Surgical treatment of high imperforate anus with definition of the puborectalis sling by an anterior perineal approach. An operative technique in which the sling of the puborectalis muscle is seen through an anterior perineal approach in the treatment of high imperforate anus is described. The operation has been performed, on children with previous colostomies, and on older children with unsuccessful previous abdomino-perineal pull-through procedures. While our series of patients is still small, 24 children, operated upon sufficiently long ago for follow-up purposes, have generally shown good to excellent functional results.


Constipation caused by anterior location of the anus and its surgical correction. Slight anterior displacement of the anus is a common developmental abnormality that represents the mild end of the imperforate anus spectrum. This malformation is a common cause of constipation. This type of constipation can be cured by posterior anoplasty. An experience is described in 134 cases who were operated upon from 1960 through 1977.


Villous adenoma of the rectum: a rare tumor in childhood. Villous adenoma of the rectum in a 14-yr-old boy is described, and the clinical features, pathology, and surgical treatment of this condition are reviewed. This appears to be the first reported case in childhood.


Giant epignathus.

Giant epignathus. The case here described is interesting because of its giant size and because it had the morphology of a head. Immediate removal was followed by uneventful recovery. The term "epignathi" has been used since the last century for teratoid tumors growing from the upper jaw or the roof of the pharynx. These tumors tend to cause obstruction to respiration.


Salivary gland tumors in children.

Salivary gland tumors in children. Tumors of salivary gland origin are relatively uncommon in children. Over a 23-yr period, there were 12 such tumors affecting children under 16 yr of age out of a total 937 cases reported by a central cancer registry. The commonest lesion was the pleomorphic adenoma involving the parotid gland. Wide focal excision seemed to be an adequate procedure as long as the tumor was completely removed. Inadequate excision resulted in multiple local recurrences with the tumor taking on more malignant characteristics. Early radical excision, with preservation of the facial nerve, is advocated.


Nasal glioma.

Nasal glioma. In this report 12 cases of nasal glioma are reviewed. It is shown that they present in three different ways. The etiology, pathology, differential diagnosis, and treatment are discussed.


Duodenal ulcer in childhood: a continuing disease in adult life. Thirty-one of the 37 children with duodenal ulcers were available for follow-up. Of the 28 patients treated medically, 22 had persistence of symptoms over periods up to 18 yr after the time of the initial diagnosis. Five patients required surgery elsewhere for complications, thirteen showed ulcer crater or duodenal deformity on a follow-up barium meal studies. Earlier surgery is recommended in chronic ulcer disease.


Neonatal urinary ascites in the absence of urinary tract obstruction. Urinary ascites in the absence of demonstrable anatomical obstruction has been reported only very infrequently. This paper reports on another case and briefly reviews the literature.


Anti-refluxing colon conduits for diversion of dilated upper urinary tracts. Ureteral tailoring and colonic conduit urinary diversion were performed in 10 dogs. 2 wk to 2 mo after ureteral ligation. Two to five months after urinary diversion, radiography and postmortem examination revealed reflux in only 11% of the ureters and no evidence of obstruction at the ureterocolonic anastomosis. Pyelonephritis was observed in a lower percentage of animals so diverted, as compared to control kidneys diverted by means of ileoconduits. These results support the use of anti-refluxing colonic conduits for diversion of dilated upper urinary tracts.


Ureteric polyp as a cause of hydronephrosis in childhood. Obstruction of the ureteropelvic junction from a polypoid lesion is considered to be an exceedingly rare cause of hydronephrosis in childhood.


Ventriculoperitoneal (VP) shunt migration causing an acute scrotum: a case report of Doppler evaluation. The diagnosis and management of a scrotal complication of a ventriculoperitoneal shunt simulating testicular torsion in a neonate is outlined. Radiologic evaluation determined the location of the shunt tube and adequate blood flow to the testicle was confirmed by use of the Doppler stethoscope, allowing for definitive therapy by extraperitoneal shortening of the shunt catheter. Surgery to the scrotum was, thus, avoided.


Bilateral granulosa cell tumors of the ovaries in infancy. A case of bilateral cystic granulosa cell tumors of the ovaries in an 11-wk-old infant is described. The patient presented with a large abdominal mass, but without sexual precocity. Treatment consisted of bilateral salpingo-oophorectomy without subsequent chemotherapy or radiation, and 2 yr follow-up has shown no evidence of recurrence of this tumor.


Retroperitoneal abscess presenting as an abdominal mass in neonate. This is the first reported case of a retroperitoneal abscess in a neonate. The patient presented with a large abdominal mass at 3 wk of age. Excretory urogram followed by surgery established the diagnosis. Retroperitoneal abscesses must be considered in the differential diagnosis of abdominal masses in the new born.


Rheology of pharmaceutical systems: oscillatory and steady shear of non-Newtonian viscoelastic liquids. A comparative analysis of oscillatory and steady shear rate measurements was made on carboxymethylcellulose solutions of two concentrations and two viscosity grades. In the oscillatory methods, the material is examined under nearly quiescent equilibrium conditions. Steady shear, conversely, produces large deformations and may yield false results, often interpreted as thixotropy, if the shear rate experiment is not conducted properly. Solutions of carboxymethylcellulose at concentrations ordinarily used in drug product formulations were examined by oscillatory and steady shear methods at low shear. Viscoelastic properties of pharmaceutical materials were measured using a newly developed oscillometric instrument. Mathematical expressions, formulated on the basis of a generalized Maxwell model for viscoelasticity and viscosity in steady shear, were correlated using these two rheological test methods. The results showed large increases in viscosity and relaxation time with increasing carboxymethylcellulose concentrations as well as with increasing molecular weights of the polymeric solute. The behavior of carboxymethylcellulose under both oscillatory and steady shear agreed with theory, linking the two methods of testing. Applications in pharmacy to this rheological analysis are presented. The present investigation attempted to bridge the gap between oscillatory and steady shear methods, demonstrating how both can find appropriate use in the analysis of non-Newtonian materials of pharmaceutical importance.


Anticonvulsant and antiproteolytic properties of 3,5-disubstituted oxadiazole-2-thiones and their inhibition of respiration in rat brain homogenates. Eight 5-(3,4-methylenedioxyphenyl)-3-arylaminomethyl-1,3,4-oxadiazole-2-thiones were synthesized, characterized by their sharp melting points, elemental analyses, and IR spectra, and evaluated for anticonvulsant activity. All substituted oxadiazole-2-thiones possessed anticonvulsant activity, which was reflected by their ability to provide 10--70% protection against pentylenetetrazol-induced convulsions in mice at 100 mg/kg ip. These compounds inhibited in vitro nicotinamide adenine dinucleotide (NAD)-dependent oxidation of pyruvate, alpha-ketoglutarate, and NADH by rat brain homogenates as well as NAD-independent oxidation of succinate by rat brain homogenates. Antiproteolytic activity of these substituted oxadiazole-2-thiones was reflected by their ability to inhibit trypsin hydrolysis of bovine serum albumin. These results indicated that the inhibition of cellular respiration and antiproteolytic activity of these substituted oxadiazole-2-thiones is not the biochemical basis for their anticonvulsant activity.


Simultaneous quantitation of morphine and paraben preservatives in morphine injectables. A high-performance liquid chromatographic method for the simultaneous determination of morphine sulfate, methylparaben, and propylparaben in morphine sulfate injection was developed. A reversed-phase system, based on an octadecylsilane stationary phase, was used with a binary solvent mobile phase consisting of methanol--phosphate buffer (pH 4.0) containing methanol (5%) delivered at a constant rate (0.6:0.4 ml/min) using a two-pump system. The detector response at 254 nm was linear with the amount injected over a wide range, allowing rapid and reproducible quantitation of each component.


Pharmacokinetics of morphine and its surrogates I: comparisons of sensitive assays of morphine in biological fluids and application to morphine pharmacokinetics in the dog. A sensitive isotope derivatization assay was developed to quantify morphine in biological fluids in the nanogram per milliliter range. Morphine, derivatized with 3H-dansyl chloride, was separated from the reaction products by TLC. The spots were scraped from the plate, and the eluted radioactivity was determined by liquid scintillation. The standard deviations of this morphine assay were +/- 18.6 ng/ml in 100 microliter of plasma and +/- 1.86 ng/ml in 1 ml of plasma. The GLC analysis of pentafluoropropionated morphine in the range of 0--5 ng of morphine/ml of plasma had a standard deviation of +/- 0.46 ng/ml when 1 ml of plasma was taken. Liquid scintillation spectrometric analysis of 14C-morphine had a sensitivity of 1.5 ng/ml of plasma at double the background. There were no significant differences among the liquid scintillation, electron-capture GLC, and radioisotpoe derivatization methods for morphine obtained from the plasma of a dog given 14.00 mg iv of morphine. Morphine conjugates were assayed as morphine after the acid hydrolysis of plasma and urine preextracted to remove unconjugated morphine, and the equivalence of various methods was demonstrated to monitor plasma and urine pharmacokinetics in a dog.


Influence of food and fluid ingestion on aspirin bioavailability. The influence of test meals and accompanying fluid volume on aspirin bioavailability from commercial tablets was determined following single oral doses to healthy male volunteers. Plasma aspirin and salicylate levels were determined simultaneously using a GLC end-point. Area analysis indicated that approximately 5--8% of absorbed drug entered the systemic circulation as unchanged aspirin in nonfasted subjects compared to 16--18% in fasted individuals. Food tended to reduce the appearance rate of aspirin into the circulation, resulting in lower and somewhat more sustained levels than with fasting. Plasma salicylate levels were not influenced markedly by the various treatments, although levels were higher in fasted than in nonfasted subjects during the 1st hr after dosing. After this time, fat pretreatment tended to produce higher levels than other treatments.


Synthesis of oximes, aziridines, and allyl alcohols derived from substituted 1-phenyl-1-nonen-3-ones as potential cytotoxic and antitumor agents. A number of nuclear-substituted 1-phenyl-1-nonen-3-one oximes were synthesized. Reduction of several of these compounds with lithium aluminum hydride yielded the corresponding 1-phenyl-2,3-epiminononanes, shown by 100-MHz NMR spectroscopy to be the cis-geometrical isomers. When several ring-substituted 4-dimethylaminomethyl-1-phenyl-1-nonen-3-ones were treated with hydroxylamine hydrochloride under forcing conditions, the product isolated was the corresponding oxime. Reaction under mild conditions led only to the isolation of the Michael addition product of the oxime in low yield. Reduction of some nuclear-substituted 4-dimethylaminomethyl-1-phenyl-1-nonen-3-ones with sodium borohydride led to the formation of the corresponding allyl alcohols, and the products were shown by 1H- and 13C-NMR spectroscopy to be the threo-isomers or, alternatively, a mixture of erythro- and threo-isomers. Reaction of phosphoric acid with one of the substituted allyl alcohols led to a diolefin, shown by NMR spectroscopy to be a mixture of (E, E)- and (E, Z)-isomers in a ratio of 65:35.


Effect of antineoplastic and cytotoxic Mannich Bases derived from conjugated styryl ketones on mitochondrial respiration in rat liver cells. Five cytotoxic Mannich bases (5-dimethylamino-1-substituted phenyl-1-penten-3-ones), three having antineoplastic activity, were evaluated for respiratory-inhibiting properties in rat liver mitochondria in the presence of four substrates: succinate, glutamate, 3-hydroxybutyrate, and palmitylcarnitine. Four compounds (Ib--Ie) showed significant inhibiting properties which, on occasion, were reversed partially by coenzyme Q10. Evaluation of the spectra of the mitochondrial cytochromes indicated that Ib--Ie blocked the electron transport chain prior to the sequence of cytochromes. Since inhibition occurred when different substrates were used, a common site of action for Ib--Ie is likely; competition of Ib--Ie with coenzyme Q10 probably occurs. Compounds Ia--Ie inhibited RNA polymerase from Swiss mouse kidney cells but were virtually bereft of activity versus RNA polymerase from L-1210 leukemia cells. Polarography of the Mannich bases and the related styryl ketones showed that antineoplastic activity was associated with higher half-wave potentials.


Synthesis and evaluation of 1-(hydroxyphenyl)-1-nonen-3-ones and related compounds for antineoplastic and antimicrobial activities. Some 1-(hydroxyphenyl)-1-nonen-3-ones, the corresponding Mannich bases, and O-benzoyl esters were synthesized. Evaluation of these derivatives against murine P-388 lymphocytic leukemia indicated that, while the hydroxyphenyl styryl ketones and related esters were devoid of significant anticancer activities, etherification of the nuclear hydroxyl group gave compounds with a discernible increase in mean survival time. The hydroxyphenyl styryl ketones showed marked potencies against two pathogenic fungi and one, yeast, while the corresponding ethers had diminished activities and the related esters were virtually devoid of antimicrobial activities. Two Mannich bases showed similar spectra of antimicrobial activities as the phenols and, in particular, were active against Trichophyton mentagrophytes and Saccharomyces uvarum.


Effect of diphenhydramine on methaqualone metabolism: an in vitro study. A GLC assay to quantitate the methaqualone metabolite 2-methyl-3-(2-hydroxymethylphenyl)-4(3H)-quinazolinone was developed. Standard curves were linear, and recovery of the metabolite from tissue homogenates averaged 89%. In vitro metabolism of methaqualone by the 10,000Xg supernatant fraction of rat liver homogenate was measured by monitoring metabolite formation with the GLC assay. Diphenhydramine inhibited the in vitro metabolism of methaqualone. The percentage inhibition increased with increasing diphenhydramine concentration. The significance of this inhibition in relation to use and abuse of methaqualone--diphenhydramine combinations is discussed.


Radioimmunoassay of oxfendazole in bovine, equine, or canine plasma or serum. A simple radioimmunoassay was developed for the determination of oxfendazole in plasma. Oxfendazole N-1(3)-valerate was coupled to polylysine via a carbodiimide reaction, and antiserum was developed in rabbits after inoculation with oxfendazole--polylysine conjugate. The assay was developed so that oxfendazole could be measured directly in a 0.1-ml aliquot of diluted or undiluted plasma. With the developed procedure, 200 pg of oxfendazole/ml of plasma can be determined quantitatively. Cross-reactivity was determined for closely related compounds and metabolites. The method was used to determine plasma concentration--time profiles in dogs and calves.


Radioimmunoassay for psychotropic drugs I: synthesis and properties of haptens for chlorpromazine. For the development of radioimmunoassay procedures for chlorpromazine and its active metabolites, three chlorpromazine haptens, 7-(or  8-)(3-carboxypropionyl)chlorpromazine,  N-(3-carboxypropionyl)desmethylchlorpromazine, and N-(2-carboxyethyl)desmethylchlorpromazine, were synthesized and characterized by GLC--mass spectrometry, PMR spectrometry, and IR spectrophotometry. Each hapten was coupled to bovine serum albumin, and the number of hapten residues per mole of bovine serum albumin was calculated by UV spectrophotometric methods. Antibodies to each hapten--protein conjugate were obtained in rabbits, and titers of the antiserums were checked by evaluating their binding characteristics to tritiated chlorpromazine.


Radioimmunoassay for psychotropic drugs II: synthesis and properties of haptens for tricyclic antidepressants. For the development of radioimmunoassay procedures for tricyclic antidepressants, two drug haptens were synthesized for each of the two amitriptyline--nortriptyline and imipramine--desipramine groups. In one case, nortriptyline or desipramine was treated with succinic anhydride to yield N-(3-carboxypropionyl) derivatives; in the other case, the haptens were novel N-(2-carboxyethyl) derivatives. The hapten and its corresponding ester were characterized by GLC--mass spectrometry, PMR spectrometry, and IR spectrophotometry. Each hapten was coupled to bovine serum albumin, and the number of hapten residues per mole of bovine serum albumin was determined by UV spectrophotometric methods. Antibodies to each hapten--protein conjugate were developed in rabbits, and titers of the antiserums were checked by evaluating their binding characteristics to tritiated drug.


Pharmacokinetic evaluation of a drug interaction between kaolin--pectin and clindamycin. The effect of a kaolin--pectin antidiarrheal suspension on the bioavailability of orally administered clindamycin was evaluated by model-dependent pharmacokinetic techniques. Each subject's serum clindamycin concentration--time data in the absence of the kaolin--pectin suspension were fitted to a one-compartment open model with first-order absorption and lag time. The resulting disposition parameters were used to construct individual Wagner-Nelson absorption profiles, expressed as the cumulative relative fraction of clindamycin absorbed versus time following combined antidiarrheal--antibiotic therapy. For each subject, absorption persisted to varying degrees through 14 hr. On the average, the half-time for absorption was prolonged 20-fold (from about 16 min to more than 300 min). In contrast, extrapolation of the individual time courses of relative absorption to infinity revealed that the antidiarrheal had no effect on the extent of clindamycin absorption.


Influence of kaolin--pectin suspension on digoxin bioavailability. The effect of a kaolin--pectin suspension on the bioavailability of orally administered digoxin was evaluated when both drugs were given concomitantly and when their time of administration was separated by 2 hr. Coadministration of the antidiarrheal with the cardiac glycoside delayed absorption of the latter and, at the same time, decreased by 62% the amount of drug absorbed. Intersubject variation in digoxin bioavailability also was increased more than twofold. When the kaolin--pectin suspension was given 2 hr before the cardiac glycoside, the digoxin absorption rate was not affected, although its relative extent of absorption was reduced by about 20%. In contrast, when the antidiarrheal was given 2 hr after digoxin, neither the rate nor the extent of absorption of the cardiac glycoside was perturbed. No change in the intersubject variability in digoxin bioavailability was noted whether the antidiarrheal was given 2 hr before or 2 hr after the cardiac glycoside.


Pentobarbital absorption from capsules and suppositories in humans. Serum pentobarbital levels following administration of the sodium salt as a 100-mg capsule orally and as two 120-mg suppository formulations (A and B) rectally were measured. From these data and previously determined kinetic constants after intravenous administration, the absorption rates and bioavailability of pentobarbital from each dosage form were determined. All three dosage forms were 100% absorbed. Peak serum pentobarbital levels occurred at 1, 4, and 10 hr for the capsule, Suppository A, and Suppository B, respectively. In vitro studies agreed with the serum data in that Suppository A released drug in an in vitro aqueous pH 1.4 system at a much greater rate that Suppository B. The capsule and Suppository A both appeared to be absorbed by simple first-order processes; however, Suppository B had a complex absorption pattern, which was modeled using sequential zero-order and first-order absorption.


Nonisothermal aqueous calorimetry: computation of process-dependent temperature change and aspects of calorimeter design. A general method for determining the process-dependent (intrinsic) temperature change in a nonisothermal calorimeter is presented. The nonisothermal approach to calorimetric investigations requires an estimate of the magnitude of the process independent (extrinsic) temperature change during the reaction period. The proposed method can be applied to any calorimeter whose output is a discrete or continuous temperature--time profile. It is based on a first-derivative transformation of the temperature--time profile and the partitioning of the observed temperature variation into two components: pure extrinsic variation, which occurs outside the reaction period, and the combined extrinsic and intrinsic effects during the reaction period. Close examination of the pure extrinsic variation was considered essential, since it provided the basis for identifying the form of a descriptive mathematical function consistent with the observed extrinsic behavior. Once a suitable function was selected, parameters for the equation were determined through a linear regression procedure. The resulting equation was used to predict the extrinsic variation within the reaction period. Subtraction of predicted extrinsic variation from the observed total variation and integration over the time course of the experiment provide an estimate of the process-dependent temperature change. The differential approach was examined for processes performed in a calorimeter of simple design. Aspects of calorimeter design and advantages of the proposed method of data analysis are discussed.


Application of immersional calorimetry to investigation of solid-liquid interactions: microcrystalline cellulose-water system. A comprehensive characterization of the specific solid-liquid interaction for microcrystalline cellulose and water is presented. The procedure consisted of a conjoint vapor adsorption and immersional wetting experiment. The following information was obtained with respect to the solid. Estimates of the total surface are (138 m2/g) and the external surface (9.2 m2/g) were calculated from the adsorption and immersion data, respectively. Existence of an energetically homogeneous surface was verified by a linear decrease in the heat of immersion of samples containing adsorbed moisture approximately up to monolayer capacity. Integral and differential free energy, enthalpy, and entropy changes accompanying the adsorption process were calculated, and a lack of swelling was substantiated by comparison with a similar study of cellulose fibers. Immersional hysteresis was observed, and its magnitude suggested that sorption hysteresis was of enthalpic as well as entropic origin. The experimental method is potentially valuable for routine characterization of hydrophilic powders.


Glass formation in barbiturates and solid dispersion systems of barbiturates with citric acid. Glasses were prepared from a number of barbiturates. The viscosities and glass transition temperatures of the glasses were dependent on the structure of the groups present on the C-5 and N-1 atoms. Solid dispersions were prepared from three selected barbiturates formulated with citric acid. The glass transition temperatures of these systems indicated that a 1:1 molar ratio complex was formed between the two components and that intermolecular bonding was stronger in the complex than in the individual components.


Improved spectrophotometric determination of antazoline. A simple, precise, and accurate spectrophotometric determination of antazoline salts was developed by improving the ceric sulfate procedure. Replacement of water with acetic acid for the preparation of all assay solutions permitted reproducible measurements of the chromogen that absorbed at 505 nm. An appreciable increase in color stability was attained by the controlled addition of perchloric acid to the ceric reagent prior to interaction with antazoline at room temperature. Evidence is provided to account for the oxidation of antazoline at the expense of a complex ceric species. Other 2-imidazolines or phenylephrine did not interfere with the investigated color reaction. In addition to the high value of the chromogen molar absorptivity, ideal adherence of color absorption to Beer's law permitted accurate and reproducible estimation of antazoline over the 1--10-microgram range. The procedure was applied to the analysis of different antazoline dosage forms.


Effect of formulation and process variables on bioequivalency of nitrofurantoin I: preliminary studies. Fifty-two combinations of nitrofurantoin were developed to assess the effect of dosage form type, particle size, diluent, and process on in vitro availability. With the official procedure and conditions, dissolution rates fell in a 66-fold range. Statistical analysis of the dissolution rates indicated no significant differences as a result of particle size, processing method, or compression force. The diluent choice and dosage form type significantly influenced the dissolution rate. Based on in vitro screening, six formulations presenting a broad range of dissolution rates were selected for further study relating to human bioavailability and bioequivalence.


Effect of formulation and process variables on bioequivalency of nitrofurantoin II: in vivo-in vitro correlation. Based on preliminary in vitro evaluation, six formulations presenting a broad range of dissolution rates were selected for bioequivalency determination in a randomized complete block crossover. In vitro-in vivo correlations were developed relating cumulative percent dissolved to cumulative percent excreted. These correlations appear to be useful for comparing different formulations as well as different batches of the same formulation.


Evaluation of an oral prolonged-release antibiotic formulation. The antibiotic cephalexin was formulated as an oral prolonged-release tablet and evaluated by in vitro dissolution testing as well as in vivo in 10 human subjects. Comparisons were made of the time course of the blood levels among the prolonged-release formulation, the commercially available capsule, and intravenous administration. Even though lower peak blood levels were attained in the prolonged-release tablet, absorption continued for at least 6 hr. Comparison with in vitro dissolution data showed that absorption was dissolution rate limited. Bioavailability comparisons showed that the prolonged-release formulation was completely available, as was the commercial oral capsule.


High-pressure liquid chromatographic determination of 8-hydroxycarteolol in plasma and urine using electrochemical detection. Assay of 8-hydroxycarteolol (a metabolite of carteolol) was achieved using high-pressure liquid chromatography with electrochemical detection. Plasma or urine samples alkalinized by addition of a sodium carbonate solution were extracted with ethyl acetate or chloroform. The residues from evaporation of the organic extracts were redissolved in pH 2.1 phosphate buffer, and the solutions were chromatographed on a Partisil 10 SCX chromatographic column. The detection of 8-hydroxycarteolol was accomplished using an electrochemical detector. The procedure is rapid, specific, and highly sensitive. Reproducible results can be obtained, with relative standard deviations from analysis of replicate samples within +/- 8%. With 1-ml samples, the lower quantifiable concentrations of 8-hydroxycarteolol in plasma and urine are approximately 5 and 25 ng/ml, respectively.


Simultaneous programmed temperature GLC assay of phenol, chloroxylenol, and lidocaine hydrochloride in topical antiseptic cream. A simultaneous programmed temperature GLC assay for the active ingredients in a topical antiseptic cream is described. The sample is extracted directly using a dimethyl sulfoxide solution of p-cresol, 4-chlorophenol, and 2-amino-4-phenylthiazole as internal standards for phenol, chloroxylenol, and lidocaine hydrochloride, respectively. The resulting solution is chromatographed by temperature programming on an OV-225 column from 90 to 225 degrees. The internal standard calculation is accomplished using peak heights or peak areas. The relative standard deviation of all assays is less than 2%.


Drug resistance studies with topical antiseptics. Species of Proteus, Serratia, and Pseudomonas became resistant to chlorhexidine after five to eight transfers in vitro. Cross-resistance to benzalkonium chloride also was detected. Resistance to povidone-iodine was not encountered. Chlorhexidine resistance was stable after drug-free transfers of Serratia and Pseudomonas but was transitory for Proteus.


Aspirin stability in solid dispersion binary systems. The stability of aspirin in its solid dispersion with urea or povidone was investigated at two accelerated storage conditions. The observed aspirin degradation in both systems followed the first-order rate equation. The water sorption ability of the two carriers as well as the alkalinity imparted by urea could possibly be the most important factors responsible for the observed acceleration of aspirin decomposition. The results also showed that the temperature effect was more pronounced than the humidity effect. Generally, coprecipitated samples exhibited slightly higher degradation rates than physically mixed ones.


Odoratin and paucin: cytotoxic sesquiterpene lactones from Baileya pauciradiata (Compositae). An ethanol extract of Baileya pauciradiata exhibited cytotoxic activity against the human epidermoid carcinoma of the nasopharynx and the lymphocytic leukemia test systems. Two constituents responsible for this activity were isolated and identified as odoratin and paucin. Their identities were proven by IR, PMR, and mass spectral data; elemental analysis; preparation of their acetates; and melting-point determinations. Odoratin was confirmed by comparison with an authentic sample.


Determination of phenylpropanolamine salts in dosage forms through fluroescent derivative formation. Phenylpropanolamine was determined by measuring its fluorescent fluorescamine derivative. The method is rapid, sensitive, and easily automated. Statistics are presented for an effervescent cold product, and recovery data are presented for other commercially available products.


Thimerosal determination by high-pressure liquid chromatography. A sensitive and useful high-pressure liquid chromatographic method for the determination of intact thimerosal was developed. This method is extremely fast and reliable, and its inherent specificity makes it a breakthrough over other common wet chemical methods.


Hypotensive effect induced by a cyclic dopamine analog, trans-4-methyl-7,8-dihydroxy-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline. The antihypertensive effects of trans-4-methyl-7,8-dihydroxy-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline, a dopamine agonist, were investigated in dogs and spontaneous hypertensive rats. Intravenous administration of low doses of this cyclic analog of dopamine (0.25--1.00 microgram/kg) consistently reduced blood pressure and heart rate, concurrently recorded in the dog. This effect was antagonized by haloperidol, a specific dopamine antagonist. The dopamine analog also reduced systolic blood pressure of spontaneous hypertensive rats. This study confirmed the possibility that the decrease in blood pressure and heart rate elicited by the dopamine analog is attributable to an effect on specific dopaminergic receptors.


Determination of flucytosine in tablets by differential pulse polarography. A differential pulse polarographic assay was developed for determining flucytosine in tablets. The drug is extracted from the sample with water and hydrochloric acid and, after the pH is adjusted, an aliquot is added to the cell and the solution is polarographed at the dropping mercury electrode versus the saturated calomel electrode with 0.066 M Sørensen phosphate buffer (pH 5.6) as the supporting electrolyte. The polarographic peak height enables precise quantitative determination. The Ep value for flucytosine is--1.54 v versus the saturated calomel electrode. The mean recovery of the drug is 101.5% +/- 1.9 (SD). The method is simple, rapid, and precise.


Effects of pharmacological intervention on infarct size following induced myocardial infarction in rats. Several therapeutic agents that alter infarct size were administered to rats with myocardial infarcts induced by electrocauterization. The myocardial tissue damage and infarct size correlated well with the creatine phosphokinase myocardial band activity, and these markers were utilized to assess the action of the therapeutic agents on myocardial tissue damage. Hyaluronidase, insulin, potassium chloride, and isoproterenol increased myocardial tissue damage whereas heparin and prednisolone administration resulted in decreased myocardial tissue damage after induced myocardial infarction in rats.


Rapid GLC determination of chlordiazepoxide and metabolite in serum using on-column methylation. A rapid GLC method was developed for the assay of chlordiazepoxide in serum. After chlordiazepoxide was extracted with ether, it was methylated with trimethylanilinium hydroxide in the injection port and detected by electron capture. The assay is simple and sensitive and can be automated for large-scale clinical analysis.


The effects of anthopleurin-A on cardiac dynamics in conscious dogs. The effects of anthopleurin-A (AP-A), a selective cardiotonic drug, on cardiac dynamics in intact, awake animals were examined. Dogs were instrumented in order to record left ventricular pressure, the derivative of left ventricular pressure (dP/dt), arterial pressure left ventricular end-systolic and end-diastolic diameters, cardiac output, left atrial pressure and heart rate. Left ventricular pressure, dP/dt, stroke volume and cardiac output were significantly increased (16, 46, 37 and 23%, respectively) by AP-A. AP-A significantly diminished heart rate 9 beats/min and left ventricular end-systolic diameter 1.9 mm. Mean arterial pressure, mean left atrial pressure and left ventricular end-diastolic diameter were unaltered by AP-A. Autonomic blockade with atropine and propranolol did not alter these responses on the myocardium qualitatively. Thus, it appears that AP-A has a direct positive inotropic effect on the myocardium in conscious animals with little or no effect on the peripheral circulation.


The effects of verapamil and lidocaine on the automatic depolarizations in guinea-pig ventricular myocardium. Rhythmic automatic depolarizations (RAD) were produced in guinea-pig papillary muscles depolarized to membrane potentials at which depolarizations depend on membrane currents passing through the slow channel. Verapamil depressed the RAD and decreased their overshoot. These verapamil effects were dependent on its concentration either in the bath (in vitro) or in plasma and myocardium (in vivo). Increase in [Ca++] counteracted the effects of verapamil on RAD. Lidocaine concentrations ranging from 4 to 16 mg/l had no effect on overshoot and only a slight effect on the rate of RAD. We conclude that RAD are more sensitive to nonlethal and presumably therapeutic concentrations of verapamil than to high, presumably toxic, concentrations of lidocaine.


Dithiothreitol-induced alterations of blood pressure, vascular reactivity and aortic microsomal calcium uptake in spontaneously hypertensive rats. Dithiothreitol, a potent sulfhydryl reducing agent, depressed systolic blood pressure to a greater extent in genetically hypertensive rats (SHR) than in normotensive Wistar-Kyoto rats (WKY). Dithiothreitol depressed the contractile response to norepinephrine and potassium chloride of isolated aortic strips from both SHR and WKY. Dithio-bis-2-nitrobenzoid acid, a sulfhydryl oxidizing agent, restored the responsiveness of rat aortic strips to these contractile agents. Microsomes isolated from rat aortae sequester calcium in the presence of ATP. This activity, generally referred to as calcium-pump activity, has been postulated to function in smooth muscle relaxation, and is significantly depressed in aortic microsomes of the SHR. Dithiothreitol (10 mM) greatly increased and dithio-bis-2-nitrobenzoic acid (100 micrometer) decreased the ATP-dependent calcium pump activity of microsomes isolated from both SHR and WKY aortae. These observations indicate that sulfhydryl groups may influence systems involved in vascular reactivity and blood pressure regulation.


The sources of calcium for acetylcholine-induced contractions of dog tracheal smooth muscle. Acetylcholine (ACh)-induced contractions of dog tracheal smooth muscles were studied in order to determine the sources of Ca++ for these contractions become diminished with time at all drug doses and experiments with 45Ca indicate that this phenomenon is related to the efflux of Ca++ from the muscle. This efflux of Ca++ consists of two components, a loosely bound and a tightly bound Ca++ source, and is dependent upon the dose of drug. At low doses of ACh (less than 10(-6) M) loosely bound Ca++ plays a greater role and tightly bound Ca++ a lesser role than at higher drug doses. Verapamil, a blocker of depolarization-dependent Ca++ influx, inhibits ACh contractions at low drug doses but has no effect at higher doses. These results indicate that the sources of Ca++ for ACh contractions of the trachea are dependent upon the drug dose. At low doses of ACh (less than 10(-6) M ACh) depolarization-dependent Ca++ influx is involved in musch of the contraction. At the higher drug doses a tightly bound Ca++ source and a depolarization-independent, loosely bound Ca++ source account for the contractions.


The effects of ouabain and alterations in potassium concentration on the sensitivity to drugs and the membrane potential of the smooth muscle of the guinea-pig and rat vas deferens. Previous work has suggested partial depolarization of the smooth muscles cells to be an important factor in the post junctional supersensitivity induced in the guinea-pig vator in the post junctional supersensitivity induced in the guinea-pig vas deferens by chronic denervation or decentralization. The present experiments were undertaken to explore, under acute in vitro conditions, the relationship between membrane potential changes and sensitivity in the vasa deferentia of guinea pigs and rats. The results indicate that sensitivity was altered whenever resting potential was changed by 7 to 10 mV. The results also indicated that considerable electrophysiologic differences exist between the smooth muscles of the guinea-pig and rat vas deferens. Notably, ouabain or lowered external potassium caused a partial depolarization of the guinea-pig, but not the rat, vas deferens. The results, especially when combined with evidence that the rat vas deferens does possess a considerable amount of (Na+-K+)-adenosine triphosphatase, which is ouabain-sensitive, indicates that under the conditions of these experiments the Na pump is electrogenic in the guinea-pig, but not the rat, vas deferens.


Effects of norepinephrine, dopamine and potassium on tension and 45Ca fluxes in canine and rabbit renal arteries. The action and interactions of three vasoconstrictors, norepinephrine (NE), dopamine (DA) and elevated potassium ion (K+) on contractile responses and associated 45Ca movements were investigated in isolated rabbit and canine renal arteries (RA). Dose-response curves indicate that NE is 39 times more potent than DA in canine RA and 122 times more potent in rabbit RA. Prior exposure to 80 mM K+ did not prevent contractile responses to NE or DA but, conversely, K+ -induced responses did not occur after exposure to NE or DA. Responses to NE persisted after maximum DA-induced contractions but only a small response to DA was observed after a maximum NE-induced contraction. After 30 to 60 min in either a O-Ca or a O-Ca plus 0.05 mM EDTA solution, contractile responses were differentially inhibited (K+ more than DA more than NE). Efflux of 45Ca into a O-Ca plus EDTA solution was qualitatively similar in canine and rabbit RA. Addition of K+, DA or NE decreased the rate of 45Ca efflux in both RA; phentolamine abolished the NE-induced decrease and had no effect on the K+-induced decrease. The observed decrease in 45Ca efflux may reflect an inward shift of 45Ca from membrane binding sites. The mechanisms by which this effect is obtained appear to differ for K+, DA and NE. The differing actions of NE and DA cannot be explained solely by variations in potency at a singel type of receptor.


The effects of exogenous norepinephrine on ventilatory mechanics in the rat. The effects of intravenous administration of norepinephrine on ventilatory mechanics were assessed in the anesthetized, spontaneously breathing rat. Pulmonary resistance, dynamic compliance and functional residual capacity remained unchanged during a 10-min infusion period. After paralysis, repetition of the norepinephrine infusion caused an increase in static deflation recoil pressure at lung volumes above the tidal range but maximum expiratory flow rates at corresponding lung volumes were not increased indicating an elevation in the resistance of upstream airways. Flow rate responses to low density gas breathing were not enhanced by norepinephrine suggesting peripheral airways narrowing as the cause of the increased upstream resistance. Isoproterenol protected animals against serotonin-induced bronchoconstriction whereas norepinephrine augmented the response to serotonin. It is concluded that in intact rats norepinephrine increases the flow-resistive properties of peripheral airways, does not measurably alter the caliber of central airways and possesses no discernible bronchodilator activity. The effects of norepinephrine on small airways appear to be secondary to changes in pulmonary hemodynamics rather than the result of direct stimulation of alpha adrenoceptors in airway smooth muscle.


The effects of arachidonic acid on erythropoietin production in exhypoxic polycythemic mice and the isolated perfused canine kidney. The ability of arachidonic acid (AA), the bisenoic prostaglandin precursor to stimulate erythropoiesis and erythropoietin (Ep) production in exhypoxic polycythemic mice and the programmed isolated perfused canine kidney was investigated. Arachidonate in the lowest dose tested (50 microgram/kg i.p.) maximally stimulated erythropoiesis when administered to exhypoxic polycythemic mice. Kidneys from dogs made hypoxic for 4 hr at 0.42 atm pressure were perfused (2--3 ml/g/min, 37 degrees C) in a closed circuit system for 5 hr with blood from nonhypoxic donors. AA infusion (80 microgram/min) caused a significant (P less than .05) increase in erythropoietic activity of the perfusate as measured by the percentage of 48-hr 59Fe incorporation into red blood cells of exhypoxic polycythemic mice per milliliter of perfusate from an initial value of 1.66 +/- 0.50% to 6.05 +/- 0.96% over the 1st hr of infusion whereas vehicle controls showed no change. To determine whether this increase in Ep production was dependent on biosynthesis of renal prostaglandins and their intermediates, the ability of indomethacin to block AA-induced  Ep production was studied. When kidney donors were twice pretreated with indomethacin 12 hr and immediately before their hypoxic exposure, no increase in Ep titers were seen during AA infusion. These results support the hypothesis that endogenously synthesized prostaglandins, their intermediates and/or other products of AA metabolism, such as prostacyclin and prostaglandins play an important role in the control Ep production.


Pirbuterol, a selecttve beta2 adrenergic bronchodilator. Pirbuterol, 2-hydroxymethyl-3-hydroxy-6-(1-hydroxy-2-tert-butylaminoethyl)pyridine, is a new beta2 adrenergic agonist bronchodilator. Comparison of the relative potencies of pirbuterol, salbutamol and isoproterenol as relaxants of isolated guinea-pig tracheal muscle and as positive chronotropic agents in isolated guinea-pig atria indicate that the relative selectivity of pirbuterol for pulmonary as opposed to cardiac tissue is 9 times greater than that for salbutamol and some 1500 times greater than that for isoproterenol. Pirbuterol is effective by the oral, intravenous and inhalation routes of administration. In conscious guinea pigs, pirbuterol antagonizes both histamine- and acetylcholine-induced bronchoconstriction and "microshock" anaphylaxis; combinations of pirbuterol and theophylline cause additive effects against histamine-induced bronchoconstriction. In conscious dogs, the cardiovascular effects of pirbuterol are clearly distinguished from those of salbutamol, in that salbutamol causes a more pronounced tachycardia. In anesthetized dogs the cardiovascular effects of pirbuterol and salbutamol are comparable; they are less potent than isoproterenol and have less pronounced although longer lasting effects.


Beta adrenergic stimulation of protein carboxymethylation and amylase secretion in rat parotid gland. Protein carboxymethylase (S-adenosyl-l-methionine:protein-O-methyltransferase, EC 2.1.1.24) transfers methyl groups from S-adenosylmethionine to protein carboxyl groups. This cytosolic enzyme is found in highest concentration in secretory tissue and methylates membrane proteins. Stimulation of the parotid gland by catecholamines rapidly and reversibly increases protein carboxymethylase activity and methyl acceptor capacity of proteins in parotid homogenates. Isoproterenol was effective at concentrations causing amylase release in vivo and in vitro. Both enzyme activity and methyl acceptor capacity of proteins increased within 5 min, continued to increase for 30 min and then declined to control values within 60 min. The response to isoproterenol was stereospecific. The action of isoproterenol could be blocked by the beta adrenergic antagonist propranolol, while the alpha adrenergic agonist phenylephrine did not stimulate the enzyme or increase methyl acceptor proteins. Methyl acceptor proteins have been partially characterized by polyacrylamide gel electrophoresis. Although many proteins in the parotid are methylated, only two groups of methylated proteins increase after stimulation by isoproterenol.


Analysis of the bradykinin response in dogs and its antagonism by analgesic drugs. Dogs respond to bradykinin (triacetate) by struggling, vocalizing, and/or biting. In 128 dogs used twice, the threshold dose of the peptide increased more than 2-fold, while its onset and duration of action were unchanged. In both trials, the frequency distribution of the threshold dose was not normal; struggling occurred alone or with vocalization and/or biting in 95% of the animals in the first trial and in 96% of the animals in the second trial. In assaying analgesic drugs for antibradykinin activity, multiples of the threshold dose of the peptide were given after oral administration to compensate for tachphylaxis. The oral ED50 values (95% confidence limits) were 0.80 (0.50--1.06) mg/kg for d-amphetamine, 1.20 (0.63--2.57) mg/kg for indomethacin, 1.90 (0.50--6.48) mg/kg for methadone, 15.0 (8.0--30.9) mg/kg for phenylbutazone and 50.0 (20.0--120.0) mg/kg for acetylsalicylic acid. ED50 values for d-proproxyphene, codeine, meperidine, pentazocine and ethoheptaxine by the oral route could not be determined. The intravenous ED50 (95% confidence limits) of meperidine was 0.80 (0.30--1.90 mg/kg. The antibradykinin model in dogs is sensitive to orally administered acetylsalicylic acid-type analgesic compounds which may be a reflection of their prostaglandinsynthetase inhibiting properties.


Enhancement of morphine analgesia and brain levels by methamphetamine in mice. Methamphetamine and morphine were approximately equipotent in producing analgesia in mice using the tail-flick assay. The ED50 for morphine analgesia was significantly reduced when 3.2 mg/kg of methamphetamine was given 5 or 60 min before morphine. Methamphetamine pretreatment increased the peak effect but did not alter the duration of morphine analgesia. Enhancement of morphine analgesia was apparent when methamphetamine was given up to 60 min before morphine and it did not coincide with analgesia produced by methamphetamine alone. Brain levels of morphine were found to be significantly higher in methamphetamine- compared to saline-pretreated mice, at times when enhanced analgesia was observed. Further studies showed that morphine brain levels were increased by methamphetamine pretreatment in an apparent dose-dependent manner. The analgesia observed at several morphine brain levels was compared in order to determine whether enhanced analgesia resulted from increased morphine brain levels. Methamphetamine administration 5 or 60 min before morphine shifted the log morphine brain level-response curves for morphine analgesia to the left and the morphine brain level at a given percent analgesia was significantly lower in methamphetamine- than in saline-pretreated mice. In addition, methamphetamine pretreatment enhanced methadone analgesia but had no effect on methadone brain levels.


Effects of natural pyrimidines and of certain related compounds on the spontaneous activity of the mouse. Uracil and perhaps other natural pyrimidines may effect the level of arousal of the mammalian brain since: 1) heterocyclic 6-membered rings, which resemble uracil, form part of the structure of many hypnotics; and 2) 6-azauracil (and its riboside) have shown to be hypnotic for several mammalian species, including man. The parenteral administration of uridine, 6-azauridine, cytidine or thymidine depressed the spontaneous activity of adult male C-57 mice. 6-Azauridine was much less potent than the other ribosides tested. Cytosine, barbituric acid, 2-thiobarbituric acid, 2,4-dihydroxypyridine and a variety of pyrimidine catabolites had no effect on activity. Thymine, uracil, 6-azauracil, barbital and phenobarbital increased activity at lower doses and decreased activity at higher ones. 6-Azauracil and uracil were about equally potent as stimulants of activity, but 6-azauracil had about twice the potency of uracil as a depressant of activity. Thymine, which was more active than uracil, had about 10% the potency of barbital, both as a stimulant and as a depressant of activity. For thymine and the two barbiturates the ED50 (for depression of activity) was of the same magnitude as the LD50, while the dose which caused 50% stimulation of activity was about an order of magnitude less than the LD50. These results suggest that the barbiturates might affect arousal by simulating the structure of thymine or uracil at some receptor.


Chronic chlordiazepoxide and pentobarbital interactions on punished and unpunished behavior. Dose-effect curves were determined in rats for the effects of drugs on punished and unpunished responding maintained by fixed-interval schedules of food presentation before, during and after the drinking of large daily doses of chlordiazepoxide and pentobarbital. An average intake of 50 mg/kg/day of chlordiazepoxide produced tolerance to the rate-decreasing effects of chlordiazepoxide on unpunished responding and cross-tolerance to the rate-decreasing effects of pentobarbital. During chlordiazepoxide drinking, rate-increasing effects of both chlordiazepoxide and pentobarbital on punished responding became apparent. There was no evidence for cross-tolerance between chlordiazepoxide and chlorpromazine. An average intake of 100 mg/kg/day of pentobarbital produced similar evidence of tolerance to the rate-decreasing effects of pentobarbital on unpunished responding and cross-tolerance to the rate-decreasing effects of chlordiazepoxide. Removal of chlordiazepoxide from the drinking water temporarily increased unpunished responding; however, 6 weeks after withdrawal of chlordiazepoxide or pentobarbital from the drinking water, the dose-effect curves for injections of these drugs appeared to be returning to their original positions.


Hypothermia and the pharmacokinetics and pharmacodynamics of pancuronium in the cat. We tested the effect of hypothermia on the pharmacokinetics and pharmacodynamics of pancuronium in the cat. In 14 cats given pancuronium, 120 microgram/kg i.v., we found that neuromuscular block lasted between 2.5 and 3.0 times longer at 29 degrees C (N = 5) than at 34 degrees C (N = 5) or 39 degrees C (N = 4). The apparent plasma elimination half-life was 46 +/- 7 min (S.E.) at 29 degrees C as compared to 21 +/- 2 and 25 +/- 6 min at 34 and 39 degrees C, respectively. The volume of distribution of the central compartment and total volume of distribution at steady state were less at 29 and 34 dgrees C than at 39 degrees C. Total plasma clearance was 4.3 +/- 0.4 ml/kg/min at 29 degrees C and 10.7 +/- 0.9 and 10.9 +/- 1.5 ml/kg/min at 34 and 39 degrees C, respectively. The reduced plasma clearance resulted at least in part from a markedly reduced biliary and urinary excretion of pancuronium at 29 degrees C as compared to 34 and 39 degrees C. In four other cats, the plasma concentration of pancuronium was correlated with depression of twitch tension under steady-state conditions. The ED50 of pancuronium (plasma concentration required for a 50% depression of twitch tension) was 0.035 and 0.073 microgram/ml at 29 and 38 degrees C, respectively. We conclude that a pancuronium neuromuscular block is prolonged at 29 degrees C because of an increased sensitivity of the neuromuscular junction to pancuronium and delayed biliary and urinary excretion.


The comparative potency and pharmacokinetics of pancuronium and its metabolites in anesthetized man. To determine the potency of pancuronium and its metabolites, 3-OH-, 17-OH- and 3,17-OH-pancuronium, cumulative dose-response curves were determined in five anesthetized patients with each drug. Pancuronium (ED50 = 0.041 mg/kg) was 2 times more potent than 3-OH-pancuronium (ED50 = 0.082 mg/kg), 50 times more potent than 17-OH-pancuronium (ED50 = 2.0 mg/kg) and 54 times more potent than 3,17-OH--pancuronium (ED50 = 2.15 mg/kg). In 21 other patients, one equipotent dose of either pancuronium or one of its metabolites was given as an i.v. bolus. Onset time and duration of neuromuscular blockade from 3-OH- and 3,17-OH-pancuronium did not differ significantly from that of pancuronium; 17-OH-pancuronium had a shorter duration of action than did pancuronium. Although pancuronium tended to have a slightly longer elimination half-life, the pharmacokinetics of the four drugs did not differ significantly. The elimination half-lifes were 110, 68, 73 and 71 min for pancuronium and its 3-OH, 17-OH and 3,17-OH derivatives, respectively. We conclude that although pancuronium is more potent than its 3-OH, 17-OH and 3,17-OH metabolites, the pharmacokinetics of these three metabolites do not differ from each other and from that of pancuronium.


Metabolism of amphetamine after acute and chronic administration to the rat. The distribution of amphetamine (AMPH) and its hydroxylated metabolites p-hydroxyamphetamine (POHA), p-hydroxynorephedrine (POHNOR) and p-hydroxyamphetamine glucuronide (POHAG) in various tissues was studied after acute and chronic administration of AMPH to rats. After intraperitoneal administration of a single dose of [3H]AMPH, tissue [3H]AMPH levels increased rapidly to a maximum within 15 to 20 min of administration and then declined biphasically [(t1/2 = 0.5--0.9 hr for the distribution phase (alpha) and 5--9 hr for the elimination phase (beta)]. Tissue [3H]POHA levels and liver [3H] POHAG levels also increased rapidly and then declined exponentially (t1/2 = 4--10 hr for POHA), while tissue [3H]POHNOR increased gradually and declined with a half-life of 18 to 24 hr. The distribution of [3H]AMPH and its 3H-metabolites after a single dose of [3H] AMPH changed significantly after chronic administration of amphetamine. [3H]AMPH content in tissues of chronically treated rats was significantly greater 30 min after [3H]AMPH administration than that observed in tissues of animals not previously treated with AMPH. The disappearance of [3H]POHA from liver and [3H]POHNOR from heart was accelerated and the disappearance of [3H] POHAG from liver was slowed in chronically treated animals relative to controls, while the half-life of [3H]AMPH was unchanged in these animals. Tissue content of both AMPH and POHNOR 12 hr after the last of six doses of AMPH was significantly greater than that observed after a single dose, suggesting that significant accumulation of both compounds occurs during chronic AMPH administration. These studies suggest that the changes in the distribution of AMPH and its active metabolites which occur during chronic AMPH administration might be involved in the altered behavioral response to AMPH observed during such chronic administration.


First-pass effect of norethindrone in rabbits and rats. The influence of the route of administration on the pharmacokinetics of the synthetic progestogen norethindrone was studied in the rabbit and rat. In the rabbit, the area under the curve (AUC) after oral administration was 54% of that after i.v. administration. In the rat, the AUC after administration into the hepatic portal vein was 32% of AUCi.v.; after oral administration the AUCoral was 13.7% of AUCi.v. and 57.6% of AUCportal. Therefore, in both the rabbit and rat norethindrone is subject to a first-pass effect. Using the technique of constant withdrawal of blood from the hepatic portal vein after drug administration into the gastrointestinal tract, it was shown the norethindrone is metabolized in the gut wall. Hence, in the rat at least, there are both intestinal and hepatic components of the overall first-pass effect. In addition, increasing the time of intraportal injection from 15 sec to 2 min (thereby reducing the rate of drug delivery to the liver) resulted in the AUC being reduced by 40%. Dose-dependent kinetics were observed with doses of norethindrone greater than 500 microgram/kg.


The metabolism and active excretion of the hypoxanthine by the renal tubules in the chicken. Infusion of [14C]hypoxanthine into one renal portal circulation of the chicken resulted in an excess of [14C]uric acid excreted into the urine from the infused side kidney. No [14C]hypoxanthine appeared in the urine from either kidney. When the renal metabolism of [14C]hypoxanthine was inhibited by xanthine dehydrogenase inhibitors, almost no excess 14C-label appeared in the urine of the infused side suggesting that formation of nephrogenic urate plays an important role in the tubular excretion of hypoxanthine. A comparison of the effects of inhibitors on the renal excretion of preformed urate and nephrogenic urate suggests the existence of a p-aminohippurate-independent transport step for purines at the luminal membrane of the renal tubular cell. Studies with transport inhibitors suggest that the active transport step is anionic in character.


The rates of interaction of local anesthetics with sodium channels in nerve. Voltage clamp experiments were carried out on Rana catesbiana nodes of Ranvier in order to test predictions regarding the relationship between local anesthetic lipid solubility and the rate of development of and recovery from frequency-dependent increments of sodium channel block. Contrary to expectations, the drugs of greater lipid solubility than lidocaine showed slower rates of development of frequency-dependent block and, in addition, induced longer rather than shorter memories for recent frequency-depent increments in channel block. Relaxation time constants for bupivacaine (50 micrometer), etidocaine (15 micrometer) and tetracaine (0.7 micrometer) measured 50, 8 and 8 sec, respectively, compared to shorter time constant of 2 sec for lidocaine (250 micrometer). Rate constants were calculated for binding to channels in both open and closed states. Open channels displayed a 130- to 6000-fold greater affinity for the local anesthetics than did closed channels, verifying an important feature of the "modulated receptor" hypothesis. In addition, binding to closed channels was enhanced by holding the membrane at more depolarizing potentials, which favored the development of inactive channel states. The exceptionally large binding constants of lidocaine for interactions with both closed and open channels cannot be attributed to its lipid solubility characteristics alone.


Investigation of a dopaminergic mechanism for regulating oxytocin release. The isolated hypothalamo-neurohypophysial system (HNS) of male rats was incubated with putative neurotransmitters in vitro to determine their significance in regulating oxytocin release. Dopamine was found to inhibit the spontaneous release of oxytocin from the HNS in a dose-related manner. The maximum inhibition produced by dopamine (10(-9) M) was significantly different from control values and was blocked by haloperidol (5 x 10(-5) M). Apomorphine (10(-9) M) mimicked the effect of dopamine on this system. The type of receptor involved in the inhibitory effect on oxytocin release is unclear, although a dopaminergic mechanism in vivo. When levodopa plus carbidopa were injected into male rats, the gland content of oxytocin in these animals was significantly increased over control values. When a similar dosage regimen was employed with pregnant rats beginning on day 16 of gestation, levodopa plus carbidopa delayed the average delivery time 12 hr. The results of these studies are also consistent with a dopaminergic mechanism for the regulation of oxytocin release.


Effects of chronic marihuana use on integrated plasma testosterone and luteinizing hormone levels. Integrated plasma testosterone and luteinizing hormone levels were determined for 13 healthy adult males before, during and after a 21-day period of marihuana use. No significant relationships were found between antecedent or concurrent marihuana smoking and integrated plasma testosterone and luteinizing hormone levels. All values for all subjects obtained during the entire study were within normal limits for healthy adult males.


Nonsteroid anti-inflammatory agents: regulators of the phagocytic secretion of lysosomal enzymes from guinea-pig neutrophils. Several nonsteroid anti-inflammatory agents were evaluated for their capacity to modulate phagocytosis by and lysosomal enzyme secretion from polymorphonuclear neutrophils. During cell contact with and phagocytosis of serum-treated zymosan particles, guinea-pig neutrophils demonstrated a selective extracellular release of lysosome granule-associated beta-glucuronidase and acid protease but not cytoplasmic lactate dehydrogenase. Ketoprofen, suprofen, diftalone, benoxaprofen and Abbott 29590 inhibited particle uptake by and lysosomal enzyme release from neutrophils incubated with zymosan in Krebs-Ringer phosphate medium containing 7.5 mM glucose, pH 7.4, AT 37 degrees C. Flazalone and sulindac were inactive. In the presence of cytochalasin B, an agent which inhibits phagocytosis while having no effect on the selective discharge of lysosomal enzymes, ketoprofen, suprofen, diftalone, benoxaprofen and Abbott 29590 continued to inhibit the release of beta-glucuronidase and acid protease from neutrophils. An investigation of the properties of guinea-pig neutrophil acid protease activity revealed a pH optimum of 3.5. Activity was inhibited by diazoacetyl-DL-norleucine methyl ester and p-hydroxyphenylpyruvic acid. Sulfhydryl inhibitors, chelating agents and soybean trypsin inhibitor had no effect on neutrophil acid protease activity. These studies indicate that certain nonsteroid anti-inflammatory agents may function as regulators of the phagocytic secretion of lysosomal enzymes from neutrophils; and that these neutrophils contain an acid protease which resembles an enzyme known to mediate tissue destruction in several inflammatory diseases.


Effect of inhibitors of prostaglandin synthesis and prostaglandins E2 and F2alpha on the immunologic release of mediators of inflammation from actively sensitized guinea-pig lung. Histamine and slow reacting substance of anaphylaxis (SRS-A) were released from actively sensitized guinea-pig chopped lung fragments (100 mg) in a concentration dependent manner by 0.2 to 100 microgram/ml of antigen. Individual variation between lungs in the proportion of the total histamine released by antigen (20 microgram/ml) showed a normal frequency distribution (n = 95). The effect of inhibitors of prostaglandin (PG) synthesis on the release of histamine and SRS-A was examined. Indomethacin (0.03--13 micrometer), racemic 6-chloro-alpha-methylcarbazole-2-acetic acid (0.03--3 micrometer) and sodium salicylate (0.8--8 micrometer) stimulated histamine release by high concentrations of antigen (more than 10 microgram/ml) but had no effect at low concentrations of antigen. These agents stimulated the release of SRS-A at all antigen concentrations tested. In contrast, 5,8,11,14-eicosatetraynoic acid (0.04--42 micrometer) had no effect on the release of histamine but inhibited the release of SRS-A. Histamine release was stimulated by exogenous PGF2alpha (0.01--1 micrometer) in lungs which had control releases in the 25th percentile of the frequency distribution, but was unaffected by exogenous PGE2 (0.01--10 micrometer). In the presence of blockade of PG synthesis by indomethacin (13 micrometer), the stimulatory effect of PGF2alpha was enhanced while PGE2 antagonized the stimulatory effect of indomethacin. These results suggest that 1) histamine and SRS-A release from guinea-pig lung is regulated in part by the de novo synthesis of prostaglandins and 2) that SRS-A synthesis and release is influenced by a metabolite of arachidonic acid produced by a metabolic pathway other than cyclooxygenase.


[Studies on righting reflexes in newborn cats falling in the air (author's transl)]. The classical righting reflexes have been well illustrated in the familiar example of a falling adult cat, which always lands deftly on all four feet. It, however, has never been clear when newborn animals come to turn themselves in the air after birth. In the present studies the newborn cats were dropped in the air with legs pointed upward from a height of about 30 approximately 40 cm, and the observations were continued for the period of 36 days. The results were as follows: 1. The newborn cats fell plump on their back when they were dropped with legs pointed upward in the air. 2. No righting reflexes were observed in the cats of 27 days and downward. 3. The eyelids (rima palpebrarum) of the cats came to be open on the 8th approximately 14th after birth. 4. The cats which were suggested to obtain full eyesight judged from the observations of their behaviours had no visual righting reflexes when dropped with legs pointed upward. 5. The walking pattern of the cats changed in association with their growth. For the period of 20 days after birth the type of locomotion was creeping, for the period of 21st approximately 26th plantigradation, and after the 26th approximately 27th digitigradation. 6. It has been concluded that the righting reflexes as compound reflexes are never observed in the experimental cats for about one month after birth even though the cats have obtained each postural reflex, i.e. tonic neck or labyrinthine reflex which constitutes righting reflexes.


Linguistic negation in autistic and normal children. Young, severely maladaptive autistic children with some speech competence were compared to normally developing 3-year-old children of lower and middle class and 5-year-olds of lower class on negation tasks. All subjects were shown 12 sets of cards depicting negative contrasts designed to elicit semantic categories of nonexistence, denial, and rejection and were tested for production, imitation, and comprehension. Syntactic and semantic analysis revealed that autistic children were superior imitators and poor producers but showed skills in comprehension comparable to a 4-year-old's level of functioning. While retarded in some functions, the experimental group produced syntactic structures that were more rigid, suggesting the significantly greater use of imitation as a major strategy in linguistic coding.


Toward a differentiation of descriptive and psycholinguistic language models: perceptual and orthographic/phonological analysis of spelling strategies. Linguistic concepts of the principles and rule systems composing language are instantiated in the models known as grammars. These grammars, typically generative in format, are descriptions of those representatives of universal rule processes found in the particular language being described. Many psycholinguists are now becoming concerned with how to determine to what extent such formal descriptive language models also embody psychologically valid descriptions of speaker processes. It is this issue to which the current article is addressed. The psycholinguistic validity of a language model may be studied by experimental investigation of the degree to which speaker behaviors follow the patterns dictated by linguistic theory. In this article, English phonology, specifically the nature of phonological units in internalized phonological representations, was chosen as the area for study. The choice was made because English phonology is particularly well described by the standard theory, and because this theory contains explicit predictions about how English speakers' phonological knowledge will be realized in their control of English orthography, e.g., in spelling. The present article discusses a series of studies designed to determine whether speakers' spelling behavior follows the supposed patterns of phonological competence, wherein any divergences may lie, and to what processes they may be attributed. The results of the studies suggest the necessity for differentiating a formal description of English phonology from a psycholinguistic model.


[Cockayne's syndrome; a radiological entity: a report on two familial cases (author's transl)]. Two cases of cockayne's syndrome occurring in the same family group are reported. The authors describe the chronological evolution of the bone lesions, based on radiological examinations of the older sister made at 4, 13 1/2, and 15 years of age. Evidence that clinical signs of early ageing are associated with a rapid drop in thymic hormone levels led the authors to search for radiological signs of premature ageing. At 15 years of age only minimal signs were apparent.


[Use of radiology in the diagnosis of posttraumatic otoliquorrhea. A report on 33 operated cases (author's transl)]. The association of standard radiography and tomography can enable the origin of the fistula to be established with reasonable precision : complementary contrast cisternography should permit direct localization. Treatment is essentially the concern of the E.N.T. surgeon, but the problem cannot be resolved without a perfect understanding between the neurosurgeon, surgeon, E.N.T. specialist, and the radiologist.


[Diagnosis of a non-functioning kidney pelvis in adults: a report on 12 cases (author's transl)]. Two types of non-functioning supernumerary kidney pelvis are defined by analyzing 12 cases discovered in adult life. Those of congenital origin from glomerular aplasia, sometimes associated with a ureterocele or an ectopic anastomosis, and those due to an acquired lesion such as lithiasis, vesico-ureteral reflux, or secondary infection of a pocket of fluid. Radiological diagnosis is made by IVU with descending cystography and films taken during micturition. Cystoscopy and possibly retrograde ureteropyelography are essential in order to confirm the diagnosis.


[Echotomography in the study of abdominal lymphadenopathies. Technique of examination and typical appearances (author's transl)]. Lymphographic opacification of the abdominal nodes is only partial, and it is therefore useful to have available another examination for the diagnosis of lymphadenopathies. Echography would seem to merit an important role since out of a series of 100 patients, it led to a positive and confirmed diagnosis in 78% of cases with 22% of errors, including 4% of false positives. In almost 20% of cases, echography gave additional information to that of lymphography, this justifying the simultaneous application of both examinations, either diagnostically or in the context of the surveillance of treatment. Lymphadenopathies are regularly visible from a diameter of 3 cm upwards, their structure is generally very slightly echogenic only and they may be perfectly precisely located. Problems of differential diagnosis are minimal if the technique is applied carefully, by contrast the appearance of lymphadenopathies is very similar and offers no indication as to the aetiology.


[Current indications for barium meal examinations of the small intestine in malabsorption syndromes in children (author's transl)]. The authors study the correlation between the degree of abnormality seen on radiological examination and the extent of atrophy of the villi in 29 children suspected to have had malabsorption syndromes. The radiological signs are valid but at the present time-intestinal biopsy is the only certain diagnostic examination. Based on these observations, an attempt is made to define the indications for barium meal examination of the small intestine.


[Opacification of the aortic arch using a long needle-catheter. Modification of the catheter and precautions to be taken (author's transl)]. The authors modified the long needle-catheter used by Amplatz and Stocks, by adding lateral openings. The modified needle-catheter was used to study the aorta and its branches using the left translumbar approach. The high rate of blood flow (30 to 34 ml/s) gave excellent opacification of the thoracic and abdominal aortas, and the lower limbs.


[Use of an automatic switch mechanism during diagnostic radiological procedures of pulmonary affections in babies and infants (author's transl)]. The authors report their experience with the use of an automatic switch mechanism allowing continuous pulmonary radiograms during deep inspiration in babies and infants. The apparatus is easy to use and the films can be taken almost as quickly as normal radiograms. This automatic switch mechanism is particularly useful for polypnoeic infants and should be employed more widely.


[Mesenteric lipomas in children: a report on one case (author's transl)]. A case of mesenteric lipoma presenting as an isolated abdominal masse in a boy of 20 months is reported. Diagnosis was made from the appearance of the fatty mass in a straight abdominal film. Radiological examination was completed by urography and echotomography. The analysis of 11 identical cases found in the literature enabled the principal clinical and radiological characterists of this affection to be defined and evoked the problems of differential diagnosis from other lipomatous abdominal masses and cystic lymphangioma.


Correlations of maternal and fetal endocrine events with uterine pressure changes around parturition in the ewe. In 4 Clun Forest ewes maternal peripheral plasma concentrations of progesterone were still elevated at the onset of parturient uterine activity. Fetal and maternal plasma concentrations of oestrogen started to rise before parturition and concentrations in maternal plasma were positively correlated with parturient uterine activity (P less than 0.05; r = +0.42). Fetal plasma concentrations of corticosteroids were positively correlated with fetal plasma concentrations of oestrogen (P less than 0.01; r = +0.65), but negatively correlated with maternal peripheral plasma progesterone concentrations (P less than 0.05; r = -0.50). Before parturition plasma concentrations of PGF rose but stayed high only in maternal peripheral plasma. Maternal peripheral plasma concentrations of PGF were positively correlated with uterine activity (P less than 0.05; r = +0.79) and plasma concentrations of oestrogen (P less than 0.05; r = +0.79), but negatively correlated with plasma concentrations of progesterone (P less than 0.01; r = -0.54).


Daily sperm production and epididymal sperm reserves of pubertal and adult rats. Rats were considered to be pubertal at 50 days of age when spermatozoa were first found in the tail of the epididymis. Sperm production/g testis increased up to 75 days of age and testicular weight increased until 100 days of age. Sperm reserves in the tail of the epididymis were not maximal until 100 days of age. Therefore, Wistar rats are not sexually mature until 100 days. Sexually mature rats had testes weighing 3.7 g, produced 86 x 10(6) spermatozoa or 24 x 10(6) spermatozoa/g testicular parenchyma daily, and their paired epididymides contained 295 x 10(6) spermatozoa in the head + body and 440 x 10(6) spermatozoa in the tail.


A photographic method for the measurement of motility of bull spermatozoa. Bull spermatozoa were diluted in skim milk-egg yolk and frozen. After thawing, the samples were added to citrate buffer and photographed (1 sec exposure, 400 ASA, dark field) to identify the tracks of the moving spermatozoa. The proportions of motile spermatozoa in 1707 photographs of semen samples from 25 ejaculates were distributed binomially, and allowed motility to be estimated at a predictable level of precision, and without bias when one photograph from each of two straws was taken at random from an ejaculate. The variance was equal to its expectation and inversely proportional to the total number of spermatozoa in each photographic field.


Parallel competitive binding and metabolic endpoint assays for hCG based on rabbit granulosa cells. A competitive binding assay for hCG is described, in which live rabbit granulosa cells adhering to small tubes provide solid-phase binding sites. Parallel assays, in which the synthesis of progestagens and the incorporation of [3H]acetate into lipid serve as endpoints, are also described. The assays are sensitive, reproducible and precise and should be both economical and convenient for studies on the relationship between the molecular structure and the biological activity of hCG and LH.


Relation between daylight ratio, plasma progesterone levels and timing of nidation in mink (Mustela vison). Mink were mated between 17 February and 22 March. In females kept in natural daylight concentrations of progesterone, measured by radioimmunoassay, began to rise between 25 and 30 March, whatever the date of mating. After reaching peak values of 40--160 ng/ml, progesterone concentrations decreased before the end of pregnancy. In females given 14 h light/24 h immediately after mating, the rise of progesterone began a few days earlier, indicating that the extra light induces earlier progesterone secretion, nidation and parturition.


Relationships between short-term variations of LH, FSH, prolactin and testosterone in peripheral plasma of prepubertal bulls. In 2 prepubertal bulls 10-min blood samples collected during a 24-h period showed that gonadotrophin and testosterone peaks occurred regularly at intervals of 6h in one animal and 8h in the other. There was a clear relationship between the LH, FSH and testosterone peaks. The increase of gonadotrophin levels was followed 20 +/- 6 (s.d.) min later by an increase of testosterone; the interval between the peak values was 61 +/- 9 (s.d.) min. The pattern of prolactin concentration differed; there were two prolonged elevations rather than regular peaks.


Histochemical demonstration of prostaglandin dehydrogenases in the uterine and chorionic epithelia of the pregnant pig. The NAD-dependent 15-hydroxyprostaglandin dehydrogenase (PGDH) was active in the uterine and chorionic epithelia of the pig at 30, 60 and 90 days of pregnancy when PGs of the A, E or F series were used as the substrate. The activity of NADP-dependent PGDH in the same epithelia appeared only when PGB-1 or PGB-2 was used as the substrate.


Progesterone secretion during pregnancy in sheep with an autotransplanted adrenal and an autotransplanted ovary. Secretion rates by the major sites of progesterone synthesis were measured during pregnancy in 3 ewes with single fetuses after autotransplantation of the left adrenal and the left ovary (containing the corpus luteum) to the neck. The total production of progesterone measured by tracer kinetics increased from 12.1 +/- 2.0 (s.e.m.) to 31.3 +/- 2.4 microgram/min between 66--103 and 133--145 days p.c. Ovarian and adrenal secretion rates measured directly at the same times decreased from 5.2 +/- 0.9 to 2.1 +/- 0.9 microgram/min (ovary), or remained unchanged, about 0.03 microgrom/min (adrenal). The difference between the total production of progesterone and ovarian and adrenal secretion showed that the contribution from other endocrine tissues (presumably the placenta) increased from 6.8 +/- 1.5 to 29.2 +/- 4.1 microgram/min (P less than 0.001) during this period.


Meiosis and spermatogenesis in bulls heterozygous for a presumptive 1/29 Robertsonian translocation. Bulls heterozygous for the 1/29 Robertsonian translocation showed normal mating behaviour, semen quality and spermatogenesis. The karyotypes of 90 offspring of one heterozygous bull were consistent with a normal 1:1 segregation of the translocation. There was no difference in overall chiasma frequency at diakinesis between heterozygous and normal bulls, and while a trivalent was noted at diakinesis the chiasma position within the No. 1 arm of the trivalent did not appear to be altered when compared with that found in the normal No. 1 bivalent. An increased frequency of aneuploid secondary spermatocytes at the second meiotic division (M II) was found in the heterozygous bulls, the rate of non-disjuction based on the proportion of hypermodal cells being raised from 2.8% in the normal to 6.4% in the heterozygous animals.


Influence of seminal plasma proteins on motility of rabbit spermatozoa. Washed rabbit spermatozoa of freshly collected ejaculates were incubated in different fractions of seminal plasma proteins and examined for motility. Incubation media were protein fractions obtained by gel and ion-exchange chromatography. Motility was best maintained in the fractions which contained albumin, and rabbit serum albumin was more effective than bovine or human serum albumin. Concentrations of less than 4 mg rabbit serum albumin/ml resulted in markedly decreased motility.


Effects of duct ligation and orchidectomy on histochemical reactions in the hamster epididymis. The epididymis was ligated at the efferent ductules and at the middle segment. Histochemical changes occurred only proximal to the ligature. Orchidectomy caused progressive changes, mostly reversible by testosterone treatment throughout the epididymis. It is concluded that the integrity of the initial segment is dependent upon androgen reaching it via the testicular fluid.


A chimaeric calf with XY/XXY mosaicism and intersexuality. A Friesian calf with an elongated urethra and without a vulva was born twin to a dead bull calf. Red cell chimaerism and XY/XY/XXY lymphocytes were found in the blood, XX/XXY mosaicism was found in the skin and the minute gonads which some showed signs of early testicular development.


A freeze-etch study of dense fibres in rat spermatozoa. The presence of oblique striations on the cortex of the dense fibres of the rat spermatozoon is confirmed; they have a main periodicity of approximately 40 nm and a secondary one of about 20 nm. Disruption of spermatozoa by Triton X-100 and dithiothreitol and fixation in glutaraldehyde do not affect the pattern. The dense fibre cortex appears to consist of globular substructure units with a diameter of about 19 nm.


Effects of short photoperiods on puberty, growth and moult in the Djungarian hamster (Phodopus sungorus). Male Djungarian hamsters were raised from birth in either long (16L:8D) or short (8L:16D) photoperiods. In 16L:8D, testes were large (about 400 mg) and showed full spermatogenesis from 31 days of age, the cauda epididymidis contained motile spermatozoa from 35 days and the accessory glands were large and reached their final size at about 60 days of age. In 8L:16D, testes remained small (about 15 mg) and undeveloped up to an age of about 130 days; they then developed to reach normal size and full spermatogenesis. In 16L:8D body weight increased steadily up to an age of about 160 days, but in 8L:16D body weight increase was slower and reached normal values, after a plateua at about 80 days, at about 190--260 days. Most animals in 8L:16D moulted into winter pelage, and then into the summer pelage; those in 16L:8D kept the summer pelage throughout.


Oestrogen and progesterone concentrations in peripheral blood in pregnant red foxes (Vulpes vulpes). Oestrogen levels were low during most of gestation, but there was a significant increase (P less than 0.05) in oestradiol concentrations at implantation. Early pregnancy was characterized by high levels of progesterone which decreased significantly (P less than 0.001) thereafter, but there was no decline in progesterone or rise in oestrogen levels at parturition. There was no difference in the length of progesterone secretion between pregnant and non-pregnant females.


A nuclear DNA polymerase in bull spermatozoa. A DNA polymerase was isolated from bull spermatozoa by differential centrifugation, ultrafiltration and gel filtration. Its apparent molecular weight and synthetic template utilization resemble that of DNA polymerase gamma. Chemical and enzymic fractionation of bull spermatozoa indicate that the enzyme is most probably located in the nucleus.


Ovarian function in suckling and non-suckling beef cows post partum. Two groups, each of 7 crossbred beef cows, which were suckling or not suckling calves, were fed a high quality food ad libitum for 3 months post partum. The non-suckling cows experienced regular ovarian cycles from 10--33 days post partum while the suckling cows did not do so until at least 14 weeks post partum. There was little difference between the groups in growth rate or in plasma glucose concentration. The plasma prolactin concentrations in the non-suckling cows showed a seasonal trend which paralleled ambient temperature and daylight hours; in the suckling cows this trend was less evident. Plasma LH concentrations were lower in suckling cows before Day 30 post partum but were similar thereafter. Most suckling cows also failed to experience oestrus or to exhibit LH release in response to an injection of oestradiol benzoate at about 6 weeks post partum. This failure, together with the earlier lower levels of LH in the suckling cows, is considered to be indicative of malfunction of the hypothalamic mechanism normally responsible for the establishment and maintenance of cyclic ovarian function.


A simple and rapid technique to isolate enriched populations of spermatocytes and spermatids from the immature rat testis. A technique was developed to obtain enriched populations of large numbers of primary spermatacytes (70--81%) and of spermatids (75%) from immature rat testes (21--23 and 38 days old respectively) in a simple and rapid fashion. The cells were nearly all viable and membrane preservation was good. The testicular cells were dispersed by a mild mechanical treatment combined with an incubation with purified collagenase, and the cell populations were separated by centrifugation in a discontinuous dextran gradient in a cell culture medium.


Sex chromosome chimaerism and the transmission of blood group genes by tetraparental rams. A previously published study of 4 rams, 3 of them tetraparental chimaeras, has been extended. All were born subsequent to transplantation of separated blastomeres into intact 4--8-cell embryos which were transferred to recipient ewes. All were phenotypically normal males. Study of blood lymphocytes and red cell antigens showed that two were XX/XY chimaeras, one an XY/XY chimaera. Chimaerism was not identified in the 4th animal. The new data show that the previously reported decline in proportions of red cells derived from the one cell line has continued, although the proportions of lymphocytes entering mitosis in culture have remained nearly constant. A decline of potassium concentration in the red cells of one animal and of transferrin type in another also continued. Analysis of blood types in the offspring of the 4 rams revealed that both cell lines of the XY/XY chimaera must have produced functional spermatozoa whereas the genes transmitted by the remaining 3 rams gave evidence of spermatozoa from one cell line only.


Fetal- and uterine-specific antigens in human amniotic fluid. Removal of the major maternal serum proteins from second trimester amniotic fluid by antibody affinity chromatography revealed various soluble tissue antigens, of which two were fetal-specific skin proteins and another, of alpha2-mobility, was specific to the uterus, and was therefore designated alpha-uterine protein (AUP). These proteins could not be detected in maternal serum by antibody-antigen crossed electrophoresis. The concentration of AUP in amniotic fluid reached a maximum between 10 and 20 weeks of gestation, suggesting that there is an influx of uterine protein into the amniotic fluid at this stage of pregnancy.


Plasma progesterone levels during pregnancy and pseudo-pregnancy in the hare (Lepus europaeus syriacus). A triphasic pattern of progesterone secretion was observed in female hares sampled throughout pregnancy and pseudopregnancy. After injection of hCG and artificial insemination (Day 1), progesterone values rose to a peak of 41.4 ng/ml about Day 14, remained at this level, then declined around Day 20 before increasing sharply to maximum levels of 67.7 ng/ml after midpregnancy (Day 28). Levels remained high for several days, then declined until Day 38, increased again until Day 41, before decreasing towards parturition. Progesterone levels were still high (37.5 ng/ml) 24h before parturition. The progesterone pattern during pseudopregnancy closely resembled that observed during the first half of pregnancy: levels rose from Day 2 to a peak at Days 11--18, then declined sharply to baseline levels around Day 22. It is suggested that the control of progesterone secretion might be transferred from the pituitary to the placenta at the beginning of the second half of pregnancy.


Surgical pathology and management of anorectal Crohn's disease. The anorectal manifestations of Crohn's disease comprise a complex and heterogeneous group of conditions which fall into two main categories: primary lesions of the active disease process and secondary lesions resulting from healing of, or infective complications of, the primary lesions. The lesions are classified into distinct clinicopathological entities which may be used in assessing prognosis and determining appropriate treatment. A basic principle of management is that surgery should be avoided as far as possible in the presence of disease activity, but will frequently be necessary, and satisfactory, for secondary complications.


Calculation of genetic risks in Duchenne muscular dystrophy by geneticists in the United Kingdom. Pedigrees of Duchenne muscular dystrophy were sent to 32 geneticists in the United Kingdom, asking for their calculations for genetic risks for female relatives. Eighteen participated, of whom only 7 gave correct answers for all pedigrees. The method most used for calculations (the 'Bayesian' method) was most liable to errors in new situations. An alternative, simpler method is presented.


Genetic study of narcoleptic syndrome.

Genetic study of narcoleptic syndrome. In this family study of the narcoleptic syndrome, 52% of the probands had an affected first degree relative, 41.9% of the sibs of those probands with an affected parent were similarly affected, 33.3% of the parents of 2 affected sibs and 41.2% of the children (after a correction for age) had narcolepsy, cataplexy, or both.


Length heteromorphisms of fluorescent (f) and non-fluorescent (nf) segments of human Y chromosome: classification, frequencies, and incidence in normal Caucasians. Sixty normal male Caucasians were selected to study the length of the Y chromosome. QFQ banding was performed. Chromosomes 19 and 20 (F) and Y were measured directly from the film. Y/F, f/F, and nf/F indices (f = fluorescent; nf = non-fluorescent segment) were determined. The length of the Y chromosome was classified into 5 groups; very small, small, average, large, and very large with Y/F indices of less than 0.8, 0.81--0.94, 0.95--1.09, 1.1--1.23, and greater than 1.23, respectively. The frequencies of Y/F indices for these groups were 0 (0%), 9 (15.0%), 40 (66.7%), 8 (13.3%), and 3 (5.0%), respectively. The most frequent class was 0.95--1.09 and was defined as the 'average' Y/F index for the human Y chromosome. The variation in the total length of the Y chromosome was accounted for by variations in the length of the non-fluorescent as well as the fluorescent segments. No relation between f and nf segments was observed. The mean Y/F, f/F, and nf/F indices were 1.022, 0.441, and 0.574, respectively.


Naevoid basal cell carcinoma syndrome and Charcot-Marie-Tooth disease: two autosomal dominant disorders segregating in a family. A family is described in which 16 individuals in 3 generations have Charcot-Marie-Tooth disease. At least 6 family members also have the naevoid basal cell carcinoma syndrome. In addition, 1 subject with both disorders has 2 young daughters with the naevoid basal cell carcinoma syndrome.


Linkage analysis in dominant acrocephalosyndactyly. Linkage analysis was performed on a previously reported family in which multiple dominantly inherited acrocephalosyndactyly syndromes were present. An underlying axiom of linkaged analysis is that the trait analysed be monogenic. This prerequisite was presumptively established in the single kindred analysed because acrocephalosyndactyly was observed in multiple cases in multiple generations.


Haemoglobin H disease in 2 Filipino families. Haemoglobin H disease is described in successive generations of 2 Filipino families. The condition was asymptomatic. The inheritance pattern of haemoglobin H disease in these families appeared to be like that described for Thais.


Translocation of chromosome 4 and 9 with ring formation of chromosome 4 short arm. Cytogenetic investigation of a 3-year-old mentally retarded boy revealed a translocation of the long arm of chromosome 4 onto the short arm of chromosome 9, with ring formation of the remaining short arm of chromosome 4. The clinical features are described and correlated with the cytogenetic findings. The behaviour of the ring derived from a deleted chromosome 4 is discussed.


Bilateral renal agenesis in 2 male sibs born to consanguineous parents. Two boys with bilateral agenesis of kidneys and ureters were the product of a consanguineous marriage. This family and previous reports of familial bilateral renal agenesis support the supposition that a minor proportion of cases of BRA is caused by the homozygous state of an autosomal recessive gene.


Some business and tax aspects of clinical practice plans. Medical schools throughout the country have developed diverse organizational forms through which their faculty members provide clinical services. In this article the author reviews several of the reasons frequently offered to support involvement of a medical school in a faculty practice plan and suggests many business and tax considerations which should be taken into account by a medical school in developing a plan to meet its objectives. He also reviews many of the considerations involved in establishing and operating specific types of group practice plans. The author concludes that, with conscientious planning and implementation, faculty members can receive professional satisfaction, medical schools can obtain many benefits, and the public will benefit from improved health care.


Clinical teacher effectiveness in medicine. Characteristics of best and worst clinical teachers in medicine are described by a random sample of medical school faculty, residents, and third- and fourth-year students at the University of Washington. The responses were factor analyzed and examined to determine whether the ratings were systematically influenced by professional role, faculty department, and teaching method. Best clinical teachers are described as being enthusiastic, clear and well organized, and adept at interacting with students and residents. Worst clinical teachers lack these skills and are characterized by negative personal attributes. Using analysis of variance, the investigator found no significant differences in ratings on the three variables examined. Six of the seven hypothesized dimensions of clinical teaching were confirmed by factor analysis. The results are discussed in relation to faculty development and evaluation of clinical teaching.


Experience with the simulated patient-physician encounter. The development of computer-based simulations of the patient-physician encounter has made it possible to give students the opportunity to manage a case without jeopardizing a real patient's life. At the University of Wisconsin Medical School simulated patients have been an integral part of the third-year teaching program for the past five years. They have been used to permit the students to gain clinical experience, as part of a series of structured teaching conferences, and in a medical testing program. Student and faculty response to the program generally has been favorable.