Filtration rates of pharmaceutical suspension systems. This study was undertaken to find it a correlation exists between the filtration rate and the Hu/Ho ratio. For this purpose, flocculated and coagulated structures of sulfamerazine were used. Suspension settling profiles and filtration rates, using additives and additive-free sulfamerazine suspensions, were studied. A straight-line correlation was found. Effects of filter bed parameters on refiltration rates were studied, and a relationship was found by the use of the Kozeny-Carman equation. A straight-line relationship existed between the H1/Ho ratio and the filtration rate exhibited by the different suspension aggregates.


Nonaqueous titration of sulfates of quinine and quinidine using barium acetate. A nonaqueous titrimetric method is proposed for determining the diastereomeric sulfates of quinine and quinidine. The sulfuric acid content of the alkaloid salts is precipitated, in the form of barium sulfate, with acetous barium acetate solution before the liberated alkaloid is titrated; the necessary calculations are provided. A favorable characteristic of the proposed procedure is the accuracy, speed, and ease of performance. The mean percent recoveries (p = 0.05) obtained with the proposed method for the sulfates of quinine and quinidine were 98.84 +/- 1.00 and 99.74 +/- 1.27, respectively, compared with 100.73 +/- 1.44 and 100.82 +/- 1.16, respectively, when the BP 1968 procedure was applied.


Quantitative GLC determination of codeine in plasma. A sensitive and accurate GLC method for quantitating codeine in plasma at levels of 50 ng/ml, with limits of detection as low as 5 ng/ml, is described.


Aqueous solubility of 14C-triamcinolone acetonide. The blue tetrazolium colorimetric assay has often been employed in the analysis of corticosteroids. However, the reaction between blue tetrazolium and corticosteroids partly depends on the apparent pH of the system. In an earlier study of the temperature dependence of the solubility and dissolution of triamcinolone acetonide in aqueous dissolution media (distilled water and 0.2-1.0 M potassium chloride solutions), pH was not considered. To determine the reliability of the data previously reported, the solubility of 14C-triamcinolone acetonide was determined by a radioisotopic method. The results of the analyses, using a liquid scintillation counting system, indicate that the steroid solubility is generally about 20% lower than that reported previously.


Fluorometric assay of verapamil in biological fluids and tissues. Verapamil concentrations in blood, urinee, or tissue homogenates may be measured fluorometrically in the 0.1-10-mug/ml range after extraction into heptane and back-extraction into acid; recovery rates are above 87%. The drug apparently is eliminated rapidly in guinea pigs, with a plasma half-life of 45 min.


Homogeneity of Pasteurella avicida bacterin. A simple rapid procedure is described for determining whether an emulsified bacterin is homogenous by measuring the UV absorbances of chloroform-washed centrifugates. These absorbances appear to depend on nucleic acid content.


Binding of sulfisoxazole to protein fractions of tears. By using equilibrium dialysis experiments, it is shown that sulfisoxazole binds extensively with albumin and alpha-globulin and to a lesser extent with gamma-globulin and lysozyme, all of which are normal components of tears. The binding of sulfisoxazole to the various protein fractions quantitatively accounts for the over-all binding of this drug to human tears. It is suggested that to predict the binding of drugs to proteins in lacrimal fluid, both in normal and pathological conditions, it is necessary to conduct binding studies of the drug with the major protein fractions of tears. More-over, it is essential to know the composition of the major protein fractions of tears in both normal and various pathological conditions to conduct the necessary in vitro binding studies.


Phosphorus-nitrogen compounds XIX: distribution of 32P and effect of an active oncolytic on intracerebral leukemia in rodents. P,P-Bis(1-aziridinyl)-N-1-adamantylphosphinic amide displayed oncolytic activity against intracerebral and intraperitoneal L-1210 leukemia. Administration of the isotope-labeled compound to rats shows 32P distribution to the brain.


Influence of aspirin formulation and dose on concentration of total salicylate in rat kidney. Rats received the equivalent of 100, 250, 500, or 700 mg/kg of 14C-aspirin orally as a suspension or as a solution of a buffered, effervescent, aspirin-containing product. Animals in each dose group were sacrificed at time intervals ranging from 0.5 to 24 hr after dosing. The 14C content of whole blood, plasma, and homogenized whole kidney (after perfusion) was determined. The concentration of total salicylate proved to be dose dependent and was lower in tissues from rats receiving the buffered, effervescent product, especially at the higher doses. The results suggest that salicylate-induced renal toxicity should be less likely to occur after administration of the buffered, effervescent formulation.


Measurement of sulfamethizole clearance rate by nonthrombogenic constant blood-withdrawal system. A method for the measurement of the total body clearance rate (CR) of drugs is described. It involves a single intravenous injection of a known quantity of the drug (D) and automatic integration of the plasma concentration curve, using a portable, nonthrombogenic, constant blood-withdrawal system. When blood withdrawal is carried out until the concentration of the drug in the plasma approaches zero, the concentration of the drug in the collected pool, the integrated concentration (ICT) multiplied by the time of collection (T) yields the integral of the concentration curve: (see article). The method was tested by measuring the clearance rate of sulfamethizole in five dogs by the established constant infusion method. At three plasma levels (25, 75, and 200 mg/liter), the plasma concentration had no significant effect on the clearance rate. The clearance rate of sulfamethizole was subsequently measured in the same dogs by the new single-injection constant withdrawal method. Multiple blood samples were collected at 15-min intervals simultaneously with the constant withdrawal of blood. There was no significant difference between the clearance rate of sulfamethizole measured by the two methods. The initial peak mean concentration of the drug from the time of injection (t = 0) to the time of the first blood sampling (t = 15 min) was calculated from the difference between (see article) obtained by the constant withdrawal method and that obtained from the results of the multiple blood withdrawals by the trapezoidal rule. The integrated concentration IC15 was significantly higher than its estimation by the semilogarithmic linear regression method.


Volume of distribution as a function of time. A single definition for all volume terms in pharmacokinetic modeling is proposed; this parameter is considered as a function of time. This definition will represent the kinetic nature of pharmacokinetic models and will provide a highly sensitive parameter for correlation with pharmacological responses.


Bioavailability of flufenamic acid in hard and soft gelatin capsules. The biological availability of flufenamic acid after oral administration of the drug in both hard and soft gelatin capsules was studied in dogs and humans. The soft gelatin capsules produced consistently higher plasma concentration-time curves.


GLC determination of degradation of two related amine uptake inhibitors. A convenient GLC method was developed to assay the chemically related CNS agents dl-3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine (Ia) and dl-3-(0-methoxy-phenoxy)-N-methyl-3-phenylpropylamine (Ib). Subsequently, this GLC method was used to monitor the stability of Ia and Ib in acidic and basic media. These CNS agents were stable in basic solution but labile under acid conditions, and the degradations of both compounds approximated pseudo-first-order kinetics. Products formed during the acid hydrolysis of Ia and Ib were identified and were shown not to interfere in the GLC assays of the parent ethers.


Effects of halothane anesthesia on the biodisposition of ketamine in rats. Ketamine, a highly lipophilic drug, was rapidly distributed into highly vascular organs and subsequently redistributed to less well perfused tissues, with concurrent hepatic metabolism and urinary and biliary excretion, after both i. m. and i. v. administration in the rat. Halothane, a potent cardiovascular depressant, was found to prolong the plasma and brain half-life of ketamine (50 mg/kg i.m.) and also increased the duration of ketamine-induced ataxia when the two drugs were administered concomitantly. Halothane anesthesia (0.8% halothane in oxygen) produced a decrease in the rate of uptake and delayed distribution and redistribution of ketamine (50 mg/kg i. m.), while the rate of urinary excretion of ketamine was not significantly altered. Similarly, redistribution of intravenously administered ketamine (30 mg/kg i. v.) was slowed in the presence of halothane. In vitro hepatic microsomal metabolism of ketamine and its principle N-demethylated metabolite, metabolite I, was inhibited noncompetitively by halothane with inhibitor constants (Ki) for halothane estimated to be 1.56 and 1. 64 mM,respectively. The gas anesthetic also decreased the overall rate of in vivo metabolism of ketamine (30 mg/kg i. v.) in a concentration-dependent manner. Thus halothane anesthesia by decreasing uptake, distribution, redistribution and metabolism of intramuscularly administered ketamine produced significant prolongation of its pharmacologic action on the central nervous system. Our results imply that concomitant use of inhalational anesthetics may prolong pharmacologic actions of other agents via effects on distribution/redistribution processes as well as on metabolism.


Physiological disposition and biotransformation of (3H) cocaine in acutely and chronically treated rats. A sensitive method was developed for the estimation of [3H] cocaine in biological materials. After an injection of 8 mg/kg i.v. in male Wistar rats, peak levels in brain, tissues and plasma occurred within 15 minutes and cocaine disappeared completely from brain and plasma 6 hours postinjection. The T1/2 of cocaine in brain and plasma was 0.4 and 0.3 hour, respectively. No significant differences were observed in the rates of disappearance of cocaine from the subcutaneous site in acute and chronically treated rats after an injection of 20 mg/kg. After a 20 mg/kg s. c. dose, the peak levels of cocaine were attained gradually in 4 hours in brain, tissues and plasma with the exception of heart (0.5 hour) and fat (2 hours). These peak levels shifted from 4 to 2 hours in the chronically treated group. Consistently higher levels of cocaine were found to be sequestered in fat in the chronically treated animals. The T1/2 of cocaine in brain and plasma of chronically treated rats was approximately 1.8 to 2 hours and that in the acutely treated animals, 0.8 to 1 hour. The brain/plasma ratios were also somewhat higher in chronically treated as compared to the acutely treated animals and were indicative of a high affinity of tissue for cocaine. Although cocaine did not persist in brains of acutely treated animals, measurable amounts were shown to persist in brain and other tissues of chronically treated animals long after the disappearance in plasma. Significantly high concentrations of metabolites of cocaine persisted in brain and plasma of acutely and chronically treated animals. No significant differences were observed in the plasma protein binding of cocaine in control, acutely and chronically treated rats. Unchanged cocaine was excreted in very small amounts in rat bile and approximately 36% of the dose (5 mg/kg i. v.) was excreted as metabolites 3.5 hours after injection. Excretion of free cocaine in urine and feces after a 20 mg/kg s. c. dose in acutely and chronically treated rats was 1.2 and 1.5%, respectively. Significantly higher excretion of total radioactivity occurred in feces in the chronic group (35.9%) as compared to the acute group (22.1%). Benzoylecgonine, benzoyl norecgonine, ecgonine methyl ester and ecgonine were identified as urinary metabolites in both acute and chronic animals. In addition, evidence was obtained for the presence of a phenolic metabolite and two other hydroxylated metabolites (with hydroxylation presumably in positions 6 and 7 of the pyrrolidine ring). Implications of these observations with respect to systemic toxicity, the absence of tolerance and physical dependence liability of cocaine are discussed.


Pharmacokinetics of acetaminophen elimination by anephric patients. The pharmacokinetics of acetaminophen elimination were determined in five surgically anephric and five physiologically anephric patients on an interdialysis day, and in three normal adult volunteers. There was no significant difference in the biologic half-life and no apparent difference in the volume of distribution  of acetaminophen between the three groups of subjects but the anephrics, unlike the normal subjects, showed pronounced accumulation of acetaminophen glucuronide and sulfate in plasma. The apparent volume of distribution for conjugated acetaminophen is considerably smaller than that for the unmetabolized drug even though neither acetaminophen nor its glucuronide or sulfate is significantly bound to plasma proteins. The results of this study indicate that the kidneys do not contribute significantly to the elimination of acetaminophen in man. Sin ce acetaminophen is eliminated largely by conjugation with glucuronic acid and sulfate, it can be concluded that the kidneys do not contribute significantly to the formation of these metabolites.


Enhancement of diphenylhydantoin binding by lipid extraction. The binding of diphenylhydantoin-14C (DPH-14C) to several purified proteins and a number of tissue fractions from rats and rabbits has been studied by ultrafiltration and dynamic dialysis. In all cases the extent of binding correlated very closely with the protein concentration of the fraction investigated. Although binding to purified proteins varied considerably, binding to whole brain, subcellular fractions, liver, heart and kidney were identical. Skeletal muscle bound significantly less than other tissues. When brain homogenates were extracted with acetone or chloroform-methanol (2:1), the insoluble residue bound considerably greater amounts of DPH-14C per milligram of protein. Binding decreased after incubation with a proteolytic enzyme, but was not influenced by the addition of cations, ethylenediamine tetraacetic acid or ouabain. DPH-3H binding was constant over a large range of DPH concentrations (1 X 10(-10) to 2 X 10(-4)M) with no evidence for saturable or high affinity binding sites. It is suggested that tissue protein binding plays a role in the delayed attainment of adequate serum levels and the pharmacologic action of DPH.


The potentiation of barbiturate-induced narcosis by procarbazine. Procarbazine (MIH), N-isopropyl-alpha-(2-methylhydrazino)-p-toluamide (NSC-77213), a clinically effective antineoplastic agent, induced sleep in mice at its optimally effective dose (400 mg/kg) and prolongs hexobarbital sleeping times. MIH (400 mg/kg) increased the period of sleep following hexobarbital (100 mg/kg) nearly 10-fold. Nonhypnotic doses of MIH also significantly prolonged hexobarbital-induced sleep. Hexobarbital half-life in plasma was prolonged 6 to 7 times by prior treatment with MIH (400 mg/kg). Liver microsomes from mice treated with MIH exhibited decreased metabolism of the following substrates in vitro: hexobarbital, aminopyrine, ethylmorphine, and aniline. Cytochrome P-450 levels were also decreased by MIH treatment. Maximal decreases in enzyme activity and P-450 content occurred between 4 and 8 hours following treatment. Pretreatment with phenobarbital decreased the effectiveness of MIH to prolong hexobarbital sleeping times while pretreatment with SKF 525A added to the potentiating effect of MIH. Two major metabolites of MIH had neither central nervous system hypnotic effect nor inhibited hepatic microsomal mixed-function oxidases. Therefore, MIH potentiation of hexobarbital-induces sleep is probably due both to its direct hypnotic effect and inhibition of mixed-function oxidase activity.


Effects of alcohol, chlordiazepoxide, cocaine and pentobarbital on responding maintained under fixed-interval schedules of food or shock presentation. Responding by three squirrel monkeys was maintained under multiple-and single-component 5-minute fixed-interval (FI) schedules of either food or electric shock presentation. Under the multiple schedule, a response after 5 minutes had elapsed produced either food or shock depending on the prevailing stimulus conditions; single-component FI schedules maintained responding either by food or shock presentation alone. Responding under either the food or the shock schedules was positively accelerated throughout each FI. During certain phases of the experiment, overall response rates maintained by foor were comparable to those maintained by shock. Alcohol (1.0-3.0 g/kg), chlordiazepoxide (1.0-10.0 mg/kg) and pentobarbital (1.0-10.0 mg/kg) increased responding maintained by food but decreased responding maintained by shock. These effects were obtained under both the multiple- and single-component schedules. Low to intermediate doses of cocaine (0.1-1.0 mg/kg) increased responding maintained by either food or shock, whereas higher doses (3.0 mg/kg) generally decreased responding under these conditions. The effects of chlordiazepoxide were also studied with one monkey when response rates maintained by food or shock were equal, when rates of food-maintained responding were lower than those maintained by shock and, finally, when rates of responding maintained by food were higher than those maintained by shock. Under all of these conditions, chlordiazepoxide increased food-maintained response rates and decreased responding maintained by shock presentation.


The effects of phencyclidine, ketamine, delta-amphetamine and pentobarbital on schedule-controlled behavior in the mouse. The response of mice of breaking a light beam onto a photocell was programmed to produce food according to a multiple schedule with alternating 30-response fixed ratio, 300-second fixed interval (FR-30 FI-300 sec) components. Training was standardized for all mice, and stable patterns of responding that were similar to those described for other species and responses under this schedule developed quickly. The effects of pentobaribtal, delta-amphetamine, phencyclidine and ketamine were studied. At some dose, each of the four drugs produced an increase in rate of responding; the increase was proportionately greater at low rates of responding than at higher rates. At some dose range, delta-amphetamine, ketamine and phencyclidine produced dose-related increases in FI average rates were to 1.83, 1.25 and 1.32 times the control rate for delta-amphetamine (1 mg/kg), ketamine (100 mg/kg) and phencyclidine (3 mg/kg), respectively. Phencyclidine and ketamine thus showed some "amphetamine-like" effects in the mouse. Pentobarbital increased (1.25 times the control rate) both the FR and FI response rates at a dose of 3 mg/kg. Higher doses of pentobarbital progressively decreased both FR and FI response rates in a parallel fashion.


A positive inotropic effect of propranolol on the canine myocardium: a presynaptic effect. Administration of propranolol directly into the anterior descending branch of the left coronary artery (LAD) resulted in a localized increase in myocardial contractile force in the area of the left ventricle perfused by the LAD. The onset of the positive inotropic response occurred within 30 seconds after drug administration with a duration of action of approximately 8 minutes and was associated with a significant increase in the coronary sinus/arterial ratio of norepinephrine. Contractile force in an area of the left ventricle perfused by the circumflex artery decreased concomitantly with the characteristic negative chronotropic action of propranolol. Pretreatment with reserpine abolished the positive inotropic effect of propranolol while ganglionic blockade with hexamethonium failed to alter the character of the response. Imipramine pretreatment not only blocked the positive inotropic effect of propranolol but resulted in an exaggerated negative inotropic effect in both areas of the left ventricle along with a significant fall in systemic arterial blood pressure. The data demonstrate that propranolol can evoke the release of norepinephrine from cardiac adrenergic nerve endings and raise the possibility that propranolol may be taken up by the amine uptake system.


Effects of disopyramide phosphate on ventricular arrhythmias in experimental myocardial infarction. A myocardial infarction model in which infarction is the result of an occluding thrombus was used to evaluate the effectiveness of disopyramide phosphate (DP) in abolishing postinfarction ventricular arrhythmis. Two types of ventricular arrhythmias were observed, rapid multifocal arrhythmias. and slow unifocal rhythms. DP, in doses of 5 mg/kg, were effective against slow ventricular tachycardia. The time course of action varied with the type of rhythm present. Conversion of the slow ventricular tachycardia usually occurred within a minute whereas abolition of the rapid ventricular tachycardia took 5 to 10 minutes. Effective arrhythmia control could be maintained by a bolus dose (3 mg/kg) followed by a constant infusion at a rate of 0.2 mg/kg/min. DP had minimal effects on arterial blood pressure at antiarrhythmic doses. The drug had significant hypotensive effects if infused at rates greater than 2 mg/kg/min. However, the hypotensive effect was always transient at doses of 5 mg/kg or less. DP produced significant changes in the lead II electrocardiogram. At doses of 5 mg/kg, the drug significantly increased the P-R and Q-Tc intervals and increased the QRS duration. The drug slowed conduction through all parts of the conducting system to approximately the same degree with perhaps a slightly greater slowing through the atrioventricular node. However, the changes observed were never more than 20%


Nicotine-like actions of cis-metanicotine and trans-metanicotine. The actions of the cis- and trans-isomers of metanicotine were observed on isolated rabbit aortic strips and ileal segments. The data are interpreted as showing a nicotine-like action on these preparations for both cis-metanicotine and trans-metanicotine. This hypothesis is supported in part by the demonstration that the action of the metanicotine isomers was affected by hexamethonium, cocaine, phenotolamine, reserpine and atropine in a manner similar to that previously seen in studies with nicotine. In dose-response studies on the aortic strip, trans-metanicotine was significantly less active than nicotine. cis-Metanicotine in turn was less active than trans-metanicotine and nicotine. Additionally, four pyridino compounds, 3-pyridylacet acid, N-(3 pyridlyacetyl) glycine, nicotinuric acid and trans-4-(3-pyridyl)-3-butenoic acid, were tested for both agonist and antagonist activity. No stimulatory activity was found with these compounds in either the aortic strip or ileal preparations. In aortic strip preparations, pretreatment with either 3-pyridylacetic acid or N-(3-pyridylacetyl) glycine provided a moderate to marked reduction in the contractile response to trans-metanicotine, whereas pretreatment with trans-4-(3-pyridyl)-3-butenoic acid caused a slight reduction.


Computer simulation of local anesthetic effects using a mathematical model of myelinated nerve. A mathematical model of myelinated axon was programmed for digital computer solution of the consequences of the conduction characteristics when the model membrane was affected by local anesthetics simulated by alteration of the ionic conductance parameter. The effects of tetrodotoxin on impulse conduction were studied in detail by means of a systematic reduction in sodium conductance in 1 to 10 nodes of Ranvier. Rhis technique simulates the method used experimentally and clinically to achieve a conduction block with the circumscribed application of local anesthetics to segments of nerve axons or nerve trunks. The analysis of the tetrodotoxin "dose-response" relationships revealed the fact that the model myelinated axon could support three types of conduction when depressed by this drug. One type of conduction of a subnormal impulse at  the nodes of Ranvier; a second is characterized by a form of decremental conduction in which the rate of decrement of the nodal impulse is linear with distance. The third type is a second form of decremental conduction which is exponential in configuration and is seen when the g(Na) at the nodes of Ranvier is reduced to less than 27% of normal. Parallel experiments were performed to simulate the effects of lidocaine and some significant differences were observed. Analysis of the action potentials within the internodel region suggests that, although immune to drug action in the model, the internodal segment affects the generation of action potentials at the nodes. A commentary is presented on the limitations of the model as it reflects known pharmacologic relationships in real myelinated axons.


An investigation of the natriuretic, antidiuretic and oxytocic actions of neurohypophysial hormones and related peptides: delineation of separate mechanisms of action and assessment of molecular requirements. The substitution of the 4-glutamine of oxytocin by a lipophilic aliphatic amino acid leucine yields [4-Leu] oxytocin which possesses natriuretic-diuretic anti-arginine-vasopressin (anti-ADH) activities. Alkyl substitutions of the beta-carbon of the 1 half-cystine of oxytocin yield a series of antioxytocin analogs which inhibit the uterotonic response to oxytocin. In this paper, the results of our further investigations on the molecular requirements for natriuretic, anti-ADH and antioxytocic activities of these peptides are reported. A total of 12 analogs of oxytocin and lysine-vasopressin (LVP) with leucine and/or beta-carbon alkyl substitutions were studied. Our findings reveal that the effect of 4-leucine substitution may not be to enhance the natriuretic activity but rather to abolish the antidiuretic activity of oxytocin. The lack of antidiuretic activity of these 4-leucine analogs makes it possible to unmask the intrinsic natriuretic activity of these peptides at the high dose level. Structure-activity correlations suggest that the oxytocin molecule may be the optimal requirement for natriuretic activity of these peptides. Substitution of 4-glutamine by lipophilic aromatic phenylalanine yields [4-Phe] oxytocin which possesses anti-ADH activity with little or no natriuretic activity. The "hybrid" antioxytocin and anti-ADH molecules, beta-carbon alkyl and 4-leucine substituted analogs did not possess enhanced antihormone activity. Although they had antioxytocic and antipressor activities, they were less potent than their respective singly alkyl substituted analogs. Furthermore, they had no demonstrable anti-ADH activity. The single alkyl substituted oxytocin and LVP also had no anti-ADH activity. It therefore appears that beta-carbon alkyl substitution had different effects on activities depending on the morphological features and the functions of the target cell. In target cells of contractile smooth muscles (uterus and vascular), the alkyl substituted analogs had no intrinsic activity but retained a relatively high receptor affinity to become effective antagonists to the natural hormone. On the other hand, in target cells of the renal tubule which are noncontractile epithelial cells, both intrinsic activity and receptor affinity were reduced or abolished. Thus none of these alkyl substituted analogs possessed more than very slight antidiuretic activity, and none had any natriuretic or anti-ADH activity.


Mechanism of action of cobra cardiotoxin in the skeletal muscle. Cobra cardiotoxin (CTX) is a potent polypeptide in inducing irreversible contracture of the chick biventer cervicis muscle. this polypeptide is about 2000 times more potent than caffeine in inducing contracture of this muscle preparation but the rate of CTX contracture is slower. Studies on the interaction on CTX with divalent cations showed that low Ca0++ (10(-31-2 mM)-Krebs' enhanced markedly while ethylene glycol bis (beta-aminoethyl ether)-N,N'-tetraacetic acid-Krebs' or high Ca++ (12 mM) inhibited completely CTX contracture; 10 mM Mg++ enhanced but 20 mM Mg++ or 10 mM Zn++ inhibited CTX contracture. Neither Na+ nor tetrodotoxin affected CTX contracture. Comparison of CTX and caffeine contracture showed that ethylenediamine tetraacetic acid (1 mM) and Mn++ (5 mM) inhibited CTX contracture completely but inhibited caffeine contracture only partially; procaine did not inhibit CTX contracture but inhibited caffeine contracture competitively; by contrast, N-ethylmaleimide inhibited CTX but not caffeine contracture. Neither caffeine nor K+ contracture was inhibited by 12 mM Ca++. CTX could induce contracture in the depolarized muscle and the muscle with T-tubule destroyed or closed, whereas K+ failed to induce contracture in the latter.  Caffeine contracture was inhibited in the muscle with a previous elicitation of CTX contracture. This antagonistic effect of CTX could be prevented by calcium. Moreover, CTX increased both 45Ca++ efflux and 45Ca++ uptake. Both Zn++ (0.6 mM) and Mg++ (10 mM) but not protamine and polylysine mimicked CTX to increase 45 Ca++ uptake. Zn++ (0.6mM) was also found to be effective in replacing Ca0++ to induce CTX contracture in 10(-6) M Ca0++. CTX increased Ca and Na but decreased K contents of the muscle. The binding of radioactive iodinated CTX was inhibited not only by unlabeled CTX but also by 10mM Ca++. All of these findings suggest that CTX may affect a membrane calcium binding site and may induce contracture by releasing the membrane calcium rather than by increasing Na+ permeability of the muscle membrane.


Digoxin toxicity: primary sites of drug action on the sympathetic nervous system. Increases and decreases in sympathetic nerve activity have been reported to accompany digitalis-induced arrhythmias. These effects may result from drug action on various sites such as the central nervous system, ganglia, chemoreceptor or baroreceptor afferent fibers or peripheral efferent nerve fibers. The relative importance of each possible site of drug action has not been clarified. To define the involvement of some of these sites, digoxin was administered intravenously to cats in order to study its effects on activity of preganglionic splanchnic or postganglionic inferior cardiac nerves in the presence or absence of chemoreceptor and baroreceptor reflexes. In cats with intact reflexes, arrhythmic doses of digoxin had diverse effects on postganglionic activity. In some cats digoxin increased activity and in others it decreased activity. In contrast, digoxin consistently caused large progressive increases in postganglionic activity when baroreceptors and chemoreceptors had been denervated. Digoxin inhibited preganglionic nerve activity only in cats with intact reflexes but had no effect in those without chemoreceptor and baroreceptor reflexes. Thus, the afferent component of the baroreceptor reflex is the apparent site of digoxin-induced inhibition. Digoxin produced increases in activity above control only in postganglionic nerves. This finding suggests that digoxin acts on the ganglion to increase sympathetic activity. Digoxin had no discernible effect on preganglionic activity when baroreceptor and chemoreceptor afferent input had been eliminated. To test further for any subliminal drug effect in the brain, effects of intravenously administered digoxin were observed on centrally evoked submaximal responses in the splanchnic nerve. Lethal doses of digoxin had no effect on responses evoked from the medulla or the hypothalamus. Therefore, these data are not consistent with the hypothesis that a primary site of drug action is in the central nervous system. Instead, the data suggest that neural effects of digoxin result primarily from drug actions within the peripheral autonomic nervous system on sites such as the ganglion and peripheral afferent components of the baroreceptor reflex.


Effect of age on the cardiotoxic action of digitalis. The cardiotoxic effect of ouabain was explored in rabbits at different ages. The dose of ouabain necessary to produce ventricular tachycardia and death in 1-to 4-week-old rabbits was significantly greater than that required in older animals. In the 1 to 3-week-old animals, ventricular fibrillation occurred only once whereas in animals older than 3 weeks, fibrillation occurred in 23 of 31 animals. A similar pattern of sensitivity to ouabain was observed in bilaterally vagotomized animals. Neither the initial heart rate nor the potassium content of the ventricles in the different age groups appeared to have any influence on the change in the cardiotoxic dose of ouabain. Heart weight increased during the interval when the occurrence of fibrillation increased but it may not fully explain the alteration in the mode of death since fibrillation occurred in some of the younger animals with bilateral vagotomy before the heart weight increased. The catecholamine content of ventricles from 4-to 12-week-old rabbits was significantly greater than that in 1- or 3-week-old rabbits. The age-dependent decrease in the dose of ouabain necessary to produce ventricular tachycardia, ventricular fibrillation and death appeared to be associated with an increase oof ventricular norepinephrine content, although other factors may also play an important part in this response.


Effects of 6-hydroxydopa on noradrenergic neurons in developing rat brain. The temporal sequence of changes in norepinephrine (NE) levels in various regions of brains of control and 6-hydroxydopa (6-OHDOPA)-treated rats was determined. It was found that 6-OHDOPA (60 mug/g i.p., three doses, 48-hour intervals), when administered from birth, markedly altered the NE content of various brain regions during the following 8-week period. In telencephalic regions, such as the neocortex and hippocampus, NE levels (micrograms per tissue) increased dramatically from birth in saline-treated rats, while NE was depressed by 55 to 85% in 6-OHDOPA animals. Studies for measuring the uptake of 3H-NE (2 X 10(-7) M) by synaptosomes isolated from the neocortex showed that uptake, was reduced by approximately 40% at 2, 5 and 52 weeks of age. Therefore, it appears that 6-OHDOPA is able to permanently impair the ontogenetic development of noradrenergic neurons in regions supplied by the dorsal noradrenergic bundle. In contrast to these effects, NE levels in the cerebellum were elevated 2-fold in 6-OHDOPA-treated rats of 8 weeks, postnatal age. Uptake was not similarly increased, indicating that the elevation in NE was not due to an increase in the number of nerve endings, but rather to an increase in the intraneuronal storage depots of NE. In the hypothalamus NE levels were not dramatically altered, while uptake was reduced by about 40% up to 1 year of age. Application of Michaelis-Menten kinetics indicated a decrease in the Vmax for 3H-NE uptake in the hypothalamus of 6-OHDOPA (60 mug/g i.p., two doses, 48-hour intervals from birth)-treated rats, sacrificed at 6 months of age. The pons-medulla and midbrain regions showed moderate increases in NE levels at 5 and 8 weeks. Uptake 1 was not increased in the pons-medulla at any time, and the Vmax remained unchanged when measured in rats at 6 months of age. It is apparent that 6-OHDOPA is capable of altering the ontogenesis of noradrenergic neurons and that the effects on development are different in different areas of the brain.


Ethanol effects on muscle spindle afferent activity and spinal reflexes. The effects of ethanol on muscle spindle afferent activity and on the mono- and polysynaptic reflexes were examined in cats. Ethanol was administered incrementally as intravenous infusions of 0.7 g/kg of ethanol 30 minutes apart; mean arterial blood alcohol concentrations reached 30 minutes after the first and fourth infusions were 1.1 and 3.8 mg/ml, respectively. Ethanol produced modest, dose-related increases in the afferent activity from muscle spindles in spinal- and pentobarbital-anesthetized cats. Mean phasic and static discharge frequencies were both increased approximately 10 impulses/sec after infusions of a total of 2.8 g/kg. In unanesthetized animals, comparable blood levels of ethanol were associated with mild to marked motor incoordination. The mean amplitudes of the mono- and polysnaptic reflexes in spinal animals, elicited with supramaximal single shocks to the muscle nerve, were depressed to 92 and 84% of control levels, respectively, after 0.7 g/kg and continued to fall to 50 and 60% of control levels after 2.8 g/kg of ethanol. Ethanol failed to depress preferentially polysynaptic reflexes. It is concluded that the spindle afferent excitation was involved in the motor effects of ethanol but that it was insufficient to explain fully the skeletomotor alterations produced by ethanol; rather, ethanol actions at peripheral and spinal and, perhaps, supraspinal sites all appear to be involved in ethanol-induced impairment of motor function.


Actions of trihexyphenidyl and benztropine on squid axon membranes. Trihexyphenidyl and benztropine have potent local anesthetic action on squid axon membranes. They suppress the peak transient sodium conductance with ED50 values equal to 1.75 X 10(-4) AND 0.78 X 10(-4) M, respectively, and shift the sodium condu-tance curve along the potential axis in the direction of depolarization by 2.3 and 8.7 mV, respectively. The time for the sodium current to attain its peak is shortened. Steady-state potassium conductance is also suppressed by these drugs and undergoes an inactivation which has a potential-dependence characteristic. The local anesthetic action combined with the anticholinergic action may warrant further study of these two drugs, especially trihexyphenidyl, as a potential antiarrhythmic agent.


Methadone during pregnancy in the rat: dose level effects on maternal and perinatal mortality and growth in the offspring. Four groups of pregnant rats were administered methadone hydrochloride orally on days 8 through 22 of gestation. Each group initially received 5 mg/kg for 4 days. One group was maintained at this level and the remaining groups were increased to maintenance doses of 10, 15 or 20 mg/kg increments at 4-day intervals. An intubation control group received the vehicle only. Nontreated control mothers were left undisturbed. All offspring were fostered to other nontreated mothers at birth. Methadone, particularly at the higher dose levels, reduced maternal weight gain during pregnancy and increased both maternal mortality and total mortality among the young (resorptions plus stillbirths). Birth weight covaried with dose level and litter size: the 5, 10 and 15 mg/kg doses yielded litter sizes comparable, to, or somewhat smaller than, controls, but with lower birth weights; the 20 mg/kg doses yielded the smallest litter sizes but with birth weights greater than any other treated or control group. Beyond day 1 of life, treated and control offspring did not differ in mortality. By weaning, the low offspring weights seen at birth had been compensated for and were no longer evident. Body weights of offspring of mothers in the 20 mg/kg group remained well above average through weaning. In a second experiment, blood levels of methadone were determined for both mothers and litters in the 5, 10 and 15 mg/kg groups, sacrificed 24 hours before expected parturition. Blood levels were dose-related and corresponded to those found in human subjects receiving daily maintenance doses of approximately 30, 60 and 100 mg, respectively.


Pharmacological studies of a new 4-aminosugar cardiac glycoside (ASI-222). ASI-222,3beta-O-(4-amino-4,6-dideoxy-beta-d-galactopyranosyl) digitoxigenin, is a semi-synthetic cardiac glycoside patterned after a natural glycoside obtained from Cambodia. Effects of ASI-222 on contractile force in the isolated rabbit atria, cardiac contractile force, cardiac rate, ventricular excitability and functional refractory period in dogs, and acute toxicity in mice have been compared to those effects of ouabain. Both electrically driven and spontaneously beating atria demonstrated more rapid onset and greater maximum increases in contractile force with ASI-222 than with ouabain in equal bath concentrations. In the dog, ASI-222 increased cardiac contractile force more rapidly and at a lower cumulative dose than ouabain. Moreover, the maximum increase in contractile force obtained with ASI-222 was greater than that obtained with ouabain. The occurrence of ventricular ectopic beats was observed at a higher cumulative dose of ASI-222 than for ouabain. Also, ASI-222 produced a decrease in ventricular excitability and an increase in functional refractory period ot the ventricle. Ouabain, in the same molar dose, produced either no change or a slight increase in these parameters. Our data indicate that ASI-222 has a greater therapeutic index than ouabain. This difference may be partially explained by effects of ASI-222 on electrical properties of the heart.


Impaired tissue oxygenation in cyanate-treated animals. Carbamylation of red cells with sodium cyanate has been suggested as a potential treatment for sickle cell disease. Because carbamylation of red cells increases their oxygen affinity, the present study was done to determine whether cyanate administration caused impaired tissue oxygenation. Rats given i.p. (250 mg/kg/wk) or oral (625 mg/kg/wk) cyanate were found to have significantly reduced skin bubble oxygen tensions compared to controls. These reduced oxygen tensions were associated with significantly increased blood oxygen affinity. Treated animals developed greater red cell masses than controls, but these increases were not sufficient to compensate for increased blood oxygen affinity. These findings need to be considered when cyanate is used for treatment of sickle cell disease.


Correlation of the electrophysiological and antiarrhythmic properties of the N-acetyl metabolite of procainamide with plasma and tissue drug concentrations in the dog. N-acetylprocainamide (NAPA), a major metabolite of procainamide (PA) in man, has been reported recently to be biologically active. The present study compares the electrophysiological and antiarrhythmic effects of NAPA and PA and correlates their activity with plasma and tissue drug concentrations. In isolated canine Purkinje fibers, NAPA, in bath concentrations of 10 and 20 mg/l reduced automaticity and prolonged repolarization time. These effects were similar to those observed with similar concentrations of PA. Tissue concentrations of NAPA (77 +/- 2 mug/g) were significantly greater than those of PA (43+/-2 mug/g). Neither drug was metabolized by the fibers. In in vivo studies, NAPA (140-220 mg/kg) significantly suppressed the incidence of arrhythmias following coronary occlusion and digitalis intoxication. Similar protection was obtained with 40 to 60 mg/kg of PA. This difference in potency could not be attributed to differences in plasma and tissue concentrations of the drugs. These results show that NAPA is equally efficacious but less potent than PA as an antiarrhythmic drug in dogs.


Vascular tone and reactivity to serotonin in the internal and external carotid vascular beds of the dog. The effects of intra-arterial infusions of serotonin on internal and external carotid blood flow were determined in anesthetized dogs by electromagnetic flow measurements. Serotonin decreased flow in the internal carotid and increased it in the external carotid. Both responses were blocked by the serotonin antagonist methysergide. The alpha adrenergic antagonist zolertine, the ganglionic blocking agent chlorisondamine and the vasodilator diazoxide blocked external carotid dilator responses but did not modify constriction in the internal carotid. Blockade of external carotid responses by the three drugs was also demonstrated in experiments in which this bed was perfused at a constant rate. These results indicate that the internal and external carotid vascular beds of the dog react in opposite ways to serotonin, that both responses are mediated through the same type of serotonin receptors and that the dilator responses of the external carotid are dependent on vascular tone.


The influence of mecamylamine on contractions induced by different agonists and on the role of calcium ions in the isolated rabbit aorta. The exposure of helically cut strips of rabbit aorta to mecamylamine (1 mM) for 5 minutes blocked the histamine (3.25 muM)-induced contractions completely and reduced those induced by potassium (25mM, 68%) without affecting contractions induced by norepinephrine (3.0 muM, NE) or acetylcholine (10 muM). Mecamylamine, by itself, did not exhibit agonist activity, but it increased the contractile tension of the muscle which was contracted by NE. The responses to NE were either enhanced or not affected by small doses of mecamylamine (1 mM), but were partially blocked by large doses of mecamylamine (10 mM). The antagonism exhibited by mecamylamine in low doses (1 mM) against the above agonists was reversible. The shape of the response to NE on the muscle, which was treated with a high dose of mecamylamine (20 mM) and washed, was significantly different from that of the control. Our results are consistent with the following conclusions: 1) Mecamylamine in low doses (1 mM) blocks the histamine receptor and therefore the histamine-induced contractions. Two molecules of mecamylamine are competitive with 1 molecule of histamine. 2) Mecamylamine blocks the potassium-induced contractions, but does not block completely the calcium influx in the potassium-depolarized muscles. Therefore, it may interfere partially with the utilization of extracellular or loosely bound calcium during potassium-induced contractions. 3) Mecamylamine in high doses (10 mM) partially blocks norepinephrine-induced contractions by affecting firmly bound calcium stores. 4) Procaine antagonizes the effects of NE, histamine and acetylcholine by affecting, at least partially, the firmly bound calcium stores.


Iris pigmentation and atropine mydriasis. The experiments were designed to study the well-known pigment-dependent mydriatic effect of atropine in the eye. In vitro, relative to the accumulation of 3H-atropine by the nonpigmented rabbit iris, the pigmented iris accumulated high amounts of the drug. A nonpigmented tissue, stomch fundus strip, obtained from either albino or nonalbino animals, accumulated relatively low amounts of 3H-atropine. On repeated washings, the accumulated drug from the nonpigmented tissues was rapidly lost, T 1/2 of 14 minutes, while that accumulated by the pigmented iris was retained much longer. Although in vitro aqueous humor from serum-atropinesterase positive rabbits rapidly degraded atropine, extracts from irides of the same type of rabbit gave a single peak radioactivity, with Rf identical to the authentic atropine sulfate. The accumulation of 3H-atropine by pigmented human iris or pigment epithelium was similar to that observed for the pigmented rabbit iris. pA2 values of atropine from nonpigmented iris and from fundus strips varied between 8.58 and 8.88 with slope values close to 1. The pA2 value of atropine in pigmented iris was 8.82; at higher concentrations, atropine was less effective compared to the nonpigmented iris. In the pigmented iris, the lesser effectiveness of the drug at high concentration could be explained on the basis of accumulation of the drug by the pigment cell and its constituents. Thus, the free concentration of the drug in the vicinity of the muscarinic receptor will fall. The lesser concentration will give weaker muscarinic blockade in the pigmented iris. On repeated washing, the atropine blockade of the nonpigmented iris could be easily washed out while that in the pigmented iris was retained. In vivo, the relative T 1/2 for the duration of atropine mydriasis in rabbits were: albino atropinesterase-positive, 3.8 hours; nonalbino atropinesterase-positive, 12.4 hours; albino atropinesterase-negative is greater than or equal to 96 hours. Only the latter T 1/2 for the duration of atropine mydriasis is quite clear. The small magnitude of the mydriatic effect in humans is explained by the loss of free drug to the pigment cells and their constituents. The longer duration of mydriatic effect in the heavily pigmented eye is explained on the basis of slow release of the accumulated drug onto the muscarinic receptor.


Dopamine synthesis in rat brain striatal synaptosomes. I. Correlations between veratridine-induced synthesis stimulation and endogenous dopamine release. The effects of depolarizing concentrations of veratridine were studied to determine the degree to which dopamine synthesis stimulation was correlated with stimulated endogenous dopamine release in rat brain striatal synaptosomes. Incubations included cocaine and pargyline to prevent dopamine reuptake and metabolism, respectively. Veratridine produced a 44% increase in dopamine release in 10 minutes and a similar increase in synthesis rate. Preincubation with tetrodotoxin prevented the increase in both release and synthesis, while incubation in a calcium-free medium antagonized both responses approximately 50%. Addition of 1 mM ethylene glycol bis(beta-aminoethylether)-N, N'-tetraacetic acid to the calcium-free incubation medium further inhibited the release response, but not the synthesis stimulation. These results indicate that, in general, the degree of synthesis stimulation produced by depolarizing agents such as veratridine can be correlated with their stimulation of dopamine release, suggesting either 1)that transmitter release itself is a signal for synthesis stimulation, possibly by removal of feedback inhibition of tyrosine hydroxylase or 2) that depolarizing agents increase synthesis through a secondary metabolic change that is either caused by, or at least accompanied by, transmitter release.


The effect of external calcium and magnesium ions on the response of denervated muscle to acetylcholine. 1. The effect of external Ca and Mg on the membrane depolarization and contracture of rat denervated muscle in response to acetylcholine, ACh, was studied. 2. Raising external Ca concentration reduced the rate of rise and the amplitude of the ACh contracture, and prolonged its time course. 3. Increasing external Ca reduced the membrane depolarization in response to ACh. The dose increment required to elicit depolarization in high Ca concentration increased with external Ca, and was greater for depolarization than for contracture. 4. External Mg was less effect than Ca in reducing ACh depolarization but was more effective in reducing contracture. In contrast to Ca, Mg did not alter the time course of relaxation. 5. It is concluded that external Ca has two opposing effects on the ACh contracture: one of stabilizing the membrane and the other of increasing intracellular Ca concentration. External Mg may interfere with Ca influx and hence reduce contractility.


Quantitative assessment of the transmission of labelled protein by the proximal and distal regions of the small intestine of young rats. 1. The plasma volume in rats aged 15-16 days was measured by dilution analysis using homologous, 125I-labelled immunoglobulin G. A mean plasma volume of 5-53 ml./100 g and a mean blood volume of 8-01 ml./100 g were obtained.2. After the injection of labelled immunoglobulin G into the heart, homogenates of various abdominal organs and of the carcass were prepared. Labelled immunoglobulin G left the vascular compartment at a rate of about 9-10%/hr over a 3 hr period. About 11% of the labelled immunoglobulin G was catabolized in 2 hr. 3. The data obtained from these studies was used to make quantitative estimates of the amount of intact immunoglobulin G transmitted from the proximal intestine and from the ileum after the intra-intestinal injection of 1000 mug of labelled immunoglobulin G. Homogenates of the experimental animals were prepared and it was estimated that over 40% of the labelled immunoglobulin G was transmitted as intact protein from the proximal intestine. The results suggest that no intact immunoglobulin G was transmitted from the ileum, but about 15% of the protein removed from the ileum was recovered in the whole body as degraded fragments precipitable with trichloroacetic acid. 4. These observations are discussed in the context of the transmission of antibodies, and their relevance to the receptor hypothesis is considered.


Permeability changes produced by L-glutamate at the excitatory post-synaptic membrane of the crayfish muscle. 1. Permeability changes produced by L-glutamate at the neuromuscular junction of the crayfish (Cambarus clarkii) were investigated by application of the drug iontophoretically to the voltage-clamped junction and measuring the resulting 'glutamate current'. 2. Reversal potentials were determined by measuring the glutamate current at different membrane potentials. They were +39-1 +/- 3-6 mV (mean +/- S.E. of mean) in normal solution and +16-5 +/- 2-0 mV in solutions made twice as hypertonic by the addition of sucrose. 3. Decreasing external Na+ concentration shifted the reversal potential in the negative direction; increased Na+ in the positive direction. 4. The relation between the amplitude of the glutamate current and extracellular Na+ concentration was approximately linear. 5. Alteration of the external K+ or Cl- concentration did not affect the amplitude or reversal potential of glutamate current. 6. In Na+-free solution the application of L-glutamate produced a small inward current at the resting potential and its amplitude was augmented by increasing the external Ca2+ concentration. 7. Increasing the Ca2+ concentration in the normal Na+ media produced no appreciable effect on the reversal potential but decreased the amplitude of glutamate current. 8. The results indicate that L-glutamate increases the membrane permeability mainly to Na+ and slightly to Ca2+. 9. The time course of glutamate current was shorter than that of the concentration calculated from the diffusion equation and it was simulated more closely by the square of the concentration.


Haemodynamic responses and renin release during stimulation of afferent renal nerves in the cat. 1. Experiments were done on anaesthetized cats to study the effect of electrical stimulation of afferent renal nerves on the circulatory system and on the release of renin from the kidney. 2. Stimulation of afferent renal nerves over a wide range of parameters consistently elicited an increase in arterial pressure and heart rate. This response was still present in paralysed animals and was not accompanied by changes in respiration or in sympathetic autonomic activity usually associated with painful stimulation. Mesenteric and iliac vasoconstriction was observed concomitantly with the increase in arterial pressure. 3. Release of renin from the contralateral innervated kidney was not significantly changed by stimulation of afferent renal nerves. 4. The existence of renal vascular mechanoreceptors was investigated by altering renal circulation. Stenosis of the renal artery or a marked reduction in renal perfusion pressure elicited an increase in arterial pressure while stenosis of the renal vein elicited a decrease in arterial pressure. These responses, however, were not affected by denervation of the kidney and were therefore interpreted as not being due to neural mechanisms. 5. The precise nature, location and physiological role of renal receptors involved in the cardiovascular responses observed during electrical stimulation of afferent renal nerves remain to be determined.


The effect of hypercapnia on a blood-brain barrier mechanism in foetal and new-born sheep. 1. The effect of marked hypercapnia (arterial PCO2 100 mmHg), nonrespiratory acidosis (pH 6-95-7-15) or hypoxia (arterial PO2 10-15 mmHg) upon penetration of labelled sucrose from blood into brain and c.s.f. has been investigated in exteriorized foetal sheep and new-born lambs. 2. In hypercapnia there was a consistent increase in c.s.f./plasma sucrose ratio after 90 min I.V. sucrose to four to five times control. Brain/plasma sucrose ratios were more variable. Usually there was an increase (up to three-and-a-half-times control); sometimes there was no change or even a decrease. The effect of hypercapnia on sucrose penetration was reversible. 3. Hypercapnia reduced c.s.f. secretion rate to approximately half the control value. Hypercapnia also caused a decrease in brain extracellular space. 4. Non-respiratory acidosis did not affect sucrose penetration. Hypoxia caused a decrease in brain/plasma sucrose ratio. 5. It is concluded that hypercapnia can cuase an increase in cerebral vascular permeability to sucrose in foetal and new-born sheep. Some possible mechanisms are discussed.


The utilization of glucose and production of lactate by in vitro preparations of rat small intestine: effects of vascular perfusion. 1. The rate of metabolism of glucose to lactate has been measured in a number of non-vascularly perfused preparations of rat jejunum in vitro. The glucose and lactate metabolism was measured simultaneously and under conditions such that the uptake of glucose and the appearance of lactate were linearly related to time. 2. It is found that there is no difference between the rates at which rings of rat jejunum utilize glucose during the first 45 min of anaerobic or aerobic incubation. During the first 15 min of incubation between 60-70% of the metabolized glucose was converted to lactate under aerobic conditions; this value increased to 80-90% during the subsequent 30 min. During the period 0-15 min of incubation, lactate production was found to be higher under anaerobic than under aerobic conditions but after this initial period the rate of lactate production was the same under aerobic and anaerobic conditions. 3. For segments of rat jejunum, maintained in vitro by the recirculation of nutrient fluid through the intestinal lumen, neither the rate of production of lactate, nor the utilization of glucose, was stimulated if the preparation was maintained under anaerobic rather than aerobic conditions. The direct delivery of gas into the intestinal lumen in the form of a stream of bubbles (segmented circulation) reduced both the utilization of glucose and the production of lactate under aerobic conditions. However, not effect on glucose metabolism was observed under anaerobic conditions. The finding of a Pasteur effect with the segmented-circulated preparation, but not with the simple recirculated preparation, is associated with lower rate of aerobic lactate production in the former preparation. Reasons are given for supposing that under conditions of segmented circulation, the luminal compartment is better stirred, thereby increasing access of O2 to the tissue. 4. A preparation of rat small intestine perfused through the vascular bed is described. With this preparation the rate of glucose utilization is significantly lower than that for recirculated preparations and the rate of lactate production is substantially less than that of the other preparations studied. 5. With the preparation perfused through the vascular bed, and with glucose, 10 mM, present only in the vascular medium the addition of erythrocytes to the vascular infusate causes a significant reduction in both glucose utilization and in the rate of lactate production. The addition of erythrocytes to produce an haematocrit of 40% (v/v) causes a greater reduction in glucose utilization and lactate production than is found for an haematrocrit of 15%. About 10% of the lactate produced appears in the luminal contents. With an haematocrit of 15%, the O2 consumption of the whole wall of the jejunum was found to be 6-4 mumole O2 g dry wt.-1 min-1, equivalent of a value for the Q02 of 8-6 mul. O2 mg druwy wt.-1 hr-1. The uptake of O2 was almost entirely from the vascular infusate. 6...


[Influence of hydrothermal ambient conditions on sweat evaporation efficiency]. Sweat efficiency is defined as the ratio between evaporative and sweat rates. The work was carried out on two resting subjects acclimatised to humid heat. Body sweat rate and rate of sweat loss by dripping were recorded separately by continuous weighing. Evaporation from the skin was obtained by the difference between the two weight loss curves. The subjects were exposed for 75 minutes to increases in humidity levels as constant air temperatures (42, 44, 46, or 48 degrees C). The amplitude of the increases was successively equal to 7.5, 15.0, 22.5 or 50.0 mb of water vapor pressure. During the 75 minutes preceding each increase the water vapor pressure of the air was maintained at 20.0 mb. 1. Sweat efficiency decreases prior to complete wetting of the skin surface. The inter-individual mean value of the wetted skin area threshold over which sweat efficiency is less than 1 is around 60%. 2. Sweat efficiency is linearly related to the reciprocal of the required wetted skin area (see article). These results are compared with those of other authors. The differences observed are explained in terms of physiological or physical variables involved in the sweat rate control or in the evaporative sweat loss. These include wetness of skin, posture, activity of subjects and the velocity of air over the skin surface.


Effect of environmental salinity change on osmotic permeability of the isolated gill of the eel, Anguilla anguilla L. Net water fluxes in the isolated gills of Anguilla anguilla were studied during incubation in fresh water (FW) and in sea water (SW). When incubated in FW, water entry was greater in SW-adapted eels than in FW-adapted eels. In contrast, water loss in SW was less in SW-adapted eels than in FW-adapted eels. Rectification of osmotic water fluxes was observed for both FW and SW-adapted eels, net water fluxes in the mucosal-serosal (m-s) direction being greater than those in the opposite (s-m) direction. These results indicate that adaptation to a given external medium brings about a decrease in the osmotic permeability so that water gain in FW or water loss in SW is minimal.


[Function of different medullary neurons in respiration]. 1. We have studied the activity of 162 medullary respiratory neurones in the "encephale isole bas" cat. These neurones were classed into three groups : bulbospinal inspiratory (NBSI : 39) or expiratory (NBSE : 15) neurones whose axons enter the spinal cord ; inspiratory or expiratory laryngeal motoneurones (MLI : 17; MLE : 10) antidromically activated by vagus nerve stimulation ; propriobulbar inspiratory (NPBI : 59) or expiratory (NPBE : 22) neurones whose axons lie perhaps entirely within the medulla. 2. Correlation coefficients between number of spikes delivered in each burst and the duration of the corresponding respiratory phase (inspiration for NBSI, MLI, NPBI ; expiration for NBSE, MLE, NPBE) have been calculated for each neurone. 3. The activity of most of the NBSI and MLI is significantly correlated with the duration of the inspiration. These two groups of neurones are probably homogenous. 4. On the basis of this correlation test, NPBI do not constitute an homogeneous population ; 50% of NPBI are not significantly correlated. The same results are obtained if correlations are calculated between the number of spikes delivered and the amplitude of integrated phrenic nerve acitivty. According to the discharge pattern and correlation test, we can consider three groups of NPBI : early recruited neurones with decreasing frequency and non significantly correlated activity (23,7%); early and late neurones with increasing frequency and significantly correlated activity (32,2%); early and late neurones with increasing frequency and non significantly correlated acitivty (44,1%). 5. The activity of most of the NBSE and NPBE with increasing frequency is significantly correlated with the duration of the expiration. Among the MLE and NPBE with a decreasing frequency, a great number of neurones are not significantly correlated. 6. The functional significantion of the different neuronal types is discussed from these correlation tests and from the pattern of activity and axonal pathways.


Transfer characteristics between EMG activity and muscle tension under isometric conditions in man. The relationship between motor unit activity and a voluntarily produced, sinusoidally modulated isometric tension was evaluated as a function of the modulation frequency. These date are reported in terms of the gain and phase difference of the motor activity (input) and tension (output) relationship, the gain being the logarithmic ratio of the amplitudes of the output and input sinusoids. It was found that an increase in the modulation amplitude of the motor unit activity was required to produce the same amount of modulation of the output tension as the modulation frequency was increased. For example, the modulation amplitude of the activity is about twice as much at 2 Hz as at 0.25 Hz and about 4 times as much at 5 Hz. It was also found that the maximum tension which could be produced voluntarily during brief jerks at 5 Hz was the same as the maximum sustained tension which could be attained. This latter finding emphasizes the importance of recruitment and especially synchronization of motor unit activity to the gradation of output tension.


Risky and safe contraceptors: some personality factors. Female university students (N = 191) categorized as users of risky or safe contraceptives were compared on the following personality measures: Rotter's Internal-External Scale, Cantril's Self-Anchoring Striving Scale, Rosen's Value Orientation Scale, and Srole's Anomie Scale. Safe contraceptors had significantly higher levels of striving for the present and for five years hence than risky contraceptors. There were no significant differences between the two groups on the remaining measures.


Internal-external control, interpersonal trust, and the motive to avoid success in college women. The Internal-External Control scale, Interpersonal Trust scale, and an assessment of the Motive To Avoid Success were administered to 86 undergraduate women. As expected, external and low trust scores covaried with comparatively high levels of achievement-related anxiety. The results were interpreted in terms of possible repression tendencies of internal subjects and the defensive properties inherent in the external and low trust belief systems.


Is internal-external control an age-related variable? Following the suggestion proposed by Duke, Shaheen, and Nowicki, this study was designed to test the basic hypothesis that the meaning of internal-external control (I-E) may differ with age. Such variables as age, educational level, socioeconomic status, self-confidence, etc., which have consistently been found to relate to I-E for children through college age Ss, were examined to see if these bear a relationship to I-E for a group of parents (95 fathers and 107 mothers) of college students (father mean age 48, mother mean age 46). Results indicated that with the exception of father education, there was no significant relationship between I-E and all other variables. Thus, these findings support the notion that I-E is an age-related variable, that generalizations from previous studies to older people should be re-evaluated, and that future research should study the meaning and dynamics of I-E for older people.


Components of suicidal intent in completed and attempted suicides. An objective suicidal intent scale was completed for 235 completed suicides and 246 attempted suicides in Philadelphia. The responses to the items of the suicidal intent scale were factor analyzed separately for the two groups, and the pattern of factors compared. The major difference centered around communication. For the completed suicide the decision appears to be whether or not to communicate; for the attempted suicide the decision appears to be when to communicate.


On the question of pre-existing personality differences between users and nonusers of drugs. This study represents a beginning attempt to investigate the possible existence of predrug usage, personality differences between users and nonusers of drugs. Ss were male college students: 30 heavy marijuana (multiple drug) users, 30 light marijuana users, and 30 nonusers were compared on the results of the Gordon Personal Profile administered prior to the use of any drugs. Significant differences were found on two of the personality scales on this instrument.


Suicidal age and childhood onychophagia among veterans with personality disorders. The relationship between childhood onychophagia (finger-nail biting) and the mean age of suicidal and nonsuicidal veterans was investigated among 70 V.A. hospitalized males, diagnosed as personality disorders. The results show that the mean age of suicidal veterans was significantly lower than that of nonsuicidal veterans, and the childhood onychophagia variable, "focal suicide," significantly lowered the mean age of suicidal veterans, but did not significantly lower the mean age of nonsuicidal veterans.


A discrepancy between two modes of haptic length perception. This study investigated the possibility that systematic differences exist between the perceptions resulting from the use of two different heptic modes to know the same object. In each of three experiments 24 male and female college students chose visual comparison stimuli to match the length of haptically presented standard stimuli. In each experiment significantly smaller visual matches were made when the length of the haptic standard was perceived by holding it between the thumb and index finger than when the haptic standard was perceived by stroking it from end to end with the index finger. Experiment 1 established a significant difference (p less than .05) using a horizontal visual comparison. Experiment 2 replicated this effect (p less than .001) using vertical visual comparisons. Experiment 3 again replicated the effect (p less than .001) with visual comparisons and ruled out the possibility that the effect was due to the orientation of the haptic stimuli.


The effects of experimentally induced changes in self-concept on associative learning. It has been hypothesized that self-concept influences ability to learn. This experiment systematically manipulated the self-concepts of learners regarding their abilities to learn a foreign language and measured their subsequent learning of a synthetic foreign language vocabulary list. Eleven Ss were randomly assigned to each of three groups: self-concept raised, self-concept lowered, control. Ss were college freshman who were not enrolled in a foreign language course or had not previously taken more than one semester of a foreign language. Self-concepts were measured as self-description of ability to learn a foreign language. Self-concepts were raised or lowered by providing false scores on a foreign language aptitude test. Learning was measured as performance on a paired-associates task utilizing random shapes and CVCs. Ss with lowered self-concepts learned more slowly than control Ss or Ss with raised self-concepts.


Encoding and decoding of connected discourse during altered states of consciousness. The following hypotheses were investigated in a study of memory recall and an altered state of consciousness: (a) A direct relationship was expected between the magnitude of correct responses and task complexity. (b) Semantic context variation was expected to cause greater impairment in verbal processing than variation in syntactic constraints. (c) Under N2O fewer correct responses in verbal processing were expected to be made. Forty-four volunteers, male corpsmen in the U. S. Navy between the ages of 20 and 29, were randomly divided into two equal groups: a nitrous oxide group and an air group. After breathing either N2O or air for 10 minutes, Ss were required to repeat pairs of taped sentences of high syntax/high semantic context to low syntax/low semantic context. Responses were scored for errors. All three hypotheses were accepted. Task complexity caused the greatest magnitude of errors. Ss were able to compensate for variations in syntax and in the gas state, but low semantic quality strongly affected performance. The factors interacted in powerful ways to produce differential response errors from a low error rate for air/high syntax/high context to a high error rate for N2O/low syntax/low context.


The control of hypertension, atherosclerotic diseases, and diabetes in a family practice. A community-orientated programme for the control of hypertension, atherosclerotic disease, and diabetes has been developed in a family practice in a neighbourhood of Jerusalem. Intervention is directed mainly towards the control of risk factors associated with these diseases.The programme has specific objectives for diet, smoking, obesity, blood pressure, serum cholesterol, glucose intolerance, and diabetes mellitus, and the identification and treatment of patients with cardiovascular diseases. The survey seeks to identify the nature and extent of problems, intervention by medicinal and educational means, and continuing surveillance and evaluation.The programme aims to test and demonstrate the feasibility of carrying out multifactorial community health care within the framework of a family practice, thereby developing a joint practice of primary health care and community medicine.


High blood pressure and psychiatric disorder in general practice. A programme for the control of hypertension has been started in general practice with the principal aim of finding the most effective way of identifying and keeping patients with high blood pressure under continuing control. One objective is to determine the psychiatric state of hypertensive patients in the programme and this paper reports these results.There was no significant difference between the percentage of psychiatric patients in a hypertensive group and a control group. There was no relationship between blood pressure recorded at the initial clinic and the psychiatric state. In both hypertensive and control groups, patients who were on hypertensive treatment at the initial clinic were more likely to be ;psychiatric' than those who were not on treatment; this appears to be less likely to occur if the hypertension is controlled.


An experimental collection service for pathology specimens. The use of laboratory services made by a group of general practitioners was compared before, during and after the provision of a free collection service for transporting specimens and results between the practices and the laboratory.In comparison with the use of a control group of general practitioners, the study group made a sharply increased use of the laboratory during the 33-week survey period. In addition, both the practices. The laboratory staff welcomed the service.


Folate supplements during pregnancy.

Folate supplements during pregnancy. In a controlled, prospective trial, the effects of giving ferrous sulphate 50 mg daily to 76 pregnant women was compared with giving ferrous sulphate 50 mg daily plus folic acid 0.5 mg daily to 82 women in 12 general practices in South-east England.No differences in obstetric complications were found between the two groups, although the evidence of some of the listed complications may be too rare for detection in a sample of patients of this size.


Salpingitis: a frequent response to intrauterine contraception. Nonbacterial, chronic salpingitis was found in less than 1% of non-IUD users undergoing elective tubal sterilization, Nonbacterial, chronic salpingitis was found in 47% of IUD users undergoing elective sterilization. Speculation about the influence of this finding on inflammatory morbidity is presented.


Fimbrial microbiopsy.

Fimbrial microbiopsy. Microbiopsies from the fimbrial surface were obtained from 70 women to determine the percentage of ciliated cells. The following observations were made: 1. There is  a close correlation between the percentages of ciliated cells in each of the two oviducts; 2. The percentages of ciliated cells in normal, fertile women vary between 54 and 70 with no apparent variation between the follicular and luteal phases of the cycle; 3. The percentage of ciliated cells is reduced in hypoestrogenic amenorrhea, during pregnancy and during steroid contraception; 4. Ovarian endometriosis without tubal involvement is usually not associated with fimbrial reciliation, but sequelae of pelvic inflammatory disease can be associated with deciliation of the fimbrial surface; 5. Two cases are reported in which the fimbrial surface showed extreme deciliation in association with sqamous metaplasia of the epithelium, possibly indicating defective ovum transport over the fimbrial surface.


The control of ticks, fleas and lice on dogs by means of a Sendran--impregnated collar. Plastic collars impregnated with 9,4% Sendran effectively controlled adult Rhipicephalus sanguineus for a period of 49 days and immature ticks for a period possibly in excess of 70 days when fitted to four dogs. Four uncollared dogs served as controls. Although flea burdens were extremely low the collars were apparently effective for a period in excess of 70 days. A medicated collar killed all the ticks, fleas and lice on a severely parasited dog within a period of 48 hours.


Studies on the life cycle of the lungworm, Pneumostrongylus calcaratus, Mönnig, 1932. The morphology of the first, second and third stage larvae of Pneumostrongylus calcaratus is described. Greater numbers of larvae were present in experimentally than in naturally infested slugs. An attempt to transmit infestation to impala was unsuccessful.


Preliminary report on the intermandibular cutaneous glandular area and the infraorbital gland of the steenbok. An intermandibular glandular area, never before described in any other ungulate has been found in the steenbok (Raphicerus campestris). It consists of enlarged sebaceous and apocrine sweat glands situated in the upper two-thirds of the dermis. They produce a dirty white almost flaky odoriferous substance which clings to the hairs of the area and is easily rubbed off for marking territorial areas as well as for marking females during mating. The infraorbital gland produces a black secretion which is the combined secretion of melanaceous, branched alveolar, sebaceous and enlarged apocrine sweat glands. The function of this secretion is not known as it is not used for any obvious marking purposes.


Cryptococcosis in a dog.

Cryptococcosis in a dog. A report is presented of a fatal systemic Cryptococcus noeformans infection involving the central nervous system of a dog and complicated by a concurrent infection of the brain and splene by an unidentified filamentous fungus resembling a Paecilomyces spp. The literature on cryptococcosis in domestic animals is briefly reviewed.


Congenital diaphragmatic hiatus in a dog. The symptoms and post mortem findings of a case of diaphragmatic hiatus in a dog are described. At necropsy the caudate and right lateral lobes of the liver, the pyloric portion of the stomach, most of the small intestine and large intestines, the spleen, pancreas and omentum were found in the thoracic cavity.


Cordophilosis and fatal gastro-intestinal verminosis in eland. Fatal cases of cordophilosis and gastro-intestinal verminosis in eland are reported. Some of these cases were complicated with heartwater or cytauxzoonosis. Cordophilosis resulted in acute cardiac arrest. Infestations with gastro-intestinal namatodes were responsible for extreme emaciation. Clinically affected eland responded dramatically to systemic treatment with levamisole hydrocholride.


Myasthenia gravis in a Fox Terrier litter. A report of a myasthenia gravis-like syndrome, which occurred in two Fox Terrier litter mates, is presented. The clinical signs which appeared within 5 weeks of birth, and the subsequent course of the disease are described. Treatment with neostigmine and atropine initially provided control. Some recognised features of the condition in dogs are briefly reviewed.


Monoquaternary neuromuscular blocking agents based on 1-tetralone and 1-indanone. The preparation of three isomeric 1-tetralone hydrozones 4 and three isomeric 1-indanone hydrozones 5 possessing a single quaternary ammonium center is described. Several of the compounds possessed significant neuromuscular blocking activity, and two approached suxamethonium in potency. 1H NMR evidence obtained from a study of the N,N-dimethylhydrozones indicated that the hydrazones adopted an E configuration in solution.


Substituted alpah-methylbenzyl and tricyclic arylalkyl lactamimides as inhibitors of blood platelet aggregation. N-[1-(p-Phenoxyphenyl)ethyl]hexahydro-2H-azepin-2-imine hydrochloride (10) and N-[1-(2-dibenzothienyl)-ethyl]hexahydro-2H-azepin-2-imine hydrochloride (22) were found to inhibit in vitro aggregation of human blood platelets induced by ADP with minimal release of procoagulant platelet factor 3. The compounds were selected from a series of substituted alpha-methylbenzyl and tricyclic arylalkyl lactamimides that were free of hypoglycemic and diuretic effects. Compounds 10 and 22, as well as N-[1-(1-naphthyl)ethyl]hexahydro-2H-azepin-2-imine hydrochloride (I) and N-(2,2-diphenylpentyl)hexahydro-2H-azepin-2-imine hydrochloride (II), were evaluated for effects on ADP-induced platelet aggregation after repeated oral administration to guinea pigs. Compound II (RMI 12,366A) showed in vivo activity in this system 2 h after the last of four daily doses of 100 mg/kg po.


Central nervous system active 5-oxo-1,4,5,6,7,8-hexahydrocinnolines. Among a series of 5-oxo-1,4,5,6,7,8-hexahydrocinnolines examined for their CNS activity, 1-(2-diethylaminoethyl)-3-(p-fluorophenyl)-5-oxo-7,7-dimethyl-1,4,5,6,7,8-hexahydrocinnoline (23) and 1-(2-dimethylaminoethyl)-3-phenyl-5-oxo-7,7-dimethyl-1,4,5,6,7,8-hexahydrocinnoline (27) had sedative and anticonvulsant properties and were also acitve in tests used to characterize antidepressants. But their narrow safety margin precluded further follow-up studies. Derivatives 35-38 of 2-(omega-phenacyl)-3-hydrazino-5,5-dimethyl-2-cyclohexenone were active in tests used to characterize antidepressants and were weakly sedative but not anticonvulsant.


Circular dichroism and carbon-13 nuclear magnetic resonance spectra of (S)-5-alkyl-5-(2'-pentyl)-2-thiobarbituric acids. The circular dichroism (CD) and carbon-13 nuclear magnetic resonance (13C NMR) spectra of (S)-5-(2'-pentyl)-2-thiobarbituric acid and several (S)-5-alkyl-5-(2'-pentyl)-2-thiobarbituric acids were obtained. The results were compared to CD and 13C NMR spectral data obtained from (S)-5-(2'-pentyl)bartituric acid and (S)-5-alkyl-5-(2'-pentyl)barbituric acids.


Syntheses of heterocylic fused thiazole acetic acids. 2. A number of tricyclic and bicyclic fused thiazole-2-acetic acid derivatives were prepared and the chemistry and biological properties of these compounds are discussed. Many of the esters exhibited antitubercular activity. The bicyclic thiazole-2-acetic acids had antidepressant activity. Interesting antimetastatic activity against Lewis lung tumor in mice was found with several compounds, in particular, the thiazolo[3,2-a]benzimidazole-2-acetic acid derivative XI.


(Vinylaryloxy)acetic acids. A new class of diuretic agents. 1. (Diacylvinylaryloxy)acetic acids. A series of (diacylvinylaryloxy)acetic acids was synthesized and tested in dogs for saluretic and diuretic activity. Several compounds exhibit a high order of activity, the most active being [2,3-dichloro-4-(2,2-diacetylvinyl)-phenoxy]acetic acid (3). This compound is about three times as potent as [2,3-dichloro-4-(2-methylenebutyryl)-phenoxy]acetic acid (ethacrynic acid) but is qualitatively similar in causing a prompt increase in the excretion of water and in the excretion of sodium and chloride ions in approximately equimolar amounts. Saturation of the double bond of 3 virtually abolishes activity lending support to the hypothesis that the saluresis induced by these compounds, like that of ethacrynic acid, is related at least in part to a chemical reaction with protein-bound sulfhydryl groups. Four mercaptan adducts of 3 were prepared; these probably function as prodrugs in producing saluresis. The adduct with mercaptoacetic acid is as active as 3 itself.


Biologically active polycycloalkanes. 2. Antiviral 4-homoisotwistane derivatives. New derivatives of 4-homoisotwistane (tricyclo[5.3.1.0(3,8)]undecane) (3), the olefin (8), bromide (4), alcohols (7,9,11, and 14), ketone (10), acid (12), esters (13, 18a, and 18b), amides (5, 16, and 19a-d), nitrile (20), and amines and their hydrochlorides (6, 17, and 21), were prepared, and antiviral activities of these compounds were determined in vitro on a monolayer culture of chick embryo fibroblasts against Newcastle disease virus. 4-Homoisotwist-3-ylamine hydrochloride (6) and 4-homoisotwist-3-ylmethylamine hydrochloride (21) were found 30-50 times more potent than amantadine hydrochloride in this assay. Methods of preparing the test compounds included those functionalization reactions of 3 which revealed many interesting features of the reactivity of the recently discovered polycyclic hydrocarbon 3.


Local anesthetics. 2-Diethylamino-2',6'-acylxylidides. A series of C-alkylated derivatives of lidocaine has been synthesized, and the local anesthetic potencies were determined. Activity reached a miximum with the butyroxylidide (alpha-ethyl group), but toxicity increased regularly with the number of carboons in the side chain. Spectral data showed the compounds to exist as associated H-bonded structures, the free base most likely as intramolecularly bonded trans amides and the hydrochlorides most likely as associated cis amindes.


(Vinylaryloxy)acetic acids. A new class of diuretic agents. 2. (4-(3-Oxo-1-alkenyl)phenoxy)acetic acids. A series of (E)-[4-(3-oxo-1-alkenyl)phenoxy]acetic acids was synthesized and tested in dogs for saluretic and diuretic properties. Several compounds exhibited noteworthy activity, e.g., (E)-[2,3-dichloro-4-(3-oxo-1-butenyl)phenoxy]acetic acid (3a). While possessing only half of the dose potency of ethacrynic acid (2), the active compounds act similarly to this diuretic in causing a prompt increase in the excretion of water and in the excretion of sodium and chloride ions in approximately equimolar amounts. Potassium ion excretion is increased but less markedly than sodium excretion.


The Rockford School of Medicine undergraduate quality assurance program. An undergraduate program of ambulatory care quality assurance has been operational at the Rockford School of Medicine for three years. The original intent of the program was to increase the acceptance of quality assurance activities among student physicians, inculcating in them the importance of peer review at an early stage in professional development. The program experience is described, results of preliminary evaluation reported, and generalizations offered. Activities in the first year of a hospital care quality assurance program are described.


Teaching peer review at Michigan State University. Two groups of students at Michigan State University participated in an exercise intended to teach them the process of peer review. Neither group of students completed the exercise beyond the initial steps. The authors discuss the concerns of the students and make suggestions for implementing a program of peer review in undergraduate medical school curricula.


Comparison of a private family practice and a university teaching practice. In March 1972 a private family practice in Hamilton, Canada, became a teaching practice of McMaster University. Subsequently a before-and-after study was conducted to compare characteristics of the patients and the impact of the change on the practice. There was a 34 percent reduction in practice size. There was a shift to younger patients and a substantial drop in mean patient income. Utilization rates of health services rose, particularly hospitalization, even though the average length of stay decreased. Profiles of complaints and diagnoses remained very similar. Quality of care scores were comparable with those of community controls before and after the change. Gross income from clinical earnings dropped, but the amounts per person per year were  very similar in the two periods. It is concluded that the "transplanted private practice" which becomes part of a school of medicine is a realistic teaching resource in primary care.


A model for the improvement of medical faculty lecturing. The development of a program designed to improve the teaching effectiveness of faculty members of a new Introductory Psychopathology course at the University of Washington School of Medicine is described. Two consultants from the Office of Research in Medical Education worked closely with the faculty in designing the evaluation program during the preparation of the course. The literature on lecture effectiveness is reviewed, as are existing instructional evaluation instruments. The integration of this information and the needs of the involved faculty produced a lecture observation schedule designed to facilitate the observation of a lecture and the immediate feedback which followed each of the 15 lectures evaluated. The process of using this instrument to assist the faculty in self-improvement is discussed. While the specific evaluation method described may not be appropriate for all situations, it may serve as a  model for the development of similar programs in other settings.


Effects of selected herbicides and plant hormones on Prototheca wickerhamii. Prototheca wickerhamii was treated in vitro with 11 different herbicides and plant hormones. Growth was inhibited by indolyl-3-acetic acid, indolyl-3-butyric acid and indolyl-3-propionic acid at 400 mug per ml. Coconut milk was stimulatory.


Growth, survival, antigenic stability, and virulence of Leptospira interrogans serotype canicola. Leptospira interrogans serotype canicola (strain NADL A-13) grew from inocula as small as two cells in liquid polysorbate 80 medium (P-80 medium, in P-60, P-40 and P-20 media, and in P-80 medium from which polysorbate, NH4C1 or thiamine had been omitted. It grew well initially in vitamin B12-deleted P-80 medium, but only with inocula as large as 26 x 10(4) cells per ml. P-80 medium lacking both polysorbate and NH4Cl supported light growth from small inocula, but the omission of thiamine and vitamin B12 in addition seriously affected the properties of the medium. Where readily detectable growth did not develop in liquid nutrient-deleted medium, viable ortanisms could often be demonstrated indirectly by subculture to semisolid medium, and their occurrence was influenced by the presence of albumin, thiamine, and vitamin B12. Growth on semisolid media was comparable with that in liquid media of similar composition. The absence of polysorbate 80, thiamine, or vitamin B12 prevented the appearance of Dinger's zones of growth from small inocula. Antigenic composition as measured by microscopic agglutination tests with homologous and heterologous antisera was not appreciably affected by repeated subculturing in various complete and incomplete media. Homogenates of infected-hamster-kidney tissue in bovine serum-albumin diluent still contained viable organisms after 60 days' storage at 23-25 degrees C. Organisms derived from this material after 3 and 16 days' storage showed no loss of virulence. Organisms grown in artificial culture showed no loss of virulence after storage in bovine albumin diluent or phosphate buffer for 7 days at 23-25 degrees C. Cultures of the organism survived without loss of virulence for 15 months in 13 semisolid media of differing complexity. Single colonies derived from five different solid media were grown in semisolid forms of the parent media and stored at 23-25 degrees C for 10 months without loss of virulence.


The comparison and characterisation of glycolytic mycoplasmas isolated from the respiratory tract of sheep. Nine strains of glycolytic mycoplasmas isolated from the respiratory tract of apparently healthy sheep, pneumonic sheep and sheep with pulmonary adenomatosis (SPA) were compared with a Queensland strain (Y98) of Mycoplasma ovipneumoniae. All strains were very similar in their reactions in 14 biochemical tests and in their sensitivities to optochin, digitonin, sodium polyanethol sulphonate, and 11 antibiotics. Polyacrylamide-gel electrophoresis and serological cross-reactions by the agar-gel double diffusion, metabolic inhibition (MI) and growht-inhibition (GI) tests also showed that all strains could be classified as M. ovipneumoniae. The MI and GI tests, however, showed considerable intraspecific differences among strains, with apparent polarisation of SPA strains and non-SPA strains at opposite ends of the antigenic spectrum. Two representative strains were tested by the MI test against antisera to 39 mycoplasma species or serogroups, with negative results.


Quantitative studies on the dispersal of skin bacteria into the air. Dispersal of skin micro-organisms into the air during undressing was studied in 72 members of surgical and nursing staff. Few pathogens were found to be dispersed. Males dispersed more normal skin organisms than did females. Males were also more heavily colonised than females, and sex differences in dispersal diminished when allowance was made for the denser colonisation of males. Dispersal was correlated most strongly with the counts on the thighs and abdomen in males but on the shins in females.


Clostridia isolated from faeces.

Clostridia isolated from faeces. Clostridia were isolated from human faecal samples from England, Scotland, Wales, USA, Hong Kong, Uganda and Japan. Strains were identified on the basis of various biochemical reactions and on the type of fatty acid produced from glucose. Analysis of these acids was by gas-liquid chromatography. Clostridium paraputrificum was common in stool samples from England, Scotland, Wales, and USA, but rare in samples from Hong Kong, Uganda and Japan.


Isolation of the major intrinsic transmembrane protein of the human erythrocyte membrane. The major intrinsic protein of the human erythrocyte membrane commonly referred to as "Band 3", was isolated by a multi-step procedure. Extraction of ghost membranes in dilute solutions of lithium diiodosalicylate removed most of the proteins considered to be extrinsic to the membrane. The resulting membrane fragments were solubilized in sodium dodecyl sulfate, and the major sialoglycoprotein (glycophorin A) was removed by wheat germ agglutinin-Sepharose affinity chromatography. Gel filtration in sodium dodecyl sulfate was used as the final step to yield the band 3 polypeptide in electrophoretically homogeneous form.


Cell size and mutual cell adhesion. I. Increase in mutual adhesivenes of HeLa cells from density-inhibited suspension cultures by hypotonic treatment. HeLa cells harvested from density-inhibited or fast growing suspension cultures, were incubated in NaCl solutions of different tonicity. Cell size enlargement produced by hypotonicity is accompanied by an increased sedimentation rate of the density-inhibited cells, whereas no appreciable change is observed in the sedimentation rate of fast growing cells. Hypotonicity also has no effect on the sedimentation rate of density-inhibited cells which previously had been treated with neuraminidase or trypsin. It is shown that the effect of hypotonicity on density-inhibited cells cannot be ascribed to release of cell surface sialic acids during hypotonic incubation. Several arguments are presented which indicate that the changes in sedimentation rate, as measured in the rotating suspension system, are not the direct consequence of the alterations in cell size, but rather must be attributed to differences in intercellular adhesiveness resulting from the size alterations. Analogous changes in intercellular adhesiveness and cell size are shown to occur during growth in isotonic suspension culture. The results can be explained by assuming that changes in cell size affect the intercellular adhesiveness by modifying the extent to which cell surface sialic acids counteract adhesion.


Cell size and mutual cell adhesion. II. Evidence for a relation between cell size, long-range electrostatic repulsion and intercellular adhesiveness during density-regulated growth in suspension. The strength of the long-range electrostatic repulsion forces on HeLa cells is measured by agglutinative titration using low molecular weight polylysine (M.W. 11,000). Repulsion forces, found to be present on the smaller HeLa cells from density-inhibited suspension cultures, are weakened by incubation of the cells in hypotonic NaCl solutions. Repulsion forces, found to be absent on the larger cells from fast growing cultures, can be induced on these cells by incubation in hypertonic NaCl solutions. Both effects of anisotonicity are reversible, and disappear on restoration of the medium to normal tonicity. Induction of repulsion forces on fast growing cells is prevented by previous treatment of the cells with neuraminidase. Neuraminidase also abolishes repulsion on density-inhibited cells. It is proposed that alterations of the cell size, produced by anisotonicity or occurring during growth in isotonic suspension medium, affect mutual cell adhesiveness by modifying the strength of the repulsion forces generated by cell surface sialic acids.


Reflection coefficients of permeant nonelectrolytes for dog and beef red cell membranes. The reflection coefficient, sigma, for several small permeant nonelectrolytes was determined for dog and beef red blood cell membranes. Our sigma values were considerably higher than those previously reported for dog cells; e.g., out sigma urea was 87% higher than the sigma urea of Rich, Sha'afi, Barton and Solomon (J. Gen. Physiol. 50: 2391, 1967). Our sigma values for urea were only slightly greater in beef cells than previously reported by Farmer and Macey (Biochim. Biophys. Acta 290: 290, 1972). We found that a trend exists when (1 - sigma) is plotted against the log of the permeability coefficient, omega. This observation is also consistent with our previously reported sigma data for human red cell membranes (Owen & Eyring, J. Gen. Physiol. 66: 241, 1972). This trend suggests that small hydrophilic molecules interact highly with cell membrane water. The exceptions to this trend were lipophilic molecules, indicating they do not interact with water while penetrating the red cell membrane.