Effects of various diuretic agents in the mouse. Diuretic effects of seven orally-acting diuretic agents have been examined in the mouse. The following compounds, examples of various types of orally active compound available, produced their characteristic diuretic effects: bendrofluazide, frusemide, ethacrynic acid, acetazolamide, triamterene, aminophylline and Su 15049A. The diuretic effects of the various agents were demonstrated under both water and saline-loading conditions. After allowing for differences in baseline sodium excretion, all diuretics except acetazolamide caused a further enhancement of sodium excretion after saline-loading compared with water-loading tests. The mouse possesses several advantages over the more commonly used rat since the range of diuretic responsiveness is greater. These results suggest that the mouse is a suitable species for diuretic testing.


Effects of animal maturity on smooth muscle and blood pressure responses to prostaglandins E2 and F2alpha. The effects of prostaglandins E2 (PGE2) and F2alpha (PGF2-alpha) on muscle strips from mature and immature rats and guinea-pigs and on rat blood pressure were investigated in the presence of atropine. The colon and stomach strips from immature rats were equally responsive to PGE 2 and PGF2alpha where mature colons were significantly more sensitive to PGF2ALPHA AND MATURE STOMACH STRIPS SIGNIFICANTLY MORE SENSITIVE TO PGE2. On the ileum from immature guinea-pigs the maximum responses to PGE2 and PGF2alpha were 16 and 8% of the histamine maximum respectively. The corresponding figures on the mature ileum were 86 and 75%. Whereas PGE2 was only twice as active as PGF2alpha on immature ilea, it was ten times more active than PGF2alpha on mature muscles. On blood pressure PGF2alpha and PGE2 were both hypotensive in immature rats whereas PGE2 was hypotensive and PGF2alpha hypertensive in mature rats. The results suggest that as the animal gets older, receptors for prostaglandins became increasingly differentiated.


Actions of the muscle relaxant chandonium iodide on guinea-pig ileum and vas deferens preparations. The effects of the newly synthesized neuromuscular blocking agent, chandonium iodide (17a-methyl-3beta-pyrrolidino-17a-aza-D-homo-5-androstene dimethiodide) have been investigated on guinea-pig isolated ileum and vas deferens preparations. On the ileum, chandonium (0-1-10-0 mug ml(-1); 1-6 X 10(-7) M-1-6 X 10(-5) M) had weak muscarinic receptor blocking action (pA2 is 5-7), but no antihistamine properties at the concentration tested. No evidence for anticholinesterase actions was found. On the vas deferens, chandonium (10-50 mug ml(-1); 1-6-8-1 X 10(-5) M) potentiated responses to exogenous noradrenaline; responses to electrical stimulation were potentiated only in the presence of 50 mug ml(-1) chandonium. No adrenoceptor or adrenergic neuron blockade was found. The results provide evidence that chandonium acts selectively at acetylcholine receptors and that it is more active as a nicotinic receptor antagonist than as a muscarinic receptor antagonist.


A comparative study of the effect of bile salts on the absorption of quinalbarbitone sodium in goldfish. The goldfish has been used as a model membrane to estimate the absorption of quinalbarbitone sodium by measurement of overturn time. The effect of sodium cholate, sodium deoxycholate, sodium chenodeoxycholate and sodium taurodeoxycholate on the quinalbarbitone-induced overturn time has been investigated and differences in capacity to promote absorption have been demonstrated. These differences could not be attributed to variations in solubility or partitioning of the drug within the membrane by the bile salts or to the relative hydrophobicity of each molecule. It is suggested that the bile salts must in someway affect the integrity of the goldfish membrane rendering it more permeable to quinalbarbitone sodium.


Gels in soap stabilized emulsions.

Gels in soap stabilized emulsions. In some soap stabilized liquid paraffin emulsions a correlation has been found between emulsion type and the contact angle of the soap gel (the stabilizing agent) at the o/w interface. Two unrelated series of emulsions have been prepared, one series being stabilized by magnesium oleate gels and the other series by ammonium oleate gels. The soap gels were prepared by double decomposition and suppression of ionization respectively. Unlike the magnesium oleate system no inversion to w/o emulsions occurred with the ammonium oleate series. This dissimilarity is predicted from differences in the contact angles of the soap gels at the o/w interface.


The effect of waxes, hydrolysed gelatin and moisture on the compression characteristics of paracetamol and phenacetin. Stearic acid or hard paraffin added to crystals of paracetamol and phenacetin reduced capping of tablets prepared by direct compression but did not produce acceptable tablets because the inter-particular bonds were very weak. The pressure cycle that can be constructed form the measurement of the axial pressure and the corresponding die wall pressures offers information that is useful in the formulation of the tablets. The behaviour of paracetamol or phenacetin and their mixtures with gelatin hydrolysate or water or both shows a similarity to a Mohr body and it appears that the maximum die wall pressure is affected by the particle size of the material compressed and also by the additives present. Good transmission of radial force implies that the material can be initially consolidated, but alone it does not indicate that the tablet formed is physically stable. When the tablet formed remains coherent after the axial pressure is removed the residual die wall pressure remains high. Measurement of the residual die wall pressure might therefore be a useful indicator for identifying satisfactory formulations of substances that cap readily. Hydrolysed gelatin or water or both together produced paracetamol and phenacetin mixtures with satisfacotry compression characteristics.


Effect of disintegrant type upon the relationship between compressional pressure and dissolution efficiency. Four tablet disintegrants: a relatively insoluble sodium carboxymethyl cellulose, casein formaldehyde, calcium carboxymethyl cellulose and a cross-linked polyvinylpyrrolidone have been evaluated. Three widely used disintegrants, sodium carboxymethyl cellulose, sodium starch glycolate and a cation exchange resin were included for comparison. The effect of compressional pressure on the disintegration and dissolution behaviours of a soluble and an insoluble system containing different disintegrants were examined. The results show that disintegrant type can have a pronounced effect upon the relationship between compressional pressure and dissolution efficiency. The significance of this relationship is discussed in terms of the properties of disintegrants and the differing mechanisms by which they act.


Changes in crystallinity and solubility on comminution of digoxin and observations on spironolactone and oestradiol. Using infrared spectroscopy, X-ray diffractometry, differential thermal analysis, scanning electron microscopy, solubility and dissolution rate measurements, it was demonstrated that the comminution of digoxin results in the appearance of an amorphous phase. The examination of spironolactone and 17 beta-oestradiol by infrared spectroscopy and differential thermal analysis showed that these compounds also undergo changes in their crystallinity on grinding. Since the dissolution characteristics of poorly soluble drugs may be complex functions of surface area and crystallinity, it is concluded that the most pertinent method for standardizing a sample of a polymorphic drug of low solubility is by means of a powder dissolution test, as the results embrace the influences of particle size, aggregation and polymorphism.


Comparative stability of cephalosporins in aqueous solution: kinetics and mechanisms of degradation. The acidic, neutral, and alkaline degradations of six therapeutically useful cephalosporins (cephalothin, cephaloridine, cephaloglycin, cephalexin, cephradine, and cefazolin), 7-amino-cephalosporanic acid, 7-aminodeacetoxycephalosporanic acid, and some 7-substituted derivatives were followed by high-pressure liquid chromatographic, UV spectrometric, iodometric, and hydroxamic acid assays. The pH-rate profiles were determined at 35 degrees and mu = 0.5. The acidic degradation pathway for the 3-acetoxymethyl and 3-pyridinylmethyl derivatives was the specific hydrogen-ion-catalyzed hydrolysis of the beta-lactam bonds. The beta-lactam hydrolyses of these antibiotics exhibited half-lives of about 25 hr at pH 1.0 and 35 degrees. The acetyl functions of 3-acetoxymethylcephalosporins were hydrolyzed eight times faster than their beta-lactam moieties to yield the corresponding deacetyl intermediates, which were rapidly converted to the lactones. Deacetoxycephalosporins were fairly acid stable; e.g., cephalexin and cephradine were about 25 times more stable than cephalothin, cephaloridine, and cephaloglycin and about 180 times more stable than ampicillin at pH 1.0. In the neutral degradation of 3-acetoxymethyl compounds, the competitive reactions of the direct water attack and intramolecular catalysis by the side-chain amido upon the beta-lactams were proposed. The pH-rate profiles near pH 8 for cephaloglycin, cephalexin, and cephradine could be explained by the intramolecular-nucleophilic attack of the side-chain alpha-amino group upon the beta-lactam carbonyls to produce diketopiperazine-type compounds. The reactivity of the cephalosporins in the hydroxideion-catalyzed degradation was influenced significantly by the C-3 methylene substituents.


Simultaneous semiautomated assay of pyrrobutamine phosphate, cyclopentamine hydrochloride, and methapyrilene hydrochloride in pharmaceutical mixtures. Antihistamine preparations containing methapyrilene hydrochloride, pyrrobutamine phosphate, and cyclopentamine hydrochloride were assayed by introducing an aqueous sample solution into the appropriate automated system. Methapyrilene hydrochloride was determined by UV spectrophotometry. Pyrrobutamine phosphate was extracted as an ion-pair and quantitated colorimetrically by forming the bromcresol purple acid-dye complex. Cyclopentamine hydrochloride was determined colorimetrically by using the copper dithiocarbamate reaction for secondary amines.


Effect of polymers on dissolution from drug suspensions. The effect of three viscosity grades of methylcellulose on the dissolution-dialysis rate of nitrofurantoin suspensions was investigated using a cell designed to provide a large surface area for dialysis. Apparent dialytic rate constants of drug dispersions and solutions were measured in 0.1 N HC1 and in pH 7.4 buffer. Samples containing methylcellulose had lower rates of dialysis, with the lowest rate being observed for samples in which the polymer was used as the suspending agent. The reduced rate of dialysis of the drug suspension containing methylcellulose is thought to be due to complexation of the drug in solution with the polymer as well as formation of microscopic regions of high viscosity surrounding the undissolved drug particles leading to a reduction in the dissolution rate of the drug. An empirical relationship was obtained to enable the estimation of the effective drug concentration in the dissolution chamber for drug dispersions. The method is based on utilizing dialysis rate data of drug solutions. This relationship could be used for comparing suspension formulations in terms of the amount of drug available for dialysis.


Biotransformation of drugs: quantitative structure-activity relationships for barbiturates, tertiary amines, and substituted imidazoles. When using free energy-related physicochemical parameters, stimulation of NADPH oxidation by barbiturates and the N-oxidation of tertiary amines was found to be primarily dependent upon the lipophilic character of the substrates as measured by log P, where P is the partition coefficient from either 1-octanol-water or corn oil-water solvent systems. In contrast, the inhibition of epoxidation of aldrin by a series of substituted imidazoles appears to be much more dependent on electronic (sigma) and steric (Es) effects of the inhibitors.


Effect of topically applied pilocarpine on tear film pH. Changes in tear film pH were observed during the 1st hr after instillation of pilocarpine in various dosage forms to the rabbit eye. In anesthetized rabbits, with periodic blinking induced electrically, commercial formulations of pilocarpine salts applied as drops or a spray acutely lowered tear film pH by 1.1-1.6 pH units. The pH remained below pretreatment levels for 45-greater than 60 min after instillation. Pilocarpine base, administered continuously at the rates of 20 or 80 mug/hr from ocular therapeutic systems, had little or no effect on tear film pH in this same animal preparation. The reduction in tear film pH produced by pilocarpine eyedrops or spray solution is attributable to the acid pH and buffer capacity of these solutions. Delivery of pilocarpine base without pH change was achieved with ocular therapeutic systems, because the drug (pKa = 7.07) was delivered free, or virtually so, of excipients. These observed differences in tear film pH after application may partially explain the four- to eightfold reduction in total effective pilocarpine dose with ocular therapeutic systems compared to eyedrops or spray, since the cornea is less permeable to ionized than to unionized molecules.


Effect of formulation of intramuscular injections of phenothiazines on duration of activity. Trifluoperazine and pericyazine were formulated using both the hydrochloride and embonate salts, and some comparisons were made with the activity of fluphenazine salt and ester formulations. Simple solutions in polyethylene glycol, gelled aqueous solutions, nonaqueous suspensions, multiple emulsions, and microencapsulated preparations were formulated, and their duration of activity was tested in dogs. While the multiple emulsion system showed some promise, a nylon microcapsule system produced significant prolonged activity of the drug after deep intramuscular injection.


Pulmonary absorption studies utilizing in situ rat lung model: designing dosage regimen for bronchial delivery of new drug entities. The absorption of 7-methylsulfinylxanthone-2-carboxylic acid, 7-(methylthio)xanthone-2-carboxylic acid, and their sodium salts from the respiratory tract of anesthetized rats was studied after intratracheal administration of 0.1 ml of a solution or suspension containing the drug. At various times after administration, the lungs and trachea were removed and assayed radiochemically for unabsorbed drug. Sodium 7-(methylthio)xanthone-2-carboxylate from solution was absorbed approximately 20 times faster than sodium 7-methylsulfinylxanthone-2-carboxylate from a solution. The absorption from solutions was three to four times faster than the absorption from suspensions. For inhalation aerosol dosage  forms intended for prophylactic use, the drug entity with slower systemic absorption probably would be more desirable than the drug entity with rapid absorption. Rapid systemic absorption following inhalation of powder or liquid aerosols would lead to more frequent dosing if the biological activity is related to the drug concentration in the tracheobronchial tissues. Therefore, the powder or liquid inhalation aerosols of organic acids rather than the corresponding sodium salts may be preferable for designing a dosage regimen. However, if the dosage form is intended for utilizing the bronchodilator activity of the compound, the drug entity with rapid absorption is more desirable. Therefore, in the treatment of asthmatic attacks, liquid or powder inhalation aerosols of the sodium salt of the rapidly absorbing drug entity are preferable. The absorption rates were directly proportional to concentration when the initial concentration of sodium 7-methylsulfinylxanthone-2-carboxylate was varied over a 333-fold range. The effect of the pH of the drug solution administered intratracheally to the rat lung indicated a sharp increase in the pulmonary absorption at a pH near the pKa. The results suggested that structurally related xanthones are absorbed possibly by passive diffusion across the lipoidal region of the pulmonary membranes and that the absorption of organic acids and organic electrolytes is mainly controlled by the lipid solubility of the unionized species.


Colorimetric assay for guaiacol O-methyltransferase. A relatively simple colorimetric assay was developed for guaiacol O-methyltransferase. Monomethylated phenolic acid substrates are enzymatically methylated to their corresponding dimethoxyl compounds; S-adenosylmethionine serves as the methyl donor. Enzymatic activity is measured by colorimetric assay of the monomethylated (nonreacted) substrate by coupling of the phenolic acid with a diazotized sulfanilic acid. The methoxyl and hydroxyl groups may be in the 3,4- or 4,3-positions on the substrate molecules; however, a side chain (COOH) or a substituted side chain is necessary for enzyme action. The radioactive demonstration of guaiacol O-methyltransferase as a separate entity from catechol O-methyl-transferase was confirmed.


Investigations on metabolic modulation of p-aminohippurate accumulation by rabbit renal cortical slices. Preparation and incubation of renal cortical slices from adult, female, New Zealand white rabbit depleted tissue citrate concentration. Acetate (10.0 mM) in the incubation significantly increased slice citrate concentration and p-aminohippurate (PAH) accumulation. Physiological concentrations of citrate increased PAH accumulation and final medium pH. increasing concentrations of citrate produced a biphasic effect on PAH accumulation. These data suggested that citrate may act as an intracellular modulator of organic anion transport. This hypothesis was tested with other stimulators of PAH accumulation. Physiological concentrations of alpha-ketoglutarate or succinate increased slice accumulation of PAH. Higher concentrations of either substrate significantly inhibited PAH accumulation. Final medium pH increased with increased medium concentration of both substrates. alpha-Ketoglutarate (0.5 mM) increased PAH accumulation but had no effect on slice citrate concentration. Glucose did not alter either PAH accumulation or slice citrate concentration. Slices incubated without substrate were depleted of citrate but not of alpha-ketoglutarate. Acetate (1.0 mM) significantly increased slice concentration of both alpha-ketoglutarate and citrate. These data suggested that organic anion transport could be modulated by several metabolic intermediates acting through similar but separate mechanisms.


Properties of the larval neuromuscular junction in Drosophila melanogaster. The anatomy and physiology of the Drosophila larval neuromuscular junction were studied. 2. The dependence of muscle resting potentials on [K+]o and [Na+]o follows the Goldman-Hodgkin-Katz equation (PNa/PK=0-23). Chloride ions distribute passively across the membrane. 3. The mean specific membrane resistance of muscle fibres is 4-3 X 10(3) omega cm2, and the mean specific membrane capacitance is 7-1 muF/cm2. The muscle fibre is virtually isopotential. 4. Transmitter release is quantal. Both the miniature excitatory junctional potential and the evoked release follow the Poisson distribution. 5. Transmitter release depends on approximately the fourth power of [Ca2+]o. If Sr2+ replaces Ca2+, it depends on approximately the fourth power of [Sr2+]o. Mg2+ reduces transmitter release without altering the fourth power dependence on [Ca2+]o.


The effects of pH changes on the frequency of miniature end-plate potentials at the frog neuromuscular junction. As reported by Landau & Nachshen (1975), a decrease in extracellular pH at the frog neuromuscular junction leads to an increase in min.e.p.p. frequency. 2. Decreasing the extracellular pH still increases the min.e.p.p. frequency when the bathing Ringer contains 10 mM-Ca2+, in place of the usual 2-5 mM. At the mammalian neuromuscular junction, the elevated Ca2+ blocks the effect of the pH change on the min.e.p.p. frequency (Hubbard, Jones & Landau, 1968). 3. In Cl--free solution (isethionate or methylsulphate substitution) min.e.p.p. frequency is no longer a monotonic function of decreasing pH. Instead there is an optimum pH for spontaneous release between pH 6-6 and 8-6. 4. This suggests that in Cl- containing Ringer min.e.p.p. frequency increases with increasing extracellular acidity because there is a change in the PCl of the nerve terminal leading to a depolarization. In agreement with this idea,in low Ca2+ Ringer, acid pH has little effect on the min.e.p.p. frequency. 5. Decreasing the intracellular pH by raising PCO2 produces substantial increases in the min.e.p.p. frequency. The effects are much greater than the effects of equal changes of H+ in the extracellular solution. 6. Possible explanations for the effects of increased PCO2 are discussed. Although release of Ca2+ from mitochondria or other unknown effects of intracellular pH change or molecular CO2 are possible, the results do give some support to the hypothesis that an important step in transmitter release involves an electrostatic repulsion between fixed membrane surface charges on the transmitter containing vesicles and the inner face of the nerve terminal. The surface charge density would be decreased by a lower pH in the axoplasm, and this would increase the rate of spontaneous transmitter release, in agreement with the observations.


The effect of local changes in potassium and bicarbonate concentration on hypothalamic blood flow in the rabbit. Blood flow has been measured locally in the hypothalamus of anaesthetized rabbits by measuring the clearance of small volumes (5-20 mul.) of a mock cerebrospinal fluid solution containing 133Xe. The effect of varying the [K+] or [HCO-3] of the 133Xe-containing solution on local hypothalamic blood flow has been investigated. 2. There was an increase in local hypothalamic blood flow if the 133Xe-containing solution was HCO3--free; raising the [HCO--3,] of the solution to 40 mM caused a fall in local blood flow. 3. There was an increase in local hypothalamic blood flow when 133Xe was injectedin a mock cerebrospinal fluid containing 10 or 20 mM-[K+]. There was no significant change in  blood flow if a K+-free or a 40 mM [K+] solution was used. 4. The decrease in hypothalamic blood flow caused by injecting a 40 mM-[HCO3] solution could be reversed by the addition of 20 mM [K+] to the solution. There was no further increase in blood flow if 20 mM-[K+] was added to a HCO3--free solution. 5. It is concluded that local blood flow in the hypothalamus changes as a result of variation in local [K+] as well as local [HCO-3]. The changes in blood flow in the brain which accompany neuronal activity could be mediated by variation in local [K+].


On the receptors which mediate the hyperpolarization of salivary gland cells of Nauphoeta cinerea Olivier. The actions of sympathomimetics and of catecholamine antagonists have been investigated on the membrane potential and responses to nerve stimulation of acinar cells of the salivary gland of Nauphoeta cinerea Olivier. 2. Hyperpolarizations such as those evoked by nerve stimulation and by low concentrations of adrenaline, noradrenaline and dopamine were not produced by the alpha-agonists amidephrine and methoxamine. Isoprenaline was active, but only in concentrations above 100 muM. 3. Tyramine, an indirectly acting sympathomimetic, and high concentrations of methoxamine caused an increase in the rate of the small transient hyperpolarizations sometimes seen in the absence of stimulation. 4. The response to nerve stimulation was unaffected by propranolol (20 muM) an alpha-adrenergic antagonist. Phentolamine, an alpha-adrenergic antagonist, reduced matching responses to nerve stimulation and to dopamine to about the same extent. 5. As on other systems responsive to low concentrations of dopamine, apomorphine was active, although only in high concentration, and ergometrine and methysergide were antagonistic both to nerve stimulation and to dopamine.


Heat treatment of laser-welded gold alloys. (1) Three alloys, G-3, SMG-2,  and Ceramco-0, showed no ductility in the aswelded condition. (2) The Ney G-3 as-welded samples had no ductility, but heat treating greatly increased their yield stress. (3) The simulated ceramic firing cycle created a small amount of ductility in SMG-2, but the lowering of the yield stress in Ceramco-0 renders the welds dangerously weak even with improved ductility. (4) The Jelenko F as-welded specimens were acceptable. Heat treatment improved the joints slightly, but this is not considered necessary. (5) The Ney B-2 as-welded specimens produced satisfactory joints which did not benefit from heat treatment. The large loss in ductility with heat treatment is considered undesirable. (6) The unpredictable behavior of Ceramco-0 in this study suggests the need to evaluate each alloy individually before clinical application.


Correlation of opiate receptor affinity with analgetic effects of meperidine homologues. The affinity for opiate receptor sites in brain tissue  in a series of N-substituted meperidine homologues has been compared with the analgetic potency of these compounds in mice. There is a good correlation between affinity for opiate receptor binding sites assayed in the presence of sodium and analgetic potency for homologues whose N-substituent has six or fewer carbons. The apparent discrepancy between the weak affinity of these drugs for opiate receptors and their fairly potent analgetic effects in vivo can be explained by meperidine's efficient penetration into brain.


Pharmacological activity of nitroxide analogues of dichloroisoproterenol and propranolol. Spin-labeled analogues of dichloroisoproterenol and propranolol were synthesized. It was found that the KD's of both probes for the beta-adrenergic receptors of frog erythrocytes were about 30-fold higher than the KD's previously reported for the parent antagonists. Thus the introduction of a bulky nitroxide moiety in place of the isopropyl group on the amino nitrogen is associated with a decrease in affinity for the beta-adrenergic receptors. Nonetheless, the affinity of the spin-labeled propranolol would appear to be within a range compatible with EPR measurements.


Cycloalkanones. 9. Comparison of analogues which inhibit cholesterol and fatty acid synthesis. A number of 2,8-dibenzylcyclooctanone analogues inhibited the HMG-CoA reductases activity of Holtzman male rat liver, whereas only 2-octanone, 2-hexadecanone, 2,8-dibenzylcyclooctanone derivatives, and 2-bis(4-chlorophenyl)-3,5-dimethyltetrahydro-4-pyrone inhibited fatty acid synthetase activity. 2-Octanone significantly lowered serum cholesterol, triglycerides, and glycerol levels in Holtzman male rats and serlm cholesterol in male CF1 mice. Serum lipase activity was significantly elevated in rats administered 20 mg/kg/day of 2-octanone for 16 days. The activity of liver HMG-CoA reductase was inhibited in mice administered 10 mg/kg/day of 2-octanone for 10 days and in mouse and rat liver in vitro by 10 mg of 2-octanone. In mice, fecal excretion of [14C]cholesterol and tripalmitin was accelerated whereas palmitic acid and cholesteryl oleate were not affected by 10 mg/kg/day of 2-octanone. The LD50 in male mice for 2-octanone was 1.6g/kg.


Structural characteristics of the saxitoxin receptor on nerve. The effects of uranyl ion (UO22+; at low concentrations binds specifically to phosphate groups) and the cationic dye methylene blue (MB+; binds strongly to carboxyl groups) on saxitoxin (STX) potency in crayfish axon has been studied by means of intracellular microelectrodes. At pH 6.00 +/- 0.05 and 13.5 mM Ca2+, addition of 10.0 muM UO22+ + 5.0 nM STX had only slightly, if any, less effect on the spike's maximum rate of rise [0.79 +/- 0.04 (viz., mean +/- SEM) of control value] than did addition of 5.0 nM STX alone (0.72 +/- 0.05). Under the same conditions of pH and Ca2+ concentration, 1.0 mM MB+ had approximately the same effect: 1.0 mM MB+ + 5.0 nM STX, 0.76 +/- 0.03; 5.0 nM STX alone, 0.70 +/- 0.04. However, at pH 7.00 +/- 0.05 and lower Ca2+ concentrations, 1.0 mM MB+ significantly reduced STX potency. Using 6.0 mM Ca2+: 1.0 mM MB+ + 5.0 nM STX, 0.92 +/- 0.01; 5.0 nM STX alone, 0.68 +/- 0.08. Using 3.0 mM Ca2+, the corresponding values were 0.94 +/- 0.03 and 0.67 +/- 0.04. It is concluded that: (1) In accord with previous suggestions, the ionized acidic group known to exist in the Na channel (and to which a guanidinium group of STX appears to bind) is very likely a carboxyl group and not a phosphate group. (2) The accessible part of the Na channel mouth serving as the saxitoxin receptor probably does not include phospholipid in its structure proper.


Ca binding to the human red cell membrane: characterization of membrane preparations and binding sites. Inside out and right side out vesicles were used to study the sidedness of Ca binding to the human red cell membrane. It was shown that these vesicles exhibited only a limited permeability to Ca, enabling the independent characterization of Ca binding to the extracellular and cytoplasmic membrane surfaces...


Influence of extracellular pH on the viability and morphology of tumor cells exposed to hyperthermia. The influence of hyperthermia (42.5 degrees C) on the viability and morphology of L1A2 ascites cells incubated at various pH levels (6.4-7.2) was studied. In contrast to unheated cells, increased extracellular acidity in hyperthermically treated tumor cells was associated with markedly reduced viability of the tumor cells exposed to hyperthermia. The cells heated at neutral pH underwent ultrastructural nuclear changes; the most prominent were the appearance of filamentous bundles and increased perichromatin granules. The cells heated under more acid conditions had an increased lysosomal activity and intense cell lysis resulting in lethal damage to the entire cell population within 6 hours after treatment. The active mechanism was not clear, but cell membrane lesions combined with the increased lysosome activity seemed of major importance in the mechanism of heat-induced damage to tumor cells kept in an acid milieu.


Estrogen-induced Leydig cell tumor in the mouse: a model system for the study of carcinogenesis and hormone dependency. Malignant neoplasms of endocrine tissues represent almost half of the cancers diagnosed clinically in the United States, and many of these respond to hormonal therapies. Estrogen-induced testicular Leydig cell tumors in the mouse would seem to represent a realistic model for the laboratory investigation of this significant group of cancers. Data accumulated over the past few years clearly show that the Leydig cell is a target tissue for estrogens. Administering large doses of estrogen results in a reduction of enzymes converting progesterone to testosterone and induces a transient, but quantitatively very significant, synthesis of DNA in the Leydig cells of tumor-susceptible strains of mice. Neither of these actions of estrogen is mediated via the hypophysis. It has been demonstrated that the Leydig cells have specific protein receptors in their cytoplasm that bind estrogens and transport them to the nucleus where they are also bound. The genetic composition of the Leydig cells themselves is extremely important for the development of tumors. An adequately functioning pituitary gland is also essential for tumor formation. Confining the testes to the abdomen results in enzyme changes similar to those produced by estrogen administration and significantly augments the development of Leydig cell tumors. Once tumors form they frequently are dependent for their continued growth on estrogenic stimulation and/or on a functioning hypothysis. Regressed tumors may remain dormant for many months only to resume progressive growth when placed in and adequate hormone environment.


Metabolism of diethylstilbestrol by rat liver: a preliminary report. Aerobic incubation of a misture of E[1,1,1-D3]-3,4;bis(p-hydroxyphenyl)-hex-3-ene admixed with an approximately equimolar amount of unlabeled diethylstilbestrol and [ 2-(14)C ] diethylstilbestrol with rat liver homogenates in the presence of NADPH yielded water-soluble metabolites as well as products more and less polar than the starting material. Addition of 5-adenosyl-L-methionine increased the quantity of nonpolar metabolites. Incubation with rat liver microsomes yielded similar results. When polar metabolites from incubation with rat liver microsomes were incubated with catechol O-methyltransferase and S-adenosyl[methyl-3 H]-L-methionine there was conversion to 3H-labeled nonpolar products. Examination of reaction products by means of gas chronatography-mass spectrometry gave evidence for the formation of a dihydroxydiethylstilbestrol, a dihydroxydienestrol, and a monomethoxydiethylstilbestrol.


Reflections on Second Annual NCTR Hormone Research Symposium. Hormones have widely different effects depending on species, dosage use, timing of dosage, route of administration, status of animals (re: pregnancy, stage of estrous cycle, age), and end point being measured. Hormones are essential to both maintenance and quality of life, and they occur in our environment with regularity. Hormones are seen by some persons as a regulatory dilemma because, when characterized under conditions of marked overdosage, the biological consequences are often undesirable. Because many of the naturally occurring hormones were identified long ago and have been studied for many decades, the reality is that much more knowledge is available on hormones than on more recently discovered substances, either naturally occurring or synthetic. The effects of hormones on tumors, either increases or decreases in incidence, appear to be indirect through alterations of normal physiological processes. The mechanism of action of hormones at the cellular level suggests that hormones are not involved in cancer by causing DNA changes, but in the degree of expression of changes in DNA that have occurred by other means. Key studies, especially at the molecular level, to further define the involvement of hormones in carcinogenesis should help us to define tolerance levels and aid with the regulatory dilemma.


Bromodeoxyuridine resistance induced in mouse lymphoma cells by microsomal activation of dimethylnitrosamine. Many chemicals are not mutagenic per se, but when metabolized by mammalian tissues yield mutagenic products. Dimethylnitrosamine (DMN) is such a promutagen. It has no effect on cell growth or mutant frequency when incubated alone with L5178Y mouse lymphoma cells, but exerts both mutagenic and toxic effects when incubated in a microsome reaction mixture. Microsomes were prepared from C3H/f We 16-wk-old male mice by the calcium preciptation technique. L5178Y continuously cultured mouse lymphoma cells heterozygous for thymidine kinase (TK+/-) were incubated for 15 min with calcium-precipitated microsomes and various concentrations of DMN in appropriate reaction mixtures. After a 48-hr expression time, treated cells were cloned in soft agar with and without bromodeoxyuridine (BUdR) (50 mug/ml); 10 days later colonies grown to greater than about 200 mum diameter were counted. The frequency of BUdR-resistant (mutant) colonies increased linearly with the DMN concentration. A reconstruction experiment showed that the assay conditions did not significantly alter the relationship between parent and BUdR-resistant cells in growth and cloning efficiency. The smallest dose of DMN used in these experiments was 100mumol/liter, the one-sided (100 mumol greater than control frequency) -p value is 0.036. The locus is extremely sensitive to mutagenesis by DMN compared with other known mutagens at similar levels of cell survival.


Absorption, utilization, and safety of aspartic acid. The dicarboxylic amino acids, asparate and glutamate, occupy unique positions in intermediary metabolism, particularly in the mitochondria, where they play important roles in nitrogen and energy metabolism. Administration of large quantities of glutamate and asparate to the newborn mouse produces a variety of neurotoxic effects, the most marked of which is neuronal necrosis. Neurotoxic effects of glutamate and aspartate in animal species other than the rodent are highly controversial. In the most critical animal species, the infant subhuman primate, at least four research groups have failed to duplicate the original report of glutamate-induced neuronal necrosis. Marked elevations in plasma glutamate or aspartate must occur for development of neuronal necrosis. In the highly sensitive neonatal mouse, plasma glutamate plus plasma aspartate levels must reach 60-80 mumol/dl to produce even minimal neuronal necrosis. In the healthy neonatal primate, loads producing plasma glutamate levels ranging from 50 to 1,600 mumol/dl failed to produce neuronal necrosis in our studies. Thus, it is clear that (1) marked elevations in plasma glutamate and aspartate must occur for neuronal necrosis, and (2) threshold levels required to produce neuronal necrosis vary greatly with species. The available data indicate little danger to the healthy primate and humans from ingestion of the dicarboxylic amino acids under anything resembling a reasonable intake. However, there is no doubt that these amino acids are toxic to the neonatal mouse at high dose levels.


Medex and their physician preceptors. Quality of care. Studies of selected indicators of the process of care provided by a Medex and by a physician preceptor in seven rural practices suggest that the Medex is more likely to use appropriate laboratory tests and less likely to use inappropriate treatments. When outcomes of care were determined in 13 practices with a Medex and a preceptor, the patients seen by the Medex tended to fare about as well as those seen by a physician (71% versus 74%, respectively) in regaining their usual functional status. The addition of a Medex to a rural practice may thus produce both direct and indirected benefits.


Benzodiazepines and withdrawal psychosis. Report of three cases. Three cases of acute psychotic illness following sudden withdrawal from high daily doses of benzodiazepines were associated with agitation and confusion. Disorientation was prominent in two of the patients. None of the patients had had previous psychotic episodes. The condition of all patients was reversed dramatically with hypnotic drugs. Gradual withdrawal was successfully accomplished without relapse, with a follow-up of as much as one year. To our knowledge, this is the first such series in the literature.


Calcium uptake, release and Mg-ATPase activity of sarcoplasmic reticulum from arterial smooth muscle. Sarcoplasmic reticulum (SR) isolated from rat aorta exhibited ATP dependent Ca2+ uptake in the presence of Mg2+. The maximum capacity and apparent binding constant were 23n moles/mg and 1.8 X 10(4) M (-1), respectively. The energy source of this active Ca2+ accumulation would be Mg-ATPase associated with the membrane. Ca2+ which was taken up inside of sarcoplasmic reticulum was released rapidly by washout with the medium containing no Ca2+. These facts suggest that sarcoplasmic reticulum in vascular smooth muscle cell may play and important role in the regulation of intracellular Ca2+ concentration.


Influence of transepithelial potential difference on acidification in the toad urinary bladder. The rate of urinary acidification by toad urinary bladders was measured in vitro by following the pH changes of the HCO3-/CO2-buffered Ringer's solutions bathing the mucosal and serosal sides of the bladder. Within the tolerated range of transepithelial potential differences (PD) (-100 to +100 mv), the rate of acidification was found to be a linear function of the PD. The rate of acidification could be increased by a favorable PD whether the PD was the spontaneous transepithelial PD due to sodium transport or a PD imposed in the absence of sodium transport, as when choline was substituted for Na or when amiloride blocked sodium transport. Acetazolamide inhibited both active and PD-driven acidification. Acidification rate was the same in 2.4 mM HCO3- and 1% CO2 as in 12 mM HCO3- and 5% CO2; again, acidification was increased equally by a favorable PD. PD-driven acidification was found to be linearly correlated with acidification occurring at short-circuit conditions. These findings suggest that the rate of acidification can be accelerated by the transepithelial PD in the absence of sodium transport and that the PD-driven component of acidification utilizes a transcellular pathway.


[Early neuro-ophthalmological symptoms of periarteritis nodosa. A case report (author's transl)]. A report is given on a 47-year-old woman with periarteritis nodosa. A unilateral retinopathy with disseminated cotton-wool-spots surrounded by retinal haemorrhages and edema was observed. Fluoresceinangiography showed a multifocal constriction of the retinal capillaries. This lesion of the retinal vessels can be distinguished from those caused by hypertension. An acute immunological reaction has been suggested as the pathogenesis. Some authors have described this retinal lesion in collagen diseases as a "toxic" retinopathy. We prefer the term acute immunological microangiopathy (AIM).


Isolated cortical granules: a model system for studying membrane fusion and calcium-mediated exocytosis. Cortical granules are secretory vesicles bound to the inner surface of the plasma membrane of sea urchin eggs. Intact granules can be isolated by shearing away the cytoplasm of eggs which have been bonded to a protamine-coated surface. When Ca2+ is added to preparations of isolated granules the granules fuse with each other and release their contents. It is believed that isolated cortical granules may be an excellent model system for the biochemical study of exocytosis.


[Current status of treatment and new aspects of the problems of the undescended testicle (author's transl)]. Early treatment of the undescended testicle was first demanded by Fischer, Bramann and Ramstedt early this century. From the 2nd year of life the number of the spermatogonia decreases rapidly, the diameter of the tubuli decreases, and distension and collaginization of the interstice are revealed by electron microscopy. The descended testis is also injured in unilateral maldescensus. The damage to the undescended testicle seen in the microscopic structure is secondary. Early treatment always begins with choriogonadotropin and only if this is not successful is surgery performed. Treatment with hormones and surgery guarantee normal development of the testicle. The results of follow-up studies show that fertility is favorably influenced by very early treatment.


[Morphologic changes in cryptorchism (author's transl)]. Histologic changes caused by malposition occur in the undescended testicle after the second year of life. Histologic changes like those seen in the human are found in experimental cryptorchism in dogs. The same pathologic changes also occur in the unilaterally descended testicle. The results of preliminary experiments in dogs allow the statement that in unilateral cryptorchism the damage to the contralateral, descended, testicle is produced by an autoimmunologic mechanism.


[Surgical technique in the management of undescenced testis (author's transl)]. In cases of retentio abdominalis or inguinalis and of ectopic testis, surgery is performed about the 2nd year of life. Essentials of the operating technique are: incision of the skin must not be parallel to the spermatic cord; testes and spermatic cord must be mobilized without trauma; ideally a biopsy of the testis should be taken; any pulling of the spermatic cord and torsion of it during fixation of the testis should be avoided. If initial tensionfree placement of the testis in the scrotum is impossible, the operation should be carried out in 2 sessions with an interval of 6-12 months. In 241 cases of children operated on from 1972-1975 with 308 total operations, the author observed 2 recurrences and 1 deep infection (scrotal abscess).


Phospholipid synthesis in mammary tissue. Choline and ethanolamine kinases: kinetic evidence for two discrete active sites. Choline and ethanolamine kinases are located in the high speed supernatant of lactating bovine mammary gland. Maximum activities of choline and ethanolamine kinases were observed at pH 9.2 and 8.0, respectively, with the rate of ethanolamine phosphorylation being 1/15 that of choline phosphorylation. Activation energies of 29 joules (Q10--1.5) and 31 joules (Q10 = 1.5) were calculated between 3.4 and 31.3 C for choline kinase and ethanolamine kinase, respectively. Above 31.3 C, the Arrhenius plot deviated from linearity for both enzymes, suggesting that denaturation was occurring. An apparent Km of 0.25 mM for choline was obtained for choline kinase activity. The apparent Km of ethanolamine kinase for ethanolamine was unusually high (17 mM), the activity was not linear with increasing protein concentration. Activity was tripled and the Km decreased to 2.5 mM when the enzyme preparation was washed with butanol: benzene mixture, suggesting the presence of an endogenous competitive inhibitor(s), with respect to ethanolamine. Choline kinase was not affected by the solvent wash. Substrate competition studies revealed that choline kinase was slightly inhibited competitively by ethanolamine (apparent Ki = 19-21 mM), whereas choline was a potent competitive inhibitor of ethanolamine kinase (apparent Ki = 0.33-0.50 mM). The results indicated that these two kinase activities were mediated by two distinct active sites, possibly on a single protein. The significance of choline in the regulation of phosphatidylethanolamine synthesis is discussed.


Effect of early postnatal dietary sterculate on the fatty acid composition of rat liver and brain lipids. Pregnant rats were fed a high carbohydrate diet containing either 1% trilinolein or 1% trilinolein with 0.2% methyl sterculate from 18 day gestation to 21 day postpartum. The pups were weaned at 21 days and continued on the same diet for an additional 10 days. The microsomal stearyl CoA desaturase activities of the liver were effectively inhibited. Liver triglycerides showed increases in the saturated fatty acids concentrations at the expense of the corresponding monoenes. The concentration of cis 6-7 octadecenoic acid was elevated. In liver phospholipids, the concentration of stearic acid was increased without a corresponding decrease in the oleic acid content. A drastic decrease in the nervonic acid (24:1, n-9) concentration of liver sphingomyelin was observed. The lipids of the brain did not contain sterculic acid, and brain desaturase activity was unaffected. There was no significant change in the concentration of monoenoic acids from 16:1 to 22:1. However, nervonic acid was decreased by 32%. These results suggest that brain nervonic acid may be derived from a precursor other than oleic acid.


Effect of dietary fats on ovine adipose tissue metabolism. The effects of different dietary fats on ovine adipose tissue metabolism have been investigated. Six-month old sheep were fed for 6 weeks a control diet or diets supplemented with either tallow or a mixture of sunflower seed oil and soybean oil, treated to protect the fats from hydrolysis and hydrogenation in the rumen, or with maize oil. The rates of fatty acid, glyceride glycerol, and CO2 formation were measured in perirenal and subcutaneous adipose tissue slices by following the incorporation of either 14C from labeled acetate or glucose, or 3H from tritiated water into the appropriate product. Feeding protected tallow or maize oil but not protected sunflower seed oil plus soybean oil resulted in reduced rates of fatty acid biosynthesis in both perirenal and subcutaneous adipose tissue slices and CO2 formation in perirenal adipose tissue. Feeding the fat-supplemented diets had no effect on the rate of glyceride glycerol formation. The fat-supplemented diets also resulted in reduced activities of various enzymes, thought to be involved in lipogenesis, measured in 105,000 x g supernatant fractions from adipose tissue homogenates. The results suggested that ovine adipose tissue lipogenesis is sensitive to both the amount and the nature of dietary fat.


Effect of glucose and sucrose on the survival in batch culture of Streptococcus mutans C67-1 and a non-cariogenic mutant C67-25. Morphological studies. This study comprised an ultrastructural examination of a cariogenic strain of Streptococcus mutans, C67-1, and a non-cariogenic mutant of that strain, C67-25. The aim of the work was to define more clearly the relationship between S. mutans and dental caries and, more specifically, to elicit ultrastructural evidence for the conclusion from a previous investigation that the greater survival of the parent strain in sucrose broth at uncontrolled pH was related partly to the production in this medium of abundant extracellular polysaccharide (EPS). The strains were grown as previously in 5% (w/v) glucose or sucrose broths, the pH being either allowed to fall or maintained above 6.0, and processed by the thiosemicarbazide technique for election microscopy. It was confirmed that EPS was most abundant in the sucrose broth culture of the parent strain at uncontrolled pH. While the presence of abundant EPS relates to the greater survival of the parent strain in sucrose broth at uncontrolled pH, this organism possesses at least one other mechanism of survival in acid media, possibly dependent on cell wall properties, in view of its greater cell wall thickness and increased survival in pH-uncontrolled glucose broth in the absence of detectable EPS production. It is postulated that intracellular and extracellular polysaccharide formation, cell wall thickening and reduced viability were indicators of unfavourable growth conditions in the test media. Cariogenic strains of S. mutans appear to be able to survive better under such conditions and hence the prevalence of this and other polysaccharide-producing organisms in stagnant sites in natural dental plaques.


Current status of treatment of severe hypertension. Drug fashions have changed and older drugs have given place to others with less side effects. Drugs and combinations of drugs administered to 100 patients currently under treatment at a clinic for severe hypertensives are listed. The most popular drugs were thiazide diuretics, methyldopa, beta-adrenergic blocking drugs, clinidine and hydrallazine. A thiazide diuretic was a constant member of the drug combinations. About 60% of patients achieved "good" blood pressure control (diastolic blood pressure less than or equal to 100 mm Hg), 30% "fair" (diastolic blood pressure=100 to 110 mm Hg) and 10+ "poor" (diastolic blood pressure greater than 110 mm Hg). Similar proportions were in "good", "fair" and "poor" general health. The best prospect for improved management of hypertension probably lies in earlier treatment with current drug combinations.


[How healthy are our blood donors? Result of a liver screening in voluntary blood donors of Blutspendedienst Innsbruck]. A screening of hepatic function and HBs-antigen, made in 22344 voluntary blood donors in the bloodbank of Innsbruck, gave the following results: 0,33% HBs-AG negative donors were found to have pathological liverfunctiontests. Overweight and alcohol would be established as the most important etiological factors. 0,4% of the donors are carriers of the HBs-antigen. A control examination after 2 years showed a persistence of that antigenemia. Antigen carriers are requested to have regular examinations. Since HBs-AG positive hepatitis is not only transferred by blood and blood-constituents, it would be important to use the same screening methods applied in the blood donor organisation throughout any hospital area, to reduce the incidence of this disease.


Anatomo-pathologic observations on epidemic nephropathy. Two cases of necropsy and 5 cases of renal biopuncture were studied on the occassion of an epidemic of "hemorrhagic fever with renal syndrome" identified in mountainous areas of Transylvania. The prevalent pathogenic process was capillary toxicosis which injured the renal tubules and vessels. The severity of the disease was determined by the phenomena of tubular failure, by the hemorrhagic syndrome and shock.


Effectiveness of various food preservatives in controlling the outgrowth of Byssochlamys nivea ascospores. Potassium sorbate, sodium benzoate, sulfur dioxide, and diethylpyrocarbonate (DEPC) were tested for their effectiveness in preventing the outgrowth of Byssochlamys nivea Westling ascospores. Sulfur dioxide was the most inhibitory of the test antimycotics, complete inhibition of colony formation occuring in acidified (pH 3.5) potato dextrose agar containing 50 ppm of the preservative. Complete inhibition of B. nivea ascospore outgrowth in grape juice stored for 60 days was noted in the presence of 300 ppm sulfur dioxide, 400 ppm potassium sorbate, and 600 ppm DEPC. Growth was observed in grape juice containing 1000 ppm sodium benzoate. The presence of up to 100 ppm potassium sorbate in grape juice during heat activation appears to have a stimulatory effect on breaking dormancy, while the other test preservatives at this concentration decrease the heat resistance of B. nivea ascospores. The time elapsed between heat shock and exposure to DEPC or sodium benzoate is critical with respect to the sensitivity of ascospores to these preservatives.


[Effect of production and storage on the survival of Staphylococcus aureus in curd]. The effect of curd production on the survival of staphylococci has been studied. At the begining of the manufacture process favourable conditions exist for the development of staphylococci. Their number decreases with the increasing acidity and in the final product they occur only sporadically or quite disappeare, especially when the curd is stored at cooling chamber temperatures. The lactose-positive staphylococci take part in the splitting of milk lactose and the production of milk acid as well. Their participation in this process is statistically significant. Some biochemical properties of the used Staphylococcus aureus strain as plasma koagulation, lecithinase, phosphatase and haemolytical toxin production, glucose, mannitol and lactose fermentation under aerobic and anaerobic conditions were studied. The biochemical properties of this strain do not change during the process of curd production.


Dexclamol: effects on catecholamine metabolism and demonstration of stereochemical specificity of antagonism of central adrenergic receptors. The effects of the benzocycloheptapyridoisoquinolinol derivative (+)-dexclamol-HCl and some of those of (+/-)-dexclamol and the corresponding (-)-dexclamol were compared to those of the potent neuroleptic agents droperidol and fluphenazine on norepinephrine (NE) and dopamine (DA) turnover in the whole brain and in the striatum of rats. Differences in NE and DA depletion following tyrosine hydroxylase inhibition with alpha-methyl-p-tyrosine indicated that (+)-dexclamol and droperidol increased DA turnover with no effect on NE turnover. At a higher dose both (+)-dexclamol and droperidol, but not (-)-dexclamol, accelerated DA turnover and also that of NE. A decrease in DA concentration occurred after both drugs under the latter condition only. (+)-Dexclamol, (+/-)-dexclamol and droperidol exhibited a similar onset of action employing striatal homovanillic acid (HVA) increase as indicative of DA turnover changes. The duration of action of droperidol was shorter than for (+)-dexclamol and (+/-)-dexclamol; fluphenazine displayed a slower onset and longer duration of activity. The (-)-dexclamol was ineffective. (+)-Dexclamol, droperidol and phentolamine reduced the concentrations of 3H-NE in heart when given after the 3H-NE, a probable indication of increased NE release due to adrenergic receptor blockade. The present findings demonstrate that the neuroleptic agent (+)-dexclamol, but not (-)-dexclamol, affects central DA and NE turnover and indicates a stereochemical specificity with respect to antagonism of central DA and NE receptors.


Association between the increase of cAMP content and the trans-synaptic induction of tyrosine hydroxylase in rat adrenal medulla. Studies with dexamethasone and reserpine. When dexamethasone 0.25 or 2.5 mumole/kg i.p. was injected 2 h before reserpine (16 mumol/kg i.p.) the time course of the increase in cAMP content of rat adrenal medulla was changed. Reserpine alone caused a monophasic increase lasting between 1-2 h; reserpine after dexamethasone caused a biphasic increase: the immediate response, lasting between 15 and 30 min, was followed by a secondary increase beginning 2-3 h after reserpine and lasting for several hours. The overall increase in cAMP content elicited by reserpine during the 8 h following injection remained unchanged or was even increased, depending on the dose of dexamethasone. Pretreatment with dexamethasone, which delayed the increase in cAMP, also delayed the activation and translocation of protein kinase and the induction of tyrosine hydroxylase caused by reserpine in adrenal medulla. The action of reserpine on the cAMP content of adrenal medulla required an intact innervation and did not appear to be related to increased secretion of ACTH from pituitary. In denervated adrenals reserpine failed to increase the cAMP content of the medulla but not that of the cortex.


[Controlled clinical trial of parsalmide in patients with predominantly neuro-anxiety syndromes. Comparison with chlordiazepoxide]. The anxiolytic and tranquillizing effect of a new compound called parsalmide was studied in a group of 20 patients suffering from medium anxiety neurosis. The new drug also possesses anti-inflammatory and analgesic effects. The technique employed was the double blind, between patients, crossover system and chlordiazepoxide was used for comparison purposes. Parsalmide proved to possess an anxiolytic-tranquillizing action comparable to that of chlordiazepoxide and, unlike the latter, was quite free from unpleasant side effects, such as somnolence and asthenia.


[Double-blind comparison of parsalmide and diazepam in anxious and depressive neurotic syndromes]. Parsalmide- a new drug- is effective in the relief of inflammation and pain. In a double-blind, between-patients, cross-over trial with diazepam in 16 subjects with anxiety and depression, however, it proved less successful in relieving anxiety, though it was on a par with diazepam on an overall evaluation. The daytime somnolence and asthenia observed with diazepam were not observed with parsalmide.


[The problem of dissecting aneurysm of the aorta and its benign course]. On the basis of a personal case, the clinical, diagnostic and therapeutic problems of variants of dissecting aneurysm of the aorta with benign course are discussed. The usefulness of cardio-aortic angioscintigraphy in the interests of early diagnosis of aneurysm and aortography by catheterism for specifying its location and extent, is pointed out. Spontaneous benign development would seem to be tied up with the affected area of the aorta, the modalities of dissection, and above all with the establishment of a distal return breach for blood flow into the aortic lumen. The predominant role of cystic medionecrosis in determining dissection is stressed and the usefulness of intensive pharmacological therapy based essentially on hypotensive and beta-blocking substances confirmed.


[Temperature measurements in Wistar rats and DS carcinosarcoma under various conditions]. Temperature measurements on Wistar rats with miniature-Hg-thermometer and laser-welded thermoelements lead to the following conclusions: 1. No change of temperature-profile, especially in the liver through glucose-infusion and hyperthermia, can be noticed. 2. Glucose-infusion causes hyperthermia of about 1.5 degrees C. 3. The temperature of the subcutaneous growing DS- carcinosarcoma lies under the norm and increases with the distance from the surface of the body. 4. Hyperthermia of 3 degrees C has no influence on tumor over-acidification. 5. The substance CEU has no pyrogenic effect on the rat but potentiates the decrease of the body-temperature caused by narcosis.


Polyarteritis nodosa induced in arteriosclerotic, male and female breeder rats by chronic alloxan diabetes. Male and female virgin rats and breeder rats with naturally-occurring diabetes, hypertension and arteriosclerosis, were made severely diabetic with a single, subcutaneous injection of alloxan (10 mg/100 g b.w.), after an 18 h fast. During five months of unrelenting diabetes, some animals became obese while others became emaciated. Only the emaciated animals survived but they were blind, their adrenal glands were hemorrhagic, hypertrophied and thrombosed, thymi involuted, kidneys swollen, hearts reduced in size while testes and ovaries were atrophic. Serum CPK, SGOT and SGPT were elevated concomitant with extensive cardiovascular damage, hepatic steatosis and generalized catabolism. Circulating triglycerides and free fatty acids were markedly elevated with total cholesterol only slightly increased. BUN and serum calcium levels were also greatly elevated. Sub-normal Cmpd. B levels indicated impaired adrenal steroidogenesis. Virgin rats developed arteriosclerosis and male and female breeder rats showed exacerbation of their pre-existing aortic sclerosis as well as P.A.N. lesions in their small-sized arteries. It is believed that severe diabetes causes exacerbation of the endogenous hormonal milieu resulting from abnormal hypothalamic-pituitary-adrenal function induced by repeated breeding, which conditions the connective tissue components of the arterial wall of rats toward accelerated degenerative changes.


Conditioning of striatal dopamine metabolism with methadone, morphine or bulbocapnine as an unconditioned stimulus. Psychotropic drugs such as methadone, morphine and bulbocapnine produce increments in dopamine metabolism as an unconditioned reflex. When a buzzer noise is used as a conditioned stimulus (CS) with these drugs as unconditioned stimuli, the buzzer CS acquires the properties of the drugs in increasing dopamine metabolism. These results suggest that the brain, like other visceral organs, can be conditioned in terms of neurotransmitter release or metabolism.


Arterial and mixed venous PCO2 and hydrogen ion, bicarbonate and base excess concentrations in water-depleted dogs. The arterial (a), mixed venous (v), and arterial-mixed venous differences (A-V) of hydrogen ion concentration ([H+]), PCO2, HCO-3 and base excess (BE) were measured during 3 h in control (C), water-depleted (WD) and water- and salt-depleted (WSD) dogs. In WD animals the difference in hydrogen ion concentration between venous and arterial blood increased because the [H+] increased more in venous than in arterial blood. In WSD animals (A-V) [H+] remained unchanged since both [H+]a and [H+]v increases were parallel. [H+] variations seem to represent the changes in fixed-acid concentration of blood. The difference between both groups of animals in (A-V) [H+] changes could be ascribed to PCO2 variations. [HCO-3] values changed inconsistently. Arterial samples from the experimental groups showed a continuous decrease at the same rate of change. The mean values in WSD were lower than in WD. [HCO-3]v of WSD decreased slowly during the experiment. The rate of decrease of (A-V) [HCO-3] was higher in WD than in WSD. The different behavior of of [HCO-3] between both arterial and mixed venous samples and among experimental groups disappeared if [HCO-3] changes were corrected for bicarbonate generation due to PCO2 variation (respiratory bicarbonate). Thus [HCO-3] corrected for PCO2 variation represents metabolic changes, in good agreement with both [H+] and BE variations. The metabolic acidosis cannot be explained only on the basis of the increase in blood lactate; it is suggested that other fixed acids might contribute to the decrease in blood bicarbonate. In both experimental groups PvCO2 increased continuously. The (A-V) PCO2 showed the same rate of change. There is a good relationship between this increase and the degree of plasma volume change. It therefore might be that PvCO2 increase is a direct consequence of hemodynamic impairment. In WD and WSD, BE decreased progressively in both arterial and mixed venous samples. BEa values were lower than BEv values after the experiment began. (A-V) BE decreased in an exponential manner in both experimental groups; this change could be ascribed to the increased level of deoxygenated hemoglobin in mixed venous blood, thus giving rise to a decrease in fixed acid concentration.


Developmental changes of sugar transport in the ovine small intestine. Intestinal monosaccharide transport was studied in young lambs (age: up to 1 week) and in older lambs (age: 2.5-4 months) with well developed forestomach system employing everted sacs of small intestine. Both glucose and galactose were transported against a high concentration gradient from the mucosal to the serosal side of the intestinal wall in young lambs. In the older lambs glucose was transported only against a small concentration gradient, when intestinal glucose metabolism was diminished by reducing the pH of the incubation medium from 7 to 5. Galactose and alpha-methyl-glucoside, which are not markedly metabolized by the intestine, were transported against a small but similar concentration gradient at both pH values in these animals. In young lambs, however, at pH 5 intestinal galactose transport was lower than at pH 7. These results indicate that active intestinal monosaccharide transport becomes rudimentary in the maturing sheep.


Blood gas analyses of hibernating hamsters and dormice. Blood gases were measured in hibernating and hypothermic animals as a biological model of clinical hypothermia. Blood gas analyses from hamsters and dormice were carried out with the aid of permanent arterial catheters during normothermia and hibernation. In golden hamster pH increased from 7.30 to 7.46 during hibernation and PaCO2 decreased from 59.7 to 40.5 mm Hg. In dormice pH increased from 7.24 to 7.44 and PaCO2 decreases from 38.5 to 27.4 mm Hg. The actual bicarbonate concentration increased from 29 to 52 mMol in golden hamsters and from 16 to 34 mMol in dormice during hibernation. In experiments with induced hypothermia in golden hamsters under ketamine-anaesthesia there was no correlation between temperature and PaCO2. Despite the slight decrease in PaCO2 during hibernation we conclude that PaCO2 rather than total carbon dioxide content is held constant when temperature is changed. During clinical hypothermia it will probably be safe to keep PaCO2 constant.


(Na+K+)-activated ATPase in human cornea. Distribution within the cornea and properties of the enzyme from epithelial cells. Distribution and principal characteristics of (Na+K+)-activated ATPase in human cornea were investigated. (Na+K+)-ATPase was present in both epithelium and endothelium, whereas the corneal stroma did not exhibit significant enzyme activity. In homogenates specific activity of the (Na+K+)-ATPase was 2.3-fold higher in endothelium than in epithelium. Calculation of total enzyme activity revealed a 6.1-fold higher content of (Na+K+)-ATPase in the epithelium. In the epithelium a 7-fold enrichment of (Na+K+)-ATPase compared to the homogenate was obtained in the 150-1500 X gav fraction. Maximum enrichment in the endothelium was 3.5-fold and was achieved in the 1500-2500 X gav fraction. Both fractions showed, however, the same specific activity. The pH-optimum of (Na+K+)-ATPase in the 150-1500 X gav fraction ranged from 8.0-8.2 in both epithelium and endothelium. In the epithelial 150-1500 X gav fraction the apparent Km-values were 4.0 mM for Na+, 2.8 mM for K+ and 0.12 mM for Mg2+ - ATP in equimolar concentrations. The inhibition constant of epithelial (Na+K+)-ATPase for ouabain was determined as Ki = 3.3 X 10(-7) M. The present data support the view that control of corneal hydration in man is a function of both endothelium and epithelium.


Effect of oxygen saturation on H+ and Cl- distribution across the red cell membrane in human and ruminant blood. Alterations of red cell pH (pHc) and distribution ratios of H+ (gammaH+) and Cl (gammaCl-) between plasma and red blood cells with oxygenation of blood were studied in human blood (audult and fetal) and ruminant blood (bovine, goat and sheep). The experiments were carried out at a plasma pH of 7.0 to 7.7 and at 37 degrees C. In human blood pHc of fully oxygenated blood was 0.035 pH lower than that of fully deoxygenated blood in all ranges of plasma pH studied. In ruminant blood, however, the differences in pHc between oxygenated and deoxygenated blood were 0.011 in ox, and 0.003 in goat and sheep, all of them not being significant. The decreases in gammaH+ accompanying oxygenation were in fairly good agreement with those in gammaCl- in human blood and amounted to about 0.05. In ruminant blood, in spite of virtually zero changes in gammaH+ with oxygenation, the decreases in gammaCl- were slightly greater than those in human blood. There might be a species difference in the mechanisms of distribution of Cl- and H+ across the red cell membrane.


CD studies on the conformation of oligonucleotides complexed with divalent metal ions: interaction of Zn2+ with guanine favours syn conformation. The interaction of the divalent metal ions Mg2+, Mn2+, Zn2+ and Cu2+ with GpG and several other dinucleoside monophosphates were investigated by means of circular dichroism. The spectra of the complexes of GpG, GpU analogues and ApGpG caused in the presence of Zn2+ and other transition metals show a close similarity in the spectral CD shape to that previously reported in the literature for GpG and GpU at low pH and for m7GpG. From the results it may be concluded that transition metal ions-particularly considered for Zn2+/- tends to favour the degree of stacking with Guo in syn conformation in GpG or GpU due to the coordination of the metal ion at N-7 of the 3'-bound position while shielding of the phosphate site by Mg2+ does not influence the sugar-base torsional angle under comparable conditions. Stereochemical aspects and selectivity of the Zn2+ mediated conformation of the dinucleoside phosphates are discussed.


Pretreatment with antilymphocyte globulin and donor cells on graft prolongation in an experimental model and some observations on graft-versus-host reaction. Survival of Lewis X Brown Norway F1 renal allografts was prolonged in Lewis recipients by pretreatment with small numbers of donor marrow cells and low dose antilymphocyte globulin(ALG)in combination. Either marrow cells or ALG alone were ineffective at these doses. It was also shown that pretreatment with marrow cells and antilymphocyte serum (ALS) considerably suppressed the local graft-versus-host reaction.


The elective treatment of graft-versus-host disease following a bone marrow graft from a father to a son with severe combined immunodeficiency. The details of the first successful bone marrow graft from father to son are described. The recipient developed an acute graft-versus-host reaction on the seventh day which was successfully treated with anit-lymphocyte globulin and methotrexate. This regime did not destroy the graft and the child is alive and well with normal immunological function some 2 1/2 years later.


Use of antithymocyte serum in clinical and experimental marrow transplantation. Pre-sensitization was investigated in the dog marrow transplant model with donor and recipient mismatching at the canine major histocompatibility complex (MHC). Various prophylactic immunosuppressive regimes were used and it was concluded from these regimes that sensitization to histocompatibility antigens could be abrogated by a combination of procarbazine and antithymocyte serum (ATS) together, before total body irradiation. Subsequent work in humans showed that rejection of a bone marrow graft can be successfully treated by using the procarbazine-antithymocyte clobulin regime and a second transplant. Based upon animal studies, attempts were made to prevent graft-versus-host disease in humans by the use of methotrexate following grafting. Despite matching at the MHC and the use of methotrexate some recipients developed graft-versus-host disease with a fatal outcome. Further work using ATS in the immediate pre- and post-grafting period was inconclusive. Accordingly ATS was used in animals once graft-versus-host disease became manifest with drmatic improvement in clinical status. As a result it was decided to treat all patients who developed graft-versus-host disease with antithymocyte globulin (ATG). Under ATG therpy twelve out of nineteen patients showed complete resolution, and five showed improvement. Six patients became long term survivors. Of the remaining 13, 11 died on interstitial pneumonitis, and two of fungal and bacterial infections. ATG in estblished graft-versus-host disease appears capable of modigying an otherwise fatal disease in a therpeutically beneficial manner.


Immobilization of bacterial luciferase and FMN reductase on glass rods. Bacterial luciferase and NAD(P)H: FMN oxidoreductase isolated from Beneckea harveyi were covalently linked via diazotization to arylamine porous glass beads which had been cemented onto plain glass rods. These immobilized enzymes are individually active and also function to produce light via a coupled reaction utilizing NADH or NADPH. These enzymes have properties similar to the soluble forms with regard to pH and substrate optima and also exhibit linearity in peak intensity of the initial flash of light emitted as a function of NADH or NADPH concentration. Linearity with NADH is obtained in the range of 1 pmol to 50 nmol, and between 10 pmol to 200 nmol for NADPH. The bound enzymes are stable and reusable. This immobilized system offers a rapid and inexpensive m


Subcellular localization of S-adenosyl-L-methionine:tRNA methyltransferases with aminoacyl-tRNA synthetases in human and mouse: normal and leukemic leukocytes. The subcellular distributions of S-adenosyl-L-methionine:tRNA methyltransferases and aminoacyl-tRNA synthetases were investigated with the use of human and mouse normal and leukemic leukocyte cell lines. Differential centrifugation of homogenized cell suspensions produced three pelleted subcellular fractions (nuclear and membrane, microsomal, and postribosomal) and a supernatant fraction. Each fraction was assayed for both methyltransferase activity and synthetase activity. The largest amounts, 40-50%, of total methyltransferase and synthetase activities were localized in either the microsomal or the postribosomal fractions, depending on cell type. In addition, the highest specific activities of these two enzyme systems were found to be present in the microsomal and postribosomal fractions. The psotribosomal fraction from leukemic leukocytes had a methyltransferase specific activity higher than that of the microsomal fraction, while the same two fractions of normal leukocytes had approximately equal activities. Specific activities of aminoacyl-tRNA synthetases were found to be approximately equal for these two fractions, whether they were from normal or leukemic leukocytes. The activity of tRNA methyltransferases and synthetases within the postribosomal fraction of the cytoplasm suggests the existence of high-molecular-weight enzyme complexes for the modification as well as the aminoacylation of tRNA.


[Preparative isolation of terrilytin components and study of their enzymatic properties]. By ion-exchange chromatography the composition of the fibrinolytic enzyme from Aspergillus terricola-terrilytine-was studied. The preparation contained five components that differed in their substrate specificity. Three of the components and proteolytic and fibrinolytic activities. The isolated fractions were examined with respect to their pH stability, pH optima (casein, hemoglobin and fibrin used as substrates), fibrinolytic and fibrinohenolytic activities.


Alterations in the behavioral effects of LSD by motivational and neurohumoral variables. Forty naive male albino rats were trained to press a bar on a fixed-ratio (FR 32) schedule of water reinforcement. They were then divided into two groups, one of which (N = 20) received 5 min of extra water 12 hr before each experimental session; the other group (N = 20) received no extra water. Half of the animals in each group was given three daily doses (100 mg/kg) of the trytophan hydroxylase inhibitor p-chlorophenylalanine methyl ester (PCPA) while the remaining animals were given control injections of the PCPA vehicle. Ten days following the last administration of PCPA (or vehicle) all animals were given a low dose of LSD (20 mug/kg). Bar-pressing behavior was significantly disrupted only in those animals receiving both PCPA and extra water. Central (whold brain) concentrations of serotonin (5-HT) were significantly lower in all animals which had been treated with PCPA. These results, along with those previously reported, suggest that amount of deprivation can be an important determinant of both the ability of drugs to alter behavior and the dependence of such alterations upon underlying neuronal activity.


The organization of perpendicular fibre pathways in the insect optic lobe. High resolution serial photomicrography has been used to plot the axonal projection patterns between retina, lamina and medulla in the optic lobes of various insects with differing ommatidial receptor arrangements. Observations are reported on the cabbage white and skipper butterflies, the bee, locust, fly, backswimmer and waterbug. The patterns of these fibre pathways have previously eluded non-rigorous analyses primarily because of their physical dimensions but are revealed in this study to have striking precision and uniformity between species when examined at the level of individually identifiable cells. Axon bundles of the tracts between retina and lamina or lamina and medulla project between a single ommatidium and its corresponding lamina cartridge or between corresponding lamina and medulla cartridges. Lateral interweaving of axons between adjacent bundles is absent. The bundles preserve the retinotopic order within their total array, so transferring the pattern of retinulae directly upon the lamina and thence after horizontal inversion in the chiasma upon the medulla. Within the lamina neuropile on the other hand the trajectories of the individual terminals from a bundle have patterns which are species-specific, sometimes involving lateral divergences. In species with open-rhabdomere ommatidia the terminals distribute to a group of lamina cartidges with a pattern which resembles the receptor pattern in the overlying ommatidium. In species with fused-rhabdome ommatidia the terminals of a single retinula behave less interestingly and all enter the same cartridge, within which, again, each occupies a position related to its cell body position within the retinula. Long visual fibres in both eye types penetrate the lamina and terminate in the particular medulla cartridge that connects with the lamina cartridge underlying their ommatidium. The perpendicular fibre pathways therefore project the visual field exactly upon the medulla in all species while the lack of interweaving between adjacent fibre bundles precludes their involvement in lateral interactions between pathways with differing visual axes. Uniformity of these projection patterns between cell layers and species differences in retinular terminal locations in the lamina can be correlated with different modes of axon growth between and within neuropile layers during optic lobe neurogenesis. Further discussion surrounds the question of which particular receptors give rise to which type of axon, for which no clear generalization has yet emerged.


The evolution of plants and animals under domestication: the contribution of studies at the molecular level. Protein molecules are essential catalysts in life processes and also form much of the substance of living material. Their three dimensional structures determine their biological function. Their biosynthesis is primarily determined by arrays of nucleic acid macromolecules (DNA and RNA), and the amino acid sequences that constitute their long spatially organized peptide-chain molecules reflect at one remove this DNA coding system, and thus record a step-by-step history of some of the viable genetic events (natural or man-controlled) that have created the organism and the breed. Amino acid sequences can be used to trace the progress of controlled breeding in two ways: by extrapolation back from living breeds, and by analysis of ancient protein material. Of the latter, bone or tendon or skin collagens and hair keratins are the most perfectly preserved as molecular structures through 20,000 years and indeed much longer. Amino acid sequences are expensive to determine (collagen has 1052 amino acid residues), and the potential of this palaeobiological information has been as yet little exploited. The first approach has, however, been more explored, in both plants and animals. Several protein systems must be studied in conjunction to reveal the phylogenetic threads in any one breed. As the three dimensional quaternary structure of protein molecules becomes more appreciated in relation to biological function, and as new techniques and procedures are developed, amino acid sequence data can become more informative in our ultimate understanding of early selective breeding.


Organization of motoneurones in the prothoracic ganglion of the cockroach Periplaneta americana (L.). The location within the prothoracic ganglion of neurone somata with axons in identified peripheral nerves is examined by the cobalt iontophoresis technique. Axons are filled with cobalt by diffusion through their cut ends and the cobalt is then precipitated as the black sulphide inside the neurone. It is assumed that neurones with axons in peripheral nerves and somata in central ganglia are either motor or neuro-secretory. Fifteen nerves are examined and maps of the location of somata with axons in each nerve are presented. The axon distribution in peripheral nerves of three common inhibitory neurones is described. Dendritic morphology of one common inhibitory neurone and two coxal depressor motoneurones is illustrated. It is proposed that some individual neurones can be reliably identified from their soma dimensions and location within the ganglion. The number of motoneurones with somata in the prothoracic ganglion and their homology with cells in the other thoracic ganglia are discussed.


[Autogenic training within the therapeutic scope of schizophrenic patients]. The author calls the reader's attention to the rather strange fact that autogenic training, in spite of worldwide recognition and extensive uses of the method in various disciplines of medicine and spheres of live, has not so far been finding wide application in the medical specialty dealing with mental disorders. After discussing some possible causes of this situation and commenting on first signs of a necessary change in attitude toward autogenic training, he reports his own experience in the treatment of schizophrenic patients with this psychotherapeutic method, emphasizing the need for including psychotherapy in a complex concept of the treatment of psychoses.


Possible association of schizophrenia with a disturbance in prostaglandin metabolism: a physiological hypothesis. Schizophrenia may be associated with increased prostaglandin synthesis in certain parts of the brain. This hypothesis is based on the following findings: (1) Catalepsy, which is the nearest equivalent in animals to human catatonia, develops in cats when prostaglandin E1 is injected into the cerebral ventricles and when during endotoxin or lipid A fever the prostaglandin E2 level in cisternal c.s.f. rises to high levels; however, when fever and prostaglandin level are brought down by non-steroid anti-pyretics which inhibit prostaglandin synthesis, catalepsy disappears as well. (2) Febrile episodes are a genuine syndrome of schizophrenia.


Ontogenetic development of locomotor activity and rate of tyrosine hydroxylation. A combined biochemical and behavioral study was performed postnatally on albino rats. An almost linear increase in total motor activity was observed from 1 to 15 days of age followed by a pronounced decrease in motor activity between days 15 and 18. The in vivo rate of tyrosine hydroxylase activity in whole brain was estimated by means of measuring accumulation of L-3,4-dihydroxyphenylalanine (Dopa) after administration of an inhibitor of aromatic amino acid decarboxylase NSD 1015. Additionally, Dopa accumulation was studied in regional brain areas in 10 and 14-day-old animals. A slight gradual increase in the amount of Dopa accumulation in whole brain was observed from 1 to 10 days of age, followed by a pronounced increase between 10 and 14 days. Regional studies revealed that the increase in Dopa accumulation was primarily located to striatum. The data suggest an involvement of central catecholamine neurons possibly dopaminergic, terminating in striatum. The decrease in motor activity observed after 15 days of age is interpreted as involvement of maturing inhibitory pathways of noncatecholaminergic origin.


In vivo desensitization of a phobic shop steward. Techniques used in behaviour therapy effectively counteract the symptoms presented by the patient. The question arises as to the precise nature of such intervention, and whether this form of treatment is in fact a superficial one which deals only with symptom removal, or whether this is really a much more fundamental form of therapy, in which the patient alters as a whole. The case reported here is of interest in that, during a course of in vivo desensitization, in which the therapist accompanied the patient on journeys through London, it was shown that, as the symptoms were alleviated, there were concomitant changes in his whole personality structure. He no longer needed to be a militant shop steward and developed an amicable relationship with his employers, and yet he was still able to negotiate a pay rise for the men. This suggests that the treatment had an effect on his hostility level, so that he could deal effectively with his superiors without the need to fight them. This has important theoretical and ethnical implications.


Characterization of interactions of phenothiazines and related drugs with lipids by UV-spectrophotometry. The UV-spectrum of chlorpromazine undergoes a red shift in the presence of vesicles of biological membranes or phospholipids, triglycerides, serum lipoproteins or fatty acids. The resulting difference spectrum has two positive peaks at about 260 and 320 nm and two negative peaks at 250 and 290 nm. This interaction signal, which was elicited in the presence of as little as 3 muM oleic acid, was dependent on the concentrations of both ligand and binder. It was abolished by 8 M urea, diminished by temperature increase up to 70 degrees C, but not changed by varying the ionic strength from 0 to 0.5. The chlorpromazine-triglyceride interaction signal was strongly enhanced with pH increasing from 6 to 10. The signal was only obtained with ligands fulfilling specific structural requirements, e.g., phenothiazines and most iminostilbenes, but not carbamazepine, imipramine, and amitriptyline.


Discriminative response control by psychomotor stimulants. Psychomotor stimulants are capable of controlling discriminative responding in rats. Evidence suggests that response control is central, of a fairly specific nature, and dependent on intact dopaminergic functions.


Discriminable effects of benzodiazepines. In a shock-escape T-maze task, rats rapidly discriminated diazepam, flurazepam and chloridazepoxide from no drug. The discriminable effects of these benzodiazepines were not completely interchangeable with those of barbiturate anesthetics. The dose-response curve for diazepam asymptoted over the range 15 to 100 mg/kg, ip whereas dose-response curves for flurazepam and chloridazepoxide were more linear.


Effects of drugs on the uptake of acetylcholine by human term placenta fragments. An active concentrative component of the ACh accumulation in fragments of human term placenta followed kinetics predicted by the Michaelis-Menten equation (Km greater than 15 mM). This process was competitively inhibited by choline or hemicholinium-3, suggesting the possibility that a common carrier existed. Morphine reduced the 3 H-ACh uptake competitively. Imipramine, desmethylimipramine, haloperidol and chlorpromazine decreased the concentration ratios. This effect was uncompetitive with respect to chlorpromazine. Compared to drug actions on the ACh uptake in innervated tissue drug effects in the placenta were much less predictable for various classes of compounds.


Postoperative treatment with corticosteroids and salazosulphapyridine (Salazopyrin) after radical resection for Crohn's disease. In a prospective multicentre study, 97 patients with Crohn's disease and operated on by a radical excision of the Crohn-involved bowel were randomly divided into two groups, one treated 33 weeks postoperatively by corticosteroids and Salazopyrin and the other without any medical treatment postoperatively. The patients in the two groups were followed up during three years after the operation and an X-ray of the bowel was yearly performed. Thirteen patients were excluded for different reasons, which means that 84 patients were left for the study. There was no statistically significant difference in the number of recurrences after one, two, or three years of observation time in the two groups of patients. There was a statistically significantly longer time between diagnosis and operation in the group of patients with recurrences than in patients with no recurrences. This might mean that patients with Crohn's disease undergoing an early operation have a better chance of escaping recurrences.


Endogenous motilin and the LES pressure. The changes in LES pressure were measured after alkalinization and subsequent acidification of the antrum or duodenum. For the alkalinization of the antrum, a strong (sodium-hydroxide) and a weaker alkaline stimulus were used in different subjects. At the end of the experiments, glycine 5% was infused into antrum and glycine 5% or phenylalanine 0.1 N into the duodenum. Plasma samples were drawn for determination of the motilin levels. Although in some experimental situations, motilin levels and LES pressure were significantly correlated, any correlation was lacking in other test situations. It may be concluded that the role of endogenous motilin for the regulation of the LES pressure is either non-existent or frequently overwhelmed by other influences.


Relationship of plasma motilin response to lower esophageal sphincter pressure in man. The effect of intraduodenal instillation of 0.1 N hydrochloric acid or 0.9% saline (control) on lower esophageal sphincter pressure (LESP) and plasma motilin concentrations was studied in five normal volunteers. After acid, LESP and plasma motilin rose concomitantly exceeding basal by about 80% (p less than 0.025) and 90% (p less than 0.05), respectively, at 3 to 4 minutes. Control values did not significantly differ throughout the test period from the mean basal level. These results are compatible with the view that the increase in LESP after duodenal acidification may be mediated by endogenously released motilin.


Fetal thymus transplantations in severe combined immunodeficiency. Two brothers with severe combined immunodeficiency were treated with repeated transplantations of fetal thymus tissue. The first patient was not treated until he was critically ill, and the intramuscular transplants had no effect. He died at 11 months of age of overwhelming pneumonia. At postmortem examination a transplanted thymus seemed viable. In the second patient an intramuscular transplant had no effect, but three subsequent intraperitoneal transplants led to transient increase in circulating T lymphocytes with a concomitant fall in B lymphocytes. The results suggested an additive effect of each transplant. However, delayed hypersensitivity skin tests and in vitro mitogen responses were not influenced. Initially, transfer factor was given, and fetal liver was administered intraperitoneally together with the last thymic transplant. Neither of these measures had any observed effect, and this patient, similarly, died of pneumonia at nearly 12 months of age.


Partial tolerant state against H-2 disparate cells. No impaired specific reactivity in MLC, GVH, or antibody production. Injection of CBA mice with H-2-compatible lymphoid cells from C3H hybrids induces a specific reduction of the mixed lymphocyte culture (MLC) response of their lymphoytes. This is not the case after injection of H-2-disparate C3H-hybrid cells, presumably because they are rapidly eliminated due to the immune response of the host. This investigation shows that CBA mice injected with CBA X C57Bl cells (H-2-disparate) at an age of 0-3 days, but not older, develop a specifically reduced MLC response after infusion of C3H X C57Bl cells as adults, indicating that they were tolerant to the C57Bl-determined antigens. However, lymphocytes from such mice showed a normal reactivity against C57Bl as assessed by MLC, graft-versus-host tests, and capacity to produce specific antibodies.


Renal function in experimental chronic hydronephrosis. V. Net acid excretion capacity in relation to renal pelvic volume after maximal loading with NH4Cl. In 12 mongrel dogs intravenous loading with ammonium chloride (4 mmol NH4+/kg body weight) was performed before and 2-9 weeks after unilateral hydronephrosis had been produced by ligation of the ureter over an indwelling catheter. In an attempt to satisfy the demand for adequate, constant, alveolar ventilation a special respirator of the high-frequency positive-pressure ventilation (HFPPV) type was used. The acid-base status of the blood was determined before and after the loading and the acidification capacity of each kidney was assessed by measuring the amount of titratable acid and ammonium ions excreted in the urine. In the hydronephrotic kidney the excretion of both titratable acid and ammonium ions was statistically significantly reduced, both compared with the initial values in session I and compared with the healthy kidney in session II. After additional loading with ammonium chloride in session II, however, both kidneys increased their excretions to approximately similar extents. When the excretion was calculated per ml glomerular filtrate, no statistically significant changes were found between sessions I and II, either for the intact or the hydronephrotic kidney. The renal pelvic volume on the hydronephrotic side was measured and related to the reduction of the capacity of the kidney to excrete titratable acid and ammonium ions. No statistically significant correlation was obtained.


[Graft versus host disease, a little known complication of blood transfusion]. A case of fatal graft-versus-host disease (GvHD) following blood transfusions is reported. This relatively rare complication of blood and bloodcomponent replacement therapy may occur in recipients with decreased cellular immunity, which may be due to the underlying disease, chemotherapy or radiation therapy, or a combination of both. GvHD is a result of active proliferation of transfused immunologically competent cells which attack host organs. This complication can be prevented by irradiating transfusions with 1500 rads in vitro.


[Glucagon producing adenomatosis of Islands of Langerhans with polyendocrine symptoms]. A patient in whom Cushing syndrome had been diagnosed at the age of 23 was found 14 years later to have subclinical diabetes mellitus, subcutaneous calcified fat tissue necroses, and hypergastrinemia suggesting Zollinger-Ellison syndrome. Histopathologic investigation revealed pancreatic adenomatosis of the glucagon producing A2-cells with accompanying B-cell hyperplasia, and hyperplasia of the adrenal cortex. The origin of the increased serum gastrin concentration in this patient is not yet known. The significance of A2-cell proliferation in Zollinger-Ellison syndrome and and in multiple endocrine adenomatosis is discussed.


[Diphenylhydantoin. Metabolism, pharmacokinetics, interactions and side effects]. The metabolism, mechanism of action, interactions with other drugs and side effects of diphenylhydantoin (DPH), which is probably the most commonly used antiepileptic drug are reviewed in the light of the recent literature. Some findings of practical importance are emphasized, and the resultant implications with regard to the management of epileptic patients are discussed.


[The petit-mal-status].

[The petit-mal-status]. In the light of three case histories, other personal observations and the literature, the clinical and electroencephalographical differences between absences in the limited sense and continuous LENNOX petit-mal state are described and the problems of the latter discussed. As a rule, petit-mal state is diagnosed as such in young people or adults, and practically never before the 10th year of life. In about two thirds of cases, its clinical symptomatology consists of a twilight condition lasting some hours to a few days, coupled with inertia and apathy. The remaining third of the patients usually experience milder disturbances, e.g. in the form of concentration difficulties, tiredness, and (more rarely) severe forms including lethargy. The EEG correlate of a petit-mal state is made up of continuous bilaterally synchronous, frontally marked (less frequently with exclusively frontal localization), usually irregular spike waves or poly-spike waves, which frequently occur in only rudimentary forms and register a frequency of 2 1/2-4 c/sec. For the treatment of petit-mal state, benzodiazepines and in particular clonazepam (Rivotril) (1-2 mg i.v.) are recommended. During the interval condition the same therapy as with an absence epilepsy, e.g. succinimides or dipropylacetate (Depakine) is administered. Anti-grand-mal remedies, especially hydantoins, may trigger petit-mal status.