are outlined.


Affinity chromatography of lipase with hydrophobic ligands coupled to cyanogen bromide-activated agarose. The behavior of lipase produced by Pseudomans mephitica var. lipopytica toward hydrophobic residues coupled to spacer gels that were prepared by coupling a primary amine to CNBr-activated agarose, was studied. The lipase adsorbed on the ligand of a long unbranched aliphatic chain, a benzene ring, or deoxycholic acid was only slightly or not all eluted at pH 5 or pH 11 by buffers containing 1 M NcC1. The lipase was eluted by liquid containing a surfactant or an organic solvent miscible with water, indicating greater involvement of hydrophobic forces. The adsorption of propane, cyclopentane, cyclohexane, cycloheptane, or chrysene appears to be achieved through electrostatic forces, inasmuch as desorption was caused by buffer containing 1 M NaC1 at pH 11. The amount of lipase adsorbed on these hydrophobic ligands was about the same as that adsorbed on the ligands belonging to the first group. Since little lipase wad adsorbed on cyclopropane, cycloctane, pyridine, methane, n-pentane, or branched aliphatic chains, these ligands appear to impose steric hindrance on the adsorption of lipase, or they may be too small to fit into the hydrophobic sites of lipase.


Urticaria.

Urticaria. Urticaria is a problem often as vexing to the physician as to the patient. The approach to the patient with hives first demands a search for the etiology, whether endogenous and triggered by emotions or occult systemic disease, exogenous and triggered by allergy to inhaled or ingested antigens, or physical and due to abnormal sensitivity to heat, cold, light, or pressure. Often a fruitless search, the diagnostic evaluation must be accompanied by appropriate symptomatic therapy requiring familiarity with the antihistamines and their relative advantages in the various forms of urticaria. Elimination diets are of diagnostic as well as therapeutic value: pencillin-free, yeast-free, and salicylate-free diets are particularly useful. Therapeutic trials of tetracycline, nystatin and griseofulvin may be helpful, while corticosteroids and specific desensitization are rarely of value.


Effect of amiloride and some of its analogues of cation transport in isolated frog skin and thin lipid membranes. The inhibition of short-circuit current (Isc) in isolated frog skin and the induction of surface potentials in lipid bilayer membranes produced by the diuretic drug amiloride and a number of its chemical analogues was studied. The major conclusions of our study are: (a) The charged form of amiloride is the biologically active species. (b) Both the magnitude of Isc and the amiloride inhibitory effect are sensitive to the ionic milieu bathing the isolated skin, and these two features are modulated at separate and distinct regions on the transport site. (c) Amiloride is very specific in its inhibitory interaction with the Na+ transport site since slight structural modifications can result in significant changes in drug effectiveness. We found that substitutions at pyrazine ring position 5 greatly diminish drug activity, while changes at position 6 are less drastic. Alterations in the guanidinium moiety only diminish activity if the result is a change in the spatial orientation of the amino group carrying the positive charge. (d) Amiloride can bind to and alter the charge on membrane surfaces, but this action cannot explain its highly specific effects in biological systems.


Studies on the rumen flagellate Sphaeromonas communis. The rumen flagellate Sphaeromonas communis showed a significant increase in population density 1 to 2 h after the host sheep commenced feeding, followed by a reduction in numbers to the pre-feeding level after a further 2 to 3 h. The life-history of the organism was shown to consist of a motile flagellate which germinated to produce a vegetative stage comprising a limited rhizoidal system on which up to three reproductive bodies were borne together with (in vitro) other spherical bodies of unknown function; in vivo, the reproductive bodies were stimulated to liberate flagellates by a component of the diet of the host. The vegetative stage strongly resembled that of certain species of aquatic phycomycete fungi, and the flagellates may therefore by zoospores. Flagellates liberated in vivo lost their motility within 2 to 3 h and developed into the reproductive vegetative phase, producing a rapid decrease in numbers of flagellates. Conditions of maximum flagellate production (pH 6.5, 39 degrees C, presence of CO2, absnece of oxygen) approximated to those found in the rumen. The organism was cultured in vitro in an undefined medium in the absnece of bacteria and other flagellates.


Influence of dilution rate on NAD(P) and NAD(P)H concentrations and ratios in a Pseudomonas sp. grown in continuous culture. A freshwater Pseudomonas sp. was grown in continuous culture under steady-state conditions in L-lactate-, succinate-, glucose- or ammonium-limited media. Under carbon limitation, the NAD(H) (i.e. NAD + NADH) concentration of the organisms increased exponentially from approximately 2 to 7 mumol/g dry wt as the culture dilution rate (D) was decreased from 0.5 to 0.02 h-1. Organisms grown at a given D in any of the carbon-limited media possessed very similar levels of NAD(H). Therefore, under these conditions, cellular NAD(H) was only a function of the culture O and was independent of the nature of the culture carbon source. D had no influence on the NAD(H) content of cells grown under ammonium limitation. In contrast, cellular NADH concentration was not influenced by D in carbon- or ammonium-limited media. In L-lactate-limited medium, bacteria possessed 0.14 mumol NADH/g dry wt; very similar levels were found in organisms grown in the other media. The results are consistent with those of Wimpenny & Firth (1972) that bacteria rigidly maintain a constant NADH level rather than a constant constant NADH: NAD ratio. NADP(H) (i.e. NADP + NADPH) and NADPH levels were also not influenced by changes in the culture carbon source or in D; in L-lactate-limited medium these concentrations were 0.97 and 0.53 mumol/g cell dry wt, respectively. The NADPH:NADP(H) ratio was much higher than the NADH:NAD(H) ratio, averaging 55% in carbon-limited cells.


Differences between the anorexic actions of amphetamine and fenfluramine--possible effects on hunger and satiety. The inhition of feeding in rats brought about by amphetamine and fenfluramine was continuously monitored for periods of up to 24 h using a pellet detecting eatometer. For rats tested under conditions of food deprivation the two drugs gave rise to distinctive anorexic profiles: amphetamine delayed the onset of eating whereas fenfluramine allowed eating to commence normally but brought about an early termination of the initial bout of feeding. When the drugs were administrated to rats with free access to food, analysis of the meal pattern showed that amphetamine gave rise to a small increase in the inter-meal interval while fenfluramine brought about a clear reduction tion in meal size. It is suggested that the contrasting modes of action of these drugs represent an effect of amphetamine upon hunger and an action of fenfluramine on satiety. This suggestion is in keeping with the proposed mechanisms of action of these drugs, amphetamine acting upon a hpothalamic motivational system and fenfluramine acting by means of a postulated serotoninergic satiety system. Use of the continuous monitoring technique has pointed pointed to certain limitations in the assessment of anorexic drug action by means of discrete food sampling periods.


Alpha-methyl derivatives of biogenic amines as inhibitors of monoamin oxidase. The values of Km app and Vmax for three natural substrates of monoamine oxidase have been determined at various stages in the isolation of the enzyme from rat liver tissue. The results are consistent with the presence in the enzyme preparation of at least two distinct molecular forms of the enzyme. Using the alpha-methyl derivatives of the natural substrates as inhibitors of the enzyme, the substrate dependence of Ki further substantiates this view. In addition, the kinetics of the inhibition suggest that the value of Km app may not for all substrates, necessarily be a measure of the affinity of the substrate for the enzyme.


Comparative study of the effects of mianserin, a tetracyclic antidepressant, and of imipramine on uptake and release of neurotransmitters in synaptosomes. The effects of mianserin, a tetracyclic antidepressant, on uptake and release of [3H]noradrenaline (3H-NA), [3H]dopamine (3H-DA), [3H]-5-hydroxytryptamine(3H-5-HT) and [3H]gamma-amino-butyric acid (3H-GABA) in synaptosomes from different areas of the rat brain were investigated in a comparative study with the tricyclic antidepressant imipramine. Mianserin and imipramine were inhibitors of 3H-NA uptake in the hypothalamus, but could not increase 3H-NA release from noradrenergic nerve endings. This behaviour was similar to that of (+)-amphetamine. Both mianserin and imipramine had essentially no effect on 3H-DA transport mechanisms in striatal synaptosomes. (+)-Amphetamine, in contrast, strongly affected both 3H-DA uptake and release. Imipramine was stronger than mianserin in inhibiting 3H-5-HT accumulation by striatal synaptosomes. In contrast, mianserin stimulated 3H-5-HT release whereas imipramine was ineffective. Mianserin had virtually no inhibitory activity on 3H-5-HT uptake by rat blood platelets. Imipramine was a modest inhibitor of 3H-GABA accumulation by whole brain synaptosomes; mianserin had no effect. Both drugs did not alter 3H-GABA release. These results indicate that mianserin interferes in a way different from that to tricyclic antidepressants with the neurotransmitter transport mechanisms at the presynaptic level.


Adrenergic responses of the rabbit stomach serosal strip and their modification by monoamine oxidase inhibitors and anti-adrenergic drugs. The rabbit stomach serosal strip, was found to contract to adrenaline and noradrenaline but not to isoprenaline. The contractile response could be totally abolished by phenoxybenzamine but was not influenced by propranolol, indicating that the preparation has almost exclusively alpha-adrenoceptors. The responses to adrenaline and noradrenaline were markedly potentiated in the presence of monoamine oxidase inhibitors, guanethidine or reserpine, indicating the presence of MAO activity in the tissue and possible catecholamine stores. The functional state of the latter has not been conclusively established, since tyramine, an indirectly acting amine, was unable to elicit a response qualitatively similar to that of adrenaline, even in the presence of nialamide or tranylcypromine.


The absorption of warfarin from the rat small intestine in situ. The in situ absorption from the rat small intestine of the weakly acidic drug, warfarin (pKa 5-05), at 200 mug ml-1 in the instilled fluid with initial pH levels of 3, 5, 7 or 8 has been examined. These initial pH's in the buffer changed rapidly towards neutrality. The buffers at pH's 3 and 5 probably caused different amounts of warfarin precipitation, which resulted in different rates of warfarin disappearance from the instilled fluid which paralleled the initial rates of accumulation of warfarin in (or on) the intestinal wall. Where greater drug precipitation had probably occurred the initial rates of absorption into the plasma were slower. At the initial pH of 3 and by solubilization of warfarin with propylene glycol, the rate of absorption was similar to that from a fluid of pH 7. Propylene glycol in 15% solution did not affect the system significantly. The relatively high transfer of warfarin into octanol from buffer solution at pH 7 might indicate that the small fraction of unionized drug (1 : 100) at pH 7 is enough for remarkable transfer of this highly lipid-soluble drug.


The influence of dihydroxyanthracene derivatives on water and electrolyte movement in rat colon. The purgative activities of 18 different dihydroxyanthracene derivatives, including free anthraquinones and anthrones, were investigated by determining their influence on the water, sodium and potassium absorption in the gastrointestinal tract by direct injection of the solutions in Tyrode to the rat colon in situ. The extent of the solubility of the compounds has also been assessed. The 1,8-dihydroxyanthracene structure seemed to be the best for hydragogue effect. Rhein-anthraquinone and -anthrone were the most active compounds tested.


A dual action of 5-hydroxytryptamine on the ovarian suspensory ligament of the rat. 5-Hydroxytryptamine has a dual effect on the spontaneously contracting rat ovarian ligament, in vitro, a contraction which is antagonized by the prior administration of methysergide and a relaxation of the ligament observed in the methysergide-treated preparation. The relaxatory effect was not antagonized by propranolol or tetrodotoxin but treatment of the ligament with indomethacin abolished this response. Prostaglandins of the E series produced an inhibition, and PGF2alpha a contraction of the ligament. Thin layer chromatographic separation indicates that 5-HT causes the release of a PGE2-like substance which relaxes the ovarian suspensory ligament.


A model independent method for estimating the in vivo release rate constant of a drug from its oral formulations. A simple equation by which the first-order release rate constant of a drug from its oral formulation can be calculated is derived. The derivation is independent of any hypothetical concepts of drug distribution or elimination.


The granulation of binary mixtures.

The granulation of binary mixtures. Granules have been prepared from blends of lactose and boric acid by the massing and screening method and their properties have been compared with those of granules from the individual materials, granulated separately. Increasing the volume of binder solution used produced granules stronger and of greater mean size in all blends studied. The largest and strongest granules, for any given binder solution volume and massing time, were obtained from a blend, as were the granules with the minimum pore size. The effect of massing time on granule properties was generally similar to those already reported for single component systems; prolonged massing in some blend led to a reduction in mean granule size. Variation in pre-mixing time produced no significant change in the physical properties of granules prepared from a lactose: boric acid blend.


Stereoselective and calcium-dependent contractile effects of narcotic antagonist analgesics in the vascular smooth muscle of the rat. In patients, pentazocine administered i.v. can have an unusual action for a strong analgesic-an elevation of blood pressure. The objective of this study in rats was to better quantify and explain the molecular mechanism for the vascular action of l-pentazocine and compare it with other analgesics and narcotic antagonists. In anesthetized rats, l-pentazocine (0.3-3 mg/kg i.v.) elevated blood pressure and this effect was potentiated in pithed rats. The contraction appeared to be nonadrenergic as it was not blocked by the alpha blocker, phenoxybenzamine. In vitro, morphine (ED50 = 4 X 10(-5) M) and the l-isomers of pentazocine (ED50 = 8 X 10(-6) M) contracted the spirally cut aortic strip. The l-isomers were approximately 5 times more potent than their d-enantiomers. Contraction of the aorta by l-pentazocine was not inhibited by dibenamine, atropine, diphenhydramine, pyrilamine or indomethacin nor potentiated by propranolol. On the other hand, not only was the contraction highly dependent on the concentration of calcium in the bath but it was also blocked by verapamil and SKF-525A, drugs known to inhibit transmembrane calcium influx. Naloxone (3 X 10(-4) to 1 X 10(-3) M), which produced no contractile effect by itself, reduced aortic contraction of l-pentazocine to the greatest extent, that of potassium moderately and that of norepinephrine only slightly. The naloxone blockade of l-pentazocine vascular contraction was reversed by increasing Ca++ concentration in the media, suggesting the action of naloxone may resemble a calcium blocker. It is proposed that a direct, stereoselective and calcium dependent vascular action of l-pentazocine contributes to its ability to raise blood pressure. The possibility that in high doses narcotic antagonists may decrease calcium influx should  also be considered.


Potassium release from the rat submaxillary gland in vitro. I. Induction by catecholamines. Slices of submaxillary gland were incubated in vitro in an enriched Krebs-Ringer-bicarbonate medium gassed with 95% O2-5% CO2 at 37 degrees C and the release of K+ into the medium was monitored after stimulation with alpha and beta adrenergic secretagogues under a variety of experimental conditions. K+ was released by the slice system after addition of norepinephrine, epinephrine or phenylephrine, but not after addition of isoproterenol. The extent of K+ release after norepinephrine depends on the dose of secretagogue and is higher when glucose, adenine and inosine, or all three substrates are absent from the medium. The effect of norepinephrine on K+ release is reversed by phentolamine but not by propranolol. Phentolamine also causes a 9.4-fold shift to the right in the dose-response curve to norepinephrine. Addition of ouabain to the incubation medium results in a higher extent of K+ release and prevents the reversal caused by phentolamine. The response to norepinephrine fails to occur when Ca++ is absent from the medium, either by chelation with ethylene glycol bis (beta-amino-ethyl ether)-N,N'-tetraacetic acid or by elimination from the Krebs-Ringer solution, and shows gradations depending on the Ca++ content of the medium. By itself, however, Ca++ does not induce K+ release from the slice system. The following conclusions are derived from these observations: 1) the release of K+ ions from the submaxillary gland is mediated by alpha adrenergic receptors; 2) the net amount of K+ released is the result of two opposing and almost simultaneous mechanisms, a passive extrusion and an active reuptake; 3) the active reuptake of K+ depends on the availability of energy and is mediated through the ouabain-sensitive Na+-K+ activated adenosine triphosphatase; 4) the reaction is critically dependent on the presence of Ca++ in the incubation medium and probably involves an influx of Ca++ upon stimulation with alpha adrenergic secretagogues.


Comparison of uptake and binding of disodium cromoglycate and phenol red in rat lung. In rat lung slices 3H-disodium cromoglycate (3H-DSCG) (0.001 mM) was taken up rapidly and 3H-DSCG tissue spaces, which equilibrated by 30 minutes, remained constant over a 4-hour incubation period. In contrast, 35S-phenol red (0.001 mM) accumulated in lung slices to a much greater extent than did DSCG, and the measured tissue spaces continued to increase over a 3-hour incubation period. In the presence of either phenol red (1 mM) or the metabolic inhibitors, iodoacetic acid (10(-4) M) and dinitrophenol (10(-4) M), 3H-DSCG uptake was significantly decreased. Accumulation of 3H-DSCG in lung slices and binding to tissue homogenates (pH 7.4) was also decreased when Ca and Mg ions were omitted from the bathing solution. Although DSCG and phenol red mutually inhibited the accumulation of one another over time in lung slices and 3H-DSCG (0.001 mM) binding to lung homogenates was decreased in the presence of 1 mM phenol red, 35S-phenol red efflux was not altered by the addition of 1 mM DSCG during the washout. Thus, it appears that, in rat lung, DSCG and phenol red share a common binding site(s) for uptake, possible on the transport "carrier." Also, there appear to be additional pulmonary binding sites for phenol red. These sites are not occupied by DSCG and their presence could account for the differences observed in the extent of accumulation of the two compounds in lung slices.


Effect of sympathetic blocking agents on the antinatriuresis of reflex renal nerve stimulation. To evaluate the effects of reflex renal sympathetic nerve stimulation on renal tubular sodium handling, clearance studies were performed in anesthetized dogs. With renal perfusion pressure held constant, baroreceptor reflex renal sympathetic nerve stimulation was produced by controlled arterial hemorrhage or carotid sinus perfusion. Significant decreases in urinary sodium excretion occurred in the presence of minor insignificant alterations in renal blood flow and no changes in glomerular filtration rate. Renal alpha adrenergic receptor blockade (phenoxybenzamine) or adrenergic blockade (guanethidine) completely reversed the fall in urinary sodium excretion; this could not be attributed to alterations in glomerular filtration rate or renal blood flow. These studies support the interpretation that adrenergic innervation of the renal tubules is involved in the regulation of renal tubular sodium reabsorption.


The pharmacology of flazalone: a new class of anti-inflammatory agent. The anti-inflammatory activity of flazalone, a unique chemical drug, is described. In acute irritant anti-inflammatory tests, flazalone exhibited a wide spectrum of activity. The compound was active in affecting the course of paw swelling in adjuvant arthritis when given daily either at the outset of the polyarthritis or after induction. The most unusual aspect of this compound is its ability to inhibit graft rejection in goldfish and rabbits. The pattern of anti-inflammatory activity does not allow one to classify this drug in the usual groups.


Catecholamine-induced changes in ion transport in short-circuited frog skin and the effect of beta-blockade. 1. A method for measuring bidirectional Cl fluxes has been used to estimate net Cl movements in short-circuited frog skin and to compare these with the short-circuit current (Isc) and Na fluxes. 2. In some experiments bidirectional fluxes of both Na and Cl were measured simultaneously. It was found that the algebraic sum of the net fluxes of these two ions did not differ significantly from the values of Isc, either in untreated or catecholamine-treated skins, except for the half-hour period immediately after catecholamine addition. 3. The net effluxes of Cl produced by noradrenaline (1-6 X 10(-5)M), isoprenaline (8 X 10(-7)M) and adrenaline (6 and 15 X 10(-6)M) were of similar magnitude for each catecholamine. The magnitude of the Cl response measured as a flux ratio was related to a certain extent to the precatecholamine Cl conductance. 4. The net Na influx was increased by isoprenaline and reduced by noradrenaline. 5. Addition of the beta-adrenergic blocking agent oxprenolol (4-5 X 10(-5)M) to skins stimulated by catecholamine resulted in the disappearance of the net Cl movement and fall in skin conductance and Isc. This fall was similar in magnitude to, and correlated with the mean rise in Isc produced by isoprenaline, but of significantly greater magnitude in the case of noradrenaline. 6. The changes in Na influx were strongly associated with the changes in Isc following catecholamine addition. Similarly, the changes in Na efflux and Cl efflux were correlated, suggesting the Na fluxes to be dissociated, influx and efflux changes perhaps taking place at different loci. 7. Acetazolamide (1-2 X 10(-4)M), added either before or during the noradrenaline stimulation, had no effect on the Cl efflux response. 8. The tissue exchange of Cl from the outside bathing medium after 4 hr was greater in catecholamine-stimulated skins than in those in which the response had been blocked by oxprenolol. 9. These findings were taken to support a model entailing a neutral NaCl pump resident in the mucous glands and an epithelial Na pump enhanced by beta- and inhibited by alpha-adrenergic stimulation.


The association between acidification and electrogenic events in the rat proximal jejunum. 1. Simultaneous measurement of hydrogen ion production, transmural potential difference and intermittent short-circuit current (SCC) was made in the rat proximal jejunum in vitro: similarly, potassium and sodium ion movements were measured to investigate the relationship of acidification to electrogenic events and associated ion movements in the jejunum.2. Acidification correlated significantly with the short-circuit current and both were inhibited by 10 mM serosal ouabain or 10 mM mucosal aminophylline. Both inhibitors had effects on net potassium movement but not on net sodium movement. Moreover, in isotope studies whereas 10 mM serosal ouabain reduced the J(ms) sodium flux, 10 mM mucosal aminophylline had no effect, i.e. aminophylline can reduce both short-circuit current and acidification without perceptibly altering the serosally directed sodium flux.3. In low-sodium buffers in which acidification still occurs although reduced, transmural potential differences occur of reversed polarity that are apparently unrelated to sodium diffusion potential differences (as evidenced by isotopic sodium efflux experiments) and which could be caused by hydrogen ion production. In low sodium buffers however the inhibitors have opposing effects, ouabain causing an increase and aminophylline a decrease in the reversed potential differences.4. A model for acidification (that of potassium rather than sodium ion exchange for the hydrogen ion and hydroxyl for chloride ion exchange) is proposed to explain the present experimental findings and other diverse observations in the literature: although either step might be the electrogenic step, acidification must be also considered as a component of the jejunal short-circuit current.


In vitro treatment of human root surfaces with fluorides. Two-minute topical applications with four different fluoride compounds, acidulated phosphate fluoride, sodium fluoride, sodium monofluorophosphate and stannous fluoride, were evaluated for ability to reduce the acide solubility of human root surfaces in vitro. Each fluoride was in aqueous solution with the fluoride level adjusted to 1.23 percent and the pH native. Rectangular windows were prepared on root surfaces and control versus test differences were invariably studied within teeth and not between teeth. Sodium fluoride and sodium monofluorophosphate solutions reduced root surface solubility by approximately 30 percent while acidulated phosphate fluoride and stannous fluoride were more than 2.5 times more effective, the solubility reduction exceeding 80 percent. Root surfaces thus are similar to enamel in their reactions to topically applied fluorides. Based upon these results the clinician should choose between acidulated phosphate fluoride and stannous fluoride when making the choice of a single treatment compound for office application.


10-Hydroxy-4-methyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine derivatives (homobenzomorphans) as analgesics. Six 10-hydroxy-4-methyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine derivatives 17a-f have been synthesized as potential analgesics. The synthesis of these compounds involved conversion of 4-(2-dimethylaminoethyl)-6-methoxy alpha tetralone derivatives 12a-f to their N-methyl analogues and the subsequent intramolecular mannich reaction with formaldehyde to give the 7-keto C-ring homobenzomorphans 14a-f from which 17a-f, respectively, were obtained. Compounds 17a-f are as potent as morphine as analgesics (mice).


Potential histamine H2-receptor antagonists. 3. Methylhistamines. Syntheses are described for all the mono- and some di- and trimethylhistamines. New methods are given for the known Npi, Ntau-, Nalpha-, 2-, and 4-methylhistamines and for the novel compounds, beta-methyl-, 4,Nalpha-dimethyl-, and 4,Nalpha,Nalpha-trimethylhistamines. Agonist activities are reported for stimulation of histamine H1 (guinea-pig ileum) and H2 (rat gastric acid secretion) receptors. H2-Receptor agonist activities indicate that a methyl group is more readily accommodated at the 4 and Nalpha positions than elsewhere in the histamine molecule and that receptor binding is substantially retained with a methyl substituent in these positions. Thus, for the design of potential antagonists, two sites are identified as being worthwhile exploring for the introduction of lipophilic substituents.


Permeability parameters of the toad isolated stratum corneum. A technique for isolating the stratum corneum from the subjacent layers of the epithelium was developed which permits studying the stratum corneum as an isolated membrane mounted between half-chambers. The method basically consists of an osmotic shock induced by immersing a piece of skin in distilled water at 50 degrees C for 2 min. When the membrane is bathed on each surface by NaCl-Ringer's solution, its electrical resistance is 14.1 +/- 1.3 omega cm2 (n=10). This value is about 1/100 of the whole skin resistance in the presence of the same solution. The hydraulic filtration coefficient (Lp) measured by a hydrostatic pressure method, with identical solutions on each side of the membrane, is 8.8 X 10(-5) +/- 1.5 X 10(-5) cm sec-1 atm-1 (n=10) in distilled water and 9.2 X 10(-5) +/- 1.4 X 10(-5) cm sec-1 atm-1 (n=10) in NaCl-Ringer's solution. These values are not statistically different and are within the range of 1/80 to 1/120 of the whole skin Lp. The stratum corneum shows an amphoteric character when studied by KCl diffusion potentials at different pH'S. The membrane presents an isoelectric pH of 4.6 +/- 0.3 (n=10). Above the isoelectric pH the potassium transport number is higher than the chloride transport number; below it, the reverse situation is valid. Divalent cations (Ca++ or Cu++) reduce membrane ionic discrimination when the membrane is negatively charged and are ineffective when the membrane fixed charges are protonated at low pH.


Anion transport and membrane morphology. Freeze-fracture electronmicroscopy has been used to examine the membrane ultrastructure of human red blood cells in the presence of inhibitors of chloride exchange. The extent of inhibition was correlated with a decrease of intramembrane particle density on the B-fracture face. Dimethylsulfoxide (DMSO) and glycerol, which markedly and reversibly reduced the intramembrane particle density, were shown to drastically and reversibly inhibit chloride self-exchange. DMSO was shown to be a noncompetitive inhibitor of chloride flux.


Enzyme activities associated with an invertebrate iridovirus: nucleotide phosphohydrolase activity associated with iridescent virus type 6 (CIV). A nucleoside triphosphate phosphohydrolase activity is firmly associated with a purified invertebrate iridovirus, iridescent virus type 6. The enzyme activity hydrolyzes all the nucleoside triphosphates, but has a high preference for ATP. The products of the reaction are nucleoside diphosphates. Conditions for nucleoside triphosphate phosphohydrolase activity are described.


Hemodynamic effects of beta-adrenergic blockade with pindolol, oxprenolol, propranolol and bufetolol hydrochloride in essential hypertension. Hemodynamic studies (using (131)I-labeled albumin [RISA]) Were performed before and 5 and 42 weeks after the oral administration of pindolol (av. 30 mg/day), oxprenolol (av. 216 mg/day), propranolol (av. 75 mg/day) or bufetolol hydrochloride (av. 30 mg/day) in 40 patients with essential hypertension. Responders to the antihypertensive actions of short-term (5 weeks) pindolol or bufetolol showed a reduction in total peripheral resistance (pindolol, from av. 2622 to 2022 dyne-sec-cm-5-m2; befetolol, from av. 3301 to 2620, p less than 0.05), without significant changes in cardiac index, while hypotensive actions of propranolol or oxprenolol appeared to be due mainly to a decrease in cardiac output (propranolol, from av. 4.03 to 2.99 L/min/m2; oxprenolol, from av. 3.97 to 3.29 L/min/m2), although the decrease in cardiac output was not significant. In long-term (42 weeks) oxprenolol therapy, antihypertensive effects seemed to be related to reduced cardiac output and a readaptation of peripheral resistance to chronic reduction of cardiac output was not always observed. Circulation time was determined in 9 patients with oxprenolol therapy and 8 with pindolol therapy by the measurement of the arrival time in the cerebral hemisphere of the intravenously injected radioisotope. The patients with oxprenolol therapy showed significant prolongation in circulation time (short-term administration, av. 6.6 to 8.4 sec; long-term administration av. 6.6 to 9.2 sec, p less than 0.05), while no prolongation was observed in pindolol therapy. These results suggest that hemodynamic responses to beta-blocking agents are not uniform and that the antihypertensive actions of beta-blockers depend on the effects on both cardiac output and peripheral vascular resistance.


Studies on the structure activity relationship of adrenergic beta-mimetic benzylamine derivatives. Appropriately substituted benzylamine (BZA) derivatives, fragmented derivatives of tetrahydroisoquinolines, were found to be directly acting adrenergic beta-stimulants, exhibiting tracheal relaxing, positive chronotropic and free fatty acid (FFA) releasing activities. The chemical structures essential for manifestation of the beta-action were i) 3,4-dihydroxybenzylamine, ii) arylmethyl group at position alpha, iii) lower alkyl group on the N atom. The structure activity relationships of BZA-derivatives were almost similar to, but partly different from those of tetrahydroisoquinoline- and catecholamine-derivatives. The tracheal relaxing, positive chronotropic and FFA-releasing actions of alpha-(3,4,5-trimethoxybenzyl)-N-methyl-3,4-dihydroxybenzylamine, the most active compound in the BZA-derivatives tested, were approximately one-hundred, thirty and fifty times less active than those of ISO, respectively. These results indicate that this compound is beta1-selective, while trimetoquinol is beta2-selective.


alpha-Adrenoceptors mediating positive inotropic effects on the ventricular myocardium: some aspects of structure-activity relationship of sympathomimetic amines. Experiments were carried out on the isolated papillary muscle of the rabbit in order to further characterize the alpha-adrenoceptors mediating the positive inotropic effect. For this purpose dose-response relations of seven sympathomimetic amines were compared under the influence of alpha- and/or beta-adrenolytic drugs. Phentolamine (10(-6) M) shifted the lower part of the dose-response curves for norfenephrine, synephrine and epinine as for phenylephrine and adrenaline to the right, while prindolol (10(-8) M) affected only the upper part of the curves. In the presence of both alpha- and beta-adrenoceptor blocking agents the entire dose-response curves for sympathomimetic amines were shifted in a parallel manner. Noradrenaline affected preferentially beta-adrenoceptors, whereas its effect on alpha-adrenoceptors was so weak that it could be detected only when the neuronal and extraneuronal uptake mechanism of amines were blocked by cocaine (3 X 10(-5) M) and corticosterone (4 X 10(-5) M), respectively. The effect of dopamine was not affected either by phentolamine or by prindolol, but was antagonized by the simultaneous application of both alpha- and beta-adrenoceptor blocking agents. From the present results, it appears that the following relationships are present between the structure of amines and the alpha-adrenoceptor stimulating activity in the heart: (1) N-methylation increases the potency: (2) Absence of the hydroxyl group either in 3 or in 4 position decreases the intrinsic and beta-adrenoceptor stimulating activities, but increases the alpha-adrenoceptor stimulating activity.


Desensitization of guinea pig tracheal muscle preparation to beta-adrenergic stimulants by a preceding exposure to a high dose of catecholamines. When a given concentration of a catecholamine was applied to guinea pig tracheal preparation contracted by 20 muM histamine or by 30 mM-K+-Tyrode's solution, constant relaxations were observed, if the relaxation was submaximal. When a high concentration of catecholamine, 200 times the ED50, was once applied, subsequent responses to beta-stimulants (ED80) was reduced by about 30-40%, in spite of repeated washings. The response was gradually recovered in 2 hr. Thus 45 muM epinephrine and 1 muM isoproterenol could cause desensitization to 0.65 muM EPINEPHRINE AND 0.03 muM isoproterenol, respectively. Epinephrine and isoproterenol could cause densensitization to isoprophenamine, a non-catechol beta-stimulant. Epinephrine did not affect the response to cyclic AMP, dibutyryl cyclic AMP, aminophylline and prostaglandin E1. This densensitization was not affected by phentolamine, normetanephrine nor by Ca2+ deprivation from the bathing solution. The mechanisms of the desensitization may relate to some step(s) between the receptor-drug interaction and cyclic AMP accumulation in the process of tracheal muscle relaxation induced by beta-stimulants.


Approach to acid-base problems in the critically ill and injured. The use of the Henderson-Hasselbalch equation and the relationships between bicarbonate levels and the pCO2 or carbonic acid concentration in evaluating acid-base abnormalities are explained. The etiology, pathophysiology, diagnosis and treatment of respiratory alkalosis and acidosis and metabolic alkalosis and acidosis are discussed. The results of laboratory tests should be examined in relation to the patient's condition and consistency with other laboratory tests. Therapy is directed at correcting the underlying problems and, secondarily, at correcting the numbers. Patients respond primarily to rate of change and not absolute numbers. Therefore, problems should be corrected at approximately the rate they develop. Treatment should be guided by continued patient observation and serial laboratory studies.


[Dynamic observations of tolerance to physical exercise in patients with ischemic heart disease during drug therapy]. Proceeding from a dynamic observation of the tolerance of physical exercises in the process of drug therapy of 90 patients with ischaemic heart disease the author concludes that a certain dissociation exists between the subjective effect of the antianginal drugs and the results of bicycle tests in the evaluation of the efficacy of the treatment. While a subjective improvement was declared in 2/3 of the patients, the exercise test indices improved only in 1/3. The bicylce test before and after the therapeutic course seems to facilitate a more precise evaluation of the efficacy of the antianginal drugs.


[Arterial hypertension and chronic hemodialysis]. Basing on the literature data and their own observations of patients with chronic hemodialysis the authors have analysed the pathogenesis, course, hemodynamic shifts and possibilities of purposeful treatment in terminal uremia. Besides two variants of the hypertension course (controlled and noncontrolled), a third type has been revealed--hypertension difficult to control, in the pathogenesis of which, as well as in the noncontrolled variant, an important role is played by the activization of the renin-angiotensin system. Hemodynamic mechanizms of an abrupt change in the arterial pressure (acute hypotension and hypertensive crisis) in the process of hemodialysis are analysed.


[Use of beta-blockader visken in children with primary arterial hypertension]. The effect of Visken was analysed in children with primary arterial hypertension, Stage IB, with reference to their general state, dynamics of cardiac contractions, arterial pressure, cardiac output, and vascular peripheral resistance. The treatment was undertaken in 28 children lasting from 6 to 8 weeks. A multiformity of the drug's effect upon the state of the children with early hypertension was noted. The response of different parameters of the circulatory system to Visken is individual. Side effects may develop against the background of even low doses.


Vasopressin-stimulated movement of drugs and uric acid across the toad urinary bladder. Vasopressin is known to increase the permeability of the toad bladder, an analogue of the mammalian collecting duct, to water and hydrophilic solutes such as urea. In the present study, the effect of vasopressin on the permeability of a series of lipophilic compounds, including many commonly used drugs, has been determined. In all cases, permeability increased from 50 to 100%. The response to vasopressin was mediated by cyclic adenosine monophosphate (cAMP), and was generally not altered by phloretin, an agent that inhibits amide movement through the amide transport pathway. Evidence that these compounds move directly through the lipid phase of the membrane was provided in studies of phenobarbital permeability at low and high luminal pH. We would conclude from these studies that the effect of vasopressin on the luminal cell membrane is a widespread one, modifying both lipid components and components involved in amide, sodium and water transport. This may be of importance in the renal tubular reabsorption of many drugs, including barbiturates, glutethimide and antibiotics.


Isohydric regulation of plasma potassium by bicarbonate in the rat. pH and bicarbonate affect many metabolic reactions but each may change independently. To study bicarbonate's effect onplasma potassium, blood bicarbonate in normal, hypokalemic or hyperkalemic rats was either maintained constant, lowered by hydrochloric acid or raised by sodium bicarbonate administraion. Blood pH was maintained constant by changing PCO2. In normokalemia lowering bicarbonate increased plasma potassium 2.0mEq above values obtained in the other groups. To eliminate urinary potassium losses, experiments were also performed in rats with bilateral ureteral ligation. Again, plasma potassium concentration rose significantly more in the lowered bicarbonate group. Similarly, in hypokalemia, plasma potassium rose 1.2 and 0.4mEq in the lowered and unchanged groups, but fell 0.2mEq/liter in the elevated group. Differences could not be ascribed to renal potassium losses as potassium excretion was essentially zero in each group. In hyperkalemia, plasma potassium concentration remained elevated for 150 min in the lowered bicarbonate group but fell 1.3 and 2.0mEq in the unchanged and elevated groups, respectively. Urinary potassium losses in the three groups were statistically identical. In all experiments blood pH was maintained unchanged during the experiment. The data show that bicarbonate,  independent of blood pH, alters transcellular potassium distribution suggesting the usefulness of bicarbonate therapy in hyperkalemia even at a compensated blood pH.


Lithium-induced impairment of urine acidification. The purpose of this study was to clarify the means by which lithium induced a disorder of urine acidification. Rats infused with hydrochloric acid (1 mEq/kg) developed acute metabolic acidosis (blood Ph = 7.32; bicarbonate, 18 mEq/liter) with a urine pH of approximately 5.85. The addition of lithium chloride (4 mEq/kg i.p) caused an increase in the urine pH (6.38) and a further decrease in blood bicarbonate (11.0 mEq/liter). During bicarbonate loading, lithium caused the urine PCO2 to fall significantly (urine minus blood PCO2 decreased from 25.3 +/-2.8 To 14.4 +/- 2.3 mm Hg) These changes were not seen following equimolar i.p. administration of sodium chloride. Similarly, lithium  administration depressed bicarbonate reabsorption by 11.1% (from 30.6 to 27.2muEq/ml of GFR) during alkali infusion, while saline caused only a 5% decrease (30.0 to 28.5muEq/ml of GFR). The combination of an increase in urine PCO2 in alkaline urine indicates that lithium produced a defect in distal nephron hydrogen ion secretion. The fall in bicarbonate reabsorption following lithium administration oculd be due to a mild hydrogen ion secretory defect located in the proximal tubule or a severe defect in the distal nephron.


Immunoregulation and autoimmunity.

Immunoregulation and autoimmunity. The immunologic responses, both cell-mediated and humoral, to exogenous antigens reflect a crucial balance between extrinsic forces which can either augment or suppress the reactivity of T and B effector cells. It is probable that similar immunoregulatory influences play a key role in maintaining tolerance to some self-antigens. Thus, despite the presence of cells potentially capable of reacting to autologous antigens, lack of autoimmunity might reflect either an absence of amplifying or a preponderance of suppressive immunoregulatory forces. Within this framework, data obtained indicating aberrances of immunoregulation in patients with systemic lupus erythematosus are discussed, specifically as the aberrances may be causally related to the autoimmune nature of this disease.


Properties of monomeric paramyosin using a transient electric birefringence techniques. Paramyosin samples obtained from the chowder clam, Mercenaria mercenaria, by different extraction techniques were studied using transient electric birefringence techniques. The protein remain monomeric (unaggregated) in 1 mM buffer solution at pH 3.1 to 3.8 and near pH 10. At pH 3.2, the molecules obtained by different extraction techniques exhibit rotational diffusion constants that indicate a 5% difference in length between them, with the probable native form of paramyosin being the longer species. This difference in rotational diffusion constant disappears at higher pH, and, in addition, a large difference in dipole moment between the molecules observed at pH 3.2 also disappears at high pH. These results are used to hypothesize that the rodlike native paramyosin molecules have one or two partly flexible portions on their ends; at one end of each molecule this portion probably contains excess basic amino acids which are charged at low pH to account for the higher dipole moment of this form of paramyosin at these low pH values. At pH 3.2, these portions of the macromolecule are not flexible and act as stiff parts of the rodlike molecules, but they gradually become flexible at higher pH. Possible mechanisms for this change in flexibility are discussed.


Ageing of Neurospora crassa. IV. Induction of senescence in wild type by dietary amino acid analogs and reversal by antioxidants and membrane stabilizers. The extensional growth rate of wild-type 74A8 N. crassa in the presence of various concentrations of 19 amino acid analogs was measured. Seven analogs were not inhibitory at concentrations in the range of one to 10mM. Of the remaining 12 analogs, nine inhibited growth in a novel way. The kinetics of growth in the presence of these analogs at 30 degrees were characterized by seven sequential phases: (1)lag; (2) acceleration of growth rate; (3) steady-state growth rate; (4) exponential rate of decline of growth rate; (5) no growth or growth rate less than or equal to 0.1 mm h-1; (6) accleration of growth rate; and (7) steady state. At 33 degrees, phases 6 and 7 did not occur and irreparable death of the clones occurred. The mechanism by which the clones acquired resistance at 30 degrees appeared to involve a combination of physiological adaptation and cellular selection. Dietary application of either free radical scavengers or surface-active membrane 'stabilizers' alleviated or prevented the inhibition and deterioration of growth rate which occurred in the presence of the nine amino acid analogs. Culture with either 4-fluorophenylalanine or ethionine led to an increase of the activities of antioxygenic enzymes glutathione peroxidase, glutathione reductase and superoxide dismutase. The amino acid analogs that cause senescence and death of growing cells are known to be incorporated into proteins and such proteins are generally abnormal. Because a substantial fraction of cellular protein occurs in membranes and the proteins synthesized by mitochondria are exclusively intrinsic membrane proteins, we suggest that  a primary consequence of errors in protein synthesis is the production of faulty membranes. The deterioration of such membranes with associated lipid autoxidation and free radical production proceeding as a chain reaction at an exponential rate may in itself contribute to the exponential rate of cellular deterioration which is characteristic of the ageing process. According to this hypothesis, dietary membrane stabilizers, free radical scavengers and antioxygenic enzymes protect cells from error catastrophy arising from the chain of events leading from membrane deterioration.


[Binding of silver ions by Candida utilis cells]. Binding of silver ions by the cells of Candida utilis involves their adsorption on the cell surface. It was found that 90% of all silver bound by the cells was localized in the fraction of cell walls and cytoplasmic membranes. The sensitivity of protoplasts to the toxic action of silver ions is much higher than that of intact cells. The toxic effect of silver ions is supposed to be related to changes in the functions of cytoplasmic membranes.


The possible role of beta-adrenergic and alpha-adrenergic antagonist sensitive systems in the brain in the mechanism of psychosis. On the basis of clinical observations on psychotic patients during treatment with adrenergic blocking drugs it is postulated that normally the activities of two systems in the brain are balanced: one of these systems can be blocked by beta-adrenergic blocking drugs and the other is responsive to alpha-adrenergic blocking drugs. Psychosis may occur when either the total activity is too high or too low, or when the balance is disturbed. Specific psychiatric syndromes are outlined as related to either of these systems.


[The mechanism of action of d-amino acid oxidase. I. Evidence for a free radical mechanism of the reaction catalyzed b a dimeric form of the enzyme]. d-Amino acid oxidase can oxidize the substrate to a ketoacid in the absence of oxygen. The stoichiometry of this reaction is precisely 1 molecule of keto acid for 1 molecule of enzyme, containing two flavin groups. Hence, the flavin must be in the semi-reduced free radical state. But these free radicals cannot be visualized by ESR spectroscopy because of closeness and strong interaction. After the acid denaturation of the protein the coenzyme is released as a semi-reduced free radical. An alternative method of registration is the transfer of the free radical state to an added excess of free flavin molecules. By both methods it is quantitatively determined that each flavin of the enzyme is reduced to a free radical. Therefore, we believe to have evidenced unambiguously that this enzymatic reaction proceeds via a free radical transition state.


[The fluorescence of pepsin conjugates with DNS-chloride]. Parameters of rotational relaxation of pepsin conjugated in neutral and slightly alkaline solutions with a fluorescent label 1-dimethylaminonaphthalene-5-sulphonyl chloride (DNS-Cl) are measured by a fluorescence polarization method. It is shown that the globule of pepsin denatured and loose at lakaline pH values converts into a compact form after transfer to acidic solution. The compactness of this new form is close to that of native inhibited pepsin. A new globule is distinguished from the native by the absence of segmental flexibility. Conjugated with a DNS at pH less than or equal to 7.0 pepsin relaxes in solution as catalytically active dansylated aminopepsin (DNS-3-aminotyrosine pepsin). Evidence is presented that these conjugates are also characterized by segmental flexibility.


Rat and mouse tissue-mediated mutagenicity of ring-substituted 3,3-dimethyl-1-phenyltriazenes in Salmonella typhimurium. 3,3-Dimethyl-1-phenyltriazene and a series of ring-substituted derivatives (X-phi-N=N-N-(CH3)2:X=substituent(s); phi=phenyl) were tested for their mutagenic and toxic action upon Salmonella typhimurium G-46 in a liquid incubation system containing 9000 g tissue supernatants and an NADPH-generating system. The compounds could be grouped into four classes according to their toxicity and mutagenicity after 1 h incubation at 37 degrees C at a concentration of 5 mM in the presence of liver supernatant fractions from phenobarbitone-pretreated mice. When a liver supernatant from untreated mice was compared with one from phenobarbitone-pretreated animals, the mutagenic effect of a series of triazenes (with X=H; 4-chloro; 4-chloro; 4-bromo; 2,4,6-trichloro) in vitro was enhanced twice to ten times. The toxicity of triazenes with X=4-methoxy or 4-acetamido was strongly decreased by a liver fraction from phenobarbitone-pretreated mice in the presence of an NADPH-generating system. With 3,3-dimethyl-1-phenyl-triazene, rat liver fractions caused a lower enzyme-mediated mutagenicity in S. typhimurium G-46 than those of mouse liver, whereas a 9000 g supernatant from brain, a major target organ for the carcinogenic action of certain triazenes, was unable, in either species, to generate metabolites mutagenic for S. typhimurium G-46.


[Fibrinogen and fibrin monomer conformation changes dependent of pH magnitude]. Conformational states of fibrinogen and fibrin monomer were studied by methods of differential and solvent-perturbation spectrophotometry and ultraviolet fluorescence at about neutral pH (6.5) and in the region of lower pH, 3.2 to 4.0. To prevent repolymerization of fibrin monomer at pH 6.5, urea was added in a non-denaturing concentration of 1.7 M. In the acid region specified, the immediate environment of tyrosine and tryptophan residues was found to be more polar and the accessibility to perturbants higher than at pH 6.5. Much more drastic changes of the same type occurred at pH less than 3 when denaturation of the protein takes place. The conformation of fibrinogen altered progressively upon lowering pH from 4.0 to 3.2. This acidity increase, practically, did not influence the conformation of fibrin monomer. Thus the tolerance of the latter to the appearance of the new positively changed groups seems to be comparably high. The bulk of the conformational changes subsequent upon neutralization of an acid fibrin monomer solution proceeds at a higher rate than the activation transition, i.e. the acquirement of a state of polymerization readiness by fibrin monomer molecules.


Chemical composition and some properties of modified buffalo milk for infant feeding. A proposed formula for modifying buffalo milk for infant feeding was described. Buffalo milk was diluted with four parts of whey that was produced by addition of citric acid or lemon juice to milk and neutralization with sodium bicarbonate. The chemical composition and the properties of the proposed formula were compared with raw buffalo milk, human milk and buffalo milk modified by the ordinary method. The proposed formula was characterised by low casein/whey protein N comparable to human milk and by curd tension.


[Retention of apple starch in production of pectin by the aluminum pectinate procedure]. Apple pectin produced by means of the aluminum pectinate procedure contains less starch than apple pectin obtained by precipitation with ethanol. The degradatin of the starch which occurs during production depends to a great extent upon the conditions of pomace digestion. The absorption maxima of the amylose-iodine complexes range in general from 550 to 570 nm. Model experiments with highly esterified pectin and partially degraded (by mechanolysis) apple starches were performed to establish favourable conditions for fractionating the pectin and starch components which are obtained when the pectin is precipitated as aluminum pectinate and when the granular coagulate is washed with water.


[The circular dichroism spectrum of dinucleoside phosphate analogs]. Circular dichroism spectra of 11 analogues of the dinucleoside phosphate containing achiral 3'-terminal monomers have been measured at several pH values, various temperatures and various concentrations of ethanol. The conformation of analogues studied has been shown to by very similar to that of natural compounds. Comparison of the results obtained with the circular dichroism spectra of the corresponding natural compounds indicates that Cotton effect arises from monomeric circular dichroism, at least in main features. The exciton interaction is relatively small.


Mechanisms of tyrosine hydroxylase and dopamine beta-hydroxylase induction in organ cultures of rat sympathetic ganglia by potassium depolarization and cholinomimetics. It was the aim of the present study to elucidate the mechanisms involved in specific tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH) induction by potassium depolarization and cholinomimetics in rat superior cervical ganglia kept in organ culture. The effect of high (54 mM) potassium concentration on intact ganglia seems to result in a dual action: a) a specific induction of TH and DBH via release of acetylcholine from preganglionic cholinergic nerve terminals. b) a non-specific effect on terminal adrenergic neurons resulting in a general increase of protein synthesis as indicated by the increase in DOPA decarboxylase (DDC) and monoamine oxidase (MAO) activities. In decentralized superior cervical ganglia potassium depolarization failed to produce the specific TH and DBH induction although a small increase in DDC activity persisted. Carbamylcholine, acetylcholine and nicotine at concentrations of 10(-4) M elicited a selective induction of TH and DBH both in intact and decentralized ganglia via nicotinic receptor stimulation. Bethanechol, predominantly stimulating muscarinic receptors had no significant effect on TH activity. A 4 h pulse of 10(-4) M carbamylcholine produced optimal induction of DBH and TH 24 h and 48 h later respectively. Longer exposure to carbamylcholine resulted in a significantly smaller rise in TH activity.


Anti-dopaminergic and anti-muscarinic effects of dibenzodiazepines: relationship to drug induced Parkinsonism. 1. The anti-dopaminergic effects of several dibenzodiazepines were examined on the dopamine-stimulated adenylate cyclase in rat striatal homogenates. The "cis" isomer of clozapine, HF-2046, was the most potent in this respect and perlapine, which is devoid of neuroleptic activity, was the weakest. 2. The anti-muscarinic effects of the same compounds were measured by using the muscarinic affinity label 3H-propylbenzilylcholine mustard. HF-2046 was the most potent and loxapine the least potent of the drugs used. 3. The anti-dopaminergic effects of the drugs correlate well with neuroleptic but not with extrapyramidal effects. The anti-dopaminergic/anti-muscarinic ratio, however, correlates well with extrapyramidal rather than neuroleptic effects.


[A study of the physico-chemical properties of lecithin membranes using hydrophobic and hydrophilic spin probes]. Some physico-chemical properties of lecithin lyposomes and the effects of pH, temperature and ionic strength changes are studied by ESR using hydrophobic and hydrophylic nitroxyl radicals as spin probes. The structure differences between outer and inner layers of bilayer liposomes are observed using auxiliary water soluble paramagnetic complex and attributed tentatively to the different curvature signs of both layers. Lower estimates of transversal diffusion rates of both probes throught the membrane are obtained using exchange broadening technique and water soluble reducing agent. The limiting step in this diffusion is revealed, caused by the transport of a charged group of the diffusing molecule through the hydrophobic membrane space.


Lack of correlation between changes in cyclic nucleotides and subsequent induction of tyrosine hydroxylase in rat adrenal medulla. Pretreatment of rats with dexamethasone (2.5 mumol/kg, a dose which blocks the release of ACTH from the pituitary gland) abolished the reserpine mediated increase in cAMP and the increase in the cAMP/cGMP ratio in the adrenal medulla. In contrast, the reserpine-mediated induction of tyrosine hydroxylase (TH) remained unchanged. Hypophysectomy had a similar effect to dexamethasone treatment. Since changes in cAMP and changes in the cAMP/cGMP ratio are not indispensible prerequisities for the subsequent induction of TH, a causal relationship between the two phenomena seems to be excluded.


[Kinetic patterns of bacterial hydrogenase inactivation]. Kinetics of inactivation of hydrogenases is exemplified with the enzyme from Chloropseudomonas ethylica. The effect of gaseous phase, temperature, pH on the inactivation kinetics has been studied. Inactivation of the hydrogenase during incubation of an enzyme solution in air has been studied. Analysis of the kinetic data allowed the conclusion to be made that inactivation involves two forms of the enzyme which differ in their activity and resistance to inactivating actions. Stabilities of the mean time of operation of hydrogenases from Chloropseudomonas ethylica and Thiocapsa roseopersicina are compared. The mechanism of inactivation of hydrogenases from the two sources were found to be similar in many ways.


Prolonged infusion of diazoxide in the management of premature labor in the baboon. The management of premature labor by the prolonged infusion of diazoxide was evaluated in 33 pregnant baboons. The drug was administered intravenously to the mother with an average rate of 0.065 mg/kg/min for 4 hours. Mild to moderate spontaneous labors were significantly inhibited by diazoxide without jeopardizing the fetus. Diazoxide produced a significant increase in maternal heart rate, but its effect on fetal circulation was minimal. Fetal acid-base state and arterial oxygenation remained essentially unchanged throughout the period of observation. Intravenous administration of this drug to the fetuses caused only mild cardiovascular changes irrespective of its preexisting conditions. Thus, a slow intravenous infusion of diazoxide to the mother in a low dosage appears to be of value for inhibiting the uterine activity in early labor, without interfering with the fetal well-being.


[Effect of actinomycin D on transformation of the planulae of Obelia loveni (Allman)]. The incubation of planulae Obelia loveni in the actinomycin D solution (40 mug/ml) for 3 hrs at 17--20 degrees resulted in the marked inhibition of the process of attachment of planulae to the substrate and their transformation in polyps. A suggestion is put forward that at the final phase of larval development a special RNA is synthesized which participates in the genetically determined control of the complicated morphogenetic phenomenon of attachment and transformation of the planula in polyp.


Leukocyte function and characterization of leukocyte glucose-6-phosphate dehydrogenase in Sicilian mutants. Nine Sicilian children known to be deficient in glucose-6-phosphate dehyrdrogenase (G6PD) were studied to see if there were anomalies of bactericidal activity in peripheral blood phagocytes. The type of deficiency was established. The G6PD levels in the leukocyte were found to be 26% of the controls (0.094 +/- 0.03, normal controls 0.360 +/- 0.12). The Michaelis constant for NADP and glucose-6-phosphate (G6P) was lower than the control. Conversely, the utilization of the analogous 2-deoxyglucose-6-phosphate (2dG6P) and galactose-6-phosphate (Ga16P) was higher. The thermostability of the enzyme in the deficient subjects was lower and the pH optima (8 and 9.5) were different from the controls. An identical electrophoretic pattern was found in both normal and deficient subjects. The bactericidal activity in the deficient subjects was normal. There was no difference in the results of nitroblue tetrazolium (NBT) tests in either group.


Child's urinary lithiasis revealing a complete deficit in adenine phosphoribosyl transferase. In one case of a urinary lithiasis, termed "uric lithiasis" on biochemical examination, the authors describe the symptomatology of a child with a complete deficit in adenine phosphoribosyl transferase. After more intensive investigation the calculi have been found to be composed of a new clinical compound: 2,8-hydroxyadenine.


Milk protein quantity and quality in low-birthweight infants: I. Metabolic responses and effects on growth. The optimal quantity and quality of protein for low-birthweight infants is undefined. In this study, 106 well, appropriate-for-gestational age, low-birthweight infants weighing 2,100 gm or less were grouped in three gestational age categories: T1 = 28 to 30 weeks; T2 = 31 to 33 weeks; T3 = 34 to 36 weeks. Each group was assigned randomly to either banked human milk (BM) or to one of four isocaloric formulas varying in quantity and quality of protein but not in mineral content or in fat content: formula 1 = 1.5 gm of protein per 100 ml, 60 parts bovine whey proteins to 40 parts bovine caseins; formula 2 = 3.0 gm of protein per 100 ml, 60:40; formula 3 = 1.5 gm of protein per 100 ml, 18:82; formula 4 = 3.0 gm of protein per 100 ml, 18:82. Caloric intake was 117 kcal/150 ml/kg/day for the formulas. Human milk was fed at 170 ml/kg/day in order to attain a caloric intake approximately equal to that of the formulas. No significant differences were found in the rate of growth in crown-rump length, in femoral length, in head circumference, or in rate of gain in weight from time of regaining birthweight to time of discharge at 2,400 gm. Blood urea nitrogen, urine osmolarity, total serum protein, serum albumin, and serum globulin varied directly with the quantity of protein in the diet: F2, F4 greater than F1, F3 greater than BM. Blood ammonia concentration varied with both quantity and quality of protein in the diet: F2, F3, F4 greater than F1, BM. Metabolic acidosis was more frequent, more severe, and more prolonged in the infants fed the casein-predominant formulas (F3,F4) than in those fed the whey protein-predominant formulas (F1, F2).


Pneumothorax in the respiratory distress syndrome: incidence and effect on vital signs, blood gases, and pH. We determined the incidence of pneumothorax in 295 infants (mean birthweight, 1,917 gm) with the respiratory distress syndrome (RDS) treated according to the same protocol. Fifty-five infants (mean birthweight, 1,594 gm) developed pneumothorax (incidence, 19%); incidence varied with severity of RDS and intensity of respiratory assistance. Pneumothorax occurred in 3.5% (2 of 58) of infants who received no assisted ventilation and in 11% (14 of 124) of infants who received continuous positive airway pressure (CPAP) as the only form of assisted ventilation; the difference between these two groups is not significant. Forty-nine infants initially treated with CPAP later required mechanical ventilation with positive end-expiratory pressure (PEEP). Pneumothorax occurred in 12 of the 49 (24%) and in 21 of 64 (33%) of those infants initially treated with PEEP; the incidence of pneumothorax for both these groups was significantly higher than for those treated with no assisted ventilation or CPAP only. To assess the value of frequent measurement of vital signs, blood gas tensions, and pH in the recognition of pneumothorax, we analyzed these variables by the cumulative sum statistical technique. We noted the following significant changes associated with pneumothorax: arterial blood pressure, heart rate, and respiratory rate decreased in 77% of cases; pulse pressure narrowed in 51% of cases; Po2 decreased in 17 of 20 cases in which ventilatory settings were constant for at least three hours prior to pneumothorax. However, pH and Pco2 showed consistent changes. Frequent measurements of vital signs and Po2 aid in the early diagnosis of pneumothorax.


Acid-base measurements of arterial, venous and capillary blood in the dog. A method of arterial blood sampling acceptable for clinical purposes for acid-base estimations in dogs is described. A comparison of acid-base variables from fourteen canine arterial, venous and capillary blood samples revealed in most cases that venous and capillary blood samples showed unsatisfactory agreement with corresponding arterial blood samples. Two commercial automatic pH and blood-gas analysing systems are compared.


The occurrence of Bacillus cereus in Finnish dog food sausages; a microbiological and physiochemical survey. A bacteriological survey of five brands of commercial dog food sausages showed that two of them were heavily contaminated with B. cereus. One of the two brands had a suspected association with food-poisoning incidents in dogs. In addition to B. cereus the other sausage brand was found to contain a high number of sulphite reducing anaerobes. B. cereus was detected in almost every raw material of the two brands of sausages. The pasteurization during manufacturing did not kill all the sporeforming organisms. The water activity of the sausages were equal to or more than 0.99 and pH in a range from 6.2 to 7.0. Methods of preventing the growth of microbes in the sausages after manufacturing are discussed.


New fluorescent cytidine 5'-phosphate derivatives. Interaction of cytidine 5'-phosphate with chloroacetone or p-tosyloxyacetone leads to 2-methyl-5,6-dihydro-5-oxo-6-(5-0-phospho-beta-D-ribofuranosyl)-imidazo/1,2-c/pyrimidine (2-methylethenocytidine 5'-phosphate) whereas analogous reaction with phenacyl bromide produces similar 2-phenyl-derivative. The bicyclic nucleotides obtained showed significant UV absorption at long wavelength where common nucleotides and proteins exhibited no absorption. These derivatives are highly fluorescent when heterocyclic ring is protonated. The absorption and fluorescent properties of the substituted ethenocytidine 5'-phosphoate derivatives seem to be suitable for their use as fluorescent probes or labels in biochemical studies.


The effects of antipyretics on metabolism processes in rat liver mitochondria. Part I. The action of sodium salicylate, and pyrazolones on the reaction of respiratory chain. The effects of sodium salicylate (SS), phenazone (Ph) and aminophenazone (APh) on mitochondrial respiration respiration and oxidative phosphorylation were studied in vitro, SS inhibited state 3 but stimulated state 4 of respiration, if alpha-ketoglutarate and succinate were used as the substrates. The inhibition of state 3 of respiration was not reversed by 2,4-dinitrophenol (DNP). Ph and APh inhibited the respiratory state 3 without affecting the state 4 in the presence of the same substrates, and the produced inhibition in state 3 was reversible by DNP. Studies on ATP synthesis have revealed that SS was the only antypyretic tested that exerted an uncoupling action. SS stimulated the mitochondrial ATPase activity but inhibited it after uncoupling of oxidative phosphorylation with DNP. The mitochondrial ATPase activity remained uninfluenced by Ph or APh. The only similar action of all the drugs investigated was the inhibition of oxidation in the respiratory state 3.


Crystalline free radical of chloropromazine. The method of preparation and the spectral characteristic of the crystalline free radical of chlorpromazine are described. Two absorption maxima at 770 and 860 nm concomitant with those at 530 and 277 nm were found. The highest rate of dismutation of the radical was 4-4.10(-1) M. sec-1 at pH 7-2. The mechanism of luminescence during the decay of the peroxide form of th radical is discussed.


Kinetics of drug decomposition. Part 38. Hydrolysis and autoxidation of sodium phenylbutazone and aminophenazone in binary kinetic system. The kinetics of hydrolysis and autoxidation of sodium phenylbutazone (PhB-Na) and aminophenazone (APh) was studied in ammonia-acetate, Carmody and Welford buffers at different buffer concentration, pH, ionic strengths and temperatures. The reaction in N2 atmosphere and under a constant O2 pressure, carried out in calibrated ampoules, followed the first order reaction kinetics. The assay of PhB-Na and APh in the presence of their degradation produces was carried out spectrophotometrically in the degraded solutions.


The management of ulcerative colitis.

The management of ulcerative colitis. The modern medical and surgical treatment of ulcerative colitis has been detailed. Whilst improvements in medical management have been few in the past decade there have been advances in dietary management and in the use of new drugs such as azathioprine and disodium cromoglycate which are currently being evaluated. Sulphasalazine remains a valuable drug in treating attacks of the disease and in preventing relapses, and its mode of action is now better understood. Steroid therapy, used orally, parenterally or topically, is of value in managing acute colitic attacks. Surgery is often  required and total proctocolectomy with ileostomy remains the operation of choice. Colectomy with ileorectal anastomosis still remains a controversial operation but has its enthusiastic advocates. The interesting a new operation of proctocolectomy, with the establishment of an ileal bladder and continent ileostomy, is being assessed in Sweden and in a few centres in Britain and America.


Purification, characterization, and quantitation of the antigen employed in the immunodiffusion test for diagnosis of equine infectious anemia. Equine infectious anemia (EIA) antigen extracted from the spleen of horses infected with EIA virus was purified by pH treatment, (NH4)2SO4 fractionation and affinity chromatography. The homogeneity of the antigen was indicated by sedimentation rate and sedimentation equilibrium experiments. A S20,w of 0.51 was determined and a molecular weight of 7600 was calculated from sedimentation equilibrium analysis. The amino acid composition of the pure antigen indicated the antigen is an acidic protein. Employing radical immunodiffusion (RID) and pure antigen a method for quantitating antigen content of antigen containing preparations was developed.


Hydrogen donor system for Escherichia coli ribonucleoside-diphosphate reductase dependent upon glutathione. E. coli B tsnC 7004, an E. coli B/1 mutant with normal phenotype unable to replicate phage T7 DNA [Chamberlin, M. (1974)J. Virol. 14,509-516], contained no detectable level of thioredoxin when assayed with ribonucleotide reductase (2'-deoxyribonucleoside-diphosphate:oxidized-thioredoxin 2'-oxidoreductase, EC 1.17.4.1). Gently lysed E. coli tsnC 7004 cell extracts reduced CDP when supplemented with NADPH as efficiently as the parent strain E. coli B/1 despite the lack of thioredoxin, indicating the presence of another hydrogen transport system. This could be divided into two parts by heat treatment at 85degrees; one heat-stable fraction, which was active in the presence of dithiothreitol or glutathione, and one heat-labile fraction. Addition of yeast glutathione reductase [NAD(P)H:oxidized-glutathione oxidoreductase, EC 1.6.4.2] to the heated extracts restored full activity. The results demonstrate a novel hydrogen transport system in E. coli consisting of NADPH, glutathione, glutathione reductase, and a heat-stable enzyme called "glutaredoxin". Reduced glutathione at physiological concentrations functions as hydrogen donor for ribonucleotide reduction only in the presence of glutaredoxin. Glutaredoxin was not reduced by E. coli thioredoxin reductase (NADPH:oxidized-thioredoxin oxidoreductase, EC 1.6.4.5) and showed no crossreaction with antibodies against thioredoxin. These results demonstrate the existence of two different electron transfer systems from NADPH to deoxyribonucleotides and provide a function for glutathione in DNA synthesis.


Dietary and hormonal regulation of the content of acetyl coenzyme A carboxylase-synthesizing polysomes in rat liver. Specific polysomes involved the the synthesis of acetyl-CoA carboxylase [acetyl-CoA: carbon-dioxide ligase (ADP-forming), EC 6.4.1.2] have been identified by the binding of 125I-labeled antiacetyl-CoA carboxylase to rat liver polysomes. The binding is highly specific and occurs through the recognition of the nascent peptide chains on polysomes. With the use of the 125I-labeled antibody binding technique, it has been demonstrated that the relative content of acetyl-CoA carboxylase-synthesizing polysomes in the liver correlates well with the rate of hepatic synthesis of the enzyme in rats subjected to different dietary conditions as well as in alloxan-diabetic rats with or without insulin treatment.


gamma-Glutamyl transpeptidase, a lymphoid cell-surface marker: relationship to blastogenesis, differentiation, and neoplasia. gamma-Glutamyl transpeptidase, an enzyme that catalyzes gamma-glutamyl transfer from gamma-glutamyl compounds to amino acid and peptide acceptors, and which is known to be localized in the membranes of many epithelial cells, was found in a variety of lymphoid cells. The lymphoid cell enzyme is located on the cell surface, and exhibits substantially the same substrate specificity as the enzyme found in epithelial cells. Human and rat (but not mouse) lymphocyte gamma-glutamyl transpeptidase was stimulated by treatment of the cells with mitogens. Normal human peripheral B-cells were more active than T-cells, but the reverse relationship of activities was found in chronic lymphocytic leukemia lymphocytes. Human lymphoblastic lines vary markedly in activity. In general, cell lines with B- and T-characteristics from patients with lymphoproliferative diseases had much lower activities than those of B-cell lines derived from normal subjects. The highest activity found was in a human myeloma line active in synthesis of an immunoglobulin light chain. The data indicate that gamma-glutamyl transpeptidase is a surface marker reflecting differentiation in normal and neoplastic cells.


[Allergic vasculitis].

[Allergic vasculitis]. Cutaneous allergic vasculitis alone or combined with a systemic condition is of interest to the phlebologist when it occurs in the leg. All the clinical and paraclinical examinations must be oriented towards looking for infection, toxaemia, or even a so-called auto-immune disease. Treatment, although rarely very successful as regards the etiology, includes a considerable range of therapeutic possibilities, e.g. vasculotropic and anti-inflammatory drugs and immunosuppressive chemotherapy, to induce rapid sedation and often definitive cure.


Economizing with psychotropic drugs.

Economizing with psychotropic drugs. Every health practitioner can reduce the cost of his treatments without compromising their quality. A review of the magnitude of the cost problem with regard to psychotropic drugs, variables which affect cost, the methods by which the clinician can manipulate the variables to reduce costs, and the application of these methods to the major classes of psychotropic drugs will show that substantial savings can be achieved easily and with no sacrifice in efficacy.


Liver enzymatic induction after repeated or prolonged stress. Changes in liver tyrosine aminotransferase induction were measured in mice after repeated or prolonged stressing. In the repeated chloroform stress variant the first impulse determines the amplitude of TAT induction; the second stress can only produce superinduction if repeated 40 minutes after the onset of the first one. In the prolonged irradiation stress variant the response was dependent on both the dose rate and duration of irradiation.


[Lithium tremor-combination treatment with beta receptor blockaders]. In addition to the various possibilities of influencing lithium tremor, experience gathered from the application of beta-receptor blockers is reported, and concepts investigated on the potential genesis and working mechanisms.


Intracranial self-stimulation in rats as a function of various stimulus parameters. VI. Influence of fentanyl, piritramide, and morphine on medial forebrain bundle stimulation with monopolar electrodes. The effects of different subcutaneous doses of fentanyl (0.02, 0.04, 0.08, and 0.16 mg/kg), piritramide (0.63, 2.50, 10.0 and 40.0 mg/kg), and morphine (2.50, 5.00, 10.0 and 20.0 mg/kg) on self-stimulation in rats were studied. Different stimulus parameter combinations (SPC) inducing low, high or intermediate control response rates (CRR) were applied during the same experimental sessions. The three narcotic analgesics induced response depression (RD) and response stimulation (RS). RS was mostly observed at low dose levels; RD was dose-related. SPC's inducing low CRR were more sensitive than those inducing high CRR. Fentanyl was more potent than piritramide and than morphine. The RD is related to motor incapacitation, as the doses needed to effectively reduce self-stimulation also induced obvious catatonia. The RS probably is a more specific effect reflecting sensitization of structures involved in reinforcement of behavior.


[Wet dog shake behavior in normal rates, elicited by benzylideneaminooxycarbonic acid derivatives]. Wet dog shake (WDS) behavior in rats, well known as morphine-withdrawal syndrome, could be elicited without concomitant symptoms for the first time chemically in non-morphine-addicted animals. The capability to produce WDS was correlated with a specific chemical structure among the title-compounds. The threshold-dose of the most effective agents was 25-50 mg/kg, rather independent of the mode of application. Maximal response of 10-20 WDS per min and animal were reached after application of 100-200 mg/kg. WDS behavior appeared within the first minutes after dose and lasted up to several hours. Detailed information is given on WDS-action of the substance Sgd 8473 = alpha [(4chlorobenzylideneamino)-oxy]-isobutyric acid and the influence by different pharmacologie agents thereon. Inhibition of WDS was produced by: narcotic analgesics, narcotic antagonists, psychosedativ drugs, yohimbine, dl-amphetamine, cocaine, apomorphine and clonidine. Without influence on WDS were: physostigmine, atropine, ganglionic- or adrenergic-blocking drugs, Dopa, MAO-inhibitors, serotonin- and histamin-antagonists and nonnarcotic analgesics. To some extent chemically induced WDS seemed to be susceptible like precipitated WDS. So Sgd 8473 could be qualified for differentiating narctic analgesics, for a "quasiabstinence" agent in research of dependence mechanisms and for a tool in neuroanatomical studies of the CNS.


Changes in excitability of amygdaloid and septal nuclei induced by medazepam hydrochloride. Electrical stimulations of the central and basolateral part of the amygdaloid complex and of the septum in freely moving cats elicit changes in arterial pressure (i.e., an increase in pressure during stimulation of the central part of the amygdala, and a decrease followed by an increase during stimulation of the basolateral part of the amygdala and of the septum). These changes within the cardiovascular system are followed by rage reactions when the central part of the amygdala is stimulated, defense patterns when the basolateral part of the amygdala is stimulated, and pitiful mewing as a result of septal stimulation. Medazepam hydrochloride in a dose of approximately 15 mg/kg i.v. given over a period of 3 h, in order to maintain constant blood levels of the drug, attenuated slightly the cardiovascular reactions and elevated markedly the thresholds for psychomotoric behavior. The latencies between the onset of electrical stimulation and the beginning of the increase in arterial pressure were only slightly increased, whereas the latencies for spychomotoric behavior were markedly prolonged due to drug application. The data support the view that medazepam hydrochloride exerts depressant effects on the limbic-hypothalamic level with respect to psychomotoric responses. The effect was not identical for all nuclei tested. The basolateral part of the amygdala was significantly less sensitive to medazepam hydrochloride than the central part of the amygdala.


Hormonal influences of the extinction of conditioned taste aversion. Conditioned taste aversion for a 5% glucose solution (sugar water) was induced in rats by an i.p. injection of LiCl 30 min after the first presentation of sugar water. Extinction of conditioned taste aversion was measured either in the forced-drinking test or in the preference-drinking test. In the forced-drinking test sugar water was the only fluid presented to the animals during extinction sessions. In the preference-drinking test the animals had the choice of tap water or sugar water. The rate of extinction was much slower in the preference test. The ACTH-analogues, ACTH 4-10 and ACTH 4-10 7d Phe, and alpha-MSH delayed extinction in the preference test but not extinction in the forced-drinking test. ACTH 11-24 was without any effect. MSH-release inhibiting factor (MIF) facilitated extinction in the forced-drinking test but did not alter extinction in the preference test. The peptides did not affect intake of tap water of preference of sugar water over tap water by control rats.


Studies on the effects of histaminergic agents on seizure susceptibility in mice. The influence of pharmacological modifications of the functional activity of the central histaminergic system was studied on the susceptibility of mice to pentylenetetrazol-induced minimal (clonic) and maximal (tonic) seizures. Enhancement in the functional activity of the system by central administration of histamine or 4-methylhistamine of peripheral L-histidine loading failed to modify the risk of seizures. By contrast, reduction in histaminergic function was found to alter seizure susceptibility. Brocresine, an inhibitor of histamine synthesis, decreased and increased the risk of pentylenetetrazol-induced minimal and maximal seizures, respectively. Many, but not all, classical anti-histamines (H1 antagonist) and metiamide (H2 antagonist) and metiamide (H2 antagonist) increased minimal seizure susceptibility after periheral and intraventricular administration, respectively.


[The treatment of polyphobic disturbances (author's transl)]. Clinically a combination of phenothiazine derivatives or thymoleptics with behavior-therapeutic techniques (systematic desensitation or assertive training) have proved effective in the treatment of polyphobic disturbances. Among the underlying theoretical considerations the level of activation achieves particular importance.


Drug inhibition of ecto-ATPase and of phagocytosis in leukocytes. Substituted phenothiazines and tricyclic antidepressants which inhibited the ecto-ATPase in leukocytes also markedly decreased the phagocytic activity of these cells. In affecting either the enzyme or phagocytosis the order of potency of the drugs was similar. Various other CNS drugs were ineffective. The results suggest possible involvement of ecto-ATPase in the phagocytic process, and indicate adverse effects of the aforelisted drugs on the host defense system against foreign materials, including microbes.


The excretion of phylloerythrin and bilirubin by calves and sheep. Under general anaesthesia the common bile duct was ligated in two sheep and two calves. Occlusion of the duct was permanent and was followed by portal fibrosis, proliferation of bile ducts and intrahepatic bile stasis. Mild hepatic cell damage was accompanied by the release of glutamate dehydrogenase, sorbitol dehydrogenase and arginase into serum. The release of gamma-glutamyl transpeptidase was slower but more continuous. One sheep and one calf developed peritonitis associated with the leakage of bile from a biopsy wound in the live. One of these animals and the other two on which biopsy was not performed became photosensitised on exposure to sunlight. The concentration of phylloerythrin was high in serum and urine. All animals became jaundiced and the increased concentration of bilirubin in serum and urine was mainly direct reacting, ie, conjugated with glucuronic acid.


Properties of Fcgamma receptors in normal and malignant human tissues. Properties of the IgG receptors were studied by treating tissue sections or suspensions of peripheral mononuclear cells with various chemical reagents and determining changes in their ability to react with IgG-sensitized erythrocytes (EA). A heterogeneity of the Fc receptors was revealed. Iodoacetamide, 2-mercaptoethanol, sodium azide, EDTA, and a pH varying from 6.0 to 8.2 had no effect on Fc receptors in sections of normal lymphoreticular tissue and malignant tissue. Formaldehyde, low pH, and high salt concentrations affected receptor activity to various degrees. Receptors in liver sections and on monocytes were generally more resistant than receptors in spleen sections and on B lymphocytes. Receptors in malignant tissue behaved either like receptors in spleen or like receptors in liver. Although all tissues were sensitive to periodic acid, the Fc receptors in malignant tissue were always more resistant.


Induction of tyrosine 3-monooxygenase in adrenal medulla: role of protein kinase activation and translocation. The transsynaptic induction of tyrosine 3-monooxygenase (TH) in rat adrenal medulla is preceded by an early increase in the ratio of cyclic adenosine monophosphate (AMP) to cyclic guanosine monophosphate, an activation of cytosol cyclic AMP-dependent protein kinase, and a subsequent translocation of protein kinase catalytic subunits from cytosol to subcellular particles. As a result of this translocation, nuclear protein kinase activity increases during the induction of TH. Transection of splanchnic nerve reverts these events and prevents the induction of TH. Thus, adrenal medulla activation and translocation of cyclic AMP-dependent protein kinase may act as a long-range messenger for the genetic regulation of TH synthesis.


Calcium-independent modulation of cyclic GMP and activation of guanylate cyclase by nitrosamines. Nitrosamines markedly increase concentrations of guanosine 3', 5' - monophosphate (cyclic GMP) in several tissues from the rat and in human colonic mucosa. These agents are effective in the absence of extracellular calcium and enhance guanylate cyclase activity in tissue homogenates. Stimulation of cyclic GMP was greatest in liver, where the carcinogenic activity of nitrosamines is also most pronounced.


Isoniazid and iproniazid: activation of metabolites to toxic intermediates in man and rat. Acetylhydrazine, a metabolite of isoniazid, a widely used antituberculosis drug, and isopropylhydrazine, a metabolite of iproniazid, an antidepressant removed from clinical use because of high incidence of liver injury, were oxidized by cytochrome P-450 enzymes in human and rat liver microsomes to highly reactive acylating and alkylating agents. Covalent binding of these metabolites to liver macromolecules paralleled hepatic cellular necrosis. The metabolites formed from these and probably other monosubstituted hydrazines are reactive electrophiles.


Modulation of synaptic transmitter release by repetitive postsynaptic action potentials. The effect of repetitive action potentials in the postsynaptic axon on the release of synaptic transmitter from the presynaptic terminal was investigated at the squid giant synapse. Repetitive antidromic stimulation of the postsynaptic axon resulted in a reduction in the excitatory postsynaptic potential (EPSP). The reduction in transmitter release was accompanied by a decrease in the presynaptic spike after-hyperpolarization (AH). Increasing the concentration of extracellular potassium ions also reduced the EPSP and decreased the amplitude of the presynaptic spike AH. The reduction in transmitter release resulting from repetitive postsynaptic impulses is attributed to the accumulation of extracellular potassium ions. It is proposed that the accumulation of extracellular potassium ions resulting from repetitive postsynaptic activity may modulate synaptic transmission and function as an integrative mechanism in the nervous system.


Laryngeal microsurgery without intubation. Reviewed are 200 cases in which endolaryngeal suspension microsurgical procedures were done using intravenous anesthesia and Venturi insufflation oxygenation. Patients included 177 adults and 23 children, ranging in age from 20 months to 88 years. No significant complications were observed. The technic allowed the glottic space to remain free of cumbersome intraluminal apparatus. Arterial blood studies revealed that adequate oxygenation is achieved while normal pH and PaCO2 levels are maintained.


Food-drug interactions and interference. Examples are given of interactions between foods and drugs, some of which may on occasion produce adverse effects. Such interactions are not as frequent and rarely as significant as interactions between drugs, which have become of increasing interest and importance.


Granulomatous glomerulonephritis and fulminant polyarteritis nodosa in a child. The clinical and histological findings in a 12-year-old Black child with microscopic polyarteritis nodosa are presented. Particular attention is drawn to the unusual appearance of granulomatous glomerulonephritis.