Correlation of phase inversion temperature with kinetics of globule coalescence for emulsions stabilized by a polyoxyethylene alkyl ether. The phase inversion temperatures, globule coalescence rates, and long-term stability of oil-in-water emulsions stabilized by polyoxyethylene 4 cetyl ether were measured. Addition of sodium chloride to the aqueous phase depressed the phase inversion temperatures of the emulsions and the cloud point of the surfactant. Linear correlations were obtained between phase inversion temperature and cloud point and also between phase inversion temperature and the logarithm of the globule coalescence rate at constant temperature. This latter finding is consistent with a theory of emulsion type based upon the kinetics of coalescence. The programmed viscometric technique of determining inversion revealed the presence of a liquid crystalline phase below 35 degrees, which contributes significantly to emulsion stability.


Effect of absorbents on water vapor transmission of free and applied polymer films. The influence of different types of absorbents on moisture transmission through free (cast films) and applied (coated tablets) polymer films was investigated. In free film studies, lubricated granulations were considered to be the absorbent. The compressed tablet was considered to be the absorbent in applied film studies. The results suggested that, using the same film formulation and film thickness in all cases, the polymer film reduced moisture absorption to the same degree, independent of the absorbent used, suggesting a constant moisture permeation. The results of the free film studies also simulated those of the applied films, allowing the correlation of the data.


Conversion of biguanides into substituted s-triazines assayable by GC or mass fragmentography. Substituted s-triazines were prepared by the treatment of biguanides with various organic acid anhydrides. This reaction permits the ready conversion of the hypoglycemic drugs phenformin, buformin, and metformin and of other analogous biguanides into compounds suitable for GC and mass fragmentographic determination with a high degree of sensitivity. Mass spectral data and Kováts retention indexes are presented for all s-triazines prepared for this study.


Correlation between dissolution characteristics and absorption of methaqualone from solid dosage forms. A methaqualone tablet in two strengths, 150 and 300 mg, was developed. The dissolution rate of an experimental formulation in pH 7.0 phosphate buffer, measured by the resin flask method, was shown to correlate with bioavailability in humans. The dissolution rate criterion was used to develop the final tablet formulation. Bioavailability of this formulation in two strengths was compared with a commercial capsule formulation and a slowly dissolving tablet formulation. Correlation between dissolution rate and bioavailability was shown in freshly prepared methaqualone tablet formulations. Bioavailability of tablets under accelerated stability testing conditions remained unaltered, whereas the dissolution rates in pH 7 phosphate buffer decreased, using the resin flask method. A rotating-flask method was developed, and dissolution in 0.1 N HCl at 2 rpm correlated with the bioavailability of both new and aged tablet formulations.


Hypocholesterolemic agents III: inhibition of beta-hydroxy-beta-methylglutaryl coenzyme A reductase by half acid esters of 1-(4-biphenylyl)pentanol. A series of half acid esters of 1-(4-biphenylyl)pentanol was synthesized and assayed for inhibition of rat liver beta-hydroxy-beta-methylglutaryl coenzyme A reductase. The number of methylenes separating the carboxyl and ester groups was varied from zero to six. A minimum of one methylene was required for reasonable activity. Further separation of the carboxyl and ester groups produced small changes in activity. Investigation of several isomeric (cis and trans) half acid esters indicated that activity was independent of configuration. Modification of the acid portion of the glutarate analog by incorporating a 3-hydroxyl group increased activity sixfold.


N-halo derivatives III: stabilization of nitrogen-chlorine bond in N-chloroamino acid derivatives. The chlorination of alpha-amino acids and their related derivatives was investigated. A kinetic study of the stability of these N-chlorinated products led to an elucidation of the factors that significantly influence the stability and reactivity of the nitrogen-chlorine bond in these N-chloramines. From the kinetic investigations, a series of low chlorine potential, soft antimicrobial N-chloramines was developed based on derivatives of alpha-aminoisobutyric acid and related compounds.


Isolation of flindersiamine, isoflindersiamine, and a new alkaloid, heliparvifoline, from Helietta parvifolia (Rutaceae). A phytochemical investigation of the leaves and twigs of Helietta parvifolia (Rutaceae) resulted in the isolation of heliparvifoline, a new furoquinoline alkaloid, in addition to the known bases flindersiamine and isoflindersiamine.


Improved transport apparatus for examining diffusion of drugs across isolated tissues and synthetic membranes. A three-compartment diffusion apparatus that can accommodate synthetic as well as small isolated biological membranes such as rat intestine was developed and tested. The diffusion of drug from two outer donor cells into a central recipient cell allows for more membrane surface exposure and greater sensitivity in assaying as compared with previously published techniques. Reproducibility values for the synthetic membrane were equivalent to those obtained in more elaborate designs, while the reproducibility for biological membranes compared favorably with everted gut preparations and a similar diffusion apparatus. The clearance, per square centimeter of membrane, of salicylamide at pH 7.4 and 37 degrees was 0.288 ml/hr/cm2, which agreed with previous literature reports of different techniques. Although the diffusion through  a synthetic membrane was more rapid, introduction of a nonionic surfactant enhanced the biological perfusion rate while having no significant effect on the synthetic barrier. The enhancement of the diffusion rate effected by 0.1 and 0.01% (w/v) surfactant was about twofold, rapid in onset, and not progressive, giving clearance values per square centimeter of 0.606 and 0.537 ml/hr/cm2, respectively.


Development of an aerosol dosage form containing insulin. An aerosol dosage form containing insulin was developed by suspending insulin zinc crystals in fluorocarbon propellant and using oleyl alcohol to improve the insulin suspension and to prevent valve clogging. A metered valve was used to control the amount of insulin delivered per actuation. The dose dispensed, sedimentation rate, and particle-size distribution of the aerosol formulation were evaluated. The potency of the insulin delivered from the aerosol containers stored at various temperatures and time intervals was determined using a radioimmunoassay. Based upon preliminary stability data, which were treated kinetically, it was noted that insulin aerosols stored in a refrigerator at 7 degrees would have a predicted shelflife of approximately 19 years, whereas samples stored at 25 and 37 degrees would have shelflives of 11 and 2 months, respectively. Long-term stability studies are indicated to establish this conclusion. On the basis of this study, it was concluded that an insulin-containing aerosol dosage form can be formulated and that a suitable dose of insulin can be dispensed using commercially available metered dose valves. The actual dose of insulin dispensed would have to be related to the degree of absorption of insulin one would normally expect when insulin is administered by the inhalation route.


Effect of thermal gelation on dissolution from coated tablets. Tablets with a methylcellulose coating were found to exhibit lower dissolution profiles than those coated with a hydroxypropyl methylcellulose coating at 37 degrees, and the cause was investigated. The differences are attributed to thermal gelation of the methylcellulose at temperatures near 37 degrees, which creates a barrier to the dissolution process and essentially changes the dissolution mechanism. This mechanism is substantiated by the fact that at temperatures below the gel point and at increased agitation, the effect disappears. The retarded dissolution effect is not peculiar to the drug involved.


GLC determination of plasma levels of intact chlorpropamide or tolbutamide. A GLC procedure was developed for the quantitative estimation of intact chlorpropamide and tolbutamide concentrations in plasma; the drugs are used as mutual internal standards. After extraction of plasma containing the drug and internal standard with toluene, the dried residue is treated with ethereal diazomethane to form the methyl derivatives of tolbutamide and chlorpropamide. Aliquots of the ethereal solution are injected into a gas chromatograph equipped with a glass-lined injection port and glass column packed with a phenyl methyl silicone fluid (OV-25) on Chromosorb W, which facilitates the intact determination of the methyl derivatives of the drugs. The response to the flame-ionization detector was linear over a range of 0.20-25 mug/ml, with a 0.05-mug/ml limit of detectability for both drugs. The method compares favorably with a recently developed high-pressure liquid chromatographic procedure and is adequate for following blood level profiles of single doses of chlorpropamide (125 mg) and tolbutamide (250 mg). Mass spectral evidence showing that intact sulfonylureas are measured is presented.


Mechanism of action of retinyl compounds on wound healing IV: effect of desmethylretinoic acid and its vinylogs on granuloma formation. The effect of side-chain length of desmethylretinoic acid on granuloma formation induced by implantation of cotton pellets was studied. As in the homologous series of retinoic acid studies, compounds with side chains shorter than retinoic acid were not active while compounds with side chains as long or longer than retinoic acid were active. The compound with a chain two carbons longer than retinoic acid was the most active. The hydroxyproline and hexosamine contents of the granuloma were analyzed. The mechanisms of action of these active compounds on wound healing are discussed.


Solvent-dependent conformational system in hydroxyureas detected by NMR spectroscopy. The proton magnetic resonance spectra of the antileukemia agent hydroxyurea and substituted hydroxyureas in several solvents were recorded and correlated with structural features. Solvent-dependent differences in conformational preferences due to effects on internal hydrogen bonding, a temperature-dependent conformational feature, anthe exchangeability of protons with deuterium oxide and acetone-d6 were observed. The conformational features consistent with the spectral data are discussed.


Rapid determination of dimethyl polysiloxane by proton magnetic resonance spectroscopy. A new procedure is described for the quantitative extraction and determination of dimethyl polysiloxane by 1H-NMR spectroscopy, using tetrachloroethylene as the solvent and dioxane as the internal reference.


NMR determination of enantiomers of 7-chloro-3,3a-dihydro-2-methyl-2H,9H-isoxazolo(3,2-b)(1,3)benzoxazin-9-one using chiral shift reagent, tris(3-(heptafluorobutyryl)-d-camphorato)europium(III). A simple NMR method was developed for the determination of the enantiomers of 7-chloro-3,3a-dihydro-2-methyl-2H,9H-isoxazolo[3,2-b][1,3]benzoxazin-9-one. Chiral shift reagent, tris[3-(heptafluoroburyryl)-d-camphorato]europium(III), causes the doublet assigned to the protons of the 2-methyl group, which normally appears at about 1.5 ppm, to split into two pairs of doublets and to shift downfield to about 2.0-3.5 ppm. The downfield pair of doublets represents the two enantiomers present in one racemate, designated as the beta-form, while the upfield pair represents the enantiomers of the racemate designated as the alpha-form. From the integration of the area under the doublets, the relative concentration of all four enantiomers was determined.


Comparison of protective effects of ethylestrenol, norbolethone, and spironolactone against lethality from acute doses of parathion and paraoxon in female rats. Protection against the toxicity of parathion (increased LD50) was provided by preadministered ethylestrenol and, to a lesser extent, by norbolethone and spironlactone. Ethylestrenol and norbolethone also offered protection against paraoxon toxicity. With ethylestrenol and spironolactone, the protection against parathion lethality was greater than that against paraoxon lethality.


Determination of nitrofurantoin in urine by reduction at rotating platinum electrode. The application of the reduction of nitrofurantoin at the rotating platinum electrode to the determination of the drug in the urine of clinical patients was evaluated and compared to a commonly used colorimetric method. The new electrochemical method was found to be faster and more efficient with precision and accuracy comparable to those of the colorimetric method.


Simple transformation method for predicting plasma drug profiles from dissolution rates. A transformation factor is described which related in vitro drug dissolution from a preparation to the corresponding in vivo plasma drug concentrations. This factor, derived from the dissolution profile and the corresponding in vivo plasma concentration of a single formulation, was used to predict plasma concentration profiles of similar formulations simply from dissolution data.


Protein-binding polyhedral boranes II: DL-S-(10-dimethylsulfidooctahydrodecaborane)methionine. An analog of methionine, DL-S-(10-dimethylsulfidooctahydrodecaborane)methionine, was synthesized from fully protected homoserine. A protected dipeptide with glycine is described.


High-speed liquid chromatographic determination of procaine in pharmaceuticals. The operating conditions for a quantitative method of determining procaine in pharmaceutical preparations by high-speed liquid chromatography are described. The presence of decomposition products and the possible interference of other ingredients usually present in pharmaceutical preparations were found to have no effect. The method, because of its simplicity, is highly suited for routine analysis of pharmaceutical preparations containing procaine.


GLC analysis of lidocaine in blood using an alkaline flame-ionization detector. A method was developed for the quantitative GLC determination of lidocaine and its major metabolite monoethylglycinexylidide. By using the specificity of the alkaline flame-ionization detector, this simple analytical procedure is extremely sensitive, rapid, and easily performed.


Onset of enzyme induction with pregnenolone-16alpha-carbonitrile in male and female rats. Male and female rats treated with a single 20-mg/kg ip dose of pregnenolone-16alpha-carbonitrile (PCN) produced parallel increases in hepatic cytochrome P-450 and aniline hydroxylase activity. However, the onset of increase in aniline hydroxylase activity and cytochrome P-450 content was slower in male than female animals. The maximal levels achieved in male rats were 89% of the values observed in the female animals. Furthermore, the hepatic aniline hydroxylase activity and P-450 content declined more rapidly in male than in female rats.


Synthesis and biological evaluation of 1-(4-hydroxy-2-oxo-2H-1-benzopyran-3-yl)pyridinium hydroxide inner salt derivatives. Eight 1-(4-hydroxy-2-oxo-2H-1-benzopyran-3-yl)pyridinium hydroxide inner salts were synthesized, and the antibacterial, antifungal, anticoccidial, and anthelmintic activities were determined against different microorganisms, the protozoan Eimeria tenella, and trichostrongyle nematodes. All were noninhibitory to Gram-negative bacteria and the parasites. The pyridine, 4-benzylpyridine, and 2-isoquinoline inner salt derivatives controlled only Rhizoctonia solani of the four genera of fungi challenged.


New compounds: synthesis of O-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine hydrochloride. Reaction of 2,3,4,5,6-pentafluorobenzyl bromide with N-hydroxyphthalimide produced N-(2,3,4,5,6-pentafluorobenzyloxy)phthalimide which, after hydrazinolysis and treatment with hydrogen chloride, yielded O-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine hydrochloride. The latter compound was used to derivatize keto steroids for their analysis by electron-capture GLC.


New compounds: derivatives of methyl 2-aminoacetyl-4,5-dimethoxyphenylacetate. Methyl 2-bromoacetyl-4,5-dimethoxyphenylacetate was prepared by reacting cupric bromide with methyl 2-acetyl-4,5-dimethoxyphenylacetate. Aminoacetyl derivatives formed on condensation of substituted p-aminobenzoic esters with the bromoacetyl derivative. Some prepared compounds were tested for local anesthetic and anti-inflammatory activities.


Biodisposition of ketamine in the rat: self-induction of metabolism. Four pharmacologic actions of intravenous ketamine (30 mg/kg) were studied in the rat. To elucidate the mechanism(s) terminating the pharmacologic effects, animals were pretreated with ketamine and agents anticipated to modify hepatic microsomal metabolism, including phenobarbital and SKF 525A. SKF 525A pretreatment markedly prolonged ataxia, analgesia and agitation, in addition to significantly elevating brain and plasma ketamine levels subsequent to the initial 10 minutes following injection; thus hepatic metabolism appeared to play a prominent role in the termination of the posthypnotic effects of the drug. While significantly shortening the durations of the three posthypnotic events, phenobarbital and ketamine pretreatments also lowered the brain and plasma levels of ketamine. With all pretreatments, brain ketamine levels were almost identical at the cessation of hypnosis (25 mug/g of tissue) and ataxia (8-10 mug/g of tissue). No pretreatment altered either the duration of loss of righting reflex (hypnosis) or brain and plasma ketamine levels during the initial 10 minutes after injection. Approximately 70% of the injected drug was recovered from four tissues, skeletal muscle, gut, skin and liver, at 10 minutes after injection; thus redistribution from brain to other tissues appeared to play a major role in the cessation of hypnosis. Ketamine pretreatment caused a 2-fold increase in the rate of its in vitro hepatic microsomal metabolism. Brain and plasma ketamine levels 30 minutes after injection were nearly identical in rats pretreated with ketamine and phenobarbital, although phenobarbital pretreatment resulted in a 4-fold increase in in vitro ketamine hepatic metabolism.


Specificity of release of biogenic amines from isolated rat brain tissue as a function of the meta substituent of N-ethylamphetamine derivatives. The actions of several meta-substituted N-ethylamphetamines on the release, uptake and catabolism of biogenic amines were investigated in vitro in two regions of rat brain. Each of the compounds released 3H-norepinephrine from chopped cerebral cortex, and 3H-dopamine and 3H-5-hydroxytryptamine from chopped corpus striatum. Stepwise multiple linear regression analyses indicated that the potencies (EC50 values) with which the compounds released 3H-norepinephrine were inversely related (r = 0.94) to the size of the meta substituent. Addition of substituent lipophilic or electronic effects to the regression equation did not greatly improve the correlation. However, the maximal release of 3H-norepinephrine produced by these compounds was directly related only to substituent lipophilic effects (r = 0.95). The potencies and maxima with which the compounds released 3H-dopamine or 3H-5-hydroxytryptamine and the potencies with which the compounds inhibited the uptake of the 3H-amines were not correlated with substituent size, lipophilicity or electronegativity. Variations in meta substituent also altered the degree to which the release 3H-amines were metabolized by monoamine oxidase. Multiple linear regression analyses indicated that for each of the 3H-amines, the maximal percent increase in 3H-deaminated metabolites produced by the drugs was directly correlated only with substituent size (r = 0.85, 0.89 and 0.95 for 3H-norepinephrine, 3H-dopamine and 3H-5-hydroxytryptamine, respectively). Comparisons among the potencies with which compounds released the various 3H-amines indicated that, in general,  as substituent size increased, the compounds became relatively less potent in releasing 3H-catecholamines and relatively more potent in releasing 3H-5-hydroxytryptamine. Thus, these studies indicate that variations in the meta substituent group of N-ethylamphetamine derivatives determine the affinity of the derivatives for norepinephrine nerve endings and the relative affinities of the derivatives for norepinephrine, dopamine and 5-hydroxytryptamine nerve endings.


Comparative actions of monomethoxyamphetamines on the release and uptake of biogenic amines in brain tissue. para-Methoxyamphetamine (PMA), a known hallucinogen, is the most potent compound among methoxyamphetamines in disrupting behavior in rats. PMA, unlike d-amphetamine (A), did not induce stereotyped behavior and was less effective than A in stimulation of locomotor d-amphetamine-like effects, but ortho-methoxyamphetamine (OMA) was devoid of any locomotor stimulation. To investigate the reasons for the different behavioral effects caused by PMA, meta-methoxyamphetamine (MMA), OMA and A, a comparison was made among these drugs on the release and uptake of 3H-5-hydroxytryptamine (3H-5-HT), 3H-norepinephrine (3H-NE) and 3H-dopamine (3H-DA) in tissue slices of cerebral cortex and corpus striatum of rat brain. The potencies for the increased release of 3H-5-HT were found to be PMA greater than MMA greater than or equal to A greater than OMA in cerebral cortex of 3H-NE in cortex, A greater than or equal to PMA = MMA greater than OMA, and of 3H-DA in corpus striatum, A greater than MMA greater than PMA greater than or equal to OMA. The potencies for inhibiting the uptake of 3H-5-HT in cerebral cortex and corpus striatum were found to be PMA greater than MMA greater than A greater than OMA and of 3H-NE in cortex A greater than PMA greater than or equal to MMA greater than OMA, and 3H-DA in corpus striatum A greater than MMA greater than PMA greater than OMA. d-PMA is equipotent to l-PMA in increasing the release of 3H-5-HT but is more potent than l-PMA in blocking the uptake of 3H-5-HT. The high potency of PMA on increasing the release and inhibiting the uptake of 5-HT suggests than 5-HT may be involved in the production of hallucinogenic effects of PMA.


Effects of prenatal reserpine administration on development of the rat adrenal medulla and central nervous system. Reserpine (1 mg/kg s.c.) was administered to pregnant rats at different periods of gestation. Rats born to mothers who received reserpine on days 6, 5 and 4 or 4, 3 and 2 before delivery showed early postnatal adrenal catecholamine depletion, an effect which can be attributed to a direct action of the drug; however, at no time was induction of tyrosine hydroxylase or dopamine beta-hydroxylase observed. Administration of reserpine on days 9, 8 and 7 before delivery did not alter postnatal adrenal catecholamine levels in the offspring but produced permanent elevations in enzyme activities and vesicular amine uptake beginning at 10 days of age. Studies utilizing direct stimulation with nicotine indicated that the inherent responsiveness of the adrenal medulla itself was the same in control and reserpine-exposed pups. These data all suggest that sympathoadrenal tone has been permanently increased in the offspring of rats which have been exposed to reserpine early in gestation. In the brain, administration of reserpine on days 6, 5 and 4 before delivery resulted in a delay in early postnatal development of brain weight and synaptosomal uptake mechanisms, and at later stages subnormal tyrosine hydroxylase activities. When reserpine was given on days 9, 8 and 7 before delivery, only the deficiency in tyrosine hydroxylase was seen. These studies indicate that long-lasting changes in both peripheral and central nervous system catecholamine disposition can be produced by prenatal reserpine administration.


Effects of intermittent and repeated administration of d-amphetamine on restricted water intake in rats. Eleven rats had access to water 2 hours daily and intake was measured every 20 minutes. When given intermittently, increasing doses of d-amphetamine (0.05-1.6 mg/rat) decreased total water intake and altered the within-session distribution of intake, with proportionately less intake occurring within early portions of the session after larger doses. Repeated administration of d-amphetamine (0.2, 0.8 or 1.6 mg/rat/day) completely attenuated the overall intake-decreasing effects of the drug; the time taken for recovery of total intake increased with increasing dose. Despite complete tolerance to its overall intake-decreasing effects, d-amphetamine produced persistent dose-related effects on the distribution of intake within sessions that were only partially attenuated with continued daily administration of the drug. Tolerance to the overall intake-decreasing effect of 1.6 mg was accompanied by parallel shifts toward larger doses in the dose-effect functions for total water intake and for the within-session distribution of intake. Redetermination of the dose-effect functions at several times after the repeated administration of 1.6 mg generally showed that tolerance of d-amphetamine was lost within 25 to 57 days after discontinuation of the drug.


Tolerance to the respiratory effects of marijuana in man. The respiratory depressant effect of marijuana was studied by means of carbon dioxide respiratory response curves in eight healthy male subjects participating in a study of the effects of a 90-day ad libitum intoxication to marijuana. Subjects were studied in the morning after refraining from marijuana use since the previous evening. Respiratory response curves were done before smoking and at 15, 30 and 60 minutes after smoking two 900-mg cigarettes containing 2.2% delta9-tetrahydrocannabinol. Studies were conducted 2 to 3, 5 to 6 and 8 to 9 weeks after onset of intoxication. There was a significant change from base-line controls, indicating respiratory depression following marijuana smoking. A significant change in the time-effect curve over these three study sessions, indicative of tolerance, was noted. The degree of pulse elevation also decreased over the three study sessions, but this decrease in effect was not statistically significant.


Differential effects of ethanol and mannitol on contraction of arterial smooth muscle. The present work, using isolated rat aortic strips, indicates that ethanol can inhibit development of spontaneous mechanical activity, induce contractions which are not inhibited by specific amine antagonists and potentiate or inhibit contractions induced by epinephrine and vasopressin. In addition, the data indicate that ethanol can attenuate contractions induced by K+ and can inhibit Ca++-induced contractions of K+-depolarized rat aortic strips. Experiments with a nonpenetrating substance, mannitol, suggest that the effects of ethanol are probably not solely a reflection of hyperosmolarity. Overall, the data could be used to suggest that ethanol may induce hyper- or hypoexcitability of aortic smooth muscle by affecting movement and/or translocation of Ca++.


Reduced beta adrenergic responsiveness in rats treated with estrogenic agents. Chronic treatment with ethynyl estradiol alone (48-50 mug/kg/day) and in combination with several doses of norethynodrel either attenuated or prevented the increase in tail skin temperature accompanying sC. administration of isoproterenol (200 mug/kg b.wt.) to male and female rats. Dietary administration of an oral contraceptive containing norethynodrel and mestranol (7.5 mg/kg of food) was also accompanied by an attenuated response to isoproterenol. Attenuation of the tail skin temperature response was present in all groups after 3 to 5 weeks of treatment but was detectable in the oral contraceptive-treated group after 1 week of treatment. All steroids and combinations, except norethynodrel administered alone (154 mug/kg/day), reduced body weight gain.


Inhibition of acetylcholine release from cholinergic nerves by adenosine, adenine nucleotides and morphine: antagonism by theophylline. Adenosine and adenine nucleotides [adenosine-5'-monophosphate, adenosine-5'-diphosphate, adenosine triphosphate (ATP), cyclic adenosine 3',5'-monophosphate (dbcAMP)], but not (cAMP) and dibutyryl cyclic adenosine 3',5'-monosphosphate (dbcAMP)], but not adenine or inosine, inhibited the twitch response of the electrically stimulated guinea-pig myenteric plexus-longitudinal muscle preparation. With each agent except dbcAMP, inhibition was manifest muscle preparation. With each agent except dbcAMP, inhibition was manifest from 1 to 500 muM was maximal within 1 minute. For dbcAMP, higher concentrations were required (10-fold increase) and inhibition was maximal after 20 to 30 minutes. Theophylline (0.05-0.5 mM) both reversed and prevented the inhibition produced by each of these agents. In higher concentrations (greater than 1 mM), theophylline itself depressed the twitch response. Neither propranolol nor phenoxybenzamine altered theophylline-induced depression, whereas phenoxybenzamine did not alter adenosine-induced inhibition. Adenosine, ATP, cAMP and theophylline (0.25 mM) did not alter acetylcholine-induced contractions, whereas a higher concentration of theophylline (2.5 mM) inhibited contractions. Theophylline (up to 0.5 mM) did not antagonize epinephrine- or dopamine-induced inhibition of the twitch response, but did antagonize morphine-induced inhibition. These findings suggest that adenosine and related nucleotides act at a common receptor site at which theophylline acts as a competitive antagonist and that there is a link between morphine and adenine nucleotide action in this preparation.


Ventricular electrophysiology of quinidine-propranolol combinations in the dog heart. The effects of quinidine and propranolol, singly and in combination, on certain electrophysiological responses were studied in open-chest dogs. Parameters measured were the diastolic threshold, conduction time, excitability and functional refractory period of canine right ventricular muscle. Potentiation was judged to have occurred if the combination of a half-dose of quinidine plus a half-dose of propranolol produced a significantly greater response than the full dose of either quinidine or propranolol. Two combinations were employed in this study: combination I contained 2.5 mg/kg of quinidine plus 0.1 mg/kg of propranolol while combination II contained 5.0 mg/kg of quinidine plus 0.2 mg/kg of propranolol. Results of the study indicated that combination II potentiated the activity of quinidine and propranolol to depress excitability, increase conduction time and prolong refractoriness. However, combination I only potentiated the change in refractory state. Neither combination potentiated the individual drug action to increase the diastolic threshold. From the results of this study, it may be concluded that the combination was especially effective in prolonging ventricular refractoriness which may account to a significant degree for the enhanced therapeutic effectiveness of the combination in resistant ventricular arrhythmias.


Comparative species studies on the effect of monovalent cations and ouabain on cardiac Na+, K+-adenosine triphosphatase and contractile force. The effects of ouabain, Rb+ and Tl+ on Na+, K+-adenosine triphosphatase (Na+,K+-ATPase; Mg++-dependent, Na+,K+-activated ATP phosphohydrolase, EC 3.6.1.3) and contractile force were compared in guinea-pig and rat hearts. Although ouabain produced a dose-dependent positive inotropic effect in rat as well as in guinea-pig atrial preparations, concentrations of ouabain needed to produce comparable positive inotropic effects were more than an order of magnitude higher in rats than in guinea pigs. Additionally, the time to reach the plateau of the inotropic response was significantly shorter in rat than in guinea-pig atrial preparations. Concentrations of ouabain needed to produce comparable inhibition of cardiac Na+, K+-ATPase in vitro observed with partially purified cardiac enzyme preparations were also more than an order to magnitude higher in rats than in guinea pigs.


Elimination and distribution of phenylbutazone in rats during the course of adjuvant-induced arthritis. The elimination and distribution of phenylbutazone after administration of a single intravenous dose of 25 mg/kg was investigated before and at different stages of adjuvant-induced arthritis in the same group of rats. In other groups which were studied concurrently, the cytochrome P-450 and b5 levels and ethylmorphine demethylation of liver microsomes were determined. Total plasma protein and albumin concentrations were monitored and the binding of phenylbutazone to plasma proteins was investigated. In the acute phase of adjuvant-induced arthritis, there was 1) a pronounced decrease in the elimination rate of phenylbutazone and 2) a marked increase in the apparent volume of distribution. The former could be explained by a reduced rate of hepatic biotransformation of phenylbutazone. A pronounced decrease in the microsomal cytochrome content and a slow rate of ethylmorphine demethylation is in agreement with this assumption. The latter appeared to be a result of the reduced binding capacity of the rat plasma due to the decrease in albumin concentration. The cytochrome content of liver microsomes and the plasma albumin concentration, however, were restored when arthritis reached its chronic phase. Consequently, an impairment of the elmination and distribution of phenylbutazone was no longer apparent.


Binocular visual mechanisms in cortical areas I and II of the sheep. 1. Units were recorded in the primary and secondary visual areas (V1 and V2) of the sheep. They were stimulated binocularly, using an adjustable prism to vary the disparity. 2. Cells in V1 responded optimally to stimuli with very small or zero disparities, but cells in V2 frequently preferred disparities of several degrees crossed or uncrossed. Many cells in V2 were particularly selective to disparity, often giving no response to a monocular stimulus. 3. Cells preferring the same disparity occur in discrete columns, about 400 muM wide. Changes between columns result from a step displacement of the receptive field of one eye. The disparities encoded in successive columns seem to follow a regular sequence: crossed, zero, uncrossed, zero, etc. 4. In both V1 and V2, cells are clustered, perhaps in columns, according to their orientation preference and ocular dominance. In V2, the constant disparity columns appear to be independent of the orientation clusters.


Impedance components in longitudinal direction in the guinea-pig taenia coli. 1. When the tissue impedance of the guinea-pig taenia coli was measured across a 2 mm sucrose gap in a longitudinal direction, the impedance locus could be fitted by two different circular arcs. Their characteristic frequencies were about 0-6 and 240 Hz after 60 min superfusion with sucrose solution. From the effects of changing the width of sucrose gap and of transection of tissue, and also from taking the difference between impedances measured at two distances, it was concluded that the low-frequency locus corresponds to the transverse impedance of the plasma membrane and the high-frequency locus to the longitudinal tissue impedance. 2. A change in the longitudinal tissue impedance was measured during superfusion with sucrose solution, using a frequency range between 5 Hz and 10 kHz. The admittance decreased with time of superfusion and this time course could be expressed by the sum of three exponential terms. The fastest component, having a time constant of 1-3 min at 10 kHz, was interpreted to correspond to a process of wash-out of extracellular medium. 3. Admittances at zero and infinite frequencies were obtained from the impedance locus. The decrease in these admittances with the time was analysed and the values at the start of washing were obtained by extrapolating the admittance change to zero time. 4. From these values it was estimated that the myoplasmic resistance was 214 omega cm, the junctional resistance 372 omega cm, and the junctional capacity 3-1 muF/cm at 25 degrees C. In these calculations the equivalent circuit of tissue was assumed to be expressed by two components in series: one for the myoplasmic resistance and the other for the junction which has the junctional resistance and capacity in parallel. 5. After 90 min superfusion with sucrose solution, the total tissue impedance measured at zero frequency was increased from 586 to 3034 omega cm. In the total impedance the myoplasmic resistance was increased from 214 to 914 omega cm and the junctional resistance from 372 to 2120 omega cm. Thus, the change in junctional resistance was greater than that in myoplasmic resistance during superfusion of sucrose solution.


A study of peripheral input to and its control by post-ganglionic neurones of the inferior mesenteric ganglion. 1. Intracellular recordings were made, in vitro, from neurones of guinea-pig inferior mesenteric ganglia (IMG) attached, via the lumbar colonic nerves, to segments of distal colon. 2. 'Spontaneous' synaptic input from colonic afferent fibres was observed in 79% of the neurones tested. In any given preparation, the level and pattern of this synaptic input to different neurones varied considerably. 3. Superfusion of colonic segments with drugs (papaverine, isoprenaline, and adenosine triphosphate) which reduce colonic motility decreased colonic afferent input to IMG neurones. 4. Superfusion of colonic segments with acetylcholine or stimulation of pelvic nerves, both of which increase colonic motility, increased colonic afferent input to IMG neurones. 5. Superfusion of colonic segments with either atropine or tubocurarine reduced the level of 'spontaneous', colonic afferent input. However, distension of these relaxed segments increased the colonic afferent input. 6. Repetitive stimulation of preganglionic inputs to the IMG inhibited afferent input from drug relaxed segments of colon that were moderately distended by the injection of air into the lumen. Superfusion of the colon with phentolamine blocked this inhibition. 7. The results of this study suggest that IMG neurones receive afferent input from mechanoreceptors located in the distal colon and that the mechanosensitivity of this afferent pathway is in part controlled by efferent noradrenergic neurones of the IMG. The IMG-colon neural circuitry can therefore be considered to form a feed-back control system which participates in the regulation of colonic motility.


Unmyelinated fibres in the sacral 3 and caudal 1 ventral roots of the cat. 1. 29% of the axons in the S3 and Ca 1 caudal ventral roots of the cat are unmyelinated. 2. Approximately one half of these unmyelinated axons survive in the proximal stump of a sectioned ventral root and are regarded as unmyelinated preganglionic efferents. 3. At least 27% of the preganglionic efferents in segments S3 and Ca 1 are unmyelinated. 4. The other half of the ventral root unmyelinated axons arise from dorsal root ganglion cells and survive in the distal stump of a sectioned ventral root. 5. The data in 4, combined with the receptive field data in our companion paper, show that these unmyelinated fibres are sensory. 6. Since 15% of the ventral root axons are sensory, the Law of Bell and Magendie cannot be regarded as an accurate description of the organization of these ventral roots.


Further studies of the potential-dependence of the sodium-induced membrane current in snail neurones. 1. The potential-dependence of the membrane current induced by intracellular injections of sodium ions was studied on giant neurones of the snail Helix pomatia. This current decreases with membrane hyperpolarization at room temperature and can be reversed at sufficiently negative holding potentials. The same injections at 7 degrees C, as well as injections of lithium or potassium ions do not induce membrane currents and do not increase membrane conductance. 2. An increase in the amount of injected sodium changes the potential-dependence of the induced membrane currents. Small injections (about 1 muC) induce a current that does not depend upon the membrane potential. Further increase in the injection size not only increases the induced current but also enhances its potential-dependence and often reveals the existence of a reversal potential. The latter reaches -60 to -65 mV with large sodium injections. 3. An increase in extracellular potassium concentration from 4 to 8 mM shifts the reversal potential 17 mV in the depolarizing direction, and a decrease from 4 to 2 mM shifts it 14 mV in the hyperpolarizing direction. Replacement of potassium by rubidium or elimination of sodium ions from the outside solution, does not affect the induced current or its potential-dependence. 4. The coefficient of electrogenicity (the ratio between the amount of charge transferred by the sodium-induced membrane current and the amount brought into the cell during the injection) increases with an increase in the injection size if the membrane potential is clamped near the resting potential level. This relation is reversed when the holding potential is -80 mV. The reversal takes place at holding potentials near -60 mV. 5. 10 mM TEA does not affect the induced current and its potential-dependence. 6. It is suggested that the potential-dependence of the sodium-induced membrane current is a result of a specific increase in the membrane potassium conductance that is coupled with high activity of the sodium pump.


Glycine-mediated inhibitory transmission of group 1A-excited inhibitory interneurones by Renshaw cells. 1. Electrophysiological and micro-electrophoretic studies were carried out in anaesthetized cats on spinal interneurones which were monosynaptically activated from group 1 muscle afferents and recurrently inhibited by Renshaw cells. 2. The recurrent inhibition was blocked by the iontophoretic administration of strychnine, which also blocked the action of glycine. 3. The time course of the block of synaptic inhibition by strychnine was slower than the block of glycine evoked inhibition. The significance of this observation in terms of the location of the inhibitory synapses is discussed. 4. The observation that recurrent inhibition of motoneurones and of interneurones is blocked by strychnine whereas the mutual inhibition of Renshaw cells is not is discussed in relation to the proposal that the nature of the post-synaptic inhibitory receptor is not determined solely by the innervating neurone, which is the Renshaw cell in all three instances. 5. The recurrent inhibition of the interneurones was not blocked by the iontophoretic administration of bicuculline, but difficulties were encountered in demonstrating that this agent consistently antagonized the inhibitory effects of GABA.


Influence of changes in external potassium and chloride ions on membrane potential and intracellular potassium ion activity in rabbit ventricular muscle. 1. The membrane responses of rabbit papillary muscles to rapid changes in [K](o) and [Cl](o) were measured with open-tipped micropipettes and with closed micropipettes made from K-selective glass.2. The muscle cells behaved primarily as a K electrode, and responses to changes in [K](o) with constant [Cl](o) or with constant [K](o) x [Cl](o) were substantially the same.3. When [Cl](o) was changed at a constant [K](o) the membrane potentials changed rapidly and symmetrically by a small value and remained constant for 30 min.4. Measurement of potential with K(+)-selective micro-electrodes in these experiments showed no change in intracellular K activity. In addition to permitting calculation of K permeability, these measurements reassured us that the K(+)-selective electrodes were well insulated and not influenced by electrical shunts at the impalement site.5. Although the membrane response to changes in [Cl](o) was small, it was possible to calculate that the permeability ratio (P(Cl)/P(K)), was 0.11. The Cl and K conductances were about 0.015 mmho/cm(2) and 0.09 mmho/cm(2) respectively, resulting in a conductance ratio (g(Cl)/g(K)) of about 0.17.6. The time course of depolarization by increase in [K](o) was rapid (half-time 5 sec), but repolarization on return to lower [K](o) was much slower (half-time 50 sec). The depolarization time course was easily fitted by the potential change calculated by assuming the need for K diffusion into the extracellular spaces and taking account of the logarithmic relation between membrane potential and [K](o). These calculations did not fit the time course of repolarization, which was slowed in the fashion expected from an inward-rectifying membrane.7. The influence of [K](i) on membrane potential was investigated by changes in tonicity of the external solution. Hypotonic solution produced a change in intracellular K activity close to that produced by ideal water movement. However, in hypertonic solution, intracellular K activity did not rise as much as predicted, suggesting a change in intracellular activity coefficient.


The antecedents of anger in a sample of college students. Eighty-three college students were surveyed in an attempt to identify the situations that elicit anger or a loss of temper. The 356 responses were sorted into seven rational categories with substantial interrater reliability. There were no significant sex differences; however, there were more antecedents reported for anger than for loss of temper. On a self-rating scale a high percent of Ss gave a benign report on the frequency of their anger arousal and loss of temper. However, the intensity of anger was reported as greater than that of others by 32% of the males and 20% of the females.


Relationship of self-concepts of three-, four-, and five-year-old children with mother, father, and teacher percepts. Ss were 46 preschool boys and girls, ages three, four, and five years, in a child and family development center. Each child, his mother, father, and teacher were administered, separately, 18 select items from the primary factor in the I Feel-Me Feel self-concept inventory. Results indicated that the childrens' self/social constructs scores were very stable but did not correlate with scores of mother, father, and teacher. The adult percepts of the child's self-concept were highly correlated ( less than .05) among themselves, but they were not in the same system of relationships with the children.


Anxiety as a function of environmental noise and social interaction. In a study to investigate environmental noise and social interaction as simultaneous stressors affecting anxiety, three independent groups of college students (N = 48 men and women) participated in the simulation game Starpower while exposed to different levels of background noise. Intermittent white noise at 61 dB(A) and 75 dB(A) was used for the Noisy and Very Noisy conditions, respectively, and the ambient noise level of 51 dB(A) was used for Quiet. The State-Trait Anxiety Inventory, administered before and after playing the game, was used as a direct, subjective measure of anxiety. Relatively low levels of noise superimposed on the stress of social interaction influenced the level of anxiety experienced by the Ss. Groups subjected to noisier environments reported significantly stronger feelings of anxiety than those in quieter conditions (p less than .05). Ss' eyeblink rate, used as an indirect, physiological indicator of anxiety, was not significantly affected by the stress levels produced in this experiment.


Gaze as a function of conversation and degree of love. The possibility that Rubin's findings of greater mutual gazing between strong than weak lovers and between strangers could be attributed to the occurrence of more conversation in strong love conditions was tested. Ss were selected from an undergraduate population. Ten strong love couples, determined through the use of Rubin's love scale, were compared to 10 pairs of unacquainted Ss for the amount of mutual eye contact, as well as conversation time and time spent in pure gazing without conversation. It was found that lovers did converse more with each other than with strangers. However, they also spent more time in pure gazing during periods of silence, lending credence to Rubin's results. The methodological implications of using videotape for eye contact studies were also discussed.


The modal personality of urban black middle-class elementary school children. This study attemped to identify traits that might be described as "typical" of black elementary school children. With use of the Early School Personality Questionnaire, the mean and modal scores for 13 traits were determined for 59 girls and 61 boys selected from two urban areas in two sections of the country. All were children of black middle-class families and were six and eight years old. When compared to the expected scores for children of this age range, the group as a whole differed from the average expected scores on only four factors. Analysis of the traits by sex found that black middle-class boys differed from the standardization sample boys on four of the 13 factors, and girls on eight of the 13. It was concluded that black middle-class girls, although not very different from the boys, were quite different in personality from girls of other groups, while the boys differed very little. The black sample was significantly more aloof and shrewd than the standardization group. It might be that these are traits developed by parents in black middle-class children to help them cope with a color-discriminating environment.


The dimensionality of body-cathexis.

The dimensionality of body-cathexis. In an exploratory examination of the dimensionality of body perception in terms of satisfaction with body aspects, a principal components analysis was performed on data from 226 male and female college students. Results indicate that the complex of body aspects can be discussed in terms of a relatively small number of dimensions. The variable content of the factors is interpreted as suggesting the perceptual grouping of body aspects, and in this regard the similarities and differences between males and females are discussed and related to previous research on body-cathexis.


Fine-structural aspects of microgametogenesis of Eimeria magna in rabbits and in kidney cell cultures. The fine-structural aspects of development of microgamonts of Eimeria magna were studied in kidney cell cultures and in experimentally infected rabbits. Spheroidal masses of gamont-like cytoplasm containing ribosomes, polyribosomes, and amylopectin granules were found within the parasitophorus vacuole; these bodies were apparently pinched off the surface of the gamont. Nucleoli were present in the early stages of nuclear division but disappeared as development proceeded.


Fine structure of Plasmodium gallinaceum in embryonic and neonate chicks. The erythrocytic stages of Plasmdoium gallinaceum in chicken embryos injected with parasited blood either from a syringe-passaged infection in chickens or from a chicken infected with sporozoites were characterized by abnormal structure. Particularly evident were large, unstained vacuoles within the cytoplasm; these occurred with greatest frequency in schizonts. The presence of myelin bodies within these vacuoles was revealed by transmission electron microscopy; abnormal cytokinesis and aberrant merozoites provided additional evidence of the parasite's inability to develop naturally within the milieu of the embryonic erythrocytes. Fifty-five passages were necessary to restore normal structure of the parasites in embryos, while only 5 passages were required for such restoration in neonate chicks. The probable adaptation of the parasite to the proportions of hemoglobin of the adult chicken may be responsible for the abnormal growth in the immature host.


Efficacy of antibiotics A204 sodium A28695A, and A204np against Coccidia of rabbits. Three polycyclic, polyether, monocarboxylic acid antibiotics produced by and extracted from a strain of Streptomyces albus and designated A204 sodium, A28695A, or A204-np, were specifically tested for activity against hepatic and incidentally against intestinal coccidia of rabbits. All were effective in preventing infections and acceptable to young rabbits when prepared in pelleted feed. Weight gain, however, was not as good as inoculated, medicated rabbits as in noninoculated, nonmedicated controls. No gross pathologic changes were detected except in the livers of inoculated, nonmedicated controls which were severely infected on greatly enlarged. Livers of medicated rabbits were uninfected and normal in appearance and size.


Eimeria tenella: host specificity in gallinaceous birds. Eight species representing 8 genera of gallinaceous birds were used: Alectoris graeca; Colinus virginianus; Coturnix coturnix; Gallus gallus; Meleagris gallopavo; Numidia meleagris; Pavo cristatus; Phasianus colchicus. Three week-old birds were dosed with sporulated oocysts of Eimeria tenella Beltsville strain. At 4, 24, 48, 72, 96, 120 and 144, and 168 hr after inoculation, 1-3 infected birds and uninoculated controls of each species were killed by cardiac exsanguination. Pieces of intestines were fixed and examined for stages of E. tenella as stained paraffin sections or indirect fluorescent antibody preparations. Oocyst counts were made in droppings collected for the first 6 days of the patent period. Sporozoites were found in the lamina propria of some birds of 5 species at 4 hr postinoculation, but no stages were found thereafter except in the breeds of G. gallus and A. gracea. At 144 and 168 hr postinoculation, a few macrogametes were found in the ceca of 2 A. gracea, but no oocysts were found in the feces. No statistical difference was found between the number of oocysts produced/bird in the breeds of G. gallus examined. It is evident from these observations the E. tenella did not complete its life cycle in several close phylogenetic relatives of G. gallus, even though in other studies this parasite was found to complete its life cycle in cell cultures derived from the same birds.


Laboratory and field studies on Glugea stephani (Hagenmuller), a microsporidan parasite of pleuronectid flatfishes. The microsporidan Glugea stephani is a common parasite of juvenile English sole (Parophrys vetulus) in Yaquina Bay, Oregon. Field observations indicated that fish became infected only in the upper estuary where summer temperatures were above 15C and the incidence of infection reached 79.8% in the late fall. Laboratory infections developed and parasite growth occurred only at or above 15C. The parasite was successfully transmitted to juvenile English sole by brine shrimp (Artemia salina) and amphipod (Corophium spinocorne) vectors as well as by direct ingestion of spores by the host. Infections that resulted from ingestion of spore-carrying vectors were much heavier than those resulting from the direct ingestion of spores. The speckled sanddab (Citharichthys stigmaeus), a nonpleuronectid flatfish, and chum salmon (Oncorhynchus keta) were refractory to G. stephani infection in the laboratory.


The cell surface of Trypanosoma musculi bloodstream forms. I. Fine structure and cytochemistry. An extracellular surface coat was observed at the fine-structural level on the outer lamina of the pellicular and flagellar membranes of intact Trypanosoma musculi bloodstream forms. The surface coat had a mean width of 9.2 nm, and was composed of a somewhat electron dense, uneven, fibrillar-like matrix. Brief trypsin treatment of living blood forms completely removed the cell surface coat.


Scanning electron microscope observations of Amoeba proteus during phagocytosis. Phagocytosing Amoeba proteus at different stages of forming foodcups have been observed by scanning electron microscopy. A nonphagocytosing ameba is characterized by dorsal and lateral ridges running longitudinally over the posterior half of the cell and its attachment to the substrate over small areas. When stimulated by prey organisms, the ameba loses polarity and ridges, and adheres to the substrate more firmly over a wider area of contact. Then it forms broad pseudopods to surround its prey and this results in the formation of foodcups. The surface of all ameba is covered with small projections, and membranous blebs are often seen on the surface of phagocytosing organisms.


The health of clients of a social service department. A survey was undertaken of the health problems and current medical care of new clients making contact with the Social Service Department of an outer London borough. The findings indicated that social-service clients represent a high-morbidity group of the population: 47 per cent of the survey sample showed evidence of major physical illness or disability, and 16 per cent of major mental illness. A sub-group was identified, corresponding to about 300 new clients annually, who suffered from serious ill-health or disability, but were at the time not under medical care.These findings support the argument for closer liaison between medical and social services in the community and, in particular, for more social-worker attachments in general practice.


Home deliveries in Holland. Dutch maternity care and home confinements. In the Netherlands a majority of all deliveries take place at home. The perinatal mortality rate is better than that reported from the United ffiingdom, probably because obstetric care in hospital is more active and aggressive. Dutch midwives play an important role and the specially trained home helps are most successful. I believe that, provided case selection is rigorous, many women are best delivered at home.


The provision of cottage hospital beds.

The provision of cottage hospital beds. The existence of cottage hospital beds is historically determined rather than planned, and there is apparently no official ratio for the provision of such beds. A comparative study, in North-east Scotland, of populations with and without access to cottage hospital beds suggests that providing 1.5 beds per 1,000 population is a reasonable basis for future discussion and planning.


General-practitioner maternity units.

General-practitioner maternity units. A study of information available for monitoring care was made during 1974 in 46 general-practitioner maternity units in the South-west of England. The information available did not form an adequate basis for monitoring at area level. Although many deliveries take place in general-practitioner maternity units in the South-west, perinatal mortality rates are low. Transfer of babies to a consultant unit, after the delivery is, however, commoner than elsewhere in England and Wales.


Common ground in general-practitioner and health-visitor training--an experimental course. A residential course for 21 general-practitioner vocational trainees and student health visitors is described. The aim was to introduce the two groups of trainee professionals to each other in an attempt to modify attitudes, increase knowledge of each other's work, and induce a more positive approach towards teamwork in their ultimate careers. Both groups achieved an improvement by the end, and over half said they understood the others' role better


Converting medical records to A4 size in general practice. A procedure for converting the medical record envelopes now used in general practice to an A4-sized record folder is described. The average time for conversion was 20.2 minutes per record and the cost, excluding filing equipment, averaged 41.6 pence for each record. The average cost to the practice was reduced to 16.4 pence per record by the reimbursement of 70 per cent of the clerk's salary from the local Family Practitioner Committee.


The role of practice manager--changes in attitudes promoted by the Royal College of General Practitioners. Because of the roles traditionally required of them, and because of the insularity of ancillary staff in general medical practice, many senior ancillary staff may not have been giving their doctors the most effective support of which they are capable. This is changing as a result of the change-promoting activities of the North of England Faculty of the Royal College of General Practitioners.A survey of ancillary staff and general practitioners in the North of England has shown that the Royal College of General Practitioners has assisted ancillary staff to a greater consensus of more progressive views about the emerging role of practice manager than is the case amongst general practitioners. The results also show that differences in the size of practices have determined whether or not a need for a practice manager is perceived.The focus of interest created by this faculty of the Royal College of General Practitioners has resulted in the formation of special interest groups of senior ancillary staff in the North of England. These groups form a valuable resource for exploration and innovation to discover more effective means of organising and managing general medical practice.


Reasons for referral to hospital.

Reasons for referral to hospital. In a study in North-east Scotland, nine out of ten patients had a "medical" reason for referral to hospital-in half it was the severity of their illness and in half the need for investigation or special treatment. One out of five patients was in need of intensive nursing care and one out of 20 patients had a social reason for admission to hospital. General practitioners with access to cottage hospital beds would choose to treat over one quarter of their own patients. The choice of hospital was influenced by the doctor's diagnostic certainty.


Vasectomy--a review of 100 cases.

Vasectomy--a review of 100 cases. A limited free vasectomy service providing for the needs of a rural area, with the counselling and operation conducted by a specially trained general practitioner is reported. The development of vasectomy as a contraceptive measure and some practical aspects of technique are reviewed and some characteristics of 100 patients operated on are recorded.


Fatal illness in general practice.

Fatal illness in general practice. In an investigation of fatal illness during a 12-month period in a practice of 5,897 patients in Glasgow, 58 deaths (42 male, 16 female) were recorded. Malignant neoplasms and myocardial infarction in male patients of 50 years and over accounted for 27 (46.6 per per cent) of the deaths. Thirty (51.7 per cent) of the deaths took place in hospital. Fifteen (25.9 per cent) of the deaths were sudden. In patients dying in hospital of malignant, cardiac, and respiratory disease the duration of the terminal stay in hospital represented a small proportion of the total duration of the illness, the principal burden of their care falling upon their families and community resources.In an integrated health service much yet remains to be accomplished in co-ordinating the efforts of hospital and community teams in caring for the fatally ill patient.


Regulation of gonadotrophin secretion in rams from birth to sexual maturity. I. Plasma LH, FSH and testosterone levels. Plasma LH, FSH and testosterone concentrations were measured by radioimmunoassays in male crossbred Merino/Corriedale sheep from birth to 45 weeks of age. FSH levels were 11 and 22 ng/ml at birth, increased to peak levels (mean value of 47 ng/ml) at 5 weeks and fluctuated between 25 and 35 ng/ml for the next 40 weeks. Similarly, LH (less than 0-5 ng/ml) and testosterone (less than 38 ng/100 ml) levels were low at birth and were significantly elevated by 5 weeks of age. LH values varied betwen 0-9 and 3-0 ng/ml for the next 30 weeks and then a secondary rise occurred reaching levels of 2-4 ng/ml by the 41st week after birth. Concentrations of LH subsequently fell to levels observed in adult rams. Testosterone levels rose gradually between the 5th and the 25th week, and then increased rapidly to values of 270-517 ng/100 ml by the 41st week after birth, a time coincident with the peak LH levels. Histological examination of testicular biopsies demonstrated that Sertoli cell maturation occurred 17-21 weeks after birth and was followed by activation of spermatogenesis leading to the presence of spermatozoa in the seminiferous epithelium by 39-42 weeks of age.


Effect of decidual tissue on the uterine production of prostaglandins in pseudopregnant rats. The concentration of prostaglandin F (PGF) in uterine vein plasma of non-traumatized pseudopregnant rats and pseudopregnant rats with deciduomata were not significantly different from each other at any of the times of pseudopregnancy studied (Days 7, 10 and 12). There was a significant increase in PGF levels on Day 10 in both groups of pseudopregnant animals (P less than 0-05) compared to the Day 4 values, and PGE values were significantly greater on Day 10 in the decidual tissue-bearing rats (P less than 0-01). A slight but not significant elevation in PGE concentration was observed on Days 7 and 12 in rats with deciduomata, but there was no significant difference in the control rats on Days 4, 7, 10 or 12. The results indicate that the prolongation of pseudopregnancy in rats with deciduomata is not due to a decreased production of uterine PGs and lend support to the recent suggestion of a luteotrophic effect of decidual tissue in the rat.


A study of seasonally delayed puberty in the male hare, Lepus Europaeus. The brown hare, Lepus europaeus, has a mating season which extends from January to September. Adult males exhibit pronounced seasonal changes in the reproductive tract which are associated with changes in LH secretion. Maximum plasma levels of immunoreactive LH occur between March and June and minimal levels in the autumn non-mating period from September to December; this seasonal cycle in gonadotrophin output is reflected by the appropriate changes in the secretion of testosterone from the testes and in the activity of the accessory sex glands. Juvenile animals reach puberty only during the adult mating season, and the age of puberty thus varies with the date of birth. Males born before May reach puberty and become fertile at 3 months of age, while those born from May to July grow to a mature body size during the autumn non-mating season but puberty is delayed for several months. Since some animals experiencing delayed puberty were found to have elevated plasma levels of LH and testosterone, it is concluded that puberty is not completely suppresed by the environmental effects of the autumn, but that the developmental process is prolonged, resulting in the juveniles being synchronized with the adults in their reproductive activity.


Peripheral plasma levels of oestradiol-17 beta and progesterone in the bitch during the oestrous cycle, in normal pregnancy and after dexamethasone treatment. Plasma oestradiol-17 beta concentrations in Labradors increased during pro-oestrus to an average maximal concentration of of 79-7 +/- 10-9 (S.D.) pg/ml, and then fell rapidly. In 6/7 bitches the peak occurred within 1 day of oestrus. No consistent changes in plasma oestradiol levels were observed during pregnancy and at parturition and the values were similar to those in late anoestrus. Plasma progesterone levels did not increase markedly during pro-oestrus. At oestrus, progesterone values rose and maximal concentrations, which varied from about 20 to about 55 ng/ml, were reached within a few days of the oestradiol peak. Plasma progesterone decreased in late pregnancy and in one of the three bitches studied in detail low or undetectable levels were reached 10 days before parturition. In the other two bitches an abrupt decrease in progesterone occurred just before parturition. Dexamethasone treatment (2 X 5 mg daily for 10 days) from Day 30 of pregnancy resulted in intrauterine death and resorption of the fetuses in the two bitches studied. Treatment from about Day 45 resulted in the birth of dead fetuses at Days 55 and 59 of pregnancy. The changes in plasma oestradiol levels were very small. No changes in plasma progesterone levels were seen when dexamethasone was given in late pregnancy, but an accelerated decline occurred after treatment in mid-pregnancy.


Effect of ovarian sex hormones on the pool of free amino acids in maternal tissues of pregnant rats fed a protein-free diet. The effects of s.c. injections of 5 mug oestrone/kg and 50 mg progesterone/kg on Days 5-7 of gestation were investigated in rats fed a protein-free diet. The decrease in essential and non-essential amino acid concentrations in maternal liver and the implantation site caused by dietary protein deficiency was restored to control values, whereas the alterations of the plasma free amino acid concentrations, except for arginine and glycine, were not reversed by hormone treatment.


Steroid-protein interactions in bovine plasma. The binding of testosterone, corticosterone and 17alpha-hydroxyprogesterone by bull plasma protein was studied by equilibrium dialysis. Testosterone in bovine plasma was bound by a CBG-like protein and by a specific protein (testosterone-binding protein or TBP) of limited capacity and high affinity. The TBP was specific for C18 and C19 steroids with a 17 beta-hydroxy group. Precision of the steroid-protein binding measurements was tested and was satisfactory. The testosterone-binding capacity in bull plasma samples did not seem to be related to testosterone levels in peripheral plasma. Significant differences between bulls and cows with regard to the binding capacity were observed.


Deep freezing of sheep embryos.

Deep freezing of sheep embryos. Sheep embryos, collected 1-8 days after oestrus, were placed in Dulbecco's phosphate-buffered saline medium (PBS). After treatment, the viability of the embryos was tested by temporary transfer to ligated rabbit oviducts. In Exp. 1, Days 5-8 embryos survived for at least 15 min at 0 degrees C in the presence of 1-5 M-DMSO. In Exp. 2, 12/14 Days 5-8 embryos survived after being frozen in 1-5 M-DMSO at 0-3 degrees C/min to temperatures ranging between-15 degrees and -60 degrees C and then thawed at 12 degrees C/min. In Exp. 3, Days 5-8 embryos were frozen in 1-5 M-DMSO at 0-3 degrees C/min to below-65 degrees C before being transferred to liquid nitrogen (-196 degrees C), and stored for 12 hr to 1 month. The embryos were thawed at 3 degrees C/min, 12 degrees C/MIN or 360 degrees C/min and, after transfer to rabbit oviducts, 0/4, 10/36 and 1/4, respectively, developed normally. The 11 embryos which were considered normal when recovered from the rabbit oviducts plus 1 slightly retarded embryo were transferred to 7 recipient ewes. Four ewes subsequently lambed, producing 5 lambs. In addition, 8 embryos were transferred to 4 ewes directly after thawing. Three of these ewes subsequently lambed, producing 3 lambs.


Comparison of neutral proteinase activities in cock and ram spermatozoa and observations on a proacrosin in cock spermatozoa. Cock spermatozoa, like trypsin, induced a rapid fall in the viscosity of gelatin solutions but ram spermatozoa and inhibitor-free ram acrosin were ineffective. The gelatin-hydrolysing activity in cock spermatozoa was solubilized at pH 8 in the presence of calcium ions but comparable extracts of ram spermatozoa were inactive. Both extracts showed acrosin activity (assayed with benzoylarginine ethyl ester). The two catalytic activities of cock spermatozoa were each susceptible to the same trypsin inhibitors and during fractionations they were not separable. We deduce that cock acrosin, and probably some other avian acrosins, have the power to degrade dissolved gelatin while ram acrosin does not. The acrosin in cock spermatozoa, unlike that in ram spermatozoa, was inactivated at pH 2-7. Acid extracts of the former contain an inactive precursor of acrosin which undergoes spontaneous re-activation in buffers, pH 8, containing calcium ions. In this respect it resembles the proacrosin of rabbit testis.


The storage of cow eggs at room temperature and at low temperatures. The survival and development of cow eggs in the rabbit oviduct after storage at room temperature and after cooling and storage at 0-7-5 degrees C was examined. In PBS medium at room temperature 88% of Day-5 and 85% of Day-3 eggs showed normal development, but in TCM 199, 71% of Day-5 and only 49% of Day-3 eggs showed normal development. Duration of storage (1 1/2-2 hr or 6 1/2-7 1/2 hr) and cleavage stage before storage had no appreciable effect on development. Some retardation of development occurred in Day-3 eggs after 96 hr in the rabbit oviduct when compared to Day-5 eggs after 48 hr. Cooling of Day-5 and Day-6 eggs to 0-7-5 degrees C resulted in degeneration of a large proportion of eggs. Of the factors examined, storage medium (PBS or PBS+20%FCS), storage time (2 min, 24 hr) and storage temperature (0, 2, 5 or 7-5 degrees C) had little effect, but slower cooling rates tended to improve survival of eggs although the differences were not significant. More morulae (greater than 32 cells) than 8-to 24-celled eggs developed normally.


Effects of carnitine on oxygen uptake and utilization of (U-14C)palmitate by ejaculated bull spermatozoa. Fatty acid oxidation by washed intact ejaculated bull spermatozoa was depressed by carnitine concentrations as low as 5 mM, whereas oxygen uptake was only depressed by concentrations of 20 mM or above. Incorporation of (U-14C)-palmitate into 1,2-diglycerides was stimulated, and there was some stimulation of incorporation into phospholipids.


Seasonal variations in the response of the testis and LH levels to hemicastration of adult rams. The weight and histology of the testis and plasma LH levels were analysed after hemicastration of adult Ile-de-France rams in spring or in autumn. After hemicastration, the remaining testes were significantly heavier than those of entire animals measured at the same time of year. At 4 or 6 months after hemicastration performed in spring, the remaining testes were hypertrophied by nearly 40% as compared to the testes of entire sexually active animals, assessed in autumn. The variations of intertubular tissue volume, total seminiferous tubule length, stem cell stocks, daily production of round spermatids, and cellular volume of primary spermatocytes paralleled the variations in testis weight. The annual decrease of the area of the Sertoli cell nuclei and of the yield of meiosis and beginning of spermiogenesis during the non-breeding season was prevented by hemicastration performed in autumn. Plasma LH levels were consistently elevated till autumn after hemicastration performed in spring. A positive and significant correlation was observed between LH levels and yields of spermatogonial divisions.


The effect of progesterone, oestradiol and HCG on cell-mediated immunity in pregnant mice. During pregnancy in mice, cell-mediated immunity as measured by a contact allergic reaction to picryl chloride was diminished (P less than 0.001). Mice in which delay of implantation was maintained by progesterone, and mice with progesterone- and oestradiol-maintained pregnancies, also showed a reduction in the inflammatory response. The response of pseudopregnant mice did not differ from that of the non-pregnant controls. Young mice sensitized before complete immunological competence gave a 50% response. The response doubled in animals given a second sensitization. The extent of the response in females with delay of implantation varied inversely with the dose of progesterone. A range of oestrogen doses gave the same depression in the response when given to pseudopregnant animals. Administration of HCG to pseudopregnant mice also reduced the inflammatory response.


The action of D2O on the motility of human spermatozoa. The effect of 25%, 50%, 75% and 100% D2O on the survival of human spermatozoa was investigated. More spermatozoa were affected and died more quickly as the concentration of D2O increased. Spermatozoa died instantly in 100% D2O.


Artificial insemination with spermatozoa in formaldehyde. The ability of formaldehyde to preserve the integrity of the membranes of spermatozoa, as indicated by eosin staining (Dott & Foster, 1975), prompted an investigation to discover what other properties of spermatozoa were preserved by low concentrations of formaldehyde in vitro. In a series of experiments on bull, ram and boar spermatozoa it has been shown that spermatozoa rendered immotile by formaldehyde recovered their motility when the formaldehyde was removed by washing up to 12 hr afterwards (H.M. Dott & G.C. Foster, unpublished). To find out if fertility was preserved ewes and sows were inseminated with spermatozoa rendered immotile with formaldehyde.


Changes in the composition of the excurrent duct system of the rat testis during postnatal development. The gross composition of the testicular excurrent duct system of the rat was examined and compared along the length of the duct and with samples of testis, bladder and liver. Changes in composition with age were examined by analysing tissue from animals at postnatal ages of 19, 36, 48, 60, 90 and 120 days. In adult animals, testicular tissue was characterized by having the lowest dry weight, accompanied by low levels of total protein, lipid, RNA and glycogen; DNA, phospholipids and sialic acid were at levels similar to other tissues. A high proportion of the total protein was soluble. The ductuli efferentes plus initial segment of the epididymis were characterized by high levels of total lipid. The caput epididymidis contained a low level of total protein but a high level of acid-soluble phosphorus. The cauda epididymidis had a low dry weight and low levels of total protein, soluble protein, and lipid, but high levels of acid-soluble phosphorus, DNA and sialic acid. The ductus deferens contained small amounts of RNA and DNA but had a high dry weight, high total protein, soluble protein and glycogen. Several trends were apparent with increasing age. Dry weight increased in the ductuli efferentes plus initial segment, whilst total protein decreased in the caput and cauda epididymidis. Total lipid increased in the ductuli efferentes plus initial segment and acid-soluble phosphorus and sialic acid increased in all other segments of the excurrent duct system. In all segments the content of RNA and DNA decreased as the animals matured. The concentration of calcium and magnesium in the excurrent duct system was not significantly different from those levels found in the liver. High levels of spermine and spermidine were confirmed in the prostate, and were also detected in the testis, caput epididymidis and cauda epididymidis, but at a much lower concentration.


Follicular atresia in the infant human ovary. The pattern of follicular atresia was studied in nine ovaries from children between the ages 3 months and 8 years. Atretic follicles were found among follicles at all stages of development. The percentage of follicles with signs of atresia became larger as the size of the follicles increased. Only 2% of small follicles (Type 3b) showed signs of atresia, while all follicles greater than 1 mm in diameter (Type 8) were atretic. In follicles of Type 5 and larger, four stages of atresia, which represent consecutive stages of a single atretic process, were defined. The beginning of atresia was characterized by the presence of pyknotic granulosa cells. As atresia progressed, the granulosa layer disappeared, the oocyte became necrotic, the follicle collapsed and the theca cells became hypertrophied. The oocyte can degenerate in several ways: it can be penetrated by cells, the nucleus can become pyknotic or it may complete meiotic prophase. It is suggested that the last event is only possible after the oocyte has reached its full size and has completed RNA synthesis.


Preliminary results on plasma progesterone levels during pregnancy and superfetation in the hare, Lepus Europaeus. Peripheral plasma progesterone levels were studied in pregnant hares. A rise occurred at the beginning of pregnancy, followed by a plateau from Days 10 to 35, and then a drop during the days just before parturition. No significant differences were noted between progesterone levels in pregnancies initiated at the pre-partum oestrus and those from other oestrous periods.


The binding of labelled basic proteins by boar spermatozoa. Seminal plasma basic proteins were labelled with 131I. The efficiency of the labelling was studied by superimposing protein density traces on a radioactive fractionation plot. These labelled proteins were incubated with spermatozoa and shown to bind more readily to spermatozoa from boars after the removal of the vesicular glands than to spermatozoa obtained from their normal litter mates. Most of the labelled protein became bound to the membranes which were isolated by sucrose density gradient centrifugation. The membranes were separated into two bands which equilibrated at the relative densities of 1-150 and 1-165. These fractions consisted of membrane vesicles of different size; the smaller band on the gradient, which equilibrated at 1-165, consisted of denser membrane material.


Anomalous litters in hybrid mice and the retention of spermatozoa in the female tract. Suspected superfetation was investigated in a Glasgow hybrid stock of mice. The male was removed either (i) a few days before parturition, or (ii) immediately after mating and on 23 and 25 occasions, respectively, a second litter was born. Members of the anomalous litters were inbred for 10 generations, but the incidence of supernumerary litters did not increase beyond 2-5%. The anterior part of over 500 reproductive tracts, at various stages of pregnancy and after parturition, were serially sectioned but a second set of embryos was not found. The second gestation was of normal length and superfetation was not therefore considered to be the cause of the anomalous litters. In two females, one non-pregnant and one pregnant, spermatozoa were found in the uterus and oviducts 8 days after mating and in distended uterine glands 15 days after mating respectively. It is concluded that the anomalous litters were derived from the fertilization of eggs ovulated at the post-partum oestrus by spermatozoa which had been retained in the female tract for at least 23 days.


The role of oestrogen in the control of ciliated cells of the human endometrium. The incidence of ciliated cells in the human endometrium was determined. Conditions associated with an excess of oestrogenic activity were characterized by an increased incidence of ciliated cells, whilst oestrogen deficiency was associated with decreased numbers. When endometrium was cultured, addition of oestradiol-17 beta caused an increase in the ciliated cell population.


Seminal plasma proteins and the reaction of spermatozoa from intact boars and from boars without seminal vesicles to cooling. Spermatozoa from intact boars and from boars without seminal vesicles were resuspected in diluent and cooled at different rates to 0 degrees C. Glutamic oxaloacetic transaminase and lactate dehydrogenase activities were greater in the diluents which had contained spermatozoa from intact boars than in those which contained spermatozoa from animals without seminal vesicles. The incubation of seminal plasma from an intact boar with spermatozoa from a vesiculectomized animal before cooling also increased the enzyme activity in the diluent. The factors responsible for this effect were associated with the basic protein fractions of boar seminal plasma, in particular the proteins with haemagglutinating activity which may have been adsorbed onto the spermatozoa. Spermatozoa were exposed to colloidal Fe(OH)2+ to determine by electron microscopy the charge on the surface of the plasma membrane of washed epididymal spermatozoa and ejaculated spermatozoa from intact and vesiculectomized boars. Epididymal spermatozoa bound the positively charged particles more readily than the ejaculated spermatozoa from the intact boars, due to the absence of membrane-bound protein.


Fine structural changes in the epididymal epithelium of moles (Talpa europaea) throughout the year. The epididymis of the European mole (Talpa europaea) was studied by light and electron microscopy. In the sexually active animal, spermatozoa mature during their passage through the epididymis and the structure of the cells lining the duct suggests a clear regional division into initial, middle and terminal segments. Numerous intra-epithelial vesicles were present in the distal part of the middle segment of sexually active moles and the lining epithelium in the terminal segment appeared to be secretory. Variation in the sensitivity of different regions of the epididymis to androgens was apparent: the principal cells of the initial segment were morphologically active only during the peak of the breeding season in spring, while the cells of the terminal segment became active earlier and remained so for longer. During sexual regression, many autophagic vacuoles were found in the principal cells, and these became transformed into lipofuscin pigment granules. Cells heavily laden with these granules appeared concurrently in the lining epithelium. It is suggested that such cells may be involved in the regression of principal cells by means of heterophagic activity. A similar situation was also observed, but to a lesser extent, at the beginning of the breeding season. Outside the breeding season, the organelles of the principal cells were poorly developed throughout the epididymis, and lipofuscin pigment granules remained in the principal and basal cells of adults. Such granules were seldom seen in immature animals.


Development of gonadotrophin-binding sites in the immature rat ovary. There was a temporal relationship between ovarian development and the sites to which 125I-labelled gonadotrophins became bound. Labelled human LH and FSH bound uniformly to 5- and 15-day-old ovaries. At 21 days, heavy FSH and light LH binding was observed over the granulosa cells increased at Day 33 and again at Day 38. Quantitative determination by gamma-ray spectrophotometry of binding to ovarian sections showed that LH binding gradually increased with advancing age, but FSH binding remained relatively constant between Days 5 and 33 with a significant increase between Days 33 and 38.


Hormonal control of pinocytosis in the uterine epithelium of the rat. Ovariectomized rats were treated with oestradiol-17 beta and/or progesterone to mimic the hormonal parameters inducing uterine sensitivity for implantation. The degree of pinocytosis of trypan blue and ferritin in the endometrial cells was examined. Significant epithelial pinocytosis of trypan blue occurred after a 3-day treatment of progesterone, and uptake was independently increased by priming with oestrogen and by oestradiol given on the 3rd day of progesterone treatment. Progesterone treatment caused uptake of ferritin by the epithelial cells; in control animals epithelial and stromal cells were involved. Oestrogen priming enhanced ferritin absorption, while 'nidatory' oestrogen had no effect. Oestradiol given alone completely blocked pinocytosis of both intraluminally injected substances.


Gonadotrophin-induced changes in the Sertoli cells of the immature mouse testis. Highly purified preparations of human pituitary gonadotrophins were administered to immature male mice daily for 3 days. The mice were killed on the 9th day after birth and the testes were prepared for electron microscopy. FSH treatment caused an increase in the mass of Sertoli cell cytoplasm, and FSH and LH increased the size of mitochondria in these cells. The number of polysomes in each Sertoli cell was increased after FSH treatment, but the number of ribosomes/polysome was not affected.


Inhibition of human sperm acrosin by synthetic agents. Twenty-two synthetic proteinase inhibitors were tested for their inhibitory properties towards human acrosin. p-Nitrophenyl-p1-guanidino benzoate (NPGB) was the most effective (K1 value of 1-5 X 10(-8) M), producing a non-competitive type of inhibition in contrast to all other inhibitors which showed a competitive type of inhibition. The Michaelis constant for human acrosin on BAEE at pH 8-1 was calculated to be 4-25 X 10(-5) M.


HL-A antigens in Behcet's disease.

HL-A antigens in Behcet's disease. Twenty-six patients with Behcet's disease had complete HL-A typing. No patient had an HL-A antigen in significant excess. No patient had an HL-A antigen in significant excess. Only two patients had the B27 antigen: both patients had uveitis, but eight others who also had uveitis were B27 negative. No patient had ankylosing spondylitis or sacroilitis. Behcet's disease, although bearing some clinical resemblances to diseases related to the B27 antigen, i.e. ankylosing spondylitis and Reiter's syndrome, differs from them through the absence of spondylitis and because the association with B27, if it exists, is far weaker than that in ankylosing spondylitis or Reiter's disease.


Bleeding, salicylates, and prolonged prothrombin time: three case reports and a review of the literature. Fourteen cases of ASA induced hypoprothrombinemic bleeding, including three patients reported by the authors, are reviewed. Predisposing factors toward bleeding include malnutrition and malabsorption syndrome. Although the bleeding is usually benign, it may be serious on occasion. The importance of this rarely considered cause of ASA associated bleeding lies in the fact that it is readily corrected with Vitamin K.


Liver dysfunction and polymyalgia rheumatica. A case report. Hepatic dysfunction may be a manifestation of polymyalgia rheumatica. We present a second patient with the polymyalgia rheumatica syndrome and a significantly elevated alkaline phosphtase who, on liver biopsy, demonstrated granuloma formation and massive infiltration of the portal spaces with lymphocytes. The alkaline phosphatase elevation was favorably influenced by low dose steroid therapy.


Experimental inflammation induced by naturally occurring microcrystalline calcium salts. Inflammation caused by insoluble microcrystalline calcium salts was compared with inflammation elicited by soluble carrageenan and monosodium urate crystals, in rats' paws. Local and systemic responses to four calcium crystals, viz. pyrophosphate, triphosphate, oxalate, and tartrate were studied. Changes in liver function, reflected in reduced serum albumin and increased sleep times in response to barbiturates, indicative of systemic inflammation, occurred despite the localized nature of the crystal induced inflammation. Serum thiol levels were also reduced. These altered functions were similar to, but less pronounced than, those accompanying the severe systemic inflammation produced by Freund's adjuvant. A copper glycine complex was effective in reducing foot swelling due to triphosphate, and edema due to oxalate. Colchicine had very little effect on the inflammation caused by the insoluble calcium salts but inhibited inflammation due to sodium urats crystals and soluble carrageenan. Crystal-induced inflammation that is outwardly localized may induce biochemical changes that are similar to changes found in systemic inflammation.


Abnormal esophageal motility in primary Sjögren's syndrome. Esophageal monometric studies were done in 10 unselected patients with Sjögren's syndrome, not associated with other connective tissue or chronic active hepatic disease. Nine of the patients revealed abnormal esophageal motility, consisting of absent or decreased contractility in the upper third of the esophagus. In four patients, the dysfunction also extended to other portions of the organ. Dryness of the mouth and oropharynx, or mucosal atrophy, does not explain these findings. The uniform pattern of the esophageal dysfunction found in patients with primary Sjögren's syndrome, which differs from the patterns of involvement observed in other connective tissue diseases, suggests that primary Sjögren's syndrome is probably a distinct entity.


Pseudotumor of temporomandibular joint: destructive calcium pyrophosphate dihydrate arthropathy. The clinical and pathological features of a tumor of the temporamandibular joint occurring in a 55 year old man, and subsequently identified as a calcium pyrophosphate dihydrate (CPPD) arthropathy, are reported. Crystalline deposits were identified by compensated light microscopy and confirmed with X-ray diffraction, transmission, and scanning electron microscopy. The relationship of this unique case to other clinical presentations of CPPD deposition disease and the implications of the histological features to the pathogenesis of pseudogout are discussed. This case demonstrates that CPPD arthropathy should be included in the differential diagnosis of an arthrosis or of a tumor involving the temporomandibular joint.


Multiple vacuum discs, and early sign of ochronosis. Radiologic findings in two brothers. Two brothers with ochronosis are reported and the radiological features of ochronotic vertebral disease are reviewed. A striking feature was the presence of multiple vacuum discs. This "vacuum phenomenon" constitutes one of the earliest radiologic changes in the spine and presumably represents areas of severe degeneration within the intervertebral discs. Other features included a dark pigmentation of the urine after standing or following the addition of sodium hydroxide, and calcification within the cartilages of the ears and intervertebral discs. There was no abnormality of the peripheral joints and pigmentary deposits in the ears, sclerae, or skin were not observed.


Application of SCAP to drug design. 1. Prediction of octanol-water partition coefficients using solvent-dependent conformational analyses. The solvent-dependent conformational analysis procedure (SCAP) has been used to predict the octanol-water partition coefficients of 20 different compounds with an average absolute error of 9%. SCAP predicts partition coefficients almost as well as the Hansch procedure using pi constants where the absolute error for the 20 compounds is 5%. In addition to estimating partition coefficients, SCAP allows direct calculation of the corresponding solute-solvent interaction free energies. Moreover, binding free energies, based upon hydrophobic and polar interactions, may also be computed. Such free energies are not calculable using other available methods. SCAP also allows solvation free energies to be compared to, or analyzed with, the various intramolecular free energies of the solute molecule as well as all other associated conformational properties.


Molecular connectivity. 6. Examination of the parabolic relationship between molecular connectivity and biological activity. The topologically derived, nonempirical molecular connectivity index, chi, for several classes of compounds is shown to be parabolically related to the biological activities of these compounds. Similar nonlinear relationships were previously shown between the octanol-water partition coefficients, expressed as log P, of the compounds and their biological activities. These and previous studies indicate that many physiochemical properties presently used in structure-activity studies may be intermediaries between the nonempirical molecular structure encoded in chi and measured biological activities.


Quantitative structure-activity relationships. 1. The modified Free-Wilson approach. The relationships between the linear free energy related Hansch model and the mathematical models of Free-Wilson and Bocek-Kopecký are reviewed and discuss. Some examples are given to illustrate the theoretically derived relationships and to demonstrate scope and limitations of each mathematical model. The modified Free-Wilson approach is shown to be completely equivalent to a nonparabolic Hansch approach; it can be used to study additivity or nonadditivity of group contributions and to control and improve the fitting of Hansch equations. The Bocek-Kopecký approach is related to the parabolic form of the Hansch approach; its practial use is limited by the great number of variables involved.


Quantitative structure-activity studies on monoamine oxidase inhibitors. Quantitative structure-activity studies were carried out on a series of N-isopropylaryl hydrazides which inhibits monoamine oxidase (MAO). The inhibitory potencies of these compounds of MAO were found to correlate with the electron-withdrawing capacity of the aryl ring substituents as estimated by both empirical Hammet sigma constants and electronic indices from molecular orbital calculations. Based on these correlations and previously published data on other classes of MAO inhibitors, a general model for the inhibitor pharmacophore is proposed: potent MAO of an aromatic ring; electron-withdrawing groups on the aromatic ring or replacing the phenyl ring with certain types of heterocyclic rings will tend to increase the potency.


Inhibition of dihydrofolate reductase. Structure-activity correlations of quinazolines. A quantitative structure-activity relationship (QSAR) has been formulated for quinazolines causing 50% inhibition of liver dihydrofolate reductase. The QSAR for the quinazolines is compared with QSAR for triazine and pyrimidine inhibitors. The three QSAR suggest new possibilities for the design of inhibitors of mammalian dihydrofolate reductase.


Dependence of hydrophobicity of apolar molecules on their molecular volume. Cavity size is the primary determinant of the partition coefficient (P) of apolar solutes between octanol and water. Although the energy of cavity formation would be expected to be related to cavity area, older methods of area calculation give a poorer correlation with log P than does volume. Apolar solutes clearly fall into two classes based on their log P/volume relationship, the distinction possibly being whether the solute exposes mostly hydrogen atoms or unbonded electrons.


Direct measurement of octanol-water partition coefficients by high-pressure liquid chromatography. A technique is presented for the direct measurement of octanol-water partition coefficients by HPLC. The method involves running solutes in octanol-saturated water as the mobile phase against water-saturated octanol entrained on an inert support. Log P correlates linearly with log tc for a number of standards. The measurable range in log P (so far) is -0.3 to +3.7. A critical review of chromatographic methods in Hansch analysis is given.