Effect of carbonated beverages and of an antiemetic containing carbohydrate and phosphoric acid on riboflavin bioavailability and salicylamide biotransformation in humans.

Two carbohydrate-phosphoric acid solutions, one a widely used beverage (Solution C) and the other a pharmaceutical product used as an antiemetic (Solution E), administered together with riboflavin-5'-phosphate or salicylamide to healthy human adults, significantly increased the bioavailability of riboflavin and appreciably altered the metabolic fate of salicylamide (increased conversion to the sulfate and decreased formation of the glucuronide). A beverage containing phosphoric acid but no carbohydrates (Solution T) also increased the bioavailability of riboflavin but not as much as Solution C. These effects are attributed to a decrease of the gastric emptying rate caused by carbohydrates and phosphoric acid, consistent with the empirical use of Solution C syrup and Solution E as antinauseants and antiemetics. The results demonstrate also that the choice of beverage to be taken with medication can affect the bioavailability and/or metabolic fate of medicinals with saturable absorption and/or biotransformation characteristics.


Synthesis of dl-4 xi-(4-carboxybutyl)-5-carbethoxy-cis-hexahydropyrrolo (3,4-d)imidazol-2-one (N-carbethoxyazabiotin).

The total synthesis of dl-4 xi-(4-carboxybutyl)-5-carbethoxy-cis-hexahydropyrrolo[3,4-d]imidazol-2-one (N-carbethoxyazabiotin) by a 16-step sequence, starting from 2-bromo-6-methoxyhexanoic acid, has been accomplished.


Evaluation of a convective diffusion drug dissolution rate model.

A recently introduced drug dissolution rate model based on convective diffusion was evaluated by experimentally determining dissolution rates. Alkyl p-aminobenzoates were used as the test compounds in a dissolution cell which promoted laminar flow of the liquid past the dissolving surface. The parameters evaluated were diffusivity, solubility, rate of shear, dissolving surface shape, and orientation of the surface relative to flow. The agreement between theory and experiment was quite satisfactory with respect to the functional dependence of the rate on these parameters as well as the actual magnitude of the rates.


Comparative bioavailabilities from truncated blood level curves.

The period of time after administration over which blood level measurements are required to obtain a reliable bioavailability comparison of two or more formulations of the same drug was considered by the analysis of bioavailability data taken from the literature. The drugs examined, selected to represent a range of absorption and elimination half-lives, were acetaminophen, aminosalicylic acid, chloramphenicol, chlordiazepoxide, digoxin, isoniazid, phenylbutazone, sulfamethizole, tetracycline, and warfarin. For most drugs, ratios of areas under the curve changed little between the end of the absorption period and the time when blood sampling was terminated. Reliable bioavailability comparisons among different brands of the drugs apparently could have been made by blood sampling over 24 hr or less.


Configuration of dienestrol.

Uncertainty concerning the configuration of dienestrol was resolved by a detailed spectrochemical investigation, including single-crystal X-ray diffraction, of the active drug and its stereoisomers. A symmetric structure in which the phenyl and methyl groups are cis about each double bond is unambiguously assigned.


Stabilizing effect of inorganic phosphate salts on antibiotic-steroid ophthalmic preparations.

Drocinonide phosphate potassium forms an insoluble complex with neomycin sulfate in aqueous solution. Dibasic sodium phosphate can be employed in an ophthalmic formulation to prevent the formation of this precipitate without affecting the stability of the steroid or the bioactivity of the antibiotic. Other phosphate steroid salts behaved in a like manner.


GLC determination of 7-chloro-5,11-dihydrodibenz[b,e][1,4]-oxazepine-5-carboxamide in serum or plasma.

This report describes the isolation, derivative formation, GLC, and quantitation of unmetabolized 7-chloro-5,11-dihydrodibenz[b,e][1,4]oxazepine-5-carboxamide (I) in blood serum or plasma. Carbamazepine is used as the internal standard to compensate for losses of I during extraction and handling. Essentially complete recovery (100 +/- 6%) was demonstrated over a concentration range of 1-30 mug of I/ml of serum.


Molecular arrangement in monolayers containing cholesterol and dipalmitoyl lecithin.

The molecular arrangement of dipalmitoyl lecithin and cholesterol in mixed monolayers was investigated with the aid of a physical model. The two lipids are miscible at the surface, but there is no indication of a specific interaction. In equimolar mixed monolayers at 25 and 37 degrees, the lipids are in tail contact. Lecithin molecules are able to remain hydrated in the mixed monolayers at high values of surface pressure.


High-performance liquid chromatographic analysis of ampicillin.

A high-pressure liquid chromatographic method for the analysis of ampicillin is described. The method uses a 1-m long stainless steel column packed with anionic exchange resin, with a mobile phase of 0.02 M NaNO3 in 0.01 M pH 9.15 borate buffer at a flow rate of 0.45 ml/min. The degradation products of ampicillin, penicillenic and penicilloic acids of ampicillin, can be separated and quantitated in less than 12 min of chromatographic time. The relative standard deviation for the analysis of ampicillin is less than 1%, and the method is sensitive to approximately 20 ng of ampicillin/sample injected. The method was applied to the analysis of various pharmaceutical preparations of ampicillin. It is also applicable, with a slight modification, for the analysis of penicillins G and V.


Determination of major impurity in chlordiazepoxide formulations and drug substance.

Procedures for quantitating the lactam impurity, 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide, which can be present in chlordiazepoxide formulations, is presented. The method consists of trapping chlordiazepoxide in sulfuric acid in kieselguhr, eluting the impurity with ether, and quantitating by UV spectrophotometry in absolute alcohol at 312 nm.


Spectrophotometric determination of acetaminophen and dichloralantipyrine in capsules.

A rapid method for the routine determination of acetaminophen and dichloralantipyrine in capsules is reported. The determination of acetaminophen is based on the ability of its hydrolytic product, p-aminophenol, to produce an intensive yellow color with vanillin. The determination of dichloralantipyrine is based on the fact that it, as well as its major metabolite chloral hydrate, produces a blue color with quinaldine ethiodide. No interferences were encountered, and good recovery and precision data were obtained.


Effect of surface roughness and coating solvent on film adhesion to tablets.

The adhesion of a polymer film to selected tablet substrates was studied. The effect of tablet surface roughness and film-coating solvent on the adhesion of the film to the tablet was determined. A film-coating solvent having a solubility parameter close to that of the polymer was found to produce a stronger adhesional bond than a solvent having a lower surface tension. An increase in tablet surface roughness also increased film adhesion to the tablet. The adhesion was measured as the force required to peel a section of film from the tablet with a stress-strain analyzer.


Laboratory automation of high-pressure liquid chromatography.

An automated system for high-pressure liquid chromatography was developed. The system is built around commercial modules wherever possible, modified to varying degrees. An automatic sampler, a sample pump, a high-pressure sampling valve, a recorder with an integrator, and a high-pressure liquid chromatograph comprise the commercial instruments. Relays, solenoid valves, and timers control chromatographic events, i.e., duration of sampling and rinse, mobile phase pump refill, sample injection, and chromatographic time. The automated system is dependable over long periods of unattended operation. With the 40-sample capacity of the sample tray and the last sample stop capability, the automated system produces, for example, 40 20-min chromatograms in approximately 13 hr of unattended operation. Data demonstrate the reliability and utility of the system.


Relationship of in vitro hydrolysis of 17-chloroacetylajmaline and 17-acetylajmaline in different animal species.

17-Chloroacetylajmaline and 17-acetylajmaline are reported to have in vivo antiarrhythmic activity and are metabolized by hydrolysis. Since the hydrolysis product, ajmaline, may be the actual antiarrhythmic agent, the hydrolysis of these derivatives by various tissues of the guinea pig, rat, and mouse was determined in vitro by a titrimetric method and compared to hydrolysis by alpha-naphthylacetate. The heart is the most active tissue in the guinea pig for hydrolyzing 17-chloroacetylajmaline. The hydrolyzing activity is greater in the guinea pig than in rat or mouse heart, corresponding with the more significant pharmacological activity in the guinea pig. 17-Chloroacetylajmaline has a significantly lower Km value than 17-acetylajmaline, which is in agreement with the in vivo activity.


Influence of monovalent and divalent electrolytes on sorption of neomycin sulfate to attapulgite and montmorillonite clays.

Langmuir isotherms for the adsorption of neomycin sulfate to clays such as attapulgite, bentonite, and magnesium aluminum silicate were constructed. Monovalent and divalent cations were investigated for their influence on the formation of neomycin-clay adsorbates and the resulting equilibrium concentration in a neomycin solution. Divalent magnesium ions were more effective in displacing the antibiotic from each clay than were monovalent sodium ions. Ions present in the GI fluid might increase the bioavailability of neomycin from such neomycin-clay adsorbates.


Deviation of dielectric constant from ideality for certain binary solvent systems.

An equation was derived which relates the dielectric constant of mixtures of a binary solvent system to the mole fraction of the polar and nonpolar components of the system. The coefficients of the formula are readily calculated from the dielectric constant and the molar volume of the pure components of the binary solvent system. These calculated values are employed in graphical representations of the theoretical relationship of the dielectric constant of the binary solvent system and the mole fraction of the polar component of the solvent system. Experimental measurements are employed to demonstrate deviations from ideality.


Alkaloids of Papaver orientale and papaver pseudo-orientale.

Dry latex of Paaver orientale was shown to contain 20% oripavine and 9% thebaine. Dry latex of Papaver pseudo-orientale contained two major alkaloids, isothebaine (11.7%) and orientalidine (0.5%), and the minor alkaloids bracteolin, salutaridine, Or1, Or2, PO-4, alborine (PO-5), and a novel alkaloid aryapavine.


Antitumor agents. XV: Deoxyelephantopin, an antitumor principle from Elephantopus carolinianus Willd.

The active principle responsible for the significant inhibitory activity against the Walker 256 carcinosarcoma (ascites) in rats, isolated from the chloroform extract of the whole plant of Elephantopus carolinianus Willd., was characterized as deoxyelephantopin, a sesquiterpene lactone.


Reduction of doxorubicin (adriamycin) bone marrow toxicity.

Doxorubicin (adriamycin), an antineoplastic antibiotic, is a potent suppressant of bone marrow. Previous studies on doxorubicin disposition indicated that its diversion from bone marrow in the first few minutes after administration should result in a marked decrease in total exposure to the drug (concentration X time) with a concomitant reduction in concentration-time-dependent toxicity. To test this hypothesis, the descending aorta of rabbits was occluded just proximal to the iliac bifurcation for 30 min to deprive bone marrow of blood flow. Both these rabbits and the control rabbits were given 5 mg/kg of doxorubicin intravenously, and the total white cell could in peripheral blood was monitored periodically for 15 days. The decrease in toxicity produced by the occlusion was quite evident by comparison of white cell counts and deaths in all groups. A possible mechanism of this effect was shown to be a decreased doxorubicin exposure of bone marrow tissue in the occluded animals as judged by relative doxorubicin concentration-time curves in rabbits with and without the aortic occlusion.


Renal blockade to angiotensin II in acute and chronic sodium-retaining states.

Acute thoracic inferior vena cava constriction results in alterations in renal hemodynamics which may explain the characteristic antinatriuretic response. Since adrenalvein-aldosterone secretion is increased within 30 minutes of acute caval constriction and elevated plasma-renin activity is found in the chronic caval dog, we sought to determine whether the renal hemodynamic alterations observed in acute caval constriction are due to the intrarenal action of angiotensin II. The renal response to acute caval constriction in dogs receiving unilateral renal arterial infusion of a specific competitive antagonist of angiotensin II, 1-sarcosine-8-alanine-agiotensin II, was studied. Effective blockade did not alter the renal hemodynamic or antinatriuretic response to acute caval constriction. As a model of chronic sodium retention, dogs with chronic congestive heart failure produced by tricuspid insufficiency and pulmonary stenosis were similarly studied. Effective renal blockade to antiotensin II did not affect renal hemodynamics or urinary sodium excretion. The renal hemodynamic and antinatriuretic responses to acute caval constriction and chronic congestive heart failure are not dependent on the intrarenal action of angiotensin II.


Effects of aprindine HCL on cardiac tissues.

The effects of aprindine HCL on cardiac tissues were studied in anesthetized, open-chest dogs pretreated with atropine (0.8 mg/kg) and propranolol (1.0 mg/kg). Aprindine (10(-5)-10(-3) g/ml), injected into the sinus node artery, decreased the spontaneous sinus rate; when injected into the atrioventricular nodal artery, aprindine (10(-4) g/ml) prolonged the conduction time and functional refractory period of the atrioventricular node. Intravenous administration of aprindine (1.4, 2.8 and 4.2 mg/kg cumulative dose) prolonged atrial and ventricular conduction time and prolonged the effective refractory period of both tissues. The results from this study indicate that aprindine has a negative dromotropic effect on all cardiac tissue.


The effect of lidocaine on components of excitability in long mammalian cardiac Purkinje fibers.

In contrast to the usual microelectrode techniques employing extracellular tissue stimulation, the double microelectrode technique of intracellular constant current application and intracellular transmembrane voltage recording permits quantitative definition of the components of cardiac excitability. This technique was employed to assess the effect of lidocaine, in a concentration equivalent to clinically effective antiarrhythmic plasma levels (5 mug/ml), on membrane characteristics, cable properties, strength-duration curves and change-duration curves in long sheep Purkinje fibers in normal Tyrode's solution at [K]0 = 4.0 mM. As determined by small hyperpolarizing pulses, lidocaine increased membrane conductance (GM) where GM approximates membrane potassium conductance (GM congruent to GK congruent to gK1) and decreased both the membrane length (lambdam) and time (taum) constants. Lidocaine shifted non-normalized strength-duration curves (threshold current, Ith, vs. current duration, t) and charge-duration curves (charge threshold th, vs. t) upward without altering either the resting transmembrane voltage (Vr) or threshold voltage (Vth). Normalized strength-duration curves and charge-duration curves, however, were superimposable during the control and lidocaine periods. This is best explained by lidocaine altering passive resistance-capacitance properties by increasing membrane potassium conductance without influencing active generator properties dependent on sodium conductance. Lidocaine did not alter the passive or active membrane properties relevant to conduction velocity. By increasing membrane potassium conductance, lidocaine decreases excitability in long Purkinje fibers by increasing Ith without altering Vr or Vth, by increasing Qth; by decreasing lambdam and by rendering local circuit currents less effectual in eliciting an action potential.


The effect of temperature on a d-tubocurarine neuromuscular blockade and its antagonism by neostigmine.

In 19 cats anesthetized with chloralose and urethrane, d-tubocurarine (d-TC) was continuously infused to produce constant 90% depression of twitch tension prior to injection of 5, 10 or 20 mug/kg of neostigmine. The required mean infusion rates of d-TC were 3.6 +/- 0.6, 5.1 +/- 0.3, 8.5 +/- 0.3 and 8.9 +/- 0.5 mug/kg/min at body and muscle temperatures of 28, 31, 37 and 41 degrees C, respectively. The doses of neostigmine needed for 50% antagonism of the d-TC-induced depression of twitch height were 8.7, 9.2, 10.5 and 12.0 mug/kg at 28, 31, 37 and 41 degrees, respectively. The time to peak effect and duration of action of 5 and 10 mug/kg of neostigmine were longer at 28 and 31 degrees C than at 37 and 41 degrees C. Although these times also were longer at 27 and 31 degrees C with the 20 mug/kg dose of neostigmine, they were not statistically different. We conclude that hypothermia augments a d-TC neuromuscular blockade. Hypothermia prolongs time-to-peak effect and duration of neostigmine but does not affect peak magnitude of antagonism of d-TC by neostigmine.


Binding of d-tubocurarine di (methyl-14C) ether iodide and other amines to cartilage, chondroitin sulfate and human plasma proteins.

The binding of d-tubocurarine di [methyl-14C] ether iodide (d-TCE) and other amines to bovine nasal septum, chondroitin sulfate (CS) and human plasma proteins was examined by equilibrium dialysis. Bovine nasal septum and CS bound d-TCE to a greater extent than they did morphine, d-methadone (d-ME) and l-methadone (l-ME). Cartilage, relative to an equal weight of pure CS, bound slightly more d-TCE, 50% more d-ME and l-ME, and the same amount of morphine. The amount of d-TCE bound to pure CS was similar to that of decamethonium [methyl-14C] dibromide but less than that of two new iodinated bisquaternary compounds: 1,6-bis(N,N-dimethyl-3-iodobenzylamino)hexane dichloride and 1,6-bis[dimethyl-(3-amino-4,6-diiodo-benzyl)amino]hexane dichloride. The binding of d-TCE is greater for pure CS than for impure CS which contains 26% protein, and binding to either preparation was inversely related to sodium ion concentration. In the drug concentration range explored, 30 to 40% of d-TCE is bound to plasma proteins, which is twice that of decamethonium binding but equivalent to the binding of morphine and about one-half the binding of d-ME and l-ME. In this same drug concentration range, each gram of cartilage (dry weight) can bind about 10(-7) mol of d-TCE. This study suggests that the binding of d-TCE to cartilage is an ionic type bonding to the anionic sites of the ester sulfates and glucuronate moieties of CS and that the binding of d-TCE to the protein fraction of cartilage is probably equal to, or less than, its binding to the CS fraction. It is concluded that cartilage may represent a measurable distribution pool for d-tubocurarine.


A comparison of the potencies of a series of barbiturates at the neuromuscular junction and on the central nervous system.

The ability of a series of barbiturates to depress the depolarizing action of carbachol at the end-plate of guinea-pig lumbrical muscle was studied. The compounds studied were: amorbarbital, aprobarbital, barbital, barbituric acid, butabarbital, butalbital, dimethylbutylethyl barbituric acid, hexobarbital, mephobarbitak, secobarbital, thiamylal, and thiopental. The depressant activity was sensitive to small changes in structure of the compounds strongly suggesting that a specific receptor site was involved in the interaction of the drug with the tissue. The observed relative potencies on the motor end-plate were compared with their anesthetic potencies assayed on tadpoles. The two potencies went hand-in-hand for all the compounds studied, including the convulsant member of the series.


Differential sensitivity of two dopaminergic structures in rat brain to haloperidol and to clozapine.

The mechanisms underlying the dissociation of the extrapyramidal and antipsychotic properties of haloperidol as compared to clozapine were explored by studying the effects of these drugs on dopamine metabolism in the straitum and tuberculum olfactorium (TO) of the rat. Homovanillic acid and 3,4-dihydroxyphenylacetic acid were simutaneously measured in these regions by a gas chromatographic techinque after treating the rats with different doses of the drugs. Dose-response curves and time-action curves were generated. For both drugs, a higher dose was required to achieve half-maximal metabolite elevation in the TO as compared to the striatum. The apparent differential sensitivity to haloperidol was attributed to differences in time to peak response. The time to peak response to clozapine was similar in both structures. Thus, the striatum appears to be more sensitive to clozapine than the TO with respect to elevation of dopamine metabolites. The effect of haloperidol on dopamine metabolism in the striatum was more persistent than that in the TO. After 4 hours, metabolite levels were still elevated in the striatum, whereas after 2 hours they returned to base line in the TO. The extrapyramidal effects of haloperidol may be due to the persistent action of this drug on dopamine metabolism in the striatum, and the lack of extrapyramidal effects of clozapine may be due to its brief action on dopamine metabolism in the striatum.


Schedule-induced oral narcotic self-administration: acute and chronic effects.

A pattern of lever pressing was maintained in rats by presenting a food pellet following the first lever press to occur after at least 90-seconds had elapsed (fixed-interval 90-second schedule of food presentation, FI 90-second). With a drinking solution available, a pattern of excessive postpellet drinking (schedule-induced polydipsia) developed and was used to induce rats to drink solutions containing varying concentrations of narcotics. During acute exposure to morphine HCl, morphine SO4 or methadone HCl in the drinking solution, drinking decreased as a function of increasing drug concentration (from 0.3-1 mg/ml), but the total dose of narcotic ingested increased as a function of increasing drug concentration. The highest average dose of morphine HCl consumed in tap water was 30 mg/kg within an hour session. When morphine HCl was presented in an isotonic saline solution, drinking was increased and the highest average dose of morphine HCl ingested was 60 mg/kg within an hour session. The use of an isotonic saline solution did not appreceiably enhance the ingestion methadone HCl (about 30 mg/kg/hr). After chronic exposure to drug solutions for daily 4-hour sessions, the doses ingested averaged between 150 and 250 mg/kg/4 hr for 1 mg/ml solutions of morphine HCl and morphine SO4. The stable pattern of drinking exhibited by rats on the 0.5 mg/ml morphine HCl solution was characterized by a dissociation of drinking from pellet presentation. Chronic exposure to methadone HCl solutions (1 mg/ml) produced less drinking and lower doses ingested (approximately 100 mg/kg) than was obtained with either morphine HCl or morphine SO4 at an equal concentration.


Effects of heroin and methadone on plasma cortisol and testosterone.

Narcotic addicts self-administered heroin intravenously for 10 days under controlled research ward conditions and were subsequently detoxified with methadone for 7 days. Plasma testosterone levels decreased signifcantly when heroin dosage was between 45 and 65 mg/day contrasted to predrug base-line levels. Testosterone levels remained depressed during methadone withdrawal. No statistically significant changes in a.m. plasma cortisol levels were observed during both heroin acquisition and methadone withdrawal.


Studies of the enterohepatic circulation of morphine in the rat.

The disposition of 14C-morphine was studied after gastrointestinal and subcutaneous administration to female Sprague-Dawley rats. Morphine was found to be rapidly and nearly completely absorbed from the small intestine. After s.c. administration, approximately half the 5 mg/kg dose of morphine was excreted via the bile into the intestinal tract, largely as morphine glucuronide. Unlike morphine, the glucuronide conjugate in bile was poorly absorbed from the small intestine where its hydrolysis occurred slowly. After administration into the cecum, however, hydrolysis of the conjugate was rapid, and the rate of absorption of radioactive material was similar to that of free morphine. Treatment of rats with lincomycin (500 mg/1 in drinking water and 25 mg twice a day by gastric intubation for 4 days) significantly decreased cecal hydrolysis of the conjugate and the cecal absorption of radioactive material. Lincomycin treatment also increased fecal excretion of the conjugate in rats given morphine s.c. (5 mg/kg). These findings indicated that hydrolysis of morphine glucuronide is dependent upon the status of enteric bacteria and is a prerequisite to the enterohepatic circulation of morphine. In addition, after lincomycin treatment, a greater percentage of radioactivity excreted in the urine was associated with free morphine. This finding could be expained by the demonstration of pH dependence of renal excretion of morphine and a first-pass effect for this drug.


Biliary excretion of drugs: role of ligandin in newborn immaturity and in the action of microsomal enzyme inducers.

Microsomal enzyme inducers such as phenobarbital, spironolactone and pregnenolone-16alpha-carbonitrile increase the rate of disappearance of drugs such as sulfobromophthalein and ouabain, from the plasma, to a similar extent by increasing their rate of excretion into bile. However, this effect is not observed after 3-methylcholanthrene. The enhanced biliary excretion is not dependent on increased biotransformation only, since ouabain is not biotransformed before excretion. Newborn rats are immature in their ability to excrete drugs such as BSP and ouabain. Since a hepatic cytosol protein, ligandin, has been shown to bind many drugs and is suggested to be important in the hepatic removal of drugs from the plasma, the correlation between the hepatic content of ligandin and hepatic excretory function was measured. Treatment of adult rats for 4 days with phenobarbital increased the amount of ligandin by 85%, whereas spironolactone increased it by 35% and 3-methylcholanthrene by 17%. The amount of ligandin in the livers of 5-day-old rats was about 10% that of adults and increased until the rats were about 35 days of age. Althoughh ligandin bound sulfobromophthalein, it did not bind ouabain. Since little correlation between the ability of microsomal enzyme inducers to increase ligandin and to increase biliary excretion exists, and since ouabain is excreted at a faster rate after administration of microsomal enzyme inducers and at a slower rate in newborn rats, even thoug ligandin does not bind ouabain, it is suggested that the amount of ligandin in the liver is not related to the increased biliary excretion after micromomal inducers, nor to the decreased hepatic excretory function in newborn rats.


Circadian rhythms in drug action and drug metabolism in the mouse.

The relationship between circadian rhythms in the pharmacological actions of meperidine and hexobarbital and similar rhythms in the hepatic metabolism of these drugs was examined in mice under a variety of environmental alterations to determine whether such rhythms may be causally related. The rate of metabolism of p-nitroanisole and hexobarbital by hepatic 9000 X g supernatant fractions was found to be higher at 2400 hours (middark phase) compared to 1200 hours (midlight phase). The rhythms in in vitro hexobarbital and in vivo merperidine metabolism were inversely related in time with similar rhythms in duration of hexobarbital sleep time and meperidine analgesia. Exposure of mice to continuous lighting abolished the rhythms in metabolism and response to meperidine and hexobarbital. Reversal of the usual lighting cycle inverted the rhythm in hexobarbital metablism while abolishing the rhythm in pharmacological response to hexobarbital; meperidine was similarly affected. Adrenalectomy abolished the rhythm in hexobarbital metabolism, diminished the amplitude of the circadian variation in meperidine metabolism and abolished the rhythm in hexobarbital hypnosis and meperidine analgesia. These results indicate that circadian rhythms in the action of hexobarbital and meperidine are well correlated with similar rhythms in the disposition of these drugs.


Bioavailability of sodium cyanate in patients with sickle cell disease and the lack of inhibition in vitro of globin synthesis at in vivo concentrations of cyanate.

Studies have been made on the bioavailability in blood of sodium cyantate administered orally in gelatin capsules, in gelatin capsules plus antacid, in enteric-coated capsules and in cocoa butter suppositories administered rectally to patients with sickle cell disease. Maximal blood concentrations of cyanate did not exceed 0.4 mM. Sodium cyanate taken orally in gelatin capsules yielded the highest blood concentrations of the drug, but the peak concentrations and curve areas were not necessarily dose-related. The duration of the drug in the circulation was about 210 minutes. Administration of sodium cyanate in the gelatin capsules, taken with an antacid, improved the dose-response relationship within a given patient. Enteric-coated capsules and suppositories were found to show variable and low bioavailability profiles, respectively. Variability in bioavailability between patients with a given dosage form requires further study. Since the concentration of cyanate attainable in vivo does not inhibit synthesis of either the alpha- or beta-chain of hemoglobin in vitro, previous reports on the inhibitory effects of 10 to 100 mM cyanate on globin synthesis in vitro do not appear to be relevant.


Comparison of the effects of carbamyl phosphate and sodium cyanate on protein synthesis and glutathione concentration in human sickle cell and rabbit reticulocytes.

Two carbamylating agents, carbamyl phosphate and sodium cyanate, are currently being evaluated as therapeutic drugs for the treatment of sickle cell anemia. Since the clinical usefulness of these drugs might be limited by toxicity, a comparative in vitro study of the relative inhibition of human sickle cell and rabbit reticulocyte protein synthesis was performed. Sodium cyanate was found to inhibit human sickle cell protein synthesis at concentrations one-eighth that of carbamyl phosphate. Carbamyl phosphate lowered reduced glutathione levels to a similar degree as sodium cyanate and was slightly more effective as an in vitro antisickling agent, which is evidence that carbamyl phosphate enters these cells. When rabbit reticulocyte protein synthesis was investigated, carbamyl phosphate was found to be noninhibitory at concentrations as high as 128 mol/mol of hemoglobin in the incubation medium, while cyanate was inhibitory at much lower concentrations. The effect of carbamyl phosphate on glutathione concentrations, however, was virtually identical to that of cyanate. These results show that the effect on protein synthesis does not result from the lowered glutathione levels. It is concluded that both the therapeutic and toxic effects of sodium cre, there might be differences in toxicity between animals and humans.


Actions of ricinoleic acid and structurally related fatty acids of the gastrointestinal tract. I. Effects on smooth muscle contractility in vitro.

Ricinoleic acid and several structurally related compounds were tested for their effects on the smooth muscle contractions of the coaxially stimulated guinea-pig ileum, the spontaneously contracting rabbit jejunum, 90 mM potassium depolarized guinea-pig taenia coli and rat colon. In concentrations of 1.25 X 10(-5) to 4 X 10(-4) M, ricinoleate produced a dose-dependent depression of the stimulated guinea-pig ileum. This action was not produced by matching concentrations of oleate, elaidate, linoleate, 12-hydroxystearic acid, 10(9)-hydroxystearate, the methyl ester of ricinoleic acid or the trans isomer, recinelaidate. The alcohol derivative, ricinoleyl alcohol, was active and, although the depression produced by it took longer to maximize, the dose-response curves for ricinoleate and ricinoleyl alcohol on this tissue were almost superimposable. Ricinoleate showed the same qualitative and quantitative effects on the spontaneously contracting rabbit jejunum, but several differences were noted on the depolarized preparations. Ricinoleate-induced depression of depolarized smooth muscle was much slower in onset and required about 10 times higher concentrations to achieve equivalent responses. The results show that ricinoleic acid, the active ingredient in castor oil, is not a stimulant or irritant to isolated intestinal smooth muscle.


Actions of ricinoleic acid and structurally related fatty acids on the gastrointestinal tract. II. Effects on water and electrolyte absorption in vitro.

Ricinoleic acid, the active component of castor oil, and related fatty acids were studied to determine their relative inhibitory effects on water and electrolyte absorption using everted hamster jejunal and ileal segments. Differences were found between hydroxylated and nonhydroxylated congeners as well as between cis and trans geometric isomers. At a mucosal concentration of 2.0 mM, the unsaturated fatty acids had the following rank order of potency on inhibition of water absorption: ricionoleate greater  than or equal to ricinelaidate- greater than equal to linoleate greater than oleate greater than linelaidate greater than elaidate. Ricinoleyl alcohol was  effective at 2.0 mM but the methyl ester of ricinoleic acid was ineffective at this concentration. Among a series of saturated fatty acids including palmitate, stearate, a mixture of 9- and 10-hydroxystearate, and 12-hydroxystearate, only the last compound had any inhibitory effect on water absorption. The results define those portions of the ricinoleic acid molecule required for its effect on water and electrolyte absorption and suggest that classification of this cathartic as an "irritant" or "stimulant" should be re-evlauated.


The effects of electrical stimulation of the autonomic nerves and of drugs on the size of salivary glands and their rate of cell division.

The effects of electrical stimulation of the sympathetic and of the parasympathetic nerves on the size of rat salivary glands have been investigated and compared with those caused by isoproterenol. Sympathetic nerve stimulation increased the size and the mitotic index in the parotid acini; in the submaxillary acini, only the size was increased. These responses varied with the gland studied and the duration of stimulation; the parotid showed the larger increase in the mitotic index and thymidine uptake, the submaxillary the greater degree of cell enlargement. Prolonged electrical stimulation beyond that required to produce the maximum increase in size reduced the enlargement. Sympathetic nerve stimulation caused no enlargement in the extraorbital lacrimal or major sublingual glands. The responses to sympathetic nerve stimulation were inhibited by propranolol (17 nmol/pg), normetanephrine (2 X 45 nmol/g) and mecamylamine (50 nmol/g) but not by phentolamine (13.0 nmol/g) or atropine (7.5 nmol/g). Electric stimulation of the parasympathetic nerves produced no increase in the size or in the mitotic index.


Reconstruction of the electrical activity of cardiac Purkinje fibres.

1. The electrical activity of Cardiac Purkinje fibres was reconstructed using a mathematical model of the membrane current. The individual components of ionic curent were described by equations which wee based as closely as possible on previous experiments using the voltage clamp technique. 2. Membrane action potentials and pace-maker activity were calculated and compared with time course of underlying changes in two functionally distinct outeard currents, iX1 and iK2. 3. The repolarization of the theoretical action potential is triggered by the onset of iX1, which becomes activated over the plateau range of potentials. iK2 also activates during the plateau but does not play a controlling role in the repolarization. Hwever, iK2 does govern the slow pace-maker depolarization through its subsequent deactivation at negative potentials. 4. The individual phases of the calculated action potential and their 'experimental' modifications were compared with published records. The upstroke is generated by a Hodgkin-Huxley type sodium conductance (gNa), and rises with a maximum rate of 478 V/sec, somewhat less than experimentally observed values ( up to 800 V/sec). The discrepancy is discussed in relation to experimental attempts at measuring gNa. 5. The ole of the transient outward chloride current (called igr) was studied in calculations of the rapid phase of repolarization and 'notch' configuration...


Responses of hair cells in the statocyst of Hermissenda.

Responses to mechanical stimulation were recorded from hair cells in the statocyst of Hermissenda crassicornis. The response to a brief stimulus is a depolarizing wave which reaches peak in about 25 msec and decays slowly. 2. Hyperpolarization by extrinsic currents increases the amplitude of the response; depolarization decreases it and eventually reverses its polarity. It is inferred from these results that the primary outcome of the transduction process is an increase of membrane conductance and that the voltage change (generator potential) follows as a secondary event. 3. The features of the conductance change were reconstructed from the time course of the generator potential and the passive properties of the membrane. It was found that the increase of membrane conductance develops slowly and is roughly proportional to the energy delivered by the stimulus. 4. The time course of the conductance change required to reproduce the generator potential is similar to the output of a model involving a sequence of transformations. 5. The generator potential is sensitive to temperature, becoming faster as temperature is raised. This effect is reproduced by the model if the transition rates are assumed to be temperature-dependent, with a Q10 of about 2. 6. It is concluded that a chain of temperature-sensitive processes is interposed between the stimulus and the increase of membrane conductance.


The effect of curare on the release of acetylcholine from mammalian motor nerve terminals and an estimate of quantum content.

Curarized and non-curarized rat hemidiaphragm muscles were indirectly stimulated in vitro. 2. The fluid bathing the active curarized muscles was eluted through a dextran gel (Sephadex G-10), effecting a complete separation of ACh from curare. The acetylcholine fraction was then assayed on an isometric leech muscle preparation. 3. Prostaglandin (PGE1) in a concentration fifteen times that estimated to be released from the skeletal muscle preparation did not affect the response of leech muscle to ACh. 4. The amount of ACh released by curarized muscles (4-9 X 10(-18) mole/impulse-junction) was not significantly different from that released by non-curarized muscles (4-6 X 10(-18) mole/impulse-junction). These quantities are similar to those obtained by previous workers. It is concluded that curare in a paralytic dose does not affect the output of ACh from motor nerve terminals stimulated at low frequencies. 5. Spontaneous release of ACh from non-curarized muscles was estimated at 0-45-0-65 p-mole/min. hemidiaphragm. It is calculated that only 2% of this amount could give rise to post-synaptic electrical events, the remainder having a non-synaptic source. 6. The number of molecules of 'quantal' ACh released by stimulated muscle is calculated as 2-5 X 10(6)/impulse-junction, taking account of the non-synaptic release. The number of ACh molecules in one quantum was estimated to be 6250, an amount that could be easily accommodated in one synaptic vesicle.


Horizontal cell responses in the retina of the larval tiger salamander.

The responses to light of horizontal cells were recorded intracellularly in the retina of the larval tiger salamander. 2. All the units studied had a large summation area and were hyperpolarized by circles of light of any wave-length centred on the recording electrode, but two types could be distinguished according to the properties of their receptive fields. Type A units were hyperpolarized following illumination of any portion of their receptive field, while type B units were not hyperpolarized by illumination of their surround unless the centre was simultaneously illuminated, stimulation of the surround alone resulting in either a small depolarization or virtually no response. 3. Procion yellow injections showed that type A responses are recorded from thick and long processes not directly continuous with an identifiable cell body, while type B responses originate from the cell body of cells that send very fine and tortuous processes towards the receptors. The histological observations also suggested that the type A units represent expansions or swellings of one or more of the fine processes originating from the type B units. Therefore, it seems possible that both types of units are just different parts of a single kind of horizontal cell, and that a majority of the dye injections failed to stain them simultaneously because of the small diameter of the connecting process. 4. The large summation area of type A units can be explained, just as for horizontal cells in other retinae, by supposing that they are electrically coupled to other units of the same type. The receptive field properties of type B units, however, can only be partly explained by electrical coupling, and then only if the existence of voltage-dependent junctions is postulated. Instead, the reversal of the polarity of responses to an annulus of light during steady illumination of the centre, plus the available electron microscopic evidence, suggest that the effect of the surround on the type B units is due to a chemical synaptic impingement from the type A units.


The sinus nerve and baroreceptor input to the medulla of the cat.

Electrical stimulation within the medulla of cats revealed that myelinated primary afferent fibres of the sinus nerve terminated within the immediate vicinity of the tractus solitarius and its nucleus. 2. The activity of neurones within this area was also evoked on sinus nerve stimulation, although few (17%) were activated within a latency compatible with monosynaptic excitation. Additional projections over polysynaptic pathways have been shown to the parahypoglossal area and to the area of the nucleus ambiguus. 3. These three areas were shown to contain neurones whose activity was enhanced by stimulation of the baroreceptor endings of the ipsilateral carotid sinus. 4. No evidence for a projection of sinus nerve afferents to the medial reticular formation (an area extending medially from the hypoglossal nucleus and nerve tract and including the paramedian reticular nucleus) was obtained in either antidromic or orthodromic studies. 5. The organization of the central pathway of the carotid sinus baroreceptor reflex is discussed in the light of these results.


Sodium/sodium exchange in the smooth muscle of the guinea-pig taenia coli.

External Na has been shown to initiate a loss of 24 Na from high-Na smooth muscle of the guinea-pig taenia coli. This is an ouabain-insensitive effect, and there appears to be a 1:1 exchange of Na ions, suggesting a classical Na/Na exchange mechanism. 2. The Na/Na exchange has many properties in common with a similar exchange studied in high-Na beef erythrocytes by Motais (1973), and Motais & Sola (1973). It is very temperature-sensitive, it is partially inhibited by the sulphydryl reagents studied and it has a fairly low external affinity for Na. 3. The affinity of the external site for alkali metal cations is Na greater than Li greater than K greater than Rb greater than Cs. 4. It has proved impossible to estimate the affinity of the intracellular sites for Na. The curve relating intracellular Na content with the stimulated efflux reaches a maximum and then declines slightly. 5. Another unexpected finding was that after the rate of loss of Na has been reduced in a Na-free medium, reintroducing Na causes an overshoot in the rate, it increases to a value beyond the original one, and then slowly declines to it. 6. Unlike the classical Na/Na mechanism, the process is reduced, but not abolished by metabolic inhibition that depletes the tissue of ATP. 7. The results are interpreted to suggest that the Na/Na exchange is occurring from a cellular compartment of limited volume, which is itself exchanging with the main cell compartment. It is suggested that this small compartment is the sarcoplasmic reticulum, and the effect of metabolic inhibition is to interfere in some way with the relationship between this compartment and the cell membrane.


Metabolic changes associated with the slowing of relaxation in fatigued mouse muscle.

1. The biochemical basis of the slowing of relaxation seen in fatigue has been examined using an isolated mouse soleus preparation. 2. Slowing of relaxation occurred during prolonged tetani under anaerobic conditions when ATP and PC fell and lactate accumulated. 3. Slowing of relaxation was also demonstrated with muscles poisoned with cyanide and iodoacetic acid when there was a fall in ATP and PC but no accumulation of lactate. During a period of anaerobic recovery following a fatiguing tetanus, relaxation became faster at a time when lactate was accumulating in the muscle. 4. It is concluded that the slowing of relaxation in fatigue is not a consequence of lactate accumulation, and a relationship is demonstrated between the ATP content of the muscle and the rate of relaxation in muscles fatigued by prolonged stimulation, 5. Rates of ATP turn-over in fresh muscle, and at intervals throughout a tetanus are consistent with the suggestion that the rate limiting step for myofibrillar ATPase may be directly related to the rate limiting step for the decay of tension during relaxation.


Heat production and chemical changes during isometric contractions of the human quadriceps muscle.

1. Development of a new thermal probe and use in conjunction with chemical analysis of needle biopsy samples, has made possible a thermodynamic study of the energetics of muscular contraction in the human quadriceps. 2. The observed rate of muscle temperature rise was proportional to the force of the contraction. During maximal contractions the rate of heat production was 54 +/-8-5 W/kg wet muscle (mean +/- s.d.). 3. The observed rates of muscle temperature rise agreed well with the rates calculated from the measured metabolite changes when standard values for the enthalpy changes of the reactions involved were used. 4. During prolonged stimulation of the quadriceps at 15/sec via the femoral nerve, the rate of heat production per unit force fell to nearly half the initial value. It is estimated that this represented a two- to fourfold increased in economy of ATP turn-over required to maintain a given force. 5. Relaxation becomes progressively slower during prolonged contractions and it is suggested that the slowing of relaxation and the increased economy of force maintenance may both be due to an increased cross-bridge cycle time in the fatigued muscle.


Some differences in contractile responses of isolated longitudinal and circular muscle from the guinea-pig stomach.

The mechanical and electrical properties of the longitudinal (fundus and corpus) and circular (antrum) muscle fibres of the guinea-pig stomach were investigated. 1. In the longitudinal but not in the circular muscle isotonic K Krebs and Na-free (sucrose) Krebs solutions produced a contracture with a tonic component. The different mechanical responses were not accompanied by different membrane responses. Verapamil abolished both phasic and tonic components of K-induced contracture. 2. During the tonic response of the K-induced contracture, repolarization of the membrane by current pulses relaxed the tissue; after cessation of the current pulse, rebound contracture occurred. In the circular muscle, the Q10 value for the rate of relaxation induced by inward current pulse was 3-1 and for the development of rebound contracture was 2-4. 3. After the tissue had been immersed in Ca-free isotonic K Krebs solution, application of Ca produced a large contracture in the longitudinal muscle, but contracture in the circular muscle was small or absent. However, the amplitude of subsequent carbachol-induced contracture in the above solution was enlarged in proportion to the durations of Ca treatment in both tissues. 4. Direct tetanic electrical stimulation could produce tension in both tissues. With low frequency of stimulation (0-1 Hz) a positive staircase was observed in the circular but not in the longitudinal muscle. 5. It is concluded from these results that topical differences of the motility in the stomach may be due not only to the activity of nervous elements, but also to differences in the properties of the muscle fibres themselves.


The relative unimportance of the temporal pattern of the primary afferent input in determining the mean level of motor firing in the tonic vibration reflex.

1. A study has been made of the effect of varying the temporal arrangement of the mechanical stimuli used to elicit the tonic vibration reflex in the soleus muscle of the decerebrate cat. The reflex was elicited by brief mechanical pulses, applied repetitively, either as a regular series or, at the same mean frequency, in groups of 2, 3 or 4 pulses with a separation between the pulses of 3-5 msec. Mean frequencies of 140/sec and 100/sec were used. The amplitude of the pulses was such that it could be presumed that each pulse excited every Ia fibre from soleus to discharge a spike, irrespective of the patterning employed. 2. Alterations in the stimulus pattern produced only minimal alterations in the size of the resultant reflex recorded myographically. The grouped stimulation regularly tended to produce the larger effect, but even with groups of 4 at 100/sec the modal effect was only 10% of the pre-existing response; expressed another way this was equivalent to an increase of 11 Hz in the mean frequency of stimulation. Thus under these conditions grouping the stimuli cannot have had an appreciable effect either in increasing the firing frequency of those motoneurones which were already active, or in recruiting those which were initially quiescent. 3. Recording from individual motor units with fine electrodes placed on the surface of the muscle showed that they were not significantly changing their frequency of firing on altering the pattern of stimulation. 4. Gross electromyographic recording showed that the motor discharge was locked in time to the mechanical stimuli and of appropriate latency for it to be presumed that the actual discharge of impulses was triggered by Ia monosynaptic action. 5. Similar insensitivity to the temporal pattern of the afferent input was found when the motoneurones were excited via two separate channels, one being the pulsed mechanical stimulation of soleus, the other being the weak electrical stimulation of the nerve to the medial head of gastrocnemius; altering the relative timing of the two sets of stimuli had little effect on the myographic result. 6. Thus, during tonic firing the timing of the motor output reflects the timing of the afferent input while the mean motor output reflects the mean value of the afferent input, as seems physiologically appropriate. The latter finding is, however, paradoxical; as detailed in an appendix the amount of motor firing produced by synchronous Ia monosynaptic action might be expected to increase on grouping the stimuli and so apparently favouring e.p.s.p. summation.


Autonomic nerve stimulation, kallikrein content anc acinar cell granules of the cat's submandibular gland.

The parasympathetic and sympathetic nerves to the submandibular gland of the anaesthetized cat were stimulated under specific conditions. 1. It was possible to decrease the kallikrein (kininogenase) content of the gland by as much as 90-95% by sympathetic nerve stimulation. In such a gland the appearance and concentration of secretory granules in the acinar cells were indistinguishable from an unstimulated gland. 2. Parasympathetic nerve stimulation, in contrast to sympathetic nerve stimulation, whilst having no significant effect on the kininogenase content of the gland, resulted in the disappearance of a great majority of the acinar granules. 3. These results demonstrate that the acinar granules in the submandibular gland of the cat are not a significant source of kallikrein. 4. Our experiments also failed to indicate any obvious correlation between the granules of the demilune cells and the kallikrein content of the gland. 5. The possibility is raised that kallikrein is located in the cells of the striated ducts.


Gas transit times in the pig lung.

1. A method of measuring the time taken by a front of gas to pass from the carina to individual small airways in the lung is described. 2. This method has been used to investigate the movement of a gas front through hollow lung casts, excised lungs, and excised lungs subjected to a gradient of pleural pressure. 3. The results obtained support the suggestion of morphometric studies that the asymmetrical anatomy of the bronchial tree plays a part in the uneven distribution of ventilation in the lung. 4. The effect of a gradient of pleural pressure over the surface of the upright lung was to increase the time taken by a gas front to reach dependent regions.


Localization and electrical characteristics of a giant synapse in the spinal cord of the lamprey.

1. Physiological and morphological experiments were carried out to determine the characteristics of a giant synapse in the lamprey spinal cord. The presynaptic element is a Müller fibre, running the length of the spinal cord, and the post-synaptic element is a lateral interneurone. 2. Injection of the interneurone with fluorescent dye revealed several dendritic processes extending into the region of the Müller fibres and spreading over a longitudinal distance of about 150 mum. Electron microscopic examination of the Müller fibres confirmed that they do not send out processes to form synapses. Thus, the synapse is between the cylindrical fibre and one or more dendritic branches of the interneurone. 3. Measurements with intracellular electrodes showed the Müller fibres to have input resistances of about 1 Momega and space constants of 1-0-1-7 mm. The space constant was larger for hyperpolarizing pulses than for depolarizing pulses because of delayed recitification. The interneurones had input resistances of about 6 Momega. 4. The neurones were electrically as well as chemically coupled. When a current-passing electrode was placed in the fibre and hyperpolarizing pulses applied, the amplitude of the electrical coupling potential recorded from the interneurone was maximal at one position of the current-passing electrode and decreased as the electrode was moved away from the optimal position. The decrease in amplitude with electrode displacement indicated that the region of synaptic contact was very restricted. 5. The electrical synapse was highly rectifying, the forward resistance being about nine-times smaller than the backward resistance.


Synaptic actions on mitral and tufted cells elicited by olfactory nerve volleys in the rabbit.

1. A unitary study has been carried out of mitral and tufted cell responses to olfactory nerve volleys in the olfactory bulb of rabbits lightly anaesthetized with urethane-chloralose. 2. With volleys of different strengths, some mitral cells responded with a spike whose latency decreased considerably as the strength increased (elastic response); other cells responded at an invariant latency (inelastic response). The former may reflect diffuse olfactory nerve inputs to the dendritic tufts in the olfactory glomeruli, while tha latter may reflect input from discrete bundles of fibres. 3. The shortest spike latencies are consistent with monosynaptic excitation by the olfactory nerves; longer latencies may be due to longer pathways through the nerves, or polysynaptic pathways within the glomerular layer. 4. Facilitation, in terms of lower threshold and shorter spike latency, was found when testing with paired volleys of weak intensity at relatively short intervals (less than 40 msec). Suppression, in terms of raised threshold, longer latency and briefer repetitive discharges, was found at intervals up to several hundred msec. The facilitation and suppression are consistent with the hypothesis of synaptic excitation and inhibition, respectively, mediated through interneurones in the olfactory bulb. 5. Presumed tufted cells were similar in response properties to identified mitral cells. 6. Intracellular recordings revealed long-lasting hyperpolarization and in some cases, an initial depolarization leading to spike initiation, in response to an olfactory nerve volley.


Short-axon cells in the olfactory bulb: dendrodendritic synaptic interactions.

1. In the rabbit olfactory bulb, analysis has been carried out of extracellular unitary responses in the glomerular layer to olfactory nerve volleys. 2. Units in the glomerular layer responded to single volleys with single, double, triple or longer repetitive spike discharges. The shortest initial latencies are consistent with monosynaptic excitation from the olfactory nerves; longer latencies may reflect longer nerve pathways or polysynaptic connexions in the glomerular layer. 3. Like mitral and tufted cells, some glomerular layer units gave evidence of activation by discrete nerve bundles. This correlates with recent anatomical evidence for projections of discrete olfactory nerve bundles to the glomeruli. 4. Facilitation of glomerular layer units took the form of lower spike thresholds and shorter latencies, when testing with paired olfactory nerve volleys of weak strength at relatively short intervals (less than 40 msec). Supression took the form of raised thresholds, longer latencies and briefer repetitive discharges; this was particularly evident with strong volleys at long testing intervals. 5. The early period of facilitation and later period of suppression did not correlate with the recovery cycle of the olfactory nerves; the nerves had an absolute refractory period of approximately 3 msec, relative refractory period of 15-30 msec, and a small supernormal period of several hundred msec or more. 6. The evidence that the facilitation and suppression are mediated by dendrodendritic pathways through the periglomerular short-axon cells is discussed in relation to recent electronmicroscopical studies. The results have implications for similar pathways through short-axon cell dendrites in other parts of the nervous system.


Gradation of the reflex response from atrial receptors.

1. In anaesthetized dogs, distension of balloons so as to stimulate atrial receptors resulted in a reflex increase in heart rate. 2. Successive distensions of one, two and three balloons positioned in the left upper and middle pulmonary vein-atrial junctions and in the left atrial appendage resulted in a progressive increase in the magnitude of this response. 3. It is concluded that the magnitude of the increase in heart rate is related to the extent of receptor area stimulated.


Cortical and long spinal actions on lumbosacral motoneurones in the cat.

1. The effects of stimulating forelimb afferents on various ipsilateral motoneurones of the hind limb have been compared with those of volleys set up in the contralateral pericruciate cortex in cats anaesthetized with chloralose. 2. With intact neuraxis, brachial plexus volleys evoke discharge of flexor and extensor motoneurones; short cortical tetani also elicit discharge mainly of flexor motoneurons. After a pyramid-sparing brainstem lesion, little or no firing is evoked by either input. 3. Monosynaptic reflex testing and intracellular recording reveal subthreshold actions on hind-limb motoneurones, inhibition of FDHL and later facilitation of extensors and flexors by forelimb volleys, facilitation of flexors and extensors together with inconstant inhibition of the latter, by cortical stimulation. 4. Interruption of medullary extrapyramidal paths greatly reduces intensity and duration of facilitation from the forelimb, and largely removes cortically evoked extensor facilitation. Inhibition of FDHL from forelimb and cortex is unchanged; cortical volleys continue to facilitate flexors, and have mainly inhibitory action on extensors in these 'pyramidal' preparations. 5. Hyperpolarization of FDHL motoneurones occurs in response to forelimb and cortical volleys, of time course corresponding to depression of test reflexes. Spinal pathways responsible for the two inhibitory actions are independent, and unless each is very strong, their separate actions summate when elicited together. 6. Receptive field for FDHL inhibition from the forelimb is located distally in the forepaw, and its receptors are largely served by cutaneous fibres of low threshold; some Group II fibres in distal muscle nerves also contribute. Receptive field for facilitation embraces the whole limb, and the executant afferent fibres are of higher threshold. 7. Natural stimulation of the forelimb can evoke the long spinal actions, vibration or light pressure on the forepaw eliciting FDHL inhibition, and strong pinching evoking the more general facilitation. Possible functional roles of these actions in the intact animal are discussed.


Initial and delayed membrane currents in crab muscle fibre under voltage-clamp conditions.

Membrane currents are investigated under voltage-clamp conditions in crab muscle fibre. 2. Step depolarizations elicit an initial composite current followed by a late outward current. 3. One of the components of the initial current is inward. It is sensitive to the external calcium concentration and inhibited by manganese ions, it can be carried also by strontium ions; thus it is expected to be a calcium current. 4. In TEA solution this calcium current appears alone, it reverses when the membrane polarization is carried beyond an internal potential of +30 or +35 mV. Such a low equilibrium potential for calcium ions can be explained either by a low selectivity of the calcium channel or by a local accumulation of calcium ions. 5. Calcium conductance shows voltage- and time dependence. 6. The late outward current corresponds to a potassium current and is inhibited by TEA ions. Its activation exhibits voltage- and time dependence. 7. The activation curve of the late potassium current is shifted in a depolarizing direction by addition of manganese ions. A similar shift produced by increasing [Ca]o or decreasing [Ca]i has been described on other preparations. It is then supposed that the electrical field of the membrane is modified by the gradient of double cations.


Myocardial sarcomere dynamics during isometric contraction.

1. Sarcomere lengths were measured during rest and throughout the time course of isometric contractions in thin, isolated rat papillary muscles using light diffraction techniques. 2. Shortening of the sarcomere length occurred upon contraction at all muscle lengths, averaging 7% at optimal length and more at shorter lengths. Relative to the narrow range of sarcomere lengths spanning the length--tension curve, this degree of shortening was considerable. 3. Local changes of sarcomere length were quantitatively paralleled by local changes of tissue segment length, the latter demarcated by microspheres lodged within the muscle tissue. At all but the shortest muscle lengths, sarcomere shortening was fully accounted for by equivalent lengthening of the non-striated regions near the clamped ends of the preparation. 4. It seems likely that these regions near the clamped ends of the preparation. 4. It seems constitute the source of the large series elasticity characteristic of isolated papillary muscle preparations such as this.


Breathing in man during steady-state exercise on the bicycle at two pedalling frequencies, and during treadmill walking.

1. The breathing pattern, that is the changes in tidal volume (VT), and in inspiratory (TI) and expiratory (TE) durations, has been studied as ventilation increases in exercise. 2. Five healthy subjects were studied in steady-state exercise on a bicycle ergometer, breathing air, at two speeds of pedalling and at six different loads. The pattern was recorded for single breaths. Two of the subjects were also studied while walking on a treadmill with four combinations of speed and gradient. 3. In bicycle exercise, as the CO2 output increased mean VT increased, and mean TI and TE decreased, the absolute decrease in TI being small. The pedalling speed did not affect these relationships. 4. Individual breath durations showed no tendency to group around multiples of the period of rotation of the pedals. 5. In treadmill exercise, no clear influence of stride rate on respiratory rate could be found. The pattern was similar to that found in bicycle exercise. Again no grouping could be found. 6. No evidence of an effect of frequency of limb movement on breathing pattern in submaximal exercise has been found. The selection of breathing pattern seems to be unrelated to the nature of the stimulus but closely geared to the metabolic needs of the body.


Mean and breath-by-breath pattern of breathing in man during steady-state exercise.

1. The breathing pattern, that is the relation between tidal volume (VT) and the inspiratory (TI) and expiratory (TE) durations, has been studied for individual breaths (forty in each steady state). 2. Five healthy subjects were studied in steady-state exercise on a bicycle ergometer breathing air; three of them were also studied in hypercapnia, at rest and during exercise, and two of them also during exercise on a treadmill. 3. Tidal volume and respiratory frequency both increased with work load. The increase in frequency was largely due to a progressive decrease in TE; TI also decreased. 4. At any constant level of respiratory drive (constant work load or chemical load) VT was positively correlated with both TI and TE in more than 95% of cases. 5. A simple model of the respiratory cycle which fits both the observed mean and breath-by-breath patterns and which involves no new assumptions is presented.


Influence of activity on the passive electrical properties of denervated soleus muscle fibres in the rat.

The technique of direct electrical stimulation of denervated muscle was used to study the role of muscle activity per se in controlling the passive electrical properties of muscle fibres. 2. Specific membrane resistance and capacitance of the denervated and the denervated-stimulated muscle fibres were measured by a sinewave technique at frequencies between 5 and 240 Hz. The parameter values were constant at low frequencies up to a variable transition frequency and declined rapidly at higher frequencies. 3. Following denervation the low-frequency value of specific membrane resistance increased (2291 omega cm2 for 19-day denervated fibres vs. 766 omega cm2 for innervated fibres), the specific membrane capacitance declined (2-7 muF/cm2 vs. 3-6 muF/cm2) and the transition frequency shifted towards lower frequencies. The specific internal resistance was higher in denervated fibres (301 omega cm for 19-day denervated fibres vs. 240 omega cm in innervated fibres) apart from a transient decline after 5 days of denervation (164 omega cm). 4. Direct electrical stimulation for 2 weeks beginning on the 5th day after denervation restored all parameters listed above to their original values before denervation. 5. Stimulation arrested in most cases further atrophy from the time of stimulation but did not restore normal fibre size.


Secretory activity of goat mammary glands during pregnancy and the onset of lactation.

1. The volume of the udder and the composition of the secretion have been followed in five goats through pregnancy to the onset of lactation. 2. During the middle of pregnancy udder volume was minimal and there was little or no fluid in the teats. 3. Two stages of commencing secretory activity (lactogenesis) were defined. In the first, starting up to ten weeks pre-partum, udder volume increased and the fluid in the teats changed from an extracellular-fluid-like to a milk-like composition and acquired a high concentration of immunoglobulins. Four goats accumulated several litres of a pre-colostral fluid with a high [lactose] 6-7 weeks pre-partum. 4. Comparison of the rate of increase in udder volume with previous data for the rate of increase in empty udder volume in pregnant goats showed that the rate of secretion, even in the last few days of pregnancy, was only a few per cent of the rate immediately after parturition. 5. In the last 2-3 days of pregnancy there was a three to elevenfold increase in [citrate] in the secretion; this heralded the onset of copious secretion at about the time of parturition. 6. The changes in mammary gland activities are discussed in relation to changes in plasma hormone concentrations during pregnancy.


Selective and non-selective reinnervation of fast-twitch and slow-twitch rat skeletal muscle.

1. The problem of selectivity during reinnervation of skeletal muscle fibres was investigated in the rat using the fast-twitch extensor digitorum longus (EDL) and the slow-twitch soleus muscles and their nerves. 2. After an operation on these nerves permitting them to compete for reinnervation of one or the other muscle (hereafter called Y-union), virtually the total isometric tetanic tension of EDL muscle could be elicited by stimulating the EDL nerve, while stimulating the soleus nerve yielded little or no tension. In the case of the soleus muscle, stimulation of either nerve elicited about half of the total isometric tetanic tension. 3. During the course of reinnervation of these muscles in non-competitive situations, the time course of increase in the ratio of tension elicited by nerve stimulation to that by direct stimulation was slower in the case of soleus nerve reinnervating EDL muscle, compared with cross-reinnervation in the reverse direction or reinnervation of each muscle by its own nerve. 4. Crushing the common peroneal nerve 12 days after a Y-union in an attempt to retard the EDL nerve did not favour reinnervation of the EDL by soleus nerve, but crushing the nerve again or just once at 1 month after the original operation produced substantial partial reinnervation of the EDL by the soleus nerve. 5. It is concluded that soleus nerve fibres form functioning neuromuscular synapses on EDL muscle fibres only with difficulty. The pattern of reinnervation reveals characteristic differences between fast-twitch and slow-twitch muscles on the one hand and between their respective nerves on the other.


Binding of adenosine diphosphate to intact human platelets.

1. Human platelet-rich plasma was incubated at 37 degrees C with [8-14C]ADP and with human serum albumin labelled with 125I. The platelets were rapidly separated by centrifugation through silicone oil. From radioactivity determinations of plasma and platelet pellets the uptake of ADP, without or with break-down products, by the platelets was calculated on the assumption that the 125I radioactivity in the pellet represented trapped plasma. 2. ADP radioactivity was taken up by platelets within 10 sec and increased with time of incubation. The uptake of other nucleotide diphosphates was less initially and increased much more slowly. 3. Radioactivity added as ADP was recovered as ATP to the extent of 60%; as ADP of 30%; and as AMP of 10%. 4. Prostaglandin E1 which inhibited platelet aggregation had no effect on the initial or subsequent uptake or on this distribution of radioactivity. 5. The rate of rise in uptake was much slower when platelets were resuspended in plasma heated to 56 degrees C for 30 min. 6. Unlabelled adenosine inhibited the later, but not the initial, uptake while unlabelled ADP inhibited both. Dipyridamole, which blocks adenosine uptake, prevented the later but not the initial uptake. 7. [alpha-32P]ADP radioactivity was taken up at the earliest sampling time and the extent of uptake did not further increase. 8. Guinea-pig platelets, which do not take up adenosine, took up [8-14C]ADP radioactivity from purine-labelled ADP initially. 9. It was concluded that the initial uptake represented binding of ADP and that the later uptake represented labelled adenosine originating as a break-down product of ADP. 10. A Scatchard plot of ADP uptake indicated more than one type of binding site. There were approximately 88,000 high affinity sites per platelet which had an affinity constant of 5-41 X 10(5) M-1.


Some effects of 5-hydroxytryptamine, dopamine and noradrenaline on neurones in the submucous plexus of guinea-pig small intestine.

1. Responses to the iontophoretic application of 5-hydroxytryptamine (5-HT), dopamine and noradrenaline were examined in neurones of the submucous plexus of guinea-pig small intestine. 2. Every neurone was excited by 5-HT. 3. In a proportion of cells, dopamine or noradrenaline caused an increase in membrane potential. This response was only observed in cells which received in inhibitory innervation. The responses closely resembled inhibitory synaptic potentials evoked by transmural stimulation. 4. Both inhibitory synaptic potentials and inhibitory responses to dopamine and noradrenaline were blocked by methysergide. 5. It seems possible that these two catecholamines may interact with similar receptors to those activated by inhibitory transmitter.


Screening for hypothermia in Orkney.

In a screening survey for hypothermia carried out amongst the elderly population of an island in the Orkneys, in which a 96 per cent response rate was obtained, oral temperatures were recorded using standard and low-reading thermometers. Out of 77 patients who entered the survey, only three had an oral temperature of 37 degrees C or higher. Six patients (eight per cent) had a temperature of 35 degrees C or lower, and these, depending on diagnostic criteria, could be considered to be suffering from hypothermia. A low body temperature was unsuspected in all six.


Conning the general practitioner--how drug-abusing patients obtain prescriptions.

A sample of 100 patients attending drug dependence clinics was questioned about the methods they used to obtain psychotropic drugs from general practitioners. Sixty-one per cent said they were obtaining psychotropic drugs and 39 per cent said they had obtained psychotropic drugs from this source during the preceding 12 months. Drugs obtained included minor tranquillisers, barbiturates, amphetamines, and methylphenidate (;Ritalin'). Some degree of deception of the general practitioner by the patient was almost always clear. Three recommendations to help prevent this are suggested.


The distribution of episodes of illness--a research tool in general practice?

The frequency of episodes of illness which 315,000 people brought to their doctors' attention in one year is shown to follow a geometric distribution. Some of the potential applications of this distribution in general-practice research are given.


Tests for occult blood.

Cancer of the large bowel is an important cause of morbidity and mortality. The barium enema is still the most reliable diagnostic tool, but the selection of the proper candidates for this moderately expensive and time-consuming examination presents a real problem. To wait for significant symptoms of change in bowel habits, such as unexplained anaemia, is hazardous. Testing for occult blood has fallen into disuse in most general practices. This paper discusses some of the available techniques for this procedure which I suggest offer a worthwhile aid to examination of patients with possible alimentary neoplasm.


Variations in collagen, non-collagenous proteins, and hexosamine in menisci derived from osteoarthritic and rheumatoid arthritic knee joints.

Knee joint menisci from osteoarthritic and rheumatoid knees were analyzed for nitrogen, collagen, non-collagenous proteins (NCP) and hexamine content. Degenerate areas were analyzed separately. The degenerative areas were significantly lower (P less than 0.005) in collagen but NCP and hexosamines were elevated relative to control tissue. The rheumatoid menisci revealed a reduced level of collagen and hexosamine in areas of localized degeneration. However, the collagen and hexosamine content of the remaining tissue was also diminished (P less than 0.025) relative to normal tissue of the same. age.


Carpal tunnel syndrome in temporal arteritis.

An 88 year old man presented with pain in the hands and wrists, associated with electrodiagnostic studies compatible with a carpal tunnel syndrome in the right wrist. Approximately seven months later he developed manifestations of bilateral temporal arteritis resulting in monocular blindness. Electrodiagnostic studies at this time confirmed the presence of a more severe carpal tunnel syndrome, now present bilaterally. We have been unable to find other case reports of carpal tunnel syndrome related to temporal arteritis. This association may be recognized more frequently if electrodiagnostic studies are performed in patients with temporal arteritis associated with pain in the hands and wrists.


Association of polyarthritis, subcutaneous nodules, and pancreatic disease.

A patient with nodular liquefying panniculitis, polyarthritis and an occult pancreatic neoplasm is described. The skin lesion was initially mistaken for erythema nodosum. Subcutaneous and synovial fluids demonstrated similar negatively birefringent, rectangular particles, lying in between fat globules. Serum lipase,although continuously elevated, did not fluctuate with disease activity. Biochemical evidence of lipolysis in either the synovial fluid or serum was not demonstrable. Immunologic mechanisms appeared not to be involved in the pathogensis of the panniculitis or the arthritis.


Quantitation of gold in skin in chrysiasis.

Skin, plasma, hair, and nail gold levels were determined in three groups of patients with rheumatoid arthritis comprising: I. Three patients on long term gold therapy exhibiting altered skin pigmentation (chrysiasis); II. Five patients on long term gold therapy exhibiting normal skin pigmentation; III. Two patients starting gold therapy. Group I had higher skin gold levels (50-140 mug/g) than Group II (7.5-13 mug/g) while Group II had minimal levels. Hair and nail gold levels were not much higher than gold levels in non-gold treated individuals. The possible role of skin in the storage or excretion of gold is discussed.


Comparative study of NZB mice under germfree and conventional conditions.

Groups of New Zealand Black (NZB) mice born and reared in germfree conditions were studied at three, six, nine, and 12 months of age. Compared with NZB mice of the same ages raised under conventional conditions, the germfree mice showed: (1) significantly lower gamma-globulin levels, (2) significantly higher frequency of serum antinuclear factor (ANF), and (3) significant decreases in the incidence and severity of renal disease. The lower gamma-globulin levels probably reflect lack of antigenic stimulation by common bacteria. The higher frequency of ANF may be a chance finding or may reflect lack of deposition of complexes in the kidneys. The latter also may explain the decreased severity of renal disease. It is possible that complexes of antibody with common antigens (such as bacteria) may deposit in diseased kidneys and aggravate the condition.


Hospital-acquired salicylate intoxication. report of a case with psychosis, acidosis, and coma.

A case of salicylate intoxication from repeated therapeutic doses of aspirin is reported in an adult with impairment of salicylate elimination. Evolution of acid-base disturbance from respiratory alkalosis to metablic acidosis is documented. Serum salicylate levels during several years of therapy demonstrate the acquisition of impaired elimination of the drug. This case illustrates the practical importance of special features of salicylate accumulation kinetics emphasized in a recent review.


Deep fungal infection in systemic lupus erythematosus - three cases reported, literature reviewed.

Three patients with systemic lupus erythematosus (SLE) and deep fungal infection are described. Two patients had disseminated cryptococcal infection and the third disseminated histoplasmosis. Allwere receiving corticosteroids at the time fungal infection developed. One patient with disseminated cryptococcosis improved after treatment with amphotericin B and 5-fluorocytosine. The other patient with disseminated cryptococcosis died before adequate therapy could be given. The patient with histoplasmosis responded satisfactorily to amphotericin B. A survey of the literature revealed 30 additional cases of deep fungal infection in patients with SLE, most of whom were on corticosteroid therapy. The majority of the patients had candidiasis (14 patients); 11 patients had severe cryptococcal infection. Other fungal infections reported were histoplasmosis, aspergillois, coccidioidomycosis, and maduromycosis caused by Allerscheria boydii. Twenty-seven patients died; in 22 death was related to the fungal infection. The fungal infection was not diagnosed until necropsy in at least 11 persons. Deep fungal infections should be considered whenever patients with SLE have fever of unknown origin, diffuse pulmonary infiltrates, or unexplained CNS symptoms.


Arthropathy, skin and bone lesions in pancreatic disease.

A patient with a history of alcoholism and pancreatic calcification, developed subcutaneous fat necrosis and an arthropathy, associated with a pancreatic pseudocyst and accompanied by an elevation of serum lipase and amylase. The illness was complicated by bacteremia and destructive bone lesions. A clinical distinction between osteomyelitis and medullary fat necrosis proved difficult. Infection of bone was demonstrated at one site but did not exclude medullary fat necrosis elsewhere.


Septic arthritis in systemic lupus erythematosus.

Five patients with systemic lupus erythematosus (SLE) developed septic arthritis. Neisseria gonorrheae, Staphyloccocus aureus, Proteus and Escherichia coli were the offending bacterial organisms. Predisposing factors included systemic and local corticosteroids, aseptic necrosis of bone and synovitis due to SLE. The diagnosis was made by culture of the organisms from the synovial fluid. Three patients recovered without residual joint damage, one required corrective arthroplasty and one died from overwhelming infection.


Spectrum of gonococcal arthritis: evidence for sequential stages and clinical subgroups.

In a series of 84 patients with gonococcal (GC) arthritis, 41 were documented as follows: 17 had positive blood culture or typical skin rash (Hematogenous Group); four had positive joint culture plus hematogenous manifestations (Transition Group); and 20 had positive joint culture without positive blood culture or skin rash (Joint Localization Group). The hematogenous group, especially patients with proved gonococcemia, presented significantly earlier after onset of symptoms than patients with joint localization alone, suggesting sequential stages of disease. Patients with verified bacteremia were significantly more toxic than those with rash or culture-proved joint infection alone. Nine of the joint localization patients had a monoarthritis with minimal systemic manifestations. The remaining 11 had a polyarthritis and were significantly more toxic. A concept of sequential stages and clinical subgroups of GC arthritis is proposed which may improve patient classification and differential diagnosis.


Destructive arthropathy in generalized osteoarthritis with articular chondrocalcinosis.

A destructive arthropathy is much more common when generalized osteoarthritis (GOA) and articular chondrocalcinosis (ACC) coexist than in GOA alone. Fifty-two patients with GOA and ACC were compared to a matched control group with GOA alone. A marked increase in the frequency of a destructive arthropathy was found in the group with both GOA and ACC. Nonweight-bearing joints were often involved in the group with GOA and ACC, whereas they were seldom involved in the group with GOA alone.


Sacro-iliac joint in renal osteodystrophy: roentgenographic-Pathologic correlation.

A detailed roentgenographic and pathologic study of the sacro-iliac joint in a cadaver with renal osteodystrophy revealed subchondral abnormalities, particularly in the ilium, which consisted of resorption of bone, substitutive fibrosis, and thickening of remaining trabeculae. Overlying articular cartilage degeneration was also apparent. The "pseudo-widening" of the joint space noted in ante and post-mortem radiographs in this patient simulated the findings in early ankylosing spondylitis.


Inflammatory involvement of vertebrae in ankylosing spondylitis.

Unusual destructive lesions of the cervical and lumbar vertebrae are described in two patients with ankylosing spondylitis. Biopsy of a lesion from one of the patients showed it to be inflammatory in nature. Possible mechanisms for vertebral centrum involvement in ankylosing spondylitis, centering on the role of enthesopathies are discussed.


Serum complement and immunoglobulin levels in sporadic and familial ankylosing spondylitis.

Serum levels of C4, C3, IgG, IgM and IgA were measured by immunodiffusion in age matched groups of 48 sporadically encountered patients with ankylosing spondylitis, 56 with rheumatoid arthritis and 52 normal controls. Mean levels of C4 and IgA were significantly elevated in the sera of patients with sporadic ankylosing spondylitis, in comparison to normal controls. Mean IgA levels were also significantly elevated in 11 HL-A 27 positive patients with familial spondylitis but no such elevation was found in the sera of their healthy first-degree relatives with and without HL-A 27. The results of these studies suggest that humoral immune mechanisms may be involved in the pathophysiology of ankylosing spondylitis.


HL-A27 and ankylosing spondylitis in B.C. Indians.

HL-A antigens were determined in Haida and Bella Coola native Indians, two communities known to have a high prevalence of ankylosing spondylitis. Tests were conducted on those with x-ray evidence of sacro-iliitis and on a sample of the community at large. Sacro-iliitis was found to prevail in approximately 10 per cent of adult Haida males and in over two per cent of Bella Coola adult males. Of 20 Haidas with sacro-iliitis, 17 were HL-A 27 positive. Fifty per cent of the Haida community at large were HL-A 27 positive. Three Bella Coolas known to have sacro-iliitis were all HL-A 27 positive, while 25 per cent of the community sampled at large were HL-A 27 positive. About one in five adult Haida males who were HL-A 27 positive showed evidence of sacro-iliitis, a proportion close to that ascertained in Caucasian communities. It would appear, therefore that the risk of disease in HL-A 27 positive Bella Coola males is considerably lower.


HL-A antigens in Europeans and Maoris with rheumatic fever and rheumatic heart disease.

Using a standard microtoxicity technique of tissue typing, the distribution of tissue antigens in 75 Maoris and 514 European disease-free blood donors was determined. Fifty Maori and 50 Europeans with rheumatic fever or rheumatic heart disease were compared with each control group. Normal Maoris had HL-A3 less frequently than Europeans (P less than .0005). HL-A28 was reduced (P less than .005) and HL-A17 increased in European patients (P less than .0005). In Maori patients there were minor differences in the frequency of HL-A3 and 8, which were increased, and HL-A10, which was diminished.


Azathioprine hypersensitivity mimicking an acute exacerbation of dermatomyositis.

We describe an unusual hypersensitivity reaction to azathioprine occurring in a patient with dermatomyositis, in which the acute manifestations suggested an exacerbation of the patient's underlying disorder. However, laboratory studies were not consistent with an acute exacerbation of dermatomyositis, and the subsequent clinical course confirmed the impression that the patient's symptoms were due to hypersensitivity to azathioprine. Physicians should be aware that a hypersensitivity reaction to azathioprine may mimic a flare of dermatomyositis.


Biochemical studies on the aqueous humour of rhesus monkeys (Macaca mulatta).

Aqueous humour of rhesus monkey eye contains lower concentration of glucose and excess of sodium and chloride irons in comparison to constituents of serum of the same animals.


The formation and cytochemical characterization of cortical granules in ovarian oocytes of the golden hamster (Mesocricetus auratus).

The formation and cytochemical characterization of cortical granules in the ovarian oocytes of the golden hamster have been investigated by use of light and electron microscopical techniques. Particular emphasis is given to the changing population of organelles associated with cortical granule formation. Our observations indicate that cortical granules are produced by the participation of both the Golgi complex and the rough endoplasmic reticulum. Ultrastructural cytochemistry reveals that the cortical granules are composed of glycoprotein. The cortical granules are released at fertilization by a merocrine-type of secretory process.


Techniques for estimating allometric equations.

Morphologists have long been aware that differential size relationships of variables can be fo great value when studying shape. Allometric patterns have been the basis of many interpretations of adaptations, biomechanisms, and taxonomies. It is of importance that the parameters of the allometric equation be as accurate estimates as possible since they are so commonly used in such interpretations. Since the error term may come into the allometric relation either exponentially or additively, there are at least two methods of estimating the parameters of the allometric equation. That most commonly used assumes exponentiality of the error term, and operates by forming a linear function by a logarithmic transformation and then solving by the method of ordinary least squares. On the other hand, if the rrror term comes into the equation in an additive way, a nonlinear method may be used, searching the parameter space for those parameters which minimize the sum of squared residuals. Study of data on body weight and metabolism in birds explores the issues involved in discriminating between the two models by working through a specific example and shows that these two methods of estimation can yield highly different results. Not only minimizing the sum of squared residuals, but also the distribution and randomness of the residuals must be considered in determing which model more precisely estimates the parameters. In general there is no a priori way to tell which model will be best. Given the importance often attached to the parameter estimates, it may be well worth considerable effort to find which method of solution is appropriate for a given set of data.


A gross and microscopic study of the respiratory anatomy of the Antarctic Weddell seal, Leptonychotes weddelli.

Four species of Phocidae, or true seals, inhabit the waters surrounding the Antarctic continent. These animals are thought to have different diving capabilities. The Weddell seal, Leptonychotes weddelli, is known to be capable of attaining depths up to 600 meters. The respiratiory system of the Weddell seal shows the usual adaptations to an aquatic environment characteristic of other marine. These include lungs that undergo compression acollapse at depths greater than 70 meters; hyaline cartilage in the tracheo-bronchial tree as far as the terminal bronchioles; and large amounts of smooth muscle surrounding the distal-most bronchioles. The collapsible lungs provide a mechanism by which air is forced from the alveoli adjacent to the pulmonary capillary beds thereby preventing the absorption of nitrogen gas into the bloodsteam. The presence of hyaline cartilage throughout most of the tracheo-bronchial tree increases the effective dead air space that accommodates most of the air forced from the collapsed lungs. The smooth muscle surrounding the respiratory bronchioles prevents their collapse while under the pressures of a deep dive. Collapse of the respiratory bronchioles not supported by cartilage would trap air in the lung alveoli during a dive. In addition, large- sac-like "diverticulae" are found in the submucosa throughout the tracheo-bronchial tree. These diverticulae, which open directly into the lumen of the tree, appear to be modified glands whose cells, in most cases, do not appear to be specialized for secretory function. They are most numerous in the more distal bronchi and terminal bronchioles where they are situated on both the luminal and adventitial sides of the hyaline cartilage supporting the walls of the air passages. Diverticulae are not found in the respiratory bronchioles or in the respiratory portion of the lungs.


Compositional nonrandomness: a quantitatively conserved evolutionary invariant.

The a priori probability that the amino acid composition of a protein will exhibit a given overall deviation from the genetic code table frequencies is the same for all protein families independent of protein length, biological function, or origin.


A genetic model for the evolution of the glycosphingolipids.

The glycosphingolipids have been found in many animal tissues, but the complexity of their molecular structure varies considerably among the different phyla. Relatively simple structures have been found in invertebrate species, while the most complex have been demonstrated in brain tissue of modern fishes and amphibians. The data on the phylogenetic distribution of the glycosphingolipids has been interpreted to indicate that a significant number of gene duplications, involving many different structural genes, may have occurred during a few specific periods of vertebrate evolution. The transition from invertebrate to jawless vertebrate, the divergence of rays and skates from true sharks, the advent of modern bony fishes and the transition from aquatic to terrestrial vertebrates, each could have veen accompained by duplications of genes involved in the synthesis and degradation of glycosphingolipids. The evolutionary study of such a multi-enzyme system may be one means to detect alterations in the genome as a whole. The apparent correspondence in time of these gene duplications involved in glycosphingolipid metabolism and periods of rapid vertebrate evolution which may have been accompanied by significant increases in the amount of cellular DNA suggests that such changes may have occurred via the mechanism of tetraploidization.


Nature genetic basis and evolution of the haemoblobin polymorphism in Chironomus.

Chironomus larvae exhibit considerable haemoblobin polymorphism. Chironomus tnetans has 10 and C. pallidivittatus has 8 electrophoretically different Hb-chains. With the exception of one Hb-chain, all are species-specific. The hybrid which is fertile, shows the Hb-pattern of both parents. In the F2 and subsequent generations, considerable chromosome rearrangements occurs. Since the chromosomes of the parent species can be distinguished in the polytene state, Hb-patterns can be correlated with specific chromosomal constitutions. All the species-specific Hb-genes are located on one chromosome. This finding suggests that the Hb-genes have evolved through multiple gene duplications. Different mechanisms for gene duplication are discussed.


Argyrophil cell microneoplasia in the Mastomys' stomach--an observation on early carcinoid formation.

To analyze the early stages of argyrophil cell carcinoid growth, complete serial sections were cut from the glandular portion of the stomachs of 22 Mastomys and submitted to Sevier-Munger's reaction. The 154 grossly invisible foci of argyrophil cell microproliferation thus detected were classified into three stages of microproliferations (I, II, and III), and the last stage was definitely a microcarcinoid. There was a gradual transition in cell proliferation among these three stages; the first stage (microproliferation I), in which the cells were morphologically indistinguishable from those of hyperplastic proliferation by general morphologic criteria, was where the initial change of argyrophil cell carcinoid formation was detectable by a light microscope. Whereas multiple occurrences of microcarcinoids accounted for the multiplicity of well-developed tumors in the stomachs of Mastomys, a well-developed carcinoid in this species was formed by the confluence of several microcarcinoids.


The architecture of 5S rRNA and its relation to function.

An extensive comparative analysis of the available primary sequence data  on 5S rRNA has been made. A universal secondary structure is presented for procaryotic 5S rRNA which contains four helical regions. Eucaryotic 5S rRNAs are found to have only three of these helices and thus have a somewhat different architecture. In addition, a highly conserved segment of more than thirty nucleotides is identified in the 5' half of the procaryotic molecule. This segment includes the oligonucleotide -CGAAC- which presumably binds to the t-RNA "common" sequence -GTpsiCG-. Among the eucaryotes, the plants display a procaryotic nature in this region, but no eucaryote has the sequence -CGAAC- in this segment. A functional role for the procaryotic 5S rRNA molecule is discussed in which it is envisioned to undergo conformational change, i.e., coiling and uncoiling of one of the helices, which can result in a cyclic interaction of the 5S rRNA molecule with two t-RNA molecules. A general principle also emerges: the natural rotational motion inherent in coiling and uncoiling of nucleic acid helices can be converted quite simply to linear mechanical motion.