Effects of chronic occupational exposure to measured concentrations of benzene. All ten employees have a history of exposure to benzene which exceeded a 25 ppm, eight-hour TWA for several years. For five of these employees this exposure level started over 20 years ago. One employee's high exposure level started over 35 years ago. All ten employees had their initial high exposure to benzene more than 16 years ago. At one period (late 1963 and early 1964) all ten employees had alterations in their peripheral blood studies, evidenced by an increase in MCV. Some of the employees had slight reduction of hemoglobin levels. No other significant blood or bone marrow abnormalities were evident. A mortality study, for the years 1940 to 1973, of 594 employees chronically exposed to benzene at the Midland, Mich., Dow location has recently been accepted for publication. This study was followed by a morbidity study of 282 employees, which were a subset of the employees in the mortality study. The morbidity study was based on health data obtained between 1967 and 1974. The ten employees described in this article were included in both the mortality study population of 594 employees and the morbidity study of the 282 employees.


Health exam findings among individuals occupationally exposed to benzene. We previously conducted a cohort mortality study of 594 individuals occupationally exposed to measured concentrations of benzene. This report presents health examination findings for a subset of 282 men from the larger group. Although slight decreases in mean total bilirubin and RBC values were detected statistically in comparing the exposed group to controls, these changes were not regarded as clinically significant. No correlations were found between peripheral blood counts and latency, duration or intensity of benzene exposure. Presently we have no indication from our data of adverse effects of benzene having occurred in our subset. Variation in latency among individuals and the possibility of subtle changes effecting an eventual pattern contribute to the need for continued surveillance.


Stress and success in dentistry. Some personality characteristics of successful dentists. This article describes a study of relationships between a selected set of personality characteristics, as measured by the 16PF, and the success outcomes of a group of 109 dentists. Results indicate that Factor C (high ego strength), Factor F (liveliness and enthusiasm), Factor H (venturesomeness), Factor Q1 (experimenting), Factor Q3 (high self-concept integration), Factor Q4 (tenseness), Factor QII (anxiety) are significantly related to one or more index of success (satisfaction, size of practice, income and professional advancement). Findings are compared to results of earlier research concerning relationships between personality and stress related illness. Implications of findings are discussed in terms of the influence of personality on individuals' capacity to cope with occupational stress.


Epidemiological requirements for medical-environmental data management. In establishing a system to provide data for epidemiological research in occupational health, it should be recognized that such studies require more information than what usually becomes available routinely in occupational health programs. Additional types of data that may have to be put into the system include supplementary diagnostic information, level and duration of exposure to potentially hazardous substances, demographic information related to socioeconomic status and fertility, population census statistics for the entire company and various company installations, and follow-up-data on retired employees. The quality of the data is especially important for epidemiologic research. Therefore, data validation procedures need to be established whereby the information that goes into the system is reviewed for precision, completeness, and reliability.


Hemophilus influenzae type b pneumonia in 43 children. Using positive blood, lung, or pleural fluid cultures as definitive criteria for bacterial infection, 43 examples of Hemophilus influenzae type b pneumonia were identified in a 43-month period. The mean age of the patients was 26 months; 12% were older than 5 years of age. Associated infections were found in 34 patients and included upper respiratory infections, otitis media, epiglottitis, and meningitis. Positive nasopharyngeal cultures were observed in only 33%. Radiologically, segmental or lobar infiltrates accounted for 85% of the pneumonias. In two cases, death was attributed to the pneumonia alone. Treatment with penicillin G or ampicillin was equally effective. Our data suggest that H. influenzae pneumonia is commonly a serious infection that cannot be distinguished clinically or radiologically from other pneumonias.


Acute poststreptococcal glomerulonephritis mimicking Henoch-Schönlein purpura. Two children with acute glomerulonephritis, cutaneous vasculitis, and abdominal pain are reported. One child also had transient arthralgia and gastrointestinal hemorrhage. Although the clinical presentation mimicked many of the features of Henoch-Schönlein purpura, both patients had unusual variants of poststreptococcal glomerulonephritis.


Diagnostic significance of antibody to native deoxyribonucleic acid in children with juvenile rheumatoid arthritis and other connective tissue diseases. Sera of children with juvenile rheumatoid arthritis and other connective tissue diseases were tested for antibodies to native DNA by a radiolabeled-binding assay. Normal values were obtained in 130 children with JRA, including 28 with uveitis and 14 with selective IgA deficiency. Normal values were also found in sera from children with dermatomyositis, scleroderma, polyarteritis, ankylosing spondylitis, and a variety of other nonconnective tissue diseases. The only sera with elevated DNA-binding assays were from children with systemic lupus erythematosus. On the basis of these data, increased levels of antibodies to native DNA distinguished patients with active SLE from children with JRA.


Treatment of complete ornithine transcarbamylase deficiency with nitrogen-free analogues of essential amino acids. A male infant with complete hereditary deficiency of hepatic ornithine transcarbamylase was fed a low-protein diet (1 gm/kg/day) supplemented with nitrogen-free analogues of essential amino acids from the age of 2 days until his death at 5 months. Blood ammonia and plasma acid concentrations were maintained in the near normal range during most of his lifetime. Growth and development were entirely normal. Abrupt, unprecipitated hyperammonemia, which could not be reversed by intensive treatment, led to his death. To our knowledge, this child lived longer than any previously reported infant with OTC deficiency of this severity.


Congenital hypothyroidism and IQ increase: a quarter century follow-up. Ten patients with a history of congenital hypothyroidism were recalled for IQ evaluation 16 to 26 years after an original IQ test at age 5 to 6. From childhood through adulthood, the IQ (Wechsler) increased (mean full scale IQ increase = 21; range = -5 to 43 points). Serial testing in three instances showed the timing of the increase to be sudden and unpredictable. Life achievements, mental health, and sexual adjustment were concordant with the IQ attained. The data suggest that in hypothyroidism intellectual growth may not occur in equal annual increments; with effective hormonal replacement and educational experience it may be subject to spurts of growth, with a resultant improved prognosis.


Standard growth curves for achondroplasia. Standard growth curves for achondroplasia, the most common form of short-limbed dwarfism, have been constructed based on measurements of height, growth velocity, upper and lower segment, and head circumference in 400 achondroplastic dwarfs. These standard curves provide the basis to assess normal growth in these individuals, to aid in the determination of superimposed disorders, and to assess any growth accelerating therapy.


Administration of prostaglandin E1 in neonates with critical congenital cardiac defects. Prostaglandin E1 was administered to 12 neonates and young infants in whom pulmonary or systemic blood flow was entirely or significantly dependent upon persistent patency of the ductus arteriosus. Nine neonates responded favorably to PGE1 infusion; their mean age was 2.8 days. Three infants who failed to respond were 10 days, 14 days, and 9 weeks of age, respectively. Six neonates with right ventricular outflow obstruction had a mean increase in arterial PO2 of 136% following administration of PGE1. In three patients in whom systemic flow was ductus dependent, PGE1 infusion was followed by improvement in arterial blood pressure, peripheral perfusion, and urine output. Complications included pyrexia, vasodilatation, and myoclonic jerks (or focal seizures). Three side effects were easily reversible by decreasing the infusion rate or altering the site of administration. PGE1 is a highly effective agent in stabilizing critically ill neonates with ductus dependent congenital cardiac lesions.


Intracerebellar hematoma in the neonate. The early diagnosis of posterior fossa hematoma in three term infants by computed tomography is described. The clinical findings included difficult labor and delivery, sudden onset of apnea during the first 24 hours of life, tense bulging fontanel, falling hematocrit, bloody cerebrospinal fluid, and cerebral obtundation. Rapid operative removal of the clot resulted in good recovery in two of the infants.


Pharmacokinetic disposition and protein binding of furosemide in newborn infants. Using a one-compartment model, the pharmacokinetic disposition of furosemide was studied in eight premature and term neonates with fluid overload. Following a single intravenous injection of furosemide (1 to 1.5 mg/kg), multiple blood samples were obtained from a heelstick or an arterial catheter and analyzed for furosemide by gas liquid chromatography. The mean (+/- SE) apparent volume of distribution was 829.2 +/- 118.9 ml/kg; t1/2 was 7.7 +/- 1.0 hour; elimination rate constant was 0.102 +/- 0.013/hour and plasma clearance was 81.61 +/- 14.98 ml/kg/hour. Compared to the disposition of furosemide in normal adults. AVd is almost fourfold greater in the neonate with an eightfold prolongation in plasma t1/2, an eightfold decrease in Ke1, and a twofold decrease in plasma clearance. Neither gestational and postnatal age nor birth weight correlated with the pharmacokinetic variables. No significant change in reserve bilirubin-binding capacity after an intravenous dose of furosemide was noted. Slow elimination of furosemide may partly explain the prolonged diuretic and saluretic effect of furosemide in the neonate.


Urinary excretion of prostaglandin E following the administration of furosemide and indomethacin to sick low-birth-weight infants. Urinary excretion of prostaglandin E was measured in seven sick low-birth-weight infants. Four had severe hyaline membrane disease and one had chronic bronchopulmonary dysplasia; all received furosemide. Two infants had patent ductus arteriosus and received indomethacin. Following administration of furosemide, urine volume and the excretion rates of sodium and calcium were significantly increased; such changes were not seen following the administration of indomethacin. Prostaglandin E excretion rate was increased from 0.4 +/- 0.04 to 1.3 +/- 0.2 ng/mg Cr (mean +/- SEM) following administration of furosemide, but decreased in two patients following administration of indomethacin. The present results demonstrate that furosemide enhances urinary excretion of prostaglandin E by mechanisms which may reflect an increase in prostaglandin synthesis, a decrease in prostaglandin renal metabolism, or both. Indomethacin, which is a prostaglandin synthetase inhibitor, decreases the urinary excretion of prostaglandin E. These observations suggest that furosemide therapy in patients receiving indomethacin may be ineffective.


A computerized single entry system for recording and reporting data on high-risk newborn infants. A computer-assisted system for data collection in an intensive care nursery is described. Maternal history, infant history, diagnoses, and treatment are sequentially identified on a single form and then entered in batches into a computer at the time of patient discharge. Computer production of a discharge summary and letters to referring and follow-up physicians from a single data-entry form account for an approximately 80% savings in physician record-keeping time per patient. Accuracy of the data is approximately two and one-half times greater than with existing methods of data gathering. Survey of disease occurrence and case fatality rates are rapidly available.


The use of developmental screening tests by primary-care pediatricians. Two-hundred-twenty-two pediatricians were surveyed to determine the use of developmental screening tests in primary-care pediatrics. Sixty-three percent of the 121 primary care pediatricians responding to this survey reported that they use developmental screening tests, but only 15 to 20% screen more than 10% of their patients with these tests. Factors associated with the use of developmental screening tests included the year of graduation from medical school, level of postinternship training, duration of current practice, training in the use of tests as a house officer or fellow or at postgraduate seminars, and belief that the use of developmental screening is a necessary part of routine health maintenance. Pediatricians use developmental screening tests infrequently and, probably, only after evidence of developmental delay has been established by other criteria.


MMPI criteria for diagnosing schizophrenia. An attempt was made to find a combination of MMPI scale relationships which were highly discriminating of schizophrenia. Through the use of a standardized structured interview and a diagnostic system for schizophrenia based on the use of discriminant function analysis with nonpathognomonic symptom combinations, a reliable and valid system was used to establish the criterion diagnosis. Approximately 72% of patients reliably diagnosed as schizophrenics were detected on the MMPI via a set of standard criteria (T score on Sc greater than or equal to 80 less than or equal to 100; total raw score on Sc consisted of no more than 35% K items; T score on F greater than or equal to 75 less than or equal to 95; T score on Pt less than or equal to Sc). Only 5.5% of nonschizophrenics obtained all these standard criteria on the MMPI. The assets and liabilities of these MMPI criteria to diagnose schizophrenia are discussed.


Overinclusion and transactional thinking on the Object Sorting Test of schizophrenic and nonschizophrenic patients. Two aspects of "disordered thinking", overinclusion and transactional thinking were studied on the Object Sorting Test responses of 20 young schizophrenic patients and 20 comparable nonschizophrenic patients. Patients' parents were also studied for comparison. In addition, idiosyncratic responses from WAIS Comprehension items were assessed for comparison of another measure on another test. Transactional thinking and idiosyncratic responses were greater in schizophrenic patients. Conceptual overinclusion and bizarre responses also tended to be more frequent in schizophrenics, but behavioral overinclusion showed no differences. Conceptual overinclusion was consistently correlated with transactional thinking and idiosyncratic responses, while behavioral overinclusion showed an inconsistent pattern. The differences were attributed to the differences in the specificity of measures of disordered thinking.


Some personality patterns and dimensions of male alcoholics: a multivariate description. The assumption that alcoholics form a homogeneous population has been found to be questionable. Recent research has been done to empirically define possible personality subtypes of alcoholics. This study extended the typological work done previously by Goldstein and Linden (1969a) and Whitelock, Overall, and Patrick (1971). They each found four alcoholic subtypes, three of which replicated across studies. For this research, MMPI profiles of 208 male alcoholics were submitted to a hierarchical clustering procedure. Seven subtypes were found. These results were compared to the results of the prior two studies, in addition to actuarial MMPI types previously delineated in clinical settings. Using a hierarchical factor analysis, these data were analyzed to determine the higher order interrelationships among MMPI scales for this alcoholic sample. These results were discussed, especially in terms of the implications for treatment and further research in alcoholism.


Similar Rorschach patterning in three cases of anorexia nervosa. The Rorschachs of three cases of ambulatory anorexia nervosa patients showed striking quantitative and qualitative similarities. Analysis of the patterning prompted a diagnosis of conversion hysteria with repressed orality as the suspected dynamism. It was suggested that the Rorschach might prove useful for diagnosing this hysteroid subgroup of patients for the purpose of differential treatment.


Social modeling influences on sensory decision theory and psychophysiological indexes of pain. Subjects exposed to social models dissimulating tolerance or intolerance generally exhibit matching behavior in their verbal ratings of painful stimulation. It has been unclear, however, whether these changes reflect voluntary alteration of evidence or genuine changes in distress. This study used alternative measures and controlled for methodological limitations of earlier studies by examining nonpalmar skin potential in addition to palmar skin conductance and heart rate indexes of psychophysiological response to electric shock, and by evaluating verbal expressions of pain with sensory decision theory methodology. Of 20 female volunteer subjects, half served as controls, and half were exposed to a tolerant female model. Both the subject and the model verbalized ratings of discomfort provoked by a series of electric shocks of increasing intensity. Subjects then underwent a series of preselected random shocks. Sensory decision theory analyses revealed lower discriminability of the shocks among subjects exposed to a tolerant model. Several indexes of nonpalmar skin potential and heart rate reactivity exhibited lower reactivity in the tolerant group. Tolerant modeling was also associated with decreases in subjective stress. The results were consistent with the position that changes in pain indexes associated with exposure to a tolerant model represented variations in fundamental characteristics of painful experiences as opposed to suppression of information.


Lottery winners and accident victims: is happiness relative? Adaptation level theory suggests that both contrast and habituation will operate to prevent the winning of a fortune from elevating happiness as much as might be expected. Contrast with the peak experience of winning should lessen the impact of ordinary pleasures, while habituation should eventually reduce the value of new pleasures made possible by winning. Study 1 compared a sample of 22 major lottery winners with 22 controls and also with a group of 29 paralyzed accident victims who had been interviewed previously. As predicted, lottery winners were not happier than controls and took significantly less pleasure from a series of mundane events. Study 2 indicated that these effects were not due to preexisting differences between people who buy or do not buy lottery tickets or between interviews that made or did not make the lottery salient. Paraplegics also demonstrated a contrast effect, not by enhancing minor pleasures but by idealizing their past, which did not help their present happiness.


Dequaternization of curare bases with sodium thiophenoxide and ethanolamine. To prepare (+)-tubocurine and O,O-dimethyl-(+)-tubocurine, the commonly used dequaternization procedures with sodium theophenoxide and ethanolamine were investigated. The quaternary compounds were (+)-tubocurarine chloride and the chloride and iodide salts of O,O-dimethyl-(+)-chondocurarine. The results obtained with ethanolamine indicate that Hofmann elimination is a major pathway and that N-demethylation is minor. The elimination products of O,O-dimethyl-(+)-chondocurarine iodide with ethanolamine were identified as O,O-dimethyltubocurinemethine, O,O-dimethyltubocurineisomethine, and O,O-dimethyltubocurinedimethine. N-Demethylation was the primary reaction with sodium thiophenoxide. Thus, dequaternization of (+)-tubocurarine chloride with sodium thiophenoxide provided (+)-tubocurine which, on diazomethylation, yielded O,O-dimethyl-(+)-tubocurine, identical to the compound obtained by N-demethylation of O,O-dimethyl-(+)-chondocurarine chloride with the same reagent.


Stereospecificity of esterases hydrolyzing oxazepam acetate. Esterases hydrolyzing the racemic acetate ester of the centrally acting drug oxazepam in mice were examined. Radiolabeled ester administered intravenously was hydrolyzed rapidly in the liver, kidneys, and brain. The distribution of the enzyme activity of liver and brain subcellular fractions was measured. Kinetic data and structure investigation of partially hydrolyzed racemic ester pointed to the stereoselectivity of liver and brain esterases. The preferred hydrolysis of the (R)-(-)-isomer in liver homogenates was attributed mainly to microsomal enzymes, while that of the (S)-(+)-isomer in brain was considered to be due to the mitochondrial fraction. This phenomenon was a common property of all species tested.


Effects of short and medium chain fatty acids on absorption of lipophilic drugs from perfused rat intestine. The absorption rates of griseofulvin and prednisolone were measured from solutions that were recirculated through a segment of in situ rat jejunum. When premicellar concentrations of butyric, octanoic, or dodecanoic acid were present in the perfusate, the griseofulvin absorption rate decreased while that of prednisolone increased. The fatty acids also increased the absorption rate of water from the perfusate, and the effect of butyric acid was attributed primarily to this increase. The absorption-altering effects of octanoic and dodecanoic acids could not be attributed solely to their effects on water absorption nor to their effects on the surface tension of the perfusate. The effects of octanoic and dodecanoic acids were explained by postulating different rate-limiting barriers to the absorption of prednisolone and griseofulvin.


Synthesis and preliminary anti-inflammatory evaluation of 17beta-amino-3beta-methoxy-5-androstene hydrochloride and related derivatives. To study the anti-inflammatory properties of 17beta-amino-steroids, some 17beta-aminoandrostene hydrochlorides based on the 3beta-methoxy-5-androstene nucleus were prepared. The syntheses were accomplished via a two-stage amination of 3beta-methoxy-5-androsten-17-one, involving reduction of an intermediate 17-imine or, for the synthesis of 17beta-amino-3beta-methoxy-5-androstene, the 17-oxime. The compounds were examined for anti-inflammatory activity in the rat cotton pellet model of inflammation. All tested aminosteroids displayed significant activity. Two compounds also were screened in an adjuvant-induced arthritis model of inflammation and displayed activity.


Antitumor agents XXX: Evaluation of alpha-methylene-gamma-lactone-containing agents for inhibition of tumor growth, respiration, and nucleic acid synthesis. Evidence is presented that a number of sesquiterpene lactones isolated from plants and synthesized pyrimidines containing the alpha-methylene-gamma-lactone moiety are potent inhibitors of Walker 256 carcinosarcoma and Ehrlich ascites tumor growth and marginal inhibitors of P-388 lymphocytic leukemia and Lewis lung tumor growth. In vitro aerobic basal respiration and oxidative phosphorylation processes of Ehrlich ascites cells were inhibited by these agents as well as deoxyribonucleic acid polymerase and thymidylate synthetase enzymatic activities. These studies indicate that the alpha-methylene-gamma-lactone moiety, the beta-unsubstituted cyclopentenone ring, and the alpha-epoxycyclopentanone system are the essential moieties for inhibition of these biochemical parameters.


Lyophilization of sincalide and correlation of headspace relative humidity with product stability. An optimum freeze-drying cycle was developed for use with industrial equipment in the processing in vials of a product degraded by traces of moisture. The relative humidity of the headspace gas of the vials, which contained only 5 microgram of active ingredient, was monitored by a GC method and was then correlated with product stability.


GLC--mass spectrometry of several important anticancer drugs I: pertrimethylsilylation and O-methoxime formation. Procedures are reported for the formation of pertrimethylsilyl and pertrimethylsilyl methoxime derivatives of the aglycones of doxorubicin, daunorubicin, carminomycin, chromomycin A3, and mithramycin. The mass spectra are consistent with the formation of these derivatives. Fragmentation patterns highly specific for these derivatives are proposed, and the potential application for the identification of metabolites of these compounds is discussed.


Applications of paired ion high-pressure liquid chromatography to catecholamines and phenylephrine. Paired ion high-pressure liquid chromatography was useful for separating intact catecholamines (epinephrine, isoproterenol, levodopa, and methyldopa) and phenylephrine from some of their decomposition products. Furthermore, methyldopa was separated from either hydrochlorothiazide of levodopa. Under identical conditions without 1-heptanesulfonic acid (a counterion for paired ion chromatography) in the mobile phase, these separations were not possible. Paired ion chromatography also was tried successfully for the quantitative determinations of isoproterenol, levodopa, methyldopa, and phenylephrine in some dosage forms. The results were compared with the results obtained using some literature methods.


High-performance liquid chromatographic assay of sulfapyridine and acetylsulfapyridine in biological fluids. A high-pressure liquid chromatographic method for the sensitive, rapid, and specific determination of sulfapyridine and its N-acetyl derivative in plasma and saliva was developed. A cyano-bonded, reversed-phase, high efficiency column was used. The system detected these sulfonamides in serum to 0.25 mg/liter and within only 6 min. Sulfapyridine was separated from its acetyl derivative with little interference from other drugs. The assay reproducibility was within 3%. The assay was highly useful for routine monitoring of patients receiving sulfasalazine for inflammatory bowel disease.


High-pressure liquid chromatographic assays for clindamycin, clindamycin phosphate, and clindamycin palmitate. High-pressure liquid chromatographic procedures are described for clindamycin, clindamycin palmitate, and clindamycin phosphate as bulk drugs and in formulations. All three procedures utilize a C18 reversed-phase chromatographic column with refractive index detection. The mobile phases are hydroalcoholic solutions containing dioctyl sodium sulfosuccinate or disodium ethylenediaminetetraacetate. Separations of related impurities or degradation products also are discussed. The relative standard deviations of the methods range from 0.8 to 1.8%.


Preservation of solubilized and emulsified systems II: Theoretical development of capacity and its role in antimicrobial activity of chlorocresol in cetomacrogol-stabilized systems. The preservation of solublized and emulsified disperse systems against microbial spoilage depends on the free (unbound) preservative concentration in the aqueous phase and the capacity of the system. The capacity may be defined as the system's ability to resist losses in free preservative concentration. The theory of capacity is developed quantitatively for solubilized and emulsified systems containing the preservative chlorocresol stabilized by the nonionic surfactant cetomacrogol. Equations are derived for solubilized systems that relate capacity to surfactant concentration and the interaction between the surfactant and the preservative. Additional terms are included in the equations to account for the effects of the oil phase on the capacity of oil-in-water emulsions.


Effect of surfactants on percutaneous absorption of naproxen I: comparisons of rabbit, rat, and human excised skin. The in vitro skin penetration model using excised skin from rats, rabbits, and humans was examined to evaluate the relative effect of surfactants on percutaneous absorption of naproxen. Differences in the magnitude of the effect of surfactants in promoting percutaneous absorption of naproxen through skins of different species were observed. For comparative evaluations of the formulation effects on percutaneous absorption, such as the effect of surfactants, in vitro studies with animal skin may not provide information in agreement with in vitro human skin.


Inlfuence of high-viscosity vehicles on miotic effect of pilocarpine. Gel formulations containing 2% pilocarpine hydrochloride were prepared from ethylene maleic anhydride, carbomer, hydroxyethylcellulose, polyacrylamide, ethylhydroxyethylcellulose, hydroxypropylcellulose, and poly(methylvinyl ether--maleic anhydride). The viscosity characteristics of each formulation were evaluated from rheograms developed at 37 degrees using a cone and plate viscometer. Single-point viscosities were determined at room temperature using a single-point rotational viscometer. Plastic viscosity parameters correlated to miosis durations in the rabbit following ophthalmic dosing of 50 microliters. Carbomer formulations varying in concentration between 0.9 and 5.0% (w/w) showed a discontinuous relationship when either yield value or plastic viscosity was plotted against miosis durations. At carbomer concentrations above 3%, miosis durations increased 1.5-fold. Above and below this range, plastic parameters did not correlate to miosis duration. It was reasoned that the increased duration was a consequence of the gel's increased yield value such that appreciable in vivo thinning of the gel does not take place with eyelid and/or eyeball movements. As a result, the residence time of the drug in the eye would be expected to increase, thus promoting an increased duration.


Comparative bioavailability of a lipophilic steroid. 17beta-Acetoxy-2alpha-chloro-3-(p-nitrophenoxy)imino-5alpha-androstane (I) is a lipophilic steroid with postimplantive antifertility activity in laboratory animals. The bioavailability of micronized I from solutions and suspensions was compared in four groups of adult female Wistar rats. Each group received varying concentrations of micronized 3H-I (specific activity of 0.38--8.94 muCi/mg) in sesame oil by oral gavage. Samples of whole blood and urine collected following drug administration were assayed for radioactive content. Calculation of the mean area under the blood radioactivity versus time curve, when corrected for the quantity of drug administered, indicated that a substantially larger fraction of the dose was absorbed in the two instances where I was present only in solution. A linear relationship between the amount of I absorbed based on whole blood radioactivity and urinary excretion and the administered dose was found primarily for groups receiving the drug in solution. Preliminary results in humans indicate that 3H-I was absorbed to a much greater extent following oral administration of the drug in sesame oil than when admixed with lactose.


Relative bioavailability of meprobamate tablets in humans. The relative bioavailability of 400-mg meprobamate tablets manufactured by 11 different firms was evaluated in two groups of healthy male subjects. Each group of six subjects received a reference standard product and five test products given at 1-week intervals. Plasma meprobamate concentrations at 1, 2, 3, 4, 6, 8, 10, 24, and 32 hr after dosing were determined using a GLC assay. Analysis of variance of the plasma level--time profiles revealed no statistically significant differences between any of the products in terms of plasma levels at the various sample times, time of peak plasma level, peak plasma level, and area under the plasma level--time curve. It was concluded that the 11 400-mg products could be considered bioequivalent.


New drug metabolism inhibitor of marine origin. Dactylyne, an acetylenic dibromochloro ether, was isolated from the sea hare Aplysia dactylomela and characterized pharmacologically. It had no direct effect on the cardiovascular, respiratory, and central nervous systems of mice, rats, and guinea pigs. However, a 25-mg/kg ip dose of dactylyne prolonged pentobarbital sleep time in mice by more than 10 hr. This potentiation was subsequently determined to be due to the inhibition of pentobarbital metabolism by dactylyne since the elimination half-life of pentobarbital in the dactylyne-treated mice increased several folds. Dactylyne was nontoxic up to 200 mg/kg iv. The unique structure, high potency, and relatively nontoxic nature of dactylyne make it an interesting pharmacological substance of marine origin.


Effect of amitriptyline on polarography of chlordiazepoxide. With increasing amounts of electroinactive amitriptyline, each of the three chlordiazepoxide reduction waves shifted to more cathodic half-wave potentials and decreased in limiting current. The shift was most pronounced up the 1:1 mole ratio but continued up to ratios of 200:1. This behavior was observed in several supporting electrolytes and was not due to change in pH since this factor was maintained constant as the amitriptyline concentration was increased. Shifts in E1/2 and reductions in limiting current may arise in several ways, such as complex formation between the two drugs or adsorption of the amitriptyline onto the surface of the dropping mercury electrode hindering chlordiazepoxide reduction. Most data point to adsorption as the cause.


USP dissolution IV: comparison of methods. The hydrodynamics of four dissolution apparatus--viz., the USP basket, the USP paddle, the stationary basket-spinning filter, and the USP disintegration apparatus, were characterized. At higher velocities, the relationship between the intrinsic dissolution rate constant and linear velocity was parabolic rather than linear.


Quantitative TLC determination of propranolol in human plasma. A spectrodensitometric assay was developed for propranolol based on measurement of the absorbance of the drug on silica gel plates irradiated at 822 nm. Quantities as low as 0.10 microgram can be detected, and a linear relationship was obtained between 0.010 and 0.400 microgram. The percent recovery from plasma spiked with known amounts of the drug was 90.0--102.0. This procedure was used to determine propranolol in the  plasma of patients receiving therapeutic doses of the drug.


Substituent constant for drug design studies based on properties of organic electron donor--acceptor complexes. A new model chemical system based on organic electron donor--aceptor complexes is described. From values of equilibrium constants measured by an NMR technique, a predictable parameter for use in quantitative structure--activity relationship techiques is discussed.


High-performance liquid chromatographic and TLC determinations of desacetylvinblastine amide (vindesine) and its monosulfate salt. High-performance liquid chromatographic and TLC methods were developed for the determination of desacetylvinblastine amide base (vindesine), a chemically modified Catharanthus alkaloid presently in clinical evaluation. Both methods permit the detection of 6,7-dihydrovindesine and vindesine Nb'-oxide, the principal by-product in the chemical conversion of vinblastine to vindesine. The methods are applicable to both the sulfate salts and the free bases of the chemical substances described.


Selective demethylation of polymethoxyxanthones with aqueous piperidine. Data are presented for selective demethylation of eight polymethoxyxanthones with aqueous piperdine. Clarification and rationalization of the present and previous observations are made. The mechanism is defined in terms of both resonance effects and steric factors.


South American plants III: Isolation of fulvoplumierin from Himatanthus sucuuba (M. Arg.) Woodson (Apocynaceae). The bark of Himatanthus sucuuba was screened for pharmacological and anticancer activities. The lactone, fulvoplumierin (C14H12O4), was isolated from the n-hexane fraction. The identity was proven by elemental analysis and IR, mass spectral, and melting-point determinations. Reference samples were used for comparison.


Synthesis and antimicrobial properties of 3-substituted 1,2-benzisothiazole 1,1-dioxides. Twenty aromatic alcohols and thiols were derivatized by reaction with 3-chloro-1,2-benzisothiazole 1,1-dioxide. The resulting 3-substituted 1,2-benzisothiazole 1,1-dioxides were tested against Staphylococcus aureus, Salmonella typhosa, and Aspergillus niger, and their activities were compared with the activities of the precursors.


Constituents of Spartina cynosuroides: isolation and 13C-NMR analysis of tricin. Tricin was isoalted from the aerial parts of the marsh plant Spartina cynosuroides, which yielded a fraction enriched in antiluekemic activity. The 13C-NMR spectrum of tricin is discussed.


Sex differences in plasma half-life of dextrorphan in rats administered dextromethorphan. Male and female rats exhibited striking differences in their ability to metabolize dextromethorphan. Upon oral administration of this drug, the plasma half-life of dextrorphan, a major biotransformation product formed by O-demethylation, was 40 min in the female rat and 18.5 min in the male.


Comparison of in vitro dissolution and in vivo bioavailability of methaqualone tablets in humans. Two methaqualone tablets that exhibited different in vitro dissolution rates were administered to 11 normal healthy male volunteers. Serial blood samples were withdrawn following administration of each tablet, and plasma methaqualone concentrations were determined by an established spectrophotofluormetric assay. Both tablets produced virtually identical plasma concentration versus time profiles in humans, and no statistically significant differences in either the rate or extent of drug absorbed were detected. The results indicate that there is no correlation between in vivo bioavailability and the modified NF in vitro dissolution test used.


Binding of drugs to ion-exchange resins in simulated gastric fluid. The binding of 13 frequently abused drugs to two ion-exchange resins was studied in simulated gastric fluid. The results were compared with those previously obtained with activated charcoal as the adsorbent. The ion-exchange resins adsorbed the drugs more slowly than activated charcoal, and the binding capacities of the resins were inferior. These ion-exchange resins are unlikely to be very useful in removing drugs from the stomach.


Rapid determination of gold in whole blood of arthritis patients using flameless atomic absorption spectrophotometry. An assay for gold in whole blood of arthritis patients was developed using the graphite furnace atomic absorption spectrophotometer. This method involves no pretreatment of the whole blood except for simple dilution, thereby eliminating some variables and saving laboratory time and expense.


Selenium heterocycles XXII: Synthesis and antibacterial antifungal activities of arylsulfonyl-1,2,3-selenadiazoles. Series of 4-arylsulfonylmethyl-1,2,3-selenadiazoles, 4-(1-arylsulfonylethyl)-1,2,3-selenadiazoles, and 4-alkyl (or aryl)-5-arylsulfonyl-1,2,3-selenadiazoles were synthesized. 4-(3-Pyridyl)-5-phenylsulfonyl-1,2,3-selenadiazole exhibited the highest activity of growth inhibition against some bacteria and fungi.


Effect of dissolved oxygen levels on oxidative degradation of pyrogallol. Pyrogallol decomposition in aqueous systems with various dissolved oxygen levels was studied. The reduced dissolved oxygen levels were produced by deaeration via gas permeation. Dissolved oxygen levels were determined using a dropping mercury electrode polarograph. Degradation rates, T90, and relative protection indexes are discussed. Even at dissolved oxygen levels of less than 0.05 ppm, some decomposition of pyrogallol occurred, indicating nonoxidative pathways or the necessity of total removal of dissolved oxygen to afford complete protection. Apparently, reducing the level of dissolved oxygen is a viable alternative to stabilization of aqueous pyrogallol solutions, since the T90 was increased from 1.9 days in water with dissolved oxygen levels of 9.05 ppm to 114.4 days in water with dissolved oxygen levels of less than 0.05 ppm.


New compounds: antitumor activity of 3beta-hydroxy-13alpha-amino-13,17-seco-5alpha-androstan-17-oic-13,17-lactam 4-[p-[bis(2-chloroethyl)amino]phenyl]butyrate. 3beta-Hydroxy-13alpha-amino-13,17-seco-5alpha-androstan-17-oic-13,17-lactam 4-[p[bis(2chloroethyl)amino]phenyl]butyrate was prepared by reacting 4-[p-[bis(2-chloroethyl)amino]phenyl]butyryl chloride hydrochloride with 3beta-hydroxy-13alpha-amino-13,17-seco-5alpha-androstan-17-oic-13,17-lactam. They cytostatic action of the ester was investigated on two tumor systems (B16 melanoma on C57 b1 mice and T8-Guerin on rats).


Volume changes in cells of the outer medulla during perfusion of the rat kidney. 1. A method is described for the perfusion of the rat kidney with a medium resembling rat plasma in its ionic constituents but with 3% polyvinylpyrrolidone (mol.wt. 44,000) replacing the plasma proteins. 2. In the early stages of perfusion, there was rapid swelling of the tubular cells in the outer medulla, a low glomerular filtration rate and a low filtration fraction. 3. After 30 min perfusion, the tubular cell volume in the outer medulla was normal and filtration had increased and stabilised. 4. Cell swelling and the low initial filtration fraction were prevented by (a) adding 50 mM-mannitol to the basic medium, (b) replacing 50 mM-NaCl with 50 mM-choline chloride, or (c) adding 5% human serum to the basic medium. 5. The addition of human serum to the perfusion medium depressed the fractional reabsorption of sodium and potassium; sodium from 0.94 +/- 0.01 (S.E. of mean) with the basic medium to 0.79 +/- 0.02 with basic medium +5% serum after 35 min perfusion; and potassium from 0.73 +/- 0.04 with the basic medium to 0.37 +/- 0.05 with the basic medium +5% serum after 35 min perfusion. 6. Two conclusions are drawn from the observations: first, that at the start of perfusion the effective internal osmolality of tubular cells of the outer medulla is greater than that of cortical cells and of the basic medium; and second, that the presence of small amounts of plasma proteins in the perfusion medium has a marked effect on the properties of plasma cell membranes.


Autoregulation of plasma flow in the isolated perfused rat kidney. 1. Autoregulation of renal plasma flow, by which flow remains constant despite changes in perfusion pressure, was studied in the isolated, perfused kidney of the rat. 2. Autoregulation did not occur in preparations perfused with a protein-free medium consisting of a balanced ionic solution resembling rat plasma in which 3% polyvinylpyrrolidone replaced the plasma proteins, changes in perfusion pressure over the normal autoregulatory range 100-150 mmHg produced a corresponding and linear change in venous outflow and no consistent change in renal vascular resistance. 3. Addition of human serum (5%, v/v) to the medium restored autoregulation; changes in perfusion pressure in the range 100-150 mmHg resulted in a stable plasma flow and a linear change in renal vascular resistance. The addition of bovine serum albumin (3 g/1.) to the protein-free medium restored autoregulation to a similar degree. 4. In kidneys perfused with the protein-free medium, the sensitivity of the renal vasculature to the vasoconstrictor drugs epinephrine and angiotensin II was only 1/40 the level seen in those kidneys perfused with media containing serum or albumin. 5. The experiments show that in the isolated, perfused kidney, autoregulation of plasma flow is not dependent on the presence of the globulin, angiotensinogen, in the perfusion medium; and suggest that failure of autoregulation in kidneys perfused with a protein-free medium could be attributed to the rapid decline in the sensitivity of the vascular smooth muscle to constrictor stimuli.


The action of adrenaline on pace-maker activity in cardiac Purkinje fibres. 1. Adrenaline is known to shift the activation curve for iK2 (s infinite curve) in a positive direction on the voltage axis. This should cause an increase in the slope of diastolic depolarization, but cannot account for the experimentally observed increase in the maximum diastolic potential (MDP). 2. On application of adrenaline, in voltage clamp studies on short sheep cardiac Purkinje fibres there is a consistent 5-15 mV negative shift of the reversal potential for the pace-maker current, iK2. This shift is not reversed on application of the beta-blockers sotalol or propranolol, or on washout for up to one hour. 3. A computer simulation, including this effect of adrenaline, shows that it can shift the maximum diastolic potential in the hyperpolarizing or depolarizing direction depending on the initial value of [K+]o. In both cases it will add to the increase in rate caused by the positive shift of the activation curve for iK2 (the s infinite shift). 4. Studies of the effects of adrenaline on the MDP and rate in long sheep Purkinje fibres show a slower reversibility of the MDP than the rate, consistent with a slower reversal of the shift in the iK2 reversal potential than the shift in s infinite. 5. Possible mechanisms of the shift in reversal potential are discussed with respect to K+ balance in the intercellular clefts of the Purkinje fibre, including a a stimulation of the Na+- K+ pump. The possible sources of voltage clamp artifact are also discussed.


On the transmission of the stimulating effects of carbon dioxide to the muscles of respiration. 1. Electromyography was used to measure the response of the diaphragm and intercostal muscles to CO2 in artificially ventilated decerebrate cats. 2. Hypocapnia produced tonic activity in either inspiratory or expiratory muscles or both, according to the preparation. 3. A graded effect of CO2 on both rhythmic and tonic activity was observed and for the latter this could be seen at as low as 10 torr PA,CO2. 4. In one human subject tonic firing of expiratory motoneurones was also induced by hypocapnia and this activity showed a graded increase with increasing (CO2. 5. A saggital incision of the medulla aimed at interrupting inspiratory bulbospinal axons abolished activity in inspiratory muscles and at eupnoeic levels of CO2 converted the activity of expiratory muscles from a periodic to a topic firing pattern. 6. Following such lesions the threshold for rhythmic excitation of expiratory muscles was elevated and this revealed that the graded effect of CO2 on tonic expiratory activity extends to as high as 60 torr. 7. The tonic activation of respiratory muscles in response to CO2 ceased after cervical cord transection or when the saggital incision in the medulla was extended caudally to the first cervical segment. 8. It is concluded that the CO2 dependent activation of spinal respiratory motoneurones is conveyed by bulbospinal axons which decussate in the vicinity of the obex and that this activation can be rhythmic or tonic. 9. It is suggested that the rhythmic excitation of expiratory muscles derives from a periodic inhibition of expiratory bulbospinal neurones which are subjected to a tonic CO2 dependent excitation which is continuously variable over the physiological range.


Certain pharmacological characteristics of the release of pancreatic glucagon in response to stimulation of the splanchnic nerves. 1. The effect of alpha- and beta-adrenoceptor blockade on the release of pancreatic glucagon, in response to stimulation of the peripheral ends of the splanchnic nerves has been examined in adrenalectomized calves 3-5 weeks after birth. In addition, the effects of insulin, atropine and somatostatin on the glucagon response to splanchnic nerve stimulation have been assessed in adrenalectomized dogs. 2. In calves release of pancreatic glucagon in response to splanchnic nerve stimulation was not suppressed by phentolamine at a dose that effectively abolished alpha-adrenergic inhibition of insulin release, or by propranolol, at a dose that completely eliminated the chronotropic action of the cardiac sympathetic innervation. 3. In dogs release of pancreatic glucagon in response to splanchnic nerve stimulation was not suppressed by atropine (0.2 mg/kg) or somatostatin, at a dose that caused a steady fall in the concentration of gastrin in the circulating plasma (0.5 microgram-kg-1 min-1). Glucagon release was apparently potentiated by exogenous insulin (4.0 u./kg). 4. The results are discussed in relation to the findings of other workers and it is concluded that the precise mechanism whereby stimulation of the sympathetic innervation to the pancreas leads to secretion of glucagon merits more detailed investigation.


The internodal axon membrane: electrical excitability and continuous conduction in segmental demyelination. 1. Longitudinal action currents were recorded from single undissected myelinated nerve fibres in intact, perfused ventral roots of normal rats and ones treated with diphtheria toxin to produce demyelination. 2. Closely spaced recording electrodes (120 micron), signal averaging and the use of a calibrating current throught the root permitted membrane currents to be determined over 240 micron lengths of nerve. Contour plotting was used to plot membrane current density as a function of space and time. 3. The previous result of Rasminsky & Sears (1972) of delayed saltation in demyelinated nerve fibres was confirmed. 4. In addition a new phenomenon of continuous conduction was observed, along distances of up to 1 1/2 times the afferent internodal distance. The continuous spatial distribution of inward current in these cases showed that electrical excitability was distributed along the internodes. 5. Internodal excitability was also revealed in demyelinated fibres by extra foci of inward current judged to be internodal on the basis of the spacing of the other (nodal) foci. 6. Continuous conduction occurred at velocities in the range of 1.1-2.3 m/sec or roughly 1/20th-1/40th of the velocities expected for normal stretches of the same fibres. 7. The continuous conduction was attributed to conduction along lengths of demyelinated axon. This was supported by estimates of 0.86 and 1.5 muF/cm2 for membrane capacity from the foot of a continuously conducted action potential. 8. The implications of internodal electrical excitability in demyelinated nerve fibres are discussed in relation to (a) recent estimates of the density of sodium channels in intact and homogenized normal nerves, (b) the pathophysiology of demyelinating disease.


Type A atrial receptors in the cat: effects of changes in atrial volume and contractility. 1. Action potentials were recorded from filaments of the right cervical vagus in anaesthetized, paralysed cats. Right atrial receptors with type A (twelve units) and Intermediate type (two units) patterns of spontaneous discharge were selected and their responses to changes in atrial volume were analysed. 2. Changes in atrial volume of similar magnitude were produced under four different conditions: a, innervated hearts; b, denervated hearts; c, depression of atrial muscle contractility induced after cardiac denervation and d, non-beating hearts. 3. In innervated hearts the systolic discharge of each receptor showed a characteristic response to changes in atrial volume. Cardiac denervation and depression of atrial contractility markedly altered this response in terms of frequency of discharge threshold and 'sensitivity'. 4. During increments in atrial volume all the receptors but one assumed an Intermediate pattern of discharge. The diastolic firing rate was, however, higher for any given atrial pressure, in innervated hearts than under conditions b, c and d. 5. In innervated hearts the response of the receptors to atrial systole was characterized by a higher frequency of discharge and a lower threshold with respect to the responses of the same receptors to atrial filling. These differences were minimized at high atrial volumes and during depression of atrial contractility. 6. The results indicate that the responses of the receptors to atrial systole are mainly dependent upon the state of contraction of atrial muscle and that the differences between systolic and diastolic discharge are mainly due to the high dynamic component of the stretch during atrial contraction.


Ouabain-sensitive fluid accumulation and ion transport by rabbit blastocysts. 1. By incubating 6-day post-coitum (p.c.) blastocysts in medium supplemented with either 20 mM-sucrose or 10 mM-KCl it was possible to show that the trophectoderm of the blastocyst prevents the concentration of K in the blastocoele fluid rising to external concentrations. 2. The concentrations of K in the blastocoele fluid are maintained predominantly by leakage of K from the trophoblast cells into the blastocoele and by ouabain-sensitive transport of K into the trophoblast cells from the blastocoele fluid. 3. Exposure of blastocysts to ouabain on the juxtacoelic, but not abcoelic, surface of the trophectoderm may inhibit blastocoele fluid accumulation.


Amino acid pharmacology of mammalian central neurones grown in tissue culture. 1. Spinal and cerebellar-brainstem areas of fetal mouse were dissociated and grown in tissue culture until large enough to permit stable intracellular recording. 2. The tissue-cultured neurones, growing as a monolayer and accessible under direct vision using phase contrast optics, allowed precise placement of intracellular recording and extracellular ionophoretic pipettes. 3. Ionophoresis of GABA and glutamate revealed a non-uniform distribution of responses over the cell surface, with a lack of spatial coincidence in sensitivity between the two. GABA inhibited and glutamate excited all cells tested. 4. GABA responses evoked at the cell body and on nearby process membrane were almost uniformly hyperpolarizing, while those at some peripheral process membrane were either hyperpolarizing, depolarizing or a combination of both events. All responses were associated with an increase in membrane slope conductance. 5. Membrane polarization showed that all hyperpolarizing events extrapolated to about the same inversion potential, which averaged about 9 mV more negative than resting potential (n = 95 cells). The depolarizing phases of responses evoked at peripheral membranes extrapolated to about 0 mV (n = 5 cells). 6. The hyperpolarization and increase in membrane conductance of GABA responses at the cell body were dependent on Cl- ions and the inversion potential of the response was dependent on the Cl- ion concentration gradient. The inversion potentials of GABA, glycine and beta-alanine responses were identical. 7. When matched in magnitude for evoked conductance increase, glycine responses decayed more rapidly than GABA. Glycine and beta-alanine voltage responses both decayed faster than GABA responses of comparable size. 8. In about half the cells tested sustained or rapidly repeated application of GABA and glycine transformed hyperpolarizing responses into depolarizations which were associated with a maintained conductance increase. Results from conditioning-test experiments with pairs of GABA and glycine responses suggest that the reversal of response polarity is due to a rapid redistribution of Cl- ions. 9. The limiting slope of log-log dose-response curves for GABA-induced conductance averaged about 2, while those for glutamate-induced depolarizations averaged about 1. The results suggest that two molecules of GABA and one molecule of glutamate participate in the respective post-synaptic responses. 10. The observation indicate that mammalian C.N.S. tissue grown in culture is a suitable model to study C.N.S. membrane pharmacology with increasing precision.


Pentobarbitone pharmacology of mammalian central neurones grown in tissue culture. 1. The effects of the barbiturate anaesthetic pentobarbitone on the membrane properties and amino acid pharmacology of mammalian C.N.S. neurones grown in tissue culture were studied using intracellular recording coupled with bath application, extracellular ionophoresis, or focal diffusion. 2. The addition of an anaesthetic concentration of pentobarbitone to the bathing medium abolished all spontaneous synaptic activity, but did not render individual cells electrically inexcitable nor prevent evoked synaptic acitivity. 3. Focal ionophoresis of pentobarbitone or diffusion from blunt micropipettes reversibly increased membrane conductance, effectively dampening excitability without directly affecting individual action potential characteristics. 4. Pentobarbitone-induced membrane conductance was reversibly blocked by picrotoxin. The inversion potential of the pentobarbitone voltage response depended on Cl- ion gradients and was similar to that of GABA. 5. Pentobarbitone reversibly enhanced the conductance increase produced by GABA with a variable slowing of response kinetics, shifting GABA dose-response curves to the left. Responses to glycine and beta-alanine were not affected. 6. Higher ionophoretic currents of pentobarbitone, which measurably increased membrane conductance, attenuated and markedly slowed GABA responses. Similar effects on GABA responses were observed by superimposing GABA pulses on low level GABA currents. 7. Pentobarbitone, in the absence of an increase in membrane conductance, reversibly depressed depolarizing responses to glutamate without changing response kinetics. Slower responses to acetylcholine which were associated with an apparent decrease in membrane conductance were not affected by the drug. 8. Analysis of double-reciprocal plot data suggested a non-competitive type of antagonism between pentobarbitone and glutamate. Pentobarbitone depression of glutamate was not affected by picrotoxin. 9. Both GABA and glutamate responses appeared to be equally sensitive to pentobarbitone. Specific interaction of the drug with amino acid receptor-coupled events is indicated by the requirement for pentobarbitone pipette placement close to the amino acid response site. 10. The results suggest that pentobarbitone depresses neuronal excitability by (1) directly activating post-synaptic GABA-receptor coupled Cl- conductance, (2) potentiating post-synaptic GABA-induced conductance events, probably at the level of the GABA receptor, and (3) depressing post-synaptic glutamate-induced excitation, probably at the level of the conductance mechanism.


The role of the autonomic nervous system in the control of pancreatic endocrine responses to milk ingestion in the calf. 1. Pancreatic endocrine responses to ingestion of milk have been investigated in conscious unweaned calves, 3-5 weeks after birth. Passage of gastric content from abomasum to small intestine was prevented by means of a cannula placed in the duodenum adjacent to the pylorus and food was witheld for at least 22 h in order to deplete liver glycogen. 2. Under these conditions ingestion of milk was followed by a prompt rise in the concentrations of pancreatic glucagon, PP and gastrin in the arterial plasma but the usual rises in plasma glucose and insulin concentration were absent. 3. Evidence was obtained to show that absorption of glucose from the small intestine occurs sufficiently rapidly to account for the initial rise in plasma glucose concentration after feeding in normal animals. However, the rise in plasma glucagon concentration was sufficient to contribute to alimentary hyperglycaemia by promoting hepatic glycogenolysis in calves with abundant liver glycogen. 4. None of the neuroendocrine responses to ingestion of milk was affected by prior section of the splanchnic nerves whereas each was blocked by atropine (0.2 mg/kg), showing that all depend upon muscarinic, parasympathetic rather than sympathetic activity, in the absence of extraneous stress.


Functional distinction between two transport mechanisms in rabbit gall-bladder epithelium by use of ouabain, ethacrynic acid and metabolic inhibitors. 1. Net fluid transport rate, transepithelial p.d. and resistance, and unidirectional Na+-fluxes were measured in rabbit gall-bladder preparations exposed on both sides to bicarbonate-Ringer solution in vitro. 2. Both ouabain and ethacrynic acid (ETCA) caused dose-dependent decreases of net fluid transport rate; ouabain inhibited fluid transport predominantly from the serosal side, whereas the inhibitory effect of ETCA was elicited mainly from the mucosal (luminal) side. Applied bilaterally, the ID50 for ouabain was 2.5 X 10(-6) M, and for ETCA 2.3 X 10(-4) M. After maximal inhibition at each concentration level of the two inhibitors fluid transport could not be reversed. 3. 2,4-Dinitrophenol (2,4-DNP) (2 X 10(-4) M) or substitution of O2 by N2 caused an 80% reversible decrease of net fluid transport. 4. The spontaneous p.d. across the rabbit gall-bladder was about 2.7 mV, mucosal side positive. 2,4-DNP, N2 and serosal application of ouabain depressed the p.d. after an initial hyperpolarization. This decrease was reversible during recovery from 2,4-DNP and N2, but irreversible after removal of ouabain at concentrations greater than or equal to 10(-4) M. Mucosal application of ETCA (10(-3) M) caused no decrease in p.d., which actually increased slightly. 5. Calculated passive serosal-to-mucosal Na+-fluxes changed in the same direction as did changes in conductance. 6. It is concluded that ETCA does not interfere primarily with the Na-K-ATPase or cellular oxidative metabolism. The data support the proposal that the pump responsible for isosmotic transepithelial fluid transfer is located in the luminal end of the cells. This pump is ETCA-sensitive. The ATPase-dependent Na-K pump, which can be inhibited by ouabain, is localized in the serosa-facing cell membrane. The data suggest that the inhibition of net fluid transport by ouabain is indirect and mediated by changes in intracellular ion concentrations. 7. The results support the concept that the transepithelial fluid transport mechanism is electroneutral, and suggest that the mucosa positive transepithelial p.d. is due to differences in electromotive forces arising from ion (mainly K+) diffusion across the mucosal and serosal cell membranes.


The metabolism of [14C]histamine during pentagastrin-stimulated acid secretion in the cat. 1. The metabolism of exogenous [14C]histamine has been examined in cats during gastric secretion. The appearance of 14C-labelled metabolites has been measured chromatographically in urine and gastric juice under non-secreting and pentagastrin-stimulated conditions, and in gastric mucosa after pentagastrin stimulation. 2. The main metabolites detected were (i) an acidic product, presumed to be methylimidazoleacetic acid, (ii) Ntau-methylhistamine, and (iii) an unidentified metabolite, moving rapidly in the chromatographic systems used, and designated 'preacetylhistamine'. No evidence was found for the presence of side chain (i.e. Nalpha)-methylated histamines, either in the non-stimulated or pentagastric-stimulated state. 3. During a 3 hr non-stimulated period, followed by 3 hr of pentagastrin administration, the relative proportions of 14C-labelled metabolites excreted in urine remained unchanged. During acid secretion there was an increase in the proportion of 'pre-acetylhistamine' in gastric juice, which occurred at the expense of the acidic metabolites. It is suggested however that this effect is more likely to be the result of a slow adaptation to the administration of exogenous [14C]histamine than the result of acid secretion. 4. The results of the present work do not appear to support the hypothesis of Code (1970), that a local control mechanism for acid secretion might involve the formation Nalpha-methylated histamine metabolites in gastric mucosa.


Influence of the autonomic nervous system on the release of vasoactive intestinal polypeptide from the porcine gastrointestinal tract. 1. The release of vasoactive intestinal polypeptide from the gastrointestinal tract in response to stimulation of the vagus nerves, the splanchnic nerves and to intra-arterial infusion of acetylcholine (ACh) was examined in pigs. 2. Stimulation of the vagus nerves caused an abrupt increase in the release of vasoactive intestinal polypeptide. The amount of the peptide released depended on the frequency at which the nerves were stimulated. Maximum release was obtained at 8 Hz. 3. Atropine and beta-adrenergic blocking agents failed to diminish the vagally induced release of vasoactive intestinal polypeptide, while the response was completely blocked by hexamethonium and increased after alpha-adrenergic blockade and after splanchnicotomy. 4. Intra-arterial infusion of ACh closely imitated the response to vagal stimulation, but the release of vasoactive intestinal polypeptide induced by ACh was abolished by atropine. 5. Stimulation of the splanchnic nerves caused a decrease in the release of vasoactive intestinal polypeptide, an action which was annulled by alpha-adrenergic blockade, but still present after the adrenal glands were isolated from the circulation. The inhibitory effect of splanchnic stimulation significantly diminished the vagally induced release of vasoactive intestinal polypeptide. 6. The results demonstrate a dual innervation with opposing effects on the neurones containing vasoactive intestinal polypeptides. The possible physiologic implication of this finding is discussed.


A study of the routes by which protein passes from the pericardial cavity to the blood in rabbits. The routes by which radioiodinated serum albumin placed in the pericardial cavity gains access to the circulation have been investigated in rabbits. 1. Eighty per cent of pericardial cavity protein passes through the parietal pericardium and into the circulation through the thoracic duct. 2. A small amount of protein is drained through the right lymph duct; this is probably derived from protein passing from the pericardial cavity into the pleural cavity. 3. There is no apparent movement of protein directly into blood vessels of the parietal pericardium. For theoretical reasons movement of protein across the visceral pericardium and into the blood vessels of the myocardium is also unlikely. 4. A small amount of protein enters the circulation when both major lymphatics are ligated. It is proposed that lymphatic uptake may continue and secondary lymphovenous junctions will open as a result of raised intralymphatic pressure.


Non-parallel enzyme secretion from rat pancreas: in vivo studies. The secretion of amylase, lipase and chymotrypsinogen was measured in the pancreatic juice of anaesthetized rats. 1. Stimulation of the protein secretion by I.V. cholecystokinin-pancreozymin (8 IDU kg-1) given together with secretin (5 CU kg-1) resulted in a change in the enzyme proportions in pancreatic juice, characterized by decreases in the amylase to chymotrypsinogen and amylase to lipase ratios. 2. The same phenomenon was elicited by pilocarpine (15 mg kg-1) associated with secretin (5 CU kg-1) but not by secretin alone. 3. Blockade of protein synthesis by cycloheximide did not suppress the induction of non-parallelism by stimulation. 4. It was concluded that the exocrine proteins are stored in two pools in which the proportions of enzymes are different. 5. With the help of a mathematical model it is proposed that one pool which corresponds to less than 0.35% of total enzyme storage, is responsible for basal secretion and is not sensitive to stimulation. The second (preponderant) pool provides secretion with a protein output increasing with stimulation.


The influx of amino acids into the heart of the rat. 1. The influx of nineteen amino acids into the heart of the living rat was studied by a method specially devised for experiments under controlled conditions in vivo. 2. When, in separate experiments, the concentration of each amino acid in turn was artificially raised in the circulation, the influx of that amino acid into the heart increased. 3. Our data indicate that at least ten of these amino acids enter the heart in vivo by means of saturable carrier-mediated transport systems. The transport rates conform, at least approximately, to Michaelis kinetics and the transport systems are clearly, in the cases of many amino acids, active, i.e. energy-dependent. 4. The amino acids which were studied had rates of influx into the heart which differed from each other over a range of more than 10 to 1, even when allowances were made for the difference in their concentration in the circulating blood. These differences in influx were not related to such factors as the molecular size of the individual amino acids. 5. The amino acids which have a high influx into the heart are mainly those which are needed either to re-synthesize contractile protein or as oxidizable substrates.


Free water clearance curves during saline, mannitol, glucose and urea diuresis in the rat. 1. Free water clearances were measured during infusion of hypotonic saline, glucose, urea, and mannitol in Brattleboro rats. For each solute the free water clearances were plotted using either V or (C(H2O) + C(Na)) as the distal tubular delivery term.2. In all cases the use of (C(H2O) + C(Na)) as distal delivery term yielded a steeper relationship than when V was used. There were no significant differences in the C(H2O) to V relationship when saline, glucose and mannitol was the solute infused. Urea, however, resulted in a curve with a slope significantly less than that for the other solutes.3. When C(H2O) was plotted against (C(H2O) + C(Na)) there was still no significant difference between the slopes of the curves during saline or mannitol infusion. Use of this delivery term, however, resulted in a slope during glucose infusion which was significantly greater than that during saline or mannitol infusion. The slope for urea infusion remained lower than that for any other solute.4. Regardless of the delivery term used, there was no significant difference in the slopes of the curves for awake Wistar and awake Brattleboro rats during mannitol infusion. This indicates that the awake rat is a suitable model for free water clearance studies.5. The results indicate that NaCl and mannitol are both adequate for free water clearance and that (C(H2O) + C(Na)) is a better index of distal delivery than V.


Acetylcholine noise in cultured chick myoballs: a voltage clamp analysis. 1. Large spherical muscle cells were grown in vitro by allowing dissociated chick myoblasts to fuse in suspension culture. 2. Myoball membranes could be adequately voltage clamped even in the face of large inward currents (ca. 100 nA) induced by ACh. 3. The single channel conductance, gamma, estimated from the ratio of the mean to the variance of ACh currents was 25-40 pmho at temperatures between 25 degrees and 37 degrees C. 4. Spectra of ACh current fluctuations declined with 1/f2. The mean channel open time (tau) estimated from the half-power frequency was 2 msec at 37 degrees C and -90 mV holding potential. At lower membrane potentials tau was decreased and on hyperpolarization tau was prolonged.


A transition temperature for acetylcholine channel conductance in chick myoballs. 1. The temperature dependence of ACh channel conductance (gamma) and channel open time (tau) was determined by analysing ACh induced membrane current fluctuations in voltage clamped chick myoballs. 2. gamma decreased from 25-30 pmho at 37 degrees C to less than 5 phmo at 10 degrees C. An Arrhenius plot of gamma vs. temperature exhibited a clear break or 'transition temperature' at 20 degrees C. 3. tau increased from 2 msec at 37 degrees C to 16 msec at 10 degrees C. The Arrhenius plot of tau vs. temperature was linear. No transition temperature was detected. 4. Submicellar concentrations of the non-ionic detergent, Triton X-100 reversibly blocked ACh respnses. The effect was all-or-none at the molecular level. 5. These results are consistent with the possibility that the fluidity of membrane lipids in the ACh receptor micro-environment may influence the degree to which the channel can open.


Changes in pigeon cone photocurrent caused by reduction in extracellular calcium activity. 1. Photocurrents have been recorded from the red spot of the isolated superfused pigeon retina. The technique used was to record photovoltage gradients and extracellular fluid resistivity in a direction parallel with the long axes of the receptors. 2. Cone and rod responses were identified, and experiments designed so that only the former were elicited. 3. In the outer portion of the receptor layer, the wave form of the cone photoresponse lacks the initial transient (the 'nose') seen in the portions of the receptor layer nearer the synapses. It is argued that this observation permits the use of a simple equivalent circuit for the generation of the extracellular photocurrent, to infer membrane properties from extracellular recordings. 4. When the superfusing Ringer is changed to one which has a very low calcium activity (2 X 10(-7)M) the first result is that photoresponses increase in magnitude (X 7.7) but the relationship between light intensity and response amplitude and the light intensity (sigma) required to produce a half maximal response remains unchanged. 5. This increase in photocurrent in low calcium also occurs if the superfusing fluid is cooled to 10 degrees. 6. After 2--3 min, the photoresponses in low calcium begin to decrease in amplitude, and the value of sigma is progressively reduced, tenfold in 10 min. 7. During this time, the wave form of the photocurrent alters, the rate of increase and decrease of the responses being slowed. 8. The relationship between peak photocurrent and duration of light flash is modified. 9. The response to a step of light is not well maintained in higher calcium, but is well maintained in low calcium. 10. In higher calcium, the current overshoots during recovery from a flash to below the previous dark level. This does not happen in low calcium. 11. In low calcium, a light adapting background illumination desensitizes the cones. All changes in wave form of the response can be accounted for in terms of the membrane non-linearities. The calculated time course of the change in concentration of the 'internal transmitter' is unaffected. The same is true of desensitization, in the dark, following exposure to intense illumination.


The effect of intravenous infusion of angiotensin II on drinking in the Australian marsupial Trichosurus vulpecula. 1. When marsupial brush-tailed possums were maintained on a normal fruit and vegetable diet with access to water ad libitum, I.V. infusion of synthetic angiotensin II at rates of 0.035-3.5 mug/kg. min caused short-latency drinking in up to seven of eleven animals tested. These rates also had significant pressor effects.2. There was a positive correlation between the rate of angiotensin infusion and the percentage of tested animals which responded by drinking, as well as the amount of water drunk by such animals. The amount drunk during a second infusion 1 hr later was reduced. There was a negative correlation between the rate of infusion and the latency to drinking.3. Of six animals given access to both water and 1.8% sodium chloride solutions, five drank some saline during maintenance and control periods and all responded with short-latency drinking of water to infusion of angiotensin II at 0.35 mug/kg. min.4. Withdrawal of 10% of blood volume, known to stimulate renin production in the possum, caused an increase in water intake in only one of six possums.5. Infusion of isoprenaline I.V. at 20 mug/kg. min, which caused a profound fall in B.P., had no effect on drinking by all six possums.6. It is concluded that these marsupials share with eutherian mammals responsiveness to a dipsogenic action of angiotensin II, which appears to be inhibited by preceding ingestion of water and potentiated by preceding ingestion of hypertonic saline. The physiological significance of this effect is uncertain.


An analysis of excitatory junctional potentials recorded from arterioles. 1. Arterioles were impaled with two independent micro-electrodes, one to pass current and the other to record membrane potential. 2. When current was injected into one branch of an arteriole, a membrane potential change could be detected either in the same branch or in an adjoining branch indicating that the arteriolar smooth muscle cells were electrically connected. 3. Fine dissection of the arteriolar tree gave short segments of arteriole which appeared to behave electrically as short cables with sealed ends. 4. Analysis of the electrotonic potentials recorded from isolated segments of arterioles allowed a determination of the arteriole cable properties. 5. Using the data from the cable analyses it was concluded that the junctional current underlying an excitatory junction potential has a duration that is brief when compared with that of the potential.


The role of the autonomic nervous system in the control of glucagon, insulin and pancreatic polypeptide release from the pancreas. 1. The mechanisms of release of pancreatic glucagon, insulin and pancreatic polypeptide (PP) in response to hypoxia and to 2-deoxyglucose have been investigated in conscious calves 3-5 weeks after birth. 2. A single injection of 2-deoxyglucose (200 mg/kg I.V.) produced an abrupt rise in the concentrations of pancreatic glucagon, insulin and PP in the arterial plasma. The changes in plasma insulin and PP concentration were unaffected by prior section of the splanchnic nerves but were effectively abolished by atropine (0-2 mg/kg I.V.). The rise in plasma pancreatic glucagon concentration was prevented in calves with cut splanchnic nerves that were given atropine but neither procedure alone suppressed the response. 3. 2-deoxyglucose also caused a substantial increase in the output of glucocorticoids from the right adrenal gland together with a pronounced rise in adrenal blood flow. There was also a small but significant increase in catecholamine output from the adrenal medullae in these animals. 4. Intense hypoxia caused a pronounced increase in the concentration of PP in the arterial plasma. This was found to resemble the glucagon response to intense hypoxia in that it persisted in animals with cut splanchnic nerves that were given atropine. Less intense hypoxia caused a rise in plasma pancreatic glucagon concentration (but not PP) that was abolished by section of the splanchnic nerves. The changes in plasma insulin concentration in these experiments were consistent with the conclusion that they were secondary to changes in plasma glucose concentration. 5. It is concluded that pancreatic endocrine responses to both moderate hypoxia and 2-deoxyglucose are mediated by the autonomic innervation.


Slow inward and outward currents of rat ventricular fibers under anoxia. Voltage and current clamp experiments were performed on rat ventricular strips under anoxia. 1. Under the influence of anoxia the membrane depolarized by 5 to 10 mV and the action potential amplitude decreased by 15 mV. The plateau disappeared and the duration of the action potential was shortened. 2. The slow inward current was reduced by 50 to 80% and its reversal potential became more negative by about 31 mV. The conductance of the slow inward channel decreased by 26%. 3. The net outward current was slightly depressed.


[Comparative study of the activity of medullary respiratory neurones during polypnea triggered by hypothalamic electrical stimulation or by hypothalamic heating (author's transl)]. We have compared in "encéphale isolé bas" cats the activity of medullary respiratory neurones during polypnea triggered by electrical stimulation (PSt) or by heating (PTh) of the hypothalamus. The medullary respiratory neurones are classified according to:--their anatomical localization (dorsal or ventral respiratory nucleus);--their axon destination (spinal : bulbo-spinal respiratory neurones; non spinal : propriobulbar neurones);--their discharge pattern;--the correlation coefficient between the number of spikes delivered in each burst and the duration of the corresponding respiratory phase (HILAIRE et MONTEAU, 1975). 1. During the two polypneas (PSt and PTh), we observe:--a reduction of activity that preferentially affects some groups of neurones (propriobulbar neurones) (fig. 3);--an inversion of the discharge firing rate, which increases during inspiration in normopnea and decreases in polypnea (fig. 1; fig. 6);--a decrease of the maximal discharge firing rate for the neurones of different groups (Table V). 2. However, two differences exist : during PSt, the maximal discharge firing rate increases for the inspiratory bulbo-spinal neurones of the dorsal nucleus and for the early-burster inspiratory propriobulbar neurones. The recruitment of the bulbo-spinal inspiratory neurones seems to be different; they are activated earlier during PSt than during PTh (Table VI). 3. Some of the observed differences are probably quantitative and we think that polypnea triggered by hypothalamic electrical stimulation is a good model for thermal polypnea.


Measuring fear of death: a reliability study. An increase in interest in death education among helping professionals and a concern for a lack of reliability and validity data on some instruments measuring attitudes about death is reviewed. The Collett-Lester Fear of Death Scale and the Lester Attitude Toward Death Scale were administered twice to 20 graduate level male and female counselor trainees over a six-week interval. Test-retest reliability coefficients on all scales and subscales were significant but low to moderate only.


Effects of extraversion, anxiety, and sex on children's verbal fluency and coding task performance. Seventy-eight boys and 71 girls (ages eight to 18 years) were assigned to one of eight groups on the basis of scores on the Junior Esysenck Personality Inventory, the Children's Manifest Anxiety Scale, and sex of the S. The Ss were administered a simple and a complex verbal fluency task and the coding subtest of the WISC. It was found that extraverted children of both sexes did better than introverted children on both measures of verbal fluency and the nonverbal coding task. Anxiety influenced girl's performance on the more complex verbal fluency task, but did not alter boys' performance. The present findings were discussed in relation to the adult literature relating extraversion, anxiety, and verbal fluency.


The abilities of retarded students: further evidence concerning the stimulus trace factor. A Wherry-Wherry hierarchical factor solution was obtained on the correlations among 11 WISC-R subtests for a sample of 79 mentally retarded boys and girls. The findings were not only congruent with Vernon's ability paradigm but also suggest that the ability structure for retardates may well be more complex than the structure for normals. The ability hierarchy for the present sample included a general (g) factor defined by positive loadings from all 11 subtests and factors corresponding to the verbal-educational (v:ed) and spatial-perceptual (k:m) parameters. In addition, a stimulus trace (ST) factor corresponding to the ability dimension described by Baumeister and Bartlett was obtained.


Memory development in learning disabled children: evidence from nonverbal tasks. The purpose of the present study was to test the developmental lag hypothesis with learning disabled children on two and three dimensional nonverbal task. Twenty-two learning disabled boys in two age groups of 11 each were tested on a probe memory recall procedure. In contrast to generalization of a developmental lag hypothesis, age-equivalent recall in primacy and recency positions reflected patterns similar to those of normal children. Further, a developmental analysis of nonverbal recall revealed constant age-related differences. Results suggested the developmental memory lag interpretation has been confounded with learning disabled children's generalized verbal deficits.


The occurrence of amphizoic Amebae in domestic animals. Random examination of domestic animals revealed the frequent presence of free-living amebae in their bodies. In diseased or dead cows, dogs, pigs, rabbits, pigeons, and turkeys 15 strains of amebae were found, belonging to the genera Acanthamoeba (A. polyphaga), Hartmannella (H. vermiformis), and Vahlkampfia (V. avara, V. enterica, V. inornata). They were usually accompanied by other infectious agents in different parts of the host bodies. Pathogenicity of 3 isolates could not be demonstrated by inoculation of laboratory animals. Some features of the isolates differed from those previously known for members of these genera. These strains may be considered amphizoic amebae according to Page (1974).


Binding of Trypanosoma congolense to the walls of small blood vessels. The mesenteric microvasculature was studied in rats and rabbits infected with Trypanosoma congolense. By examining vessels in the living animals, trypanosomes were observed to adhere to vessel walls by their anterior ends. It was evident from stained preparations of the vessels that the microcirculation contained 4-1400 times as many trypanosomes as were free in the cardiac blood. Parasites were more numerous in very small vessels than in larger vessels, and they were clustered in groups within the small vessels. The localization of T. congolense in the microvasculature is demonstrated and it is shown that this localization is established by attachment of the organism to the vessel wall.


[Radiological and surgical treatment of cancer of the thoracic oesophagus: a report on 143 cases (author's transl)]. It would appear that pre-operative radiotherapy early in the treatment of oesophageal cancer has avoided in many cases (especially those in an advanced stage), the appearance of local recurrences, which cause death very rapidly during the first year in those patients having surgical treatment only. This treatment, however, which is only localized to the mediastinum, has not prevented the appearance of metastases at a later date. It is obvious, therefore, that though we have improved local prognosis by localized and regional treatment, and the association of radiotherapy and surgery, we have not been able to act on the residual cancerous disease, and something else is needed. This "something else" must be chemotherapy, but at the present time we do not know which product, at which dose, and at which moment, this chemotherapy should be applied to be most effective.


[The use of disposable vascular catheters in interstitial brachytherapy of skin cancers (author's transl)]. Authors present technical improvements dealing with interstitial brachytherapy (Ir192) of skin cancers. They use fine disposable plastic tubes fitted with mandril, which allow loading of light radioactive material in any case. Short term results are discussed according to 101 applications.


The relationship of sperm viability and concentration to serum-induced head-to-head agglutination of bovine spermatozoa. Individual samples of bull semen were treated by filtration to remove immotile spermatozoa and by the addition of 10% heifer serum. There was significantly (P less than 0.01) greater serum-induced agglutination in the filtered than in the unfiltered samples. Head-to-head agglutination was also greater (P less than 0.01) in dilute sperm suspensions when compared to concentrated sperm suspensions.


Fertility studies of complementing genotypes at the albino locus of the mouse. Mice doubly heterozygous for two radiation-induced lethal alleles at the albino locus (C3H and C6H) show partial complementation: they are viable but runted and sterile. In C3H/C6H females oogenesis and mating are normal, but nearly all of their fetuses, even when genotypically normal (+/C3H or +/C6H), fail to survive beyond midgestation. Abnormalities of spermatogenesis, i.e. morphological defects in head condensation and a deficiency in numbers of maturing spermatids, are histologically detectable in the testes of C3H/C6H males. Spermatozoa from the vasa deferentia of such males are predominantly nonviable, immotile, and grossly abnormal in morphology.


Study of the motility of the avian oviduct with chronically implanted electrodes. Electrical activity was recorded in conscious hens from chronically implanted electrodes in the smooth muscle layers of the oviduct. Transport of the egg through the magnum resulted from an inhibition of the electrical activity in the oviduct cranial to the egg and an increased spiking activity caudally. During an ovulatory cycle the progression of the egg was related to four different patterns of the uterine motility: within a sequence, the ovulatory cycles varied according to the duration of Phases 3 and 4.


Electrical activity of the oviduct of the laying hen during egg transport. Electrical activity in the oviduct wall of the laying hen was studied. The frequency of spike discharges increased in the magnum and isthmus when the egg approached close to the recording sites. The frequency of discharge remained high in the magnum until the egg had passed, but it decreased in the isthmus during the stay of the egg. In the uterus, a relatively high activity was found immediately after oviposition and this was followed by low activity for about 5 h. Electrical activity began to increase again and reached maximum 1-2 h after the egg entered the uterus. The direction of propagation of electrical activity in the magnum was determined by using two electrodes and was towards the ovary or towards the uterus for periods of several minutes.


Patterns of oestrogen and testosterone excretion during pregnancy in a gorilla (Gorilla gorilla). Oestrogen and testosterone concentrations in the urine were determined by radioimmunoassay. Total oestrogen concentrations rose from 25 ng/mg creatinine in the non-pregnant animal to a mean of about 2 microgram/mg creatinine in the 50 days before term. There was a significant (P less than 0.001) correlation between oestrogen and testosterone concentrations until 11 days before parturition.


Effect of oestrogen on fetal survival in the rabbit. Pregnant rabbits (Day 18) were treated i.m. for 3 days with 10 microgram oestradiol 17beta/kg. The number of dead fetuses was significantly greater than in the control animals but corpus luteum weight and peripheral progesterone concentrations were not affected. Fetal death was therefore not due to luteolysis.


Effect of active immunization against oestrogens on plasma gonadotrophins in the ewe and the response to synthetic oestrogen or LH. Immunization against oestrogen resulted in elevated LH concentrations, in the form of a pulsatile release, which rose from 3 to as much as 41 ng/ml approximately every 1.5 h, even in the presence of high plasma progesterone concentrations. Elevated FSH concentrations showed only minor oscillations without consistent synchrony to the LH pulses. Injection of 250 microgram stilboestrol did not abolish the LH pulses but in 2 out of 8 ewes FSH was initially lowered. Injection of 1 mg stilboestrol abolished the LH pulses within 11 h and decreased FSH values in 2 out of 4 ewes. Between 16 and 35 h after injection there was a large increase in LH and FSH concentrations. Thus, in the ewe, the tonic secretion of LH and FSH is controlled by a negative feedback action of oestrogen, and diethylstilboestrol will exert both dose. Infusion of LH was unable to alter the frequency or height of the LH pulses, thereby excluding regulation of the LH pulses by a short feedback mechanism.


The movement of human spermatozoa in cervical mucus. Movement characteristics of freely swimming spermatozoa were studied with high-speed cinemicrography. At 21 degrees C, flagellar beat frequency was higher in midcycle human cervical mucus than in native semen or Tyrode's solution; the beat shape differed, possessing diminished amplitude and wavelength. Although the spermatozoa swam straighter in the mucus, the progressive swimming speeds did not differ in the three media. Swimming speed and beat frequency were linearly related in semen and in Tyrode, but in mucus the linearity was less certain. In midcycle cervical mucus at 37 degrees C, beat frequencies and swimming speeds were greater than at 21 degrees C, but the trajectories were equally straight, and the distances swum per beat (kinetic efficiencies) did not differ.


Effect of various hexoses on sperm capacitation and penetration of rat eggs in vitro. Fertilization of rat eggs in vitro could not be achieved when epididymal spermatozoa were preincubated and eggs in clots incubated in a chemically defined medium without D-glucose. Very high proportions (84-100%) of eggs examined were undergoing fertilization when 2.78-8.34 mM-D-glucose were included in the medium. The substitution of D-fructose or D-galactose for D-glucose resulted in very poor penetration rates (0-4%), but D-mannose was effective for fertilization (59-99% penetration). Incubations for sperm capacitation and egg fertilization in different media containing the various hexoses showed that rat epididymal spermatozoa could be partly capacitated without hexose, that D-glucose, D-mannose or D-galactose but not D-fructose is effective for sperm capacitation and that only D-glucose and D-mannose supported penetration of eggs in vitro.


Peripheral metabolism of testosterone during puberty in the male guinea-pig. Variations in the metabolic clearance rate and the production rate of testosterone during puberty in the male guinea-pig were established by single injection and constant infusion methods. Similar results were obtained; MCR (1/24h) increases from Day 20 to Day 70 and then stabilizes between Days 70 and 90 to levels comparable to those of a 6-month-old adult. MCR as 1/24 h/100 g decreases steadily between Days 20 and 60. The evolution of the testosterone production rate (PR: ng/24 h) is characterized by a marked rise between Days 20 and 70, and then a decrease up to Day 90, continuing until 6 months. PR as ng/24 h/100 g increases between Days 20 and 40, remains stable until Day 70, then decreases. Testosterone half-life is stable throughout the pubertal period. The rate of conversion of testosterone to androstenedione remains stable except for a rise between Days 50 and 60. We conclude that the increase in testosterone concentrations during puberty is due to a rise in the production rate and not to a decrease of clearance rate.


Detection of cell-mediated immunity to spermatozoa in mice and man by the leucocyte adherence-inhibition test. A modification of the leucocyte adherence-inhibition test was developed to study cell-mediated immunity to spermatozoa. The test is highly reproducible and requires very low numbers of leucocytes. Deposition of spermatozoa in the genital tract of the female mouse by one normal mating is sufficient to sensitize the female to sperm antigens and the degree of sensitization is independent of the number of matings and the strain of male, and is not enhanced by subsequent pregnancy.


Patterns of lactate dehydrogenase isoenzymes during gonadogenesis in the rat. The isoenzymes of LDH were detected by polyacrylamide gel electrophoresis. The M and H LDH subunits were present in gonads of both sexes from Day 14 1/2 p.c. and there was some variation with increased gestation. From Day 20 after birth two specific LDH-X bands (X1 and X2) were evident in the spermatocyte-rich fraction, but not in those of the Sertoli and Leydig cell fractions or those of the ovary.


Effect of a progesterone-releasing intravaginal device on the milk progesterone levels, vaginal flora, milk yield and fertility of cyclic and non-cyclic dairy cows. A progesterone-releasing intravaginal device (PRID) was inserted for 14 days into 10 lactating dairy cows at least 50 days after calving. Synchronization of oestrus was good and 5 of the cows conceived to a double insemination 48 and 72 h after PRID removal. In 9 cows vaginal infection was present when the PRID was removed but resolved spontaneously. The level of progesterone in the milk and the milk yield were similar to those in the 10 control animals. PRID treatment of 9 cows whose ovaries had remained inactive for at least 50 days after calving was followed by ovulation, as judged by the milk progesterone profile, in 8 animals after removal of the device.


The metabolism and motility of human spermatozoa in the presence of steroid hormones and synthetic progestagens. The metabolism and motility of human ejaculated spermatozoa incubated in vitro with steroids were studied. Progesterone and norethynodrel depressed the respiration, glycolytic metabolism and the motility of washed spermatozoa. Lynoestrenol did not affect the respiration or glycolysis of the spermatozoa, but did inhibit motility. Oestradiol did not cause any consistent alteration of the sperm metabolism, and did not affect the motility. Progesterone and norethynodrel appeared to act on the plasma membrane of human spermatozoa to increase its permeability and hence to facilitate the loss of essential cofactors required for the glycolytic and oxidative processes.


Luteotrophic effect of the rabbit blastocyst. Progesterone concentrations in peripheral plasma of 27 rabbits were determined by radioimmunoassay daily from Days 1 to 7. The rate of increase was significantly higher in pregnant than in pseudopregnant rabbits from Days 5 to 7 (P less than 0.02), but not before Day 5. Transfer of Day-4 or -5 blastocysts to synchronous, pseudo-pregnant recipients resulted in a significant rise in progesterone levels in comparison with those in sham-operated controls (P less than 0.01) or pseudopregnant does (P less than 0.01).


Albumin protection of mouse morulae and early blastocysts against the toxic effects of cuprous and cupric ions during development in vitro. Concentrations of cuprous and cupric chloride of 50 micrometer or greater completely inhibited the development of mouse morulae and early blastocysts into blastocysts in vitro. The zona pellucida was completely dissolved at concentrations of 250 micrometer cupric and 500 micrometer cuprous ions. No significant difference in toxicity was found between the cuprous and cupric ion at 0-50 micrometer. The addition of protein, as BSA, to the culture medium partly protected the embryos against the toxic effect of both copper ions. At a concentration of 25 micrometer a significantly higher level of BSA was required to protect against the cupric than the cuprous ion. Increasing the concentration of either ion increased the level of BSA required to exert a protective effect.