High-performance liquid chromatographic determination of perphenazine and amitriptyline hydrochloride in two-component tablet formulations.

A rapid, precise, and accurate high-performance liquid chromatographic procedure is presented for the simultaneous determination of perphenazine and amitriptyline hydrochloride in two-component tablet formulations. An aliquot of a methanolic extract of the tablet, containing trifluoperazine hydrochloride as an internal standard, is chromatographed on a nitrile bonded phase microparticulate column using a 0.005 M ammonium acetate-methanol (20:80) mobile phase. Quantitation is by peak area. The relative standard deviations for the procedure are 0.34 and 0.54% for the simultaneous determination of perphenazine and amitriptyline, respectively. Eight commercial tablet formulations were analyzed and found to contain 96.5-101.5 and 96.5-103.3% of the labeled amounts of perphenazine and amitriptyline hydrochloride, respectively.


Synthesis of various geometric and enantiomeric oxime O-(alpha- and beta-methylcholinyl) ethers as potential anticholinergic agents.

Various enantiomeric and geometric oxime O-(alpha- and beta-methylcholinyl) ethers were synthesized as potential anticholinergic agents. The synthesis, separation, resolution, and structural characterization of these compounds are reported. The first step of the synthetic pathway involved an oxime formation, with subsequent O-alkylation of the respective oxime with 2-chloro-N,N-dimethylpropylamine hydrochloride. The separation of the alpha- and beta-structural isomers utilized vacuum fractional distillation and/or column chromatography, and the resolution of the enantiomers was accomplished via the formation of tartrate diastereoisomers. A preliminary pharmacological evaluation for anticholinergic activity was conducted using a rat ileum assay. Structure-activity relationships, including some stereochemical properties and antimuscarinic activity, are discussed.


X-ray analysis of sulfur-containing colchicine derivatives.

The crystal and molecular structures of deacetylthiocolchicine hydrochloride dihydrate and thiocolchicine hexahydrate were determined by X-ray diffraction. The replacement of oxygen by sulfur on the C ring methoxy group causes greater puckering of the troponoid ring. The conformation of one A ring methoxy group differs from that of colchicine derivatives that do not contain sulfur.


Simultaneous automated determination of spironolactone metabolites in serum.

An automated two-phase method for the simultaneous fluorometric determination of the spironolactone metabolites canrenone (II) and canrenoic acid (III) in serum is described. The determination is performed by two dichloroethane extractions of the same serum sample at different pH values. The fluorescence developed in 65% (v/v) sulfuric acid is measured in two separate fluorometers (one each for canrenone and canrenoic acid). Comparable specificity and sensitivity to the manual procedure are obtained, with sensitivity limits of 20 ng of II/ml and of 30 ng of III/ml in serum. This method is applicable to the automated determination of drugs and metabolites in biological material when several extraction steps are involved.


Physiologically based pharmacokinetic model for digoxin distribution and elimination in the rat.

A plasma flow rate-limited pharmacokinetic model was developed to describe the distribution of digoxin to the heart, liver, kidneys, skeletal muscle, and GI tract in the rat. The model also provides for renal, hepatic (metabolic and biliary), and GI clearance as well as for biliary and GI secretion and GI reabsorption of digoxin. Predicted concentrations of digoxin in the heart, liver, skeletal muscle, and plasma were consistent with experimental observations in conscious rats after an intravenous dose. The model was extended to describe digoxin concentrations in the plasma of bile duct-ligated rats and ureter-ligated rats, simply by modifying appropriate clearance parameters. Excellent agreement was obtained between predicted and observed urinary excretion rates of digoxin for 12 hr after in intravenous dose to normal and bile duct-ligated rats.


Quantitative determination of isosorbide dinitrate and two metabolites in plasma.

A GLC method for the determination of plasma isosorbide dinitrate and two metabolites, isosorbide 2-mononitrate and isosorbide 5-mononitrate, is described. The three substances are extracted from alkalinized plasma with ether. Quantitation is effected by electron-capture detection after GLC separation with a 30% SE-30 column. The unusually heavy liquid phase loading is necessary to eliminate irreversible adsorption on the solid support. The electron-capture detector provides excellent sensitivity and specificity because of the electronegative nature of the nitric ester. The method was used to study the blood levels of isosorbide dinitrate and two metabolites in four beagle dogs after single oral doses of 40 mg of isosorbide dinitrate and in two human volunteers after a sublingual dose of 10 mg of isosorbide dinitrate.


Anthelmintic 2-arylhydrazino- and 2-arylazo-2-thiazolines.

Some 2-arylhydrazino- and 2-arylazo-2-thiazolines were synthesized for anthelmintic testing. The most potent compound, 2-(o-tolylazo)-2-thiazoline, was orally effective in sheep against a broad range of helminths.


Fluorescent probe study of sulfonamide binding to povidone.

The possibility of using a fluorescent probe technique for the study of drug-providone (I) interactions was investigated. 1-Anilino-8-naphthalenesulfonate (II) was used as the probe. Sulfanilamide, sulfacetamide, and sulfabenzamide were used as the binding competitors. Both sulfacetamide and sulfabenzamide decreased the fluorescence intensity of the I-II complex, while sulfanilamide increased the intensity. The fluorescence depression was greater with sulfabenzamide than with sulfacetamide, indicating that the former is more strongly bound to povidone. Since sulfabenzamide has a greater hydrophobic group (phenyl) than sulfacetamide (methyl), the binding of these sulfonamides to povidone is probably at least partially hydrophobic in nature. The enhanced fluorescence intensity of the I-II complex in the presence of sulfanilamide is believed to involve hydrogen bonding in which the sulfanilamide acts as an intermediary between I and II. Double reciprocal plots for the I-II and sulfonamide-I interactions were employed to obtain a binding constant of 3.2 X 10(4) M-1 for the I-II interaction. The association constants for sulfacetamide and sulfabenzamide were calculated by means of the Klotz equation to be 13.4 and 56.8 M-1, respectively. The povidone molecules appear to have 1.28 binding sites for these compounds under the experimental conditions.


GLC determination of free and conjugated triclosan in human plasma and urine.

A method for the determination of free and conjugated triclosan at concentrations as low as 2 ng/ml in human plasma or urine is described. Conjugated metabolites are split by enzyme hydrolysis. After addition of an internal standard, triclosan is extracted at acid pH into petroleum ether, transferred to an alkaline aqueous solution, and back-estracted into petroleum ether after acidification. Both compounds are acetylated with acetic anhydride in the presence of pyridine. The acetyl derivatives are determined by GLC using a 63Ni-electron-capture detector.


Influence of crystal form on tensile strength of compacts of pharmaceutical materials.

The tensile strengths of compacts of different crystal forms of aspirin, sulfathiazole, and barbital were determined with a modified tablet hardness tester. For each material, the tensile strength could be correlated with the amount of plastic flow and/or crushing undergone by each crystal form during compression.


Application of ion-pair methods of extraction of fluorouracil from aqueous fluids.

The polar molecule, fluorouracil, is a monoanion at pH 10 and may be quantitatively extracted from aqueous solutions with quaternary alkylammonium ions into an organic solvent such as dichloromethane as the ion-pair. Extraction constants of fluorouracil with the tetrapentylammonium ion in dichloromethane or dichloromethane-1-butanol (9:1) and with the tetrahexylammonium ion in dichloromethane were determined. Slope analysis demonstrated that association of the ion components in the aqueous phase occurred as the side reaction. A column ion-pair extraction technique, using tetrapentylammonium as the counterion and dichloromethane as the eluting phase, was developed and allowed quantitative transfer of fluorouracil to the organ solvent. The applicability of this method was shown by determining plasma levels of fluorouracil in cancer patients to whom 1 g of active substance was administered intravenously.


Polyamine metabolism II: N-(Monoaminoalkyl)- and N-(polyaminoalkyl)acetamides in human urine.

TLC and high-pressure liquid chromatographic examination of the dansyl derivatives obtained from human urine indicated the presence of N-[3-[4-aminobutyl)amino]propyl]acetamide (N1-acetylspermidine), N-[4-](3-aminopropyl)amino]buryl]acetamide (N8-acetylspermidine), N-(4-aminobutyl)acetamide (N-acetylputrescine), and N-(5-aminopentyl)acetamide (N-acetylcadaverine). The ratio of N1- to N8-acetylspermidine ranged from 10.3 in the urine of a patient with hepatoma to 1.1 in the urine of a normal subject. The three cancer patients had a considerably higher ratio of N1- to N8-acetylspermidine than did the three normal subjects. These findings indicate the ratio of N1- to N8-acetylspermidine in the 24-hr urine may serve as a biochemical marker for cancer.


Factors affecting serum oxytetracycline levels in beef calves.

Fifteen Aberdeen Angus steers, 295-364 kg, were dosed with either 4.4 or 11 mg of oxytetracycline hydrochloride/kg im. The antimicrobial activity of the serum was determined periodically, and the resulting data were treated statistically to determine the sources of variation. Variance in serum levels of oxytetracycline activity was attributed to dose, time of bleeding, order of dosing, animal, and assay. The total variance component was proportionately greater for the 11-mg/kg dose than for the 4.4-mg/kg dose. Animal variance increased with the higher dose level of oxytetracycline. The influence of dose on serum level was tested by applying a t test to the mean serum levels and their standard deviations at each bleeding time. The 4.4- and 11-mg/kg serum levels were significantly different (p less than 0.01) at all bleeding times. The 4.4-mg/kg serum levels mutliplied by 2.5 were not significantly different (p less than 0.05) from the 11-mg/kg serum levels at all bleeding times.


Anomalous chemical shifts of methyl groups of 2,4-dimethylbenzo[g]quinoline.

The chemical shifts of the methyl groups of 2,4-dimethylbenzo[g]quinoline are defined with respect to concentration, showing that the methyl resonances are reversed from their expected positions in concentrations normally used in NMR spectroscopy. The phenomenon is explained in terms of the probably "fixation" of bonds in the heteroring.


Quantitative determination of phenol by high-pressure liquid chromatography.

High-pressure liquid chromatography was used with a 5-micrometer silica gel column to quantitate the phenol in phenolated calamine lotion USP and a commercial antiseptic solution. This method requires less than 10 min/assay, and other compounds present in the products analyzed did not interfere.


Spironolactone: relationship between concentrations of dethioacetylated metabolite in human serum and milk.

The concentration of canrenone, a principal metabolite of spironolactone, was determined in human serum and milk. The milk to serum concentration ratios of this metabolite were 0.72 at 2 hr and 0.51 at 14.5 hr after ingestation of spironolactone. It was estimated that the maximum quantity of canrenone ingested daily by a human infant via its mother's milk would be approximately 0.2% of the daily dose of spironolactone given to the mother.


New compounds: total synthesis of dl-3a,4,6a-cis-4-(4-carboxybutyl)-hexahydropyrrolo[3,4-d]imidazol-2-one hydrochloride (dl-azabiotin hydrochloride).

The total synthesis of dl-3a,4,6a-cis-4(4-carboxybutyl)-hexahydropyrrolol[3,4-d]imidazol-2-one hydrochloride (dl-azabiotin hydrochloride) was accomplished in a seven-step sequence from 2-ethoxycarbonylazepin-7-one.


Lanthanum block of contraction and of relaxation in response to serotonin and dopamine in molluscan catch muscle.

Contractile and relaxing responses of the anterior byssus retractor muscle of Mytilus edulis L. were observed after exposure to La+++. After 25 minutes in 5 mM La+++, contraction in response to acetylcholine, to KCl and to stimulation of intramuscular nerves is blocked, whereas contraction in response to direct current pulses is partially blocked and caffeine contraction is unaffected. Exposure to 5 mM La+++ for 3 hours does not block relaxation of catch tension in response to serotonin and dopamine but exposure to 5 mM La+++ in the presence of a depolarizing agent (acetylcholine or KCl) for a brief period (4 minutes) abolishes the relaxing response. The authors concluded that activation of contraction in the anterior byssus retractor muscle can be effected by Ca++ influx from the bathing medium and/or by release of Ca++ from interal sites, depending on the nature of the stimulation. The authors also concluded that the relaxing action of serotonin and dopamine depends neither on Ca++ influx nor on passive efflux of Ca++, but rather on Ca++ combining at an internal site or at sites on  the cell membrane which are exposed when the muscle is depolarized.


Calcium antagonist activity of methadone, l-acetylmethadol and l-pentazocine in the rat aortic strip.

These studies described physiologic evidence that methadone and related compounds can function as calcium antagonists. Methadone (1 X 10(-5)-1 X 10(-4) M) inhibited the contraction of the isolated rat aortic strip preparation produced by potassium chloride, norepinephrine, l-pentazocine or morphine. Methadone was most effective in diminishing aortic contractions which were highly dependent on the concentration of extracellular calcium. The d- and l-isomers of methadone were equipotent inhibitors of aortic contraction. l-Acetylmethadol (1 X 10(-6)-1 X 10(-5) M) was a potent inhibitor of vascular contraction. l-Pentazocine inhibited its own ability to contract the aorta as the dose was raised 3 X 10(-5) M. The inhibition of aortic contraction produced by methadone, l-acetylmethadol and l-pentazocine was overcome by raising the concentration of calcium in the tissue baths. The inhibition of contraction and the apparent calcium-antagonist activity of these drugs best correlates with their lipid solubility. Since calcium is a critical regulator of cellular function, the calcium-antagonist action of methadone and l-acetylmethadol may prove to be important in mediating some of their pharmacologic and toxicologic effects.


Effects of acute alcohol intake on pituitary-gonadal hormones in normal human males.

Plasma luteinizing hormone and testosterone levels were determined in 16 normal adult males during a period of acute alcohol intoxication. Plasma testosterone levels were in the normal range for adult males prior to alcohol administration. Plasma testosterone levels began to fall during the ascending phase of the blood alcohol curve but plasma luteinizing hormone levels did not change significantly. At peak blood alcohol levels [109 +/- 4.6 (S.D.) mg/100 ml], plasma testosterone was significantly depressed and a significant increase in plasma luteinizing hormone values occurred. During the descending phase of the blood alcohol curve, plasma testosterone levels remained depressed and plasma luteinizing hormone levels decreased toward base-line values. These data indicate that acute alcohol intake produces a suppression of plasma testosterone via peripheral mechanisms which regulate the biosynthesis and/or biotransformation of the steroid. The surge in luteinizing hormone values at peak levels of intoxication are most likely due to stimulation of gonadotropin secretion via "long loop" mechanisms associated with low levels of plasma testosterone.


In vitro measurement of rate of fluid secretion in rat isolated seminiferous tubules: effects of metabolic inhibitors and ions.

1. An in vitro technique for measuring secretory rate in rat isolated seminiferous tubules is described. 2. The basal rate of fluid secretion was 0-44+/-0-06 nl. cm-1 min-1 (S.E.) (n=21). The rate was found to be inhibited by cooling, addition of metabolic inhibitor 2,4-dinitrophenol (2-5 x 10(-4) M) and removal of glucose from the incubating solution. This indicates that fluid secretion in isolated rat seminiferous tubules is an energy dependent process. 3. Removal of K+ from the incubating medium inhibited the secretory rate in the isolated seminiferous tubules, whereas a fivefold increase in [K+]0 to 23-5 mM had no effect. The secretory rate was also unaffected by the absence of Cl- in the peritubular fluid. 4. Removal of Ca2+ from the peritubular medium caused a rise in the secretory rate. 5. Ouabain (10(-3) M) and acetazolamide (4 x 10(-5) M) caused a fall in the rate of fluid secretion in isolated seminiferous tubules. 6. These results are discussed in relation to the nature of the ionic secretion produced in the tubules.


Adrenal and pancreatic endocrine responses to hypoxia and hypercapnia in the calf.

1. Adrenal and pancreatic endocrine responses to hypoxia and hypercapnia, of differing degrees of intensity, have been examined in conscious, unrestrained calves 3-5 weeks after birth. 2. The outputs of cortisol and corticosterone from the right adrenal gland were found to vary inversely with arterial Po2 between 17 and 55 mmHg. Significant increase in mean adrenal blood flow was not observed at arterial oxygen tensions above about 30 mmHg. 3. Release of physiologically effective amounts of catecholamines from the adrenal medulla occurred only in response to intense hypoxia (arterial Po2 17-1 +/- 2-8 mmHg) and was effectively abolished by section of both splanchnic nerves. Release of pancreatic glucagon in response to such intense hypoxia was unaffected by section of both splanchnic nerves and administration of atropine. In contrast, the rise in plasma pancreatic glucagon concentration during less intense hypoxia was abolished by autonomic blockade. 4. Hypercapnia produced by inhalation of either 5% or 10% CO2 for 30 min stimulated maximal release of adrenal glucocorticoids and caused a substantial rise in plasma glucagon concentration. In contrast, the adrenal medulla was found to be extremely resistant to hypercapnia. Significant release of catecholamines was only observed during intense hypercapnia (inhalation of 10% CO2) and noradrenaline was invariably found to be the predominant amine. 5. The results of these experiments show how endocrine responses to hypoxia and hypercapnia are graded in the conscious calf. Of the mechanisms we have examined the pituitary-adrenal cortical axis is the most sensitive and the adrenal medulla the most resistant, while the pancreatic alpha cell occupies an intermediate position.


Acetylcholine receptor distribution on myotubes in culture correlated to acetylcholine sensitivity.

1. A linear relation, with a slope of 0-9 +/- 0-2 on a log-log plot, was obtained between acetylcholine (ACh) sensitivity and alpha-bungarotoxin (alpha-BTX) binding site density in developing L6 and rat primary myotubes. ACh sensitivity was defined as g/Qn where g is conductance, Q is ACh charge and n is the Hill coefficient. Experimentally we found n approximately 1-7 for our myotubes, which is similar in value to that reported for adult systems. 2. The linear relationship is compatible with an organization whereby each ion channel is always complexed with a fixed number of ACh receptors such that the dose-response characteristics of each such complex are independent of average ACh receptor density. 3. Light microscope autoradiography showed that the alpha-bungarotoxin binding sites on L6 myotubes are uniformly distributed over the surface, while primary rat myotubes exhibit gradients and hot spots. Electron microscope autoradiography indicated that about 70% of the [125I]alpha-bungarotoxin label was on the surface of the myotubes. The alpha-bungarotoxin site density, after subtracting myoblast background, varied from 5 to 400 sites/micrometer2 on different L6 myotubes, and from 54 to 900 sites/micrometer2 on primary rat myotubes, with occasional hot spots of 3000-4000 sites/micrometer2. The conductance sensitivities varied from 10(-4) to 2 X 10(-2) Momega-1/nC1-7.


Discrimination between nicotinic receptors in vertebrate ganglia and skeletal muscle by alpha-bungarotoxin and cobra venoms.

1. We have used snake neurotoxins, alpha-bungarotoxin and venoms from Naja naja siamensis and Naja nivea, to distinguish the nicotinic receptors of ganglia from those of skeletal neuromuscular junctions. 2. These neurotoxins failed to block responses of isolated guinea-pig longitudinal muscle with adherent myenteric plexus to the nicotinic agonists, nicotine or dimethylphenylpiperazinium, to acetylcholine (ACh), or to electrical field stimulation. 3. The toxins failed to affect responses of the isolated guinea-pig stomach to pregnaglionic stimulation by way of the vagus nerves or of the vas deferens to preganglionic stimulation via the hypogastric nerves. 4. Snake neurotoxins did not block non-adrenergic inhibitory responses of the rabbit small intestine to nicotine or electrical field stimulation. 5. Neurotoxins were ineffective blockers against nicotinic agonists in new-born rabbit or embryonic chick intestine. 6. Attempts to increase the penetration of the toxins into tissues with dimethylsulphoxide, exposure to hypertonic solutions, or to ethylene-diaminetetracetic acid did not enable the toxins to act as nicotinic antagonists. 7. In contrast to diaphragmatic or oesophageal skeletal neuromuscular junctions no binding of rhodamine or tritium labelled toxins to structures in ganglia could be detected. 8. No potential permeability barriers were found by electron microscopy of the ganglia of the guinea-pig myenteric plexus. 9. The tracers, lanthanum ion and ruthenium red, readily penetrated into all regions of the myenteric plexus including synaptic gaps. 10. It is concluded that the failure of snake neurotoxins to act as nicotinic antagonists or to bind to ganglia is not due to their inability to reach ganglionic nicotinic receptors. Therefore, it is likely that ganglionic nicotinic receptors are different from those of the skeletal neuromuscular junction.


The effects of remote retinal stimulation on the responses of cat retinal ganglion cells.

1. Action potentials were recorded from optic nerve fibres of lightly anaesthetized cats while parts of the retina remote from the receptive field were stimulated by a shifting grating. 2. Vigorous responses can be obtained under these conditions, confirming McIlwain (1966), Krüger & Fischer (1973), and others. 3. These 'shift responses' are not caused by fluctuations of stray light because (a) they cannot be reduced by deliberately increasing or decreasing the light falling on the receptive field synchronously with the shifting grating; (b) a steady adapting light applied to the receptive field does not raise the threshold for the responses, whereas adapting light on the peripheral retina does, and (c) the threshold for the responses is elevated more following bleaching adaptation of the periphery than following bleaching adaptation of the centre. 4. Shift responses are strong, of short latency, and brief in duration in brisk-transient (Y-type) neurones. With few exceptions they are weak but long-lasting in brisk-sustained (X-type) neurones. 5. Shift responses are unlike responses from the main receptive field in having a distinct threshold; the magnitude of the response to weak gratings is not simply proportional to contrast, as is the case with weak stimuli applied to the receptive field. 6. It is thought that the excitatory pathway may involve amacrine cells, and that this mechanism may be concerned with the detection of the shifts of the image that occur with saccadic eye movements.


Responses of identified spinal neurones to acetylcholine applied by micro-electrophoresis.

1. The responses of identified cells in the cat Clarke's column and dorsal horn to micro-electrophoretically applied cholinomimetics and anti-cholinergic substances have been investigated. 2. Both antidromically identified (DSCT neurones) and synaptically activated neurones from the region of the Clarke's column of the spinal cord were excited by ACh. However, the proportion of ACh excited cells was greater in units synaptically activated by ipsilateral dorsolateral funiculus stimulation (78%) than in DSCT neurones (50%). In addition, about 55% of neurones activated either antidromically or synaptically by ipsilateral dorsal column stimulation were excited by ACh. 3. In contrast to a relatively weak excitatory potency on the DSCT neurones (maximum firing frequency did not exceed 130% of the control activated by ipsilateral dorsolateral funiculus stimulation (maximum firing frequency reached 430% of the control level). 4. ACh has a relatively quick and rapidly reversible excitatory effect on Clarke's column neurones and some types of dorsal horn interneurones, which can be obtained also with nicotine. However, the action of nicotine is frequently delayed in onset and recovery. This excitatory action of ACh can be blocked or markedly depressed by dihydro-beta-erythroidine. These results and those obtained with acetyl-beta-methylcholine and atropine seem to suggest that the receptors mediating excitation of the cholinoceptive spinal cells activated either antidromically or synaptically by ipsilateral dorsolateral funiculus stimulation besides predominantly nicotinic have also weak muscarinic properties. 5. Desensitization with repeated applications of ACh and nicotine has been observed in both DSCT neurones and units antidromically activated by ipsilateral dorsal column stimulation. 6. About 11% of units antidromically activated by ipsilateral dorsolateral funiculus stimulation were depressed by ACh. In addition, the depressant effect of ACh was more frequently encountered in the cells unresponsive either to the dorsolateral funiculus or dorsal column stimulation. ACh depression was also seen in units activated either antidromically or synaptically by ipsilateral dorsal column stimulation. In contrast, none of the units synaptically activated by the ipsilateral dorsolateral funiculus stimulation were depressed by ACh. The same was true for spinal neurones receiving convergent peripheral inputs activated either antidromically or synaptically by ipsilateral dorsolateral or dorsal column stimulation. 7. The findings that ACh depression of all tested DSCT neurones is blocked by atropine and readily evoked by acetyl-beta-methylcholine indicates that receptors mediating the effect are of muscarinic type.


Effect of anoxia and ATP depletion on the membrane potential and permeability of dog liver.

1. The mechanisms responsible for the depolarization of the hepatocytes secondary to anoxia have been studied in isolated perfused dog liver. It was attempted to elucidate the role of the inhibition of the sodium pump following exhaustion of the energy reserves and of the modifications of membrane permeability. Anoxia was compared to ouabain and to a reduction of the cellular ATP level. 2. Membrane potentials were measured with micro-electrodes. Potassium, sodium and chloride were determined in plasma samples and liver tissues. Extracellular space was measured with tritiated inulin or with an electrical impedance method. Adenine nucleotides were also measured in liver biopsies. 3. The fall in membrane potential produced by administration of ouabain (0-1 mM) is greater than the effect of the redistribution of sodium + potassium ions; this suggests that the sodium pump is functioning, at least partially, electrogenically. The administration of dinitrophenol (10 mM), which causes a 74% fall in the ATP level in 15 min, produces, as does ouabain, a depolarization which also corresponds to stopping an electrogenic pump. 4. A partial reduction in the level of ATP brought about by hypoxia, by an inhibitor of cellular respiration, antimycin (10 mM), or by fructose (20 mM) results in a hyperpolarization which may be attributed to an elevation of potassium permeability (PK) since it is concomitant to a loss of K from the liver. The change in membrane permeability could be related to a rise in the free calcium in the cells which has not been documented. Other possible hypothesis include a facilitated transport for potassium. 5. The administration of amobarbitone (10 mM) produces immediately a depolarization which is independent of the progressive reduction in the level of ATP. The depolarization has been attributed to a direct effect of amobarbitone on the membrane reducing the permeability for potassium ions. 6. The depolarization observed in ischaemic anoxia is greater than that produced by ouabain for the same variation in ions concentration. In addition to a likely inhibition of the electrogenic sodium pump, changes in membrane permeability inducing a rise in the PNa/PK ratio must also occur. 7. After ischaemic anoxia for 24 hr at 3 degrees C, the ratio of PNa/PK rises to 0-68 which indicates abolishment of the selective character of membrane permeability. The augmentation in cell volume produced by anoxia might result in an opening of membrane pores, which could entail the augmentation of sodium permeability; the latter would be responsible in part for the depolarization produced by anoxia. 8. According to the severity and length of oxygen deprivation an increase in PK, a cessation of the sodium pump activity and finally an increase in PNa will occur.


The role of calcium in renin secretion from the isolated perfused cat kidney.

1. Isolated cat kidneys were perfused in situ with Locke solution and renin release in response to isoprenaline was studied. 2. Perfusion with isoprenaline produced a concentration-dependent enhancement of renin secretion. Increasing the concentration of stimulant also prolonged the duration of the secretory response. 3. After a 10 min exposure to isoprenaline (0-3 micrometer), there was a rapid facilitation of renin release which diminished after 10-30 min, followed by a second transient increase which declined over the next 40-60 min. Cycloheximide did not prevent augmented release when added together with the isoprenaline but did produce a reversible inhibition of the late phase when added 10 min after the isoprenaline. 4. Omission of calcium from the perfusion medium failed to depress the renin release induced by isoprenaline, glucagon, or furosemide. However, during prolonged calcium deprivation, the cycloheximide-sensitive phase of isoprenaline-evoked release was depressed. 5. The calcium antagonist D-600 failed to block the early phase of isoprenaline-induced renin secretion but inhibited the late phase of secretion. 6. Calcium alone elicited an explosive discharge of renin when added after a prolonged period of calcium-free perfusion. 7. These results support the view that extracellular calcium does not play an essential role in the mechanism of renin secretion from the renal juxtaglomerular cells, but that an increased influx of this cation is needed for synthesis and/or mobilization of the enzyme. It is tentatively proposed that the release of calcium from intracellular storage sites may be the signal which triggers renin secretion.


Cone signals in the cat's retina.

1. The discharges of ganglion cells in the cat's retina were recorded under conditions intended to isolate the cone system.2. Stiles' two-colour threshold technique permitted the photopic system to be studied when at its highest sensitivity. The absolute sensitivity of a ganglion cell, expressed in equivalent photons of lambda(max) at the cornea per impulse discharged, was about 2500 times less when driven by cones than when driven by rods. This ratio improves to around 200 when allowance is made for the much smaller fraction absorbed by cones of photons incident on the cornea.3. The number of extra impulses discharged in response to a brief flash was approximately proportional to the number of photons in the flash, up to a limit.4. There was a region in the middle of the receptive field within which the area of a test spot and its illumination for threshold varied inversely. A flash extending over the peripheral part of the receptive field raised threshold above its minimum, presumably as a result of surround antagonism. Assessed from area-threshold curves, the balance of centre-surround antagonism in the photopic receptive field did not seem to depend upon background illumination.5. The threshold for a small (0.2 degrees ) flash confined to the middle of the receptive field was independent of background illumination until the background exceeded a particular level, the ;dark light' (I(o)). In different units this ranged about a mean of 7.89 log photons (560 nm equivalent) deg(-2) sec(-1). For backgrounds that exceeded I(o), threshold followed approximately Weber's law up to the highest illuminations that could be produced.6. With test flashes that filled the centre of the receptive field, the Weber fraction (test flash illumination/background illumination) in some units fell below 1%.7. Changes in the time course and latency of response accompanied the changes in sensitivity caused by alterations in background illumination. Responses of both X- and Y-cells became more transient and faster.8. The loss of sensitivity to a test flash brought about by a steady background light depended upon the size of that light. Sensitivity varied inversely with background area within a central region that matched closely the summing area for test flashes.


Convergence of rod and cone signals in the cat's retina.

1. In an attempt to understand the convergence of rod and cone signals in the cat's retina, ganglion cells that received inputs from both rods and cones were stimulated using lights chosen to excite one or other receptor system or both together.2. If a mesopic background was chosen to allow the ganglion cell to be excited by a blue-green test flash primarily through rods and a deep red flash primarily through cones, one light could not be alternated with the other without eliciting a response from the cell.3. This appears to be a result of the different temporal properties of the scotopic and photopic systems. On the mesopic background responses to blue-green test flashes were transient. Responses to red test flashes arose with similar latency, but were more sustained.4. Rod and cone systems responded with similar latencies in the presence of the mesopic background that substantially light-adapted the rod system but left the full sensitivity of the cone system undiminished. When equivalently light-adapted, the cone system was faster.5. When brief flashes that acted through rods were presented with flashes that acted through cones the ganglion cell's response was the sum of the responses to the two flashes presented separately, as long as the flashes were weak. This linear relation ceased to hold when flashes were strong, but the breakdown appears not to be the result of mutual inhibition between rod and cone signals.6. When a background light excited both rod and cone systems it appeared to reduce sensitivity independently in each.7. The scotopic and photopic receptive fields of a given ganglion cell always were of the same type, on- or off-centre, and, within the limits of measurement, the central regions of the receptive fields were concentric and both the same size.


Inhibition of human motoneurons, probably of Renshaw origin, elicited by an orthodromic motor discharge.

1. The pattern of variations of a test H-reflex after a conditioning H-reflex was investigated in human subjects by an experimental design in which both reflexes involved the same soleus motoneurones. This was made possible by using a method based upon a collision in the motor axons between the orthodromic conditioning reflex volley and the antidromic volley elicited by a test stimulus supramaximal for the motor axons.2. The variations of the test reflex amplitude seen when increasing the conditioning reflex discharge were studied. This was made possible by facilitating the conditioning reflex without changing the strength of the afferent volley. This facilitation was obtained through a soleus stretch elicited by a stimulation of the plantar nerves.3. The amplitude of the test reflex depended only on the size of the conditioning reflex discharge.4. As long as the conditioning reflex was of low amplitude, all the motoneurones responsible for the conditioning response could be activated by the test volley, even though these motoneurones were undergoing after-hyperpolarization. This indicates that, in man, the after-hyperpolarization of the most excitable motoneurones can be completely overcome by a large Ia afferent volley.5. Increasing the conditioning reflex beyond a specific value resulted in an absolute decrease in the number of motoneurones involved in the test reflex. The amount of this decrease was related only to the amplitude of the conditioning reflex.6. This inhibition decreased progressively as the time interval separating the test stimulus from the conditioning stimulus increased. The time course of this inhibition was studied with conditioning reflexes of different amplitudes. The duration of the inhibition increased with the size of the conditioning reflex.7. These results strongly suggest that Renshaw cells excited by the conditioning reflex are responsible for this inhibition. The results are in agreement with observations made in animals on recurrent inhibition.


Quantitative assessment of cardiac pump performance.

1. A means of quantitating left ventricular performance in the conscious dog is presented. Changes in heart rate, stroke volume and cardiac output during elevation of left atrial pressure by acute volume expansion were measured in the conscious dog. 2. The changes in heart rate and stroke volume could be described by y = ym - (ym-yi)e-kp, where yi and ym are initial and maximum values of the variable and p is the change in mean left atrial pressure. 3. Because cardiac output is a derived variable (stroke volume X heart rate) its response is described by a multiple exponential relationship. 4. For a given initial heart rate and inotropic state, the stroke volume response is determined by the Frank-Starling mechanism and the pressure-volume characteristics of the myocardium.


Calcium movements during the release of catecholamines from the adrenal medulla: effects of methoxyverapamil and external cations.

1. Cortex-free adrenal glands previously labelled with the isotope (45)Ca have been perfused with Locke or modified Locke solution to assess Ca(2+) movements under different conditions.2. Substitution of Na(+) by either sucrose or choline during perfusion with Ca(2+)-free Locke solution induced a significant and sustained decrease in the (45)Ca efflux. Concomitant with this effect there was an increase in the output of catecholamines from the perfused gland.3. In the presence of Ca(2+) (2.2 mM) in the perfusion fluid, Na(+) omission induced an increase in the (45)Ca efflux. This increase was significantly reduced if 3 x 10(-4)M methoxyverapamil (D-600) was present in the perfusion fluid. However, the increased catecholamine output in response to Na(+) deprivation remained unchanged.4. Excess of Mg(2+) (20 mM) in the extracellular medium blocked the increase in catecholamine output in response to Na(+) omission. However, the decrease in the (45)Ca efflux produced by Na(+) deprivation in the presence of this high concentration of Mg(2+) was similar to that observed in the presence of 1.2 mM-Mg(2+).5. In the absence of Mg(2+) in the extracellular medium, substitution of Na(+) by either sucrose or choline induced a sharp and transient increase in the (45)Ca efflux rate coefficient. This increased (45)Ca efflux, which has similar time course as the enhanced catecholamine output, was not affected by the presence of 3 x 10(-4)M methoxyverapamil.6. In the absence of Mg(2+), the graded substitution of Na(+) in the perfusion medium by sucrose enhanced the efflux of (45)Ca. This increase in the (45)Ca outward movement was linearly related to the logarithm of the extracellular Na(+) concentration.7. After perfusion of glands with Ca(2+)-free Locke solution, the reintroduction of Ca(2+) (2.2 mM) into the perfusion fluid produced an increase in the (45)Ca efflux. This was accompanied by a discharge of catecholamines.8. Although Mg(2+) (20 mM) was effective in blocking catecholamine release, this divalent cation did not modify the increase in the (45)Ca efflux produced by Ca(2+) reintroduction.9. In contrast to these later observations, methoxyverapamil (3 x 10(-4)M) was effective in inhibiting both increases in catecholamine output and (45)Ca efflux in response to Ca(2+) reintroduction.10. It is concluded from these experiments that (a) Ca(2+) movements in the adrenal medulla may involve both Na(+)-Ca(2+) and Ca(2+)-Ca(2+) exchange mechanisms; (b) the omission of Na(+) from the extracellular environment produces not only an increase in the output of catecholamines but it may increase the intracellular levels of Ca(2+) and that this may result in an increased Ca(2+) efflux when Mg(2+) is omitted from the perfusion fluids, and that (c) the competition between Ca(2+) and Mg(2+) during the secretory process may involve an intracellular site.


The effect of prostaglandin synthesis inhibitors on renal blood flow distribution in conscious rabbits.

1. We have studied the effects of two prostaglandin synthesis inhibitors on renal cortical blood flow distribution in conscious rabbits. 2. Renal blood flow distribution was estimated by means of radioactive microspheres injected into chronically implanted left atrial cannulae. Cardiac output was measured by a thermodilution technique. 3. Measurements were made in groups of animals treated with either indomethacin, meclofenamate or control injections of phosphate buffer. 4. A method of microtome slicing of the renal cortex was developed to standardize measurements. Microtome sections were grouped into inner, middle and outer zones. After both indomethacin and meclofenamate there was a reduction in total renal blood flow with a redistribution of flow from inner to outer cortex. 5. Estimated renal vascular resistance rose in all three cortical zones. 6. The data support the hypothesis that renal prostaglandin synthesis is necessary for maintaining flow to the deep cortex. It is suggested that renal prostaglandins may also influence flow in more superficial zones. 7. Estimated total systemic vascular resistance was increased both with meclofenamate and indomethacin, suggesting an inhibiting effect of prostaglandins on arteriolar tone throughout a major part of the systemic circulartion.


Thyroid calorigenesis in isolated, perfused rat liver: minor role of active sodium-potassium transport.

1. The effects of ouabain on hepatic oxygen uptake, cell membrane potential, and Na-K transport were examined at 37 degrees C during non-recirculating perfusion of isolated livers from fasted normal rats and rats treated with triiodothyronine (T3). The perfusate was Krebs-Ringer bicarbonate buffer containing albumin and bovine erythrocytes. 2. Treatment with T3 increased the rate of hepatic oxygen uptake by 30% (i.e. by 0-83 (micromole/min) per gram liver). 3. After shifting to perfusate containing 2-5 mM ouabain, a 4-5 mV depolarization and maximal rates of net hepatic K release and Na uptake occurred within 2 min in both thyroid states. These changes were not accompanied by any significant change in the rates of hepatic oxygen uptake. 4. T3-treatment increased the maximal, post-ouabain net flux of K by 29% (i.e. by 0-52 (muequiv/min) per gram liver). The T3-indlced increase in the net flux of Na (19%) did not achieve statistical significance. 5. In either thyroid state, the observed passive fluxes of Na and K were calculated to be balanced by active vluxes at the expense of 5-6% of the observed rate of hepatic oxygen uptake. 6. The results indicate that hyperthyroidism may enhance the rate of hepatic Na-K transport, but the energy expenditure due to this process appears to be too small to make any important contribution to thyroid calorigenesis in perfused rat liver.


Caffeine and the contractility of single muscle fibres from the barnacle Balanus nubilus.

1. In single striated muscle fibres from the barnacle Balanus nubilus tension development following axial injection of caffeine (50 mM in 150 mM-KCl, pH 7.1) was used as an index of releasable Ca. It was shown that fibres incubated in 0 Ca (Na replaced) salines for up to 400 min gave ca. 15% of the control tension response. Inclusion of 1 mM-La in the 0 Ca (Na) saline significantly reversed this decline.2. Estimates of the total fibre calcium assayed under the same experimental conditions indicated a 67% loss of fibre Ca in 0 Ca, and only a 37% loss in La-0 Ca media. No correction was made for the loss of calcium from the extracellular space.3. Experiments with (45)Ca indicated that the efflux of calcium from this preparation was inhibited by 1 mM-La externally and that this effect was still significant even in the presence of 0 Ca (Na) salines. The caffeine-stimulated efflux of Ca was also reduced by ca. 70% in the presence of 1 mM La saline externally.4. The influx and efflux of (14)C caffeine were shown to be rapid, and apparently passive. The diffusion coefficient for caffeine following intracellular injection was 2.4 +/- 0.2 x 10(-6) cm(2) sec(-1) at 18-22 degrees C.5. There was no significant loss of (140)La over a period of 2 hr following axial micro-injection into the fibres.6. In (140)La uptake experiments there was a progressive increase in the La space over 10.5 hr, in contrast to the results with [(3)H]inulin, whose uptake saturated in ca. 1.5 hr. The probability of surface binding and the precipitation of La salts in the extensive extracellular space was suggested as an explanation.7. It is concluded that internal Ca within the sarcoplasmic reticulum, and not cleft or extracellular Ca is the most significant source for these caffeine-induced contractions. Fluxes across the surface membrane can however alter the internal Ca stores over longer periods of time.


Rod-cone interaction in light adaptation.

1. The increment-threshold for a small test spot in the peripheral visual field was measured against backgrounds that were red or blue.2. When the background was a large uniform field, threshold over most of the scotopic range depended exactly upon the background's effect upon rods. This confirms Flamant & Stiles (1948). But when the background was small, threshold was elevated more by a long wave-length than a short wave-length background equated for its effect on rods.3. The influence of cones was explored in a further experiment. The scotopic increment-threshold was established for a short wave-length test spot on a large, short wave-length background. Then a steady red circular patch, conspicuous to cones, but below the increment-threshold for rod vision, was added to the background. When it was small, but not when it was large, this patch substantially raised the threshold for the test.4. When a similar experiment was made using, instead of a red patch, a short wave-length one that was conspicuous in rod vision, threshold varied similarly with patch size. These results support the notion that the influence of small backgrounds arises in some size-selective mechanism that is indifferent to the receptor system in which visual signals originate. Two corollaries of this hypothesis were tested in further experiments.5. A small patch was chosen so as to lift scotopic threshold substantially above its level on a uniform field. This threshold elevation persisted for minutes after extinction of the patch, but only when the patch was small. A large patch made bright enough to elevate threshold by as much as the small one gave rise to no corresponding after-effect.6. Increment-thresholds for a small red test spot, detected through cones, followed the same course whether a large uniform background was long- or short wave-length. When the background was small, threshold upon the short wave-length one began to rise for much lower levels of background illumination, suggesting the influence of rods. This was confirmed by repeating the experiment after a strong bleach when the cones, but not rods, had fully recovered their sensitivity. Increment-thresholds upon small backgrounds of long or short wave-lengths then followed the same course.


Differentiation of electrical and contractile properties of slow and fast muscle fibres.

1. The development of the electrical and contractile properties of slow anterior latissimus dorsi (ALD) and fast posterior latissimus dorsi (PLD) muscles of the chick was studied. 2. At the earliest ages studied (14-16 days of incubation), the membrane resistance was similar in both muscles. Subsequently the membrane resistance of PLD decreased, and that of ALD increased. Electrical differentiation continued after hatching. 3. The contractile speeds of ALD and PLD muscles were similar in embryos at 14-16 days of incubation, and suddenly differentiated at 17-18 days. Unlike the electrical properties, contractile speeds changed little after hatching. 4. It is suggested that the different electrical properties of the membrane of the two types of muscle fibre develop as a result of the particular type of excitation imposed by their nerves.


Absorption of amino penicillins from everted rat intestine.

1. Using an in vitro everted gut sac method based on that of Wilson & Wiseman (1954), a number of amino penicillins were tested in order to identify the involvement of any specialized transport mechanisms in their absorption across rat intestine. 2. Only one of the amino penicillins, cyclacillin (1-amino-cyclohexyl penicillin) was shown to be actively transported. The other penicillins appeared to diffuse passively across the intestine. 3. Cyclacillin was found to concentrate against a gradient at 37 degrees C but not at 19 degrees C. 4. Transport of cyclacillin across the mucosal membrane was saturated at mucosal concentrations greater than 1000 microgram/ml. 5. The rate of the forward flux of cyclacillin was many times that of its back flux. 6. No relationship between the active transport of cyclacillin and that of amino acids could be demonstrated.


Baroreflex inhibition of the human sinus node: importance of stimulus intensity, duration, and rate of pressure change.

1. Carotid baroreceptors were stimulated with electronically controlled neck suction in five healthy young men and pulse interval prolongation was measured. Timing of the onset of stimuli in relation to cardiac activity was held constant, and stimulus intensity, duration, and dP/dt were varied independently. 2. In the subjects studied, sinus node responses to neck suction were proportional to dP/dt. However, variations of stimulus dP/dt within or above the normal range for arterial dP/dt did not influence the magnitude of integrated baroreflex responses, or the earliest portion of baroreflex sinus node inhibition. 3. Carotid baroreflex responses were linear over a wide range which extended beyond the normal range for human systolic arterial pressures. 4. Saturation of the carotid baroreceptor-cardiac reflex occurred at distending pressures of about 160 mmHg. 5. The average baroreflex responses of the group studied were highly reproducible over time. 6. Baroreflex gain correlated very strongly with base line pulse interval. 7. The magnitude of baroreflex responses increased linearly with the duration of carotid sinus distension and reached a maximum level with stimuli lasting 0-5 sec or more. 8. The results demonstrate that carotid sinus transfer characteristics can be measured in normal man, and that human response patterns are strikingly similar to those observed earlier in experimental animals.


Adaptation of the human carotid baroreceptor-cardiac reflex.

1. Four intensities of neck suction were applied for 5 sec in healthy young men to determine the time course of decay of carotid baroreflex sinus node inhibition. 2. Peak responses occurred at about 1-25 sec after the onset of baroreceptor stimulation and were proportional to the intensity of stimulation. 3. Responses declined steadily during the remaining period of stimulation; the rate of decay of sinus node inhibition was decribed well by a power function and was proportional to the intensity of baroreceptor stimulation. 4. beta-adrenergic blockade did not alter the rate of decay of abroreflex sinus node inhibition. 5. These results suggests that adaptation of the integrated baroreceptor-cardiac reflex occurs in man and follows the same time course as adaptation of individual baroreceptor units an experimental animals.


Number of glomeruli in normal and hypertrophied kidneys of mice and guinea-pigs.

1. In mice and guinea-pigs, the number of glomeruli was counted in kidneys during normal growth and in hypertrophy induced by unilateral nephrectomy. 2. In mice, the number of glomeruli increased sharply during the first 2 weeks in life, and more slowly afterwards. Unilateral nephrectomy, when performed during this period of natural increase, induced the formation of supplementary nephrons in the contralateral kidney. 3. In guinea-pigs, the number of glomeruli was almost complete at birth. No evidence of a supplementary increase in the number of nephrons was found in hypertrophied kidneys following unilateral nephrectomy. 4. These results, together wit previous data obtained in the rat, suggest that the ability to induce new nephrons after unilateral nephrectomy in different species would depend more on the state of kidney maturity at birth than on differences in the renal mechanisms which lead to hypertrophy.


Suppression of rat stomach histidine decarboxylase activity by histamine: H2-receptor-mediated feed-back.

1. Gastrin activates rat stomach histidine decarboxylase. Exogenous histamine suppressed the basal enzyme activity in unoperated, in nephrectomized, in vagally denervated and in antrectomized rats, and counteracted the pentagastrin-induced enzyme activation in unoperated rats.2. Kinetic analysis of enzyme-catalysed histidine decarboxylation in extracts from untreated vagotomized and from histamine-treated vagotomized rats showed that the histamine-induced suppression of histidine decarboxylase activity probably reflects a reduced enzyme concentration. Moreover, the enzyme half-life in vagotomized rats after treatment with histamine was shorter than the half-life observed after inhibition of enzyme synthesis. These observations suggest that administration of histamine not only inhibits enzyme synthesis but also causes an accelerated rate of elimination of histidine decarboxylase.3. Intravenous infusion of histamine caused marked displacement of the pentagastrin dose-response curve, in a manner suggesting a reduced sensitivity to pentagastrin.4. After H(2)-receptor blockade, but not after H(1)-receptor blockade, histamine was less effective in suppressing the enzyme activity. Furthermore, H(2)-receptor blockade augmented the pentagastrin-induced enzyme activation.5. The results suggest that histamine (via H(2)-receptors) reduces the sensitivity of the histamine-storing cells to gastrin and that H(2)-receptor blockade induces the opposite effects.6. We propose that the histamine-storing cells in the rat stomach are endowed with H(2)-receptors and that exogenous histamine is capable of acting directly on the histamine cells. This may reflect a physiological control mechanism whereby mobilized endogenous histamine modifies its own synthesis and release.


The control of shivering and non-shivering thermogenesis in the rat.

1. The effect of intraperitoneal administration of propranolol (4, 8 and 12 mg/kg) on colonic temperature was studied in twelve rats during exposure to ambient temperatures of 30, 15 and 5 degrees C. 2. At 30 degrees C, propranolol had no effect on colonic temperature; at 15 and 5 degrees C, however, 4 mg propanolol/kg induced a fall in colonic temperature of about 0-8 degrees C, whereas 8 and 12 mg propanolol/kg induced a fall of about 1-5-2-0 degrees C. 3. Assuming that the temperature regulations system of the rat has a proportional controller and that the effect of propranolol was due to the blockade of non-shivering thermogenesis, the results are interpreted as showing that shivering is activated only when heat loss exceeds the capacity for non-shivering thermogenesis.


Temperature regulation and oxygen consumption in the developing macropod marsupial Setonix brachyurus.

1. When kept at ambient temperatures of 17-5 and 24 degrees C the colonic temperatures of joeys younger than 166 days declined to near ambient temperature. Pouch joeys of 166 days and older were however able to maintain their colonic temperatures at about 35 degrees C. 2. Joeys first developed the ability to sustain high O2 consumption rates in response to cooling, when aged between 144 and 169 days. Only when this latter facility was fully developed in ontogeny could body temperature be maintained in a cool environment. 3. When joeys older than 130 days were kept in a metabolism chamber at pouch temperature (37-5 degrees C) and at high humidity their body temperatures quickly rose to lethal levels, demonstrating the need for cooling mechanisms whilst still contained within the pouch.


Regulation of compensatory kidney hypertrophy by its own products.

1. The ligation of blood vessels of one kidney of adult rats resulted in the compensatory hypertrophy of the other kidney. In most animals the rate of hypertrophy was indistinguishable from that observed after unilateral nephrectomy, but in a few cases the onset was retarded when the renal artery alone had been ligated and the collateral circulation increased.2. When the blood vessels of one kidney of adult rats were ligated and the cortex was excised, the rate of compensatory renal hypertrophy was similar to that observed after unilateral nephrectomy.3. In animals operated for simultaneous partial hepatectomy and unilateral nephrectomy, there was no sign of compensatory renal hypertrophy while the liver was undergoing regeneration. Renal hypertrophy started after 7 days, when about 98% of the amount of liver removed had been regenerated.4. Neither aseptic autolysis of one kidney following suppression of its blood supply, nor unilateral nephrectomy affected the rate of liver regeneration after simultaneous partial hepatectomy.5. Total splenectomy did not affect the rate of compensatory renal hypertrophy following unilateral nephrectomy.6. The heterotopic graft of renal cortical, but not of medullary, cells inhibited compensatory renal hypertrophy in adult rats. The removal of the graft after 14 days was followed by the resumption of compensatory hypertrophy.7. The inhibiting action of fractions of renal cortical extracts fractionated on Sephadex G100 resin and DEAE-52 cellulose were assayed on the ;growth' of renal explants reared in vitro. The final material, though only partially purified, proved to have an inhibiting activity between 250 and 500 times greater than that of the initial extract.8. When injected into unilaterally nephrectomized rats, the partially purified extract from the renal cortex had an inhibiting effect on compensatory renal hypertrophy.9. Immunofluorescence technique showed that the partially purified cortical extract affected the proximal convoluted tubes specifically, irrespective of animal species.


Pancreatic acinar cells: localization of acetylcholine receptors and the importance of chloride and calcium for acetylcholine-evoked depolarization.

1. Intracellular micro-electrode recordings of acinar cell membrane potential and resistance were made from the mouse pancreas superfused in vitro. The acinar cells under investigation were stimulated by micro-iontophoretic ACh application from an extracellular AChCl-filled micro-electrode.2. Passing short-lasting ejecting current pulses through the AChCl-electrode caused acinar cell depolarization when the electrode was in an extracellular position not far (< 50 mum) from an acinus impaled by a KCl micro-electrode. After insertion of the AChCl electrode into a neighbouring acinar cell, electrically coupled to the acinar cell already impaled by the KCl-electrode, ejecting ACh current pulses only affected the membrane potential in a direct electrical manner whereas there was no sign of an effect of ACh on the membrane potential.3. Replacing extracellular chloride by sulphate caused a marked increase in the amplitude of the ACh-evoked depolarization. If the membrane potential was recorded with a KCl electrode ACh continued to evoke very large depolarizations even after more than 1 hr exposure to Cl-free solution. If the membrane potential was recorded with a K-citrate electrode the effect of Cl-removal was only transient. Removal of Na(+) during exposure to Cl-free solution reduced the amplitude of the ACh-evoked depolarization somewhat. Readmission of Cl after more than 1 hr of Cl deprivation caused an immediate reversal of the ACh effect into a hyperpolarization.4. Removal of extracellular Ca(2+) caused a marked reduction in the amplitude of small depolarizations evoked by just suprathreshold doses of ACh, whereas there was very little effect on larger depolarizations evoked by maximal or supramaximal ACh ejections. The effect of Ca removal was fully reversible. Addition of Mn after Ca-deprivation was as efficient as Ca in restoring normal electrophysiological responses to small doses of ACh.5. The acinar cell membrane seems only to be responsive to ACh added to the extracellular side and ACh probably causes an increase in membrane Cl permeability in addition to the previously described effects on Na and K permeability. Ca may be important in determining ACh receptor sensitivity.


Pancreatic acinar cells: the acetylcholine equilibrium potential and its ionic dependency.

1. Two glass micro-electrodes were inserted into neighbouring cells from rat or mouse pancreatic segments, superfused in vitro. The tip of a third glass micro-electrode, filled with 2 M-AChCl, was placed just outside the acinus under investigation. Membrane potential and resistance, and changes in these parameters in response to short pulses of ACh stimulation, were recorded.2. The resting current-voltage relationship, obtained by injecting 100 msec depolarizing or hyperpolarizing current pulses through one of the intracellular micro-electrodes and recording the membrane potential with the other intracellular electrode, was linear within the range -5 to -60 mV.3. Injecting depolarizing or hyperpolarizing current (d.c.) through one of the intracellular micro-electrodes, the membrane potential (as measured with the other intracellular micro-electrode) could be set at various levels. The effect of ACh at different membrane potentials was investigated. When the acinar cell membrane was hyperpolarized, the amplitude of ACh-evoked depolarization was increased, while ACh-evoked depolarization was reduced when the membrane potential was reduced by depolarizing current, and finally changed into a hyperpolarization at very low membrane potentials. In each acinus investigated (rat and mouse), there was a linear relationship between amplitude of ACh-evoked potential change (DeltaV) (+ value or - value according to polarity) and resting membrane potential. During superfusion with control solution, the value of the membrane potential at which ACh did not evoke a potential change (E(ACh)) was about -15 mV in the mouse and about -20 mV in the rat. During superfusion with a chloride-free sulphate-containing solution (steady state), a linear relationship between DeltaV and resting membrane potential was again found but E(ACh) (mouse) was about +10 mV.4. A continuous rough estimate of E(ACh) was obtained by injecting repetitively depolarizing current pulses (100 msec) through one intracellular micro-electrode; in this way, the effect of ACh measured by the other intracellular electrode could be assessed simultaneously at the spontaneous resting level, and at a depolarized level. The direction of change in E(ACh) following acute changes in the superfusion fluid ion composition was assessed. Replacing extracellular chloride by sulphate caused an immediate change in E(ACh) in the positive direction. Re-admission of chloride, after a long period of chloride ion deprivation, caused an immediate sharp change in E(ACh) in the negative direction. Replacing extracellular sodium by Tris caused an immediate transient negative change in E(ACh). In contrast, taking away extracellular calcium changed E(ACh) in a positive direction. Augmenting extracellular potassium concentration to 40 mM caused a change in E(ACh) in the positive direction.5. At a membrane potential (V) equal to E(ACh) the sum of ionic currents evoked by the action of ACh is zero. Using the Goldman treatment, it appears that ACh increases membrane Na, K and Cl permeability. The approximate relative ion permeabilities of the pathways opened up by ACh are: P(Na)/P(K) = 2.5 and P(Cl)/P(K) = 5. At V = E(ACh), the approximate relative sizes of the ACh-evoked currents are: I(Na)/I(K) = 2.6 and I(Cl)/I(K) = 1.6 ACh, therefore, causes influx of Na and Cl and a small efflux of K.


The carotid chemoreceptor input to the respiratory neurones of the nucleus of tractus solitarus.

1. An investigation has been made into the connexions between the carotid body chemoreceptors and the dorsal respiratory neurones of the cat's medulla.2. In confirmation of previous work these neurones were found to be all inspiratory in firing pattern and to fall into two categories, Ralpha (forty-four units) which fire only with the central inspiratory rhythm and Rbeta (thirty-two neurones) that are also excited by lung inflation. Both categories were shown to be excited by stimuli delivered to the carotid bodies during inspiration but, with a single exception, not during expiration.3. When Rbeta neurones were made to fire tonically in expiration by maintained lung inflation, chemoreceptor activation inhibited this discharge in 7/11 cases, the remainder being unaffected.4. Iontophoretically applied DL-homocysteic acid or glutamate made both Ralpha and Rbeta neurones fire tonically in expiration. Chemoreceptor stimulation during expiration inhibited this activity in all neurones tested (nine Ralpha and three Rbeta cells).5. Using the measurement of the antidromic latency to spinal stimulation as an index of membrane potential, evidence was obtained that any subthreshold influence of the chemoreceptors on dorsal respiratory neurones during expiration was inhibitory (9/18 cases).6. It is concluded that chemoreceptors do not even subliminally excite dorsal inspiratory neurones during expiration; such influence as they have then is inhibitory. Possible reasons for this difference in chemoreceptor influence during inspiration and expiration are discussed. It is suggested that chemoreceptor excitation reaches them only as part of an enhanced central inspiratory drive from an as yet unknown source.


[Biceps brachii motor unit frequency and recruitment during static work (author's transl)].

The recruitment and the changes in firing frequency of biceps brachii motor units (MU) were studied during static work in normal man. The activity of single MUs have been followed from minimal to maximal levels of force, using three selective wire-electrodes inserted in the muscle. 1. The increase of MUs firing rate contributes to the force increase during the whole of the range of forces. However, the contribution of increased firing rate is more important at low force levels. 2. The firing rate variability is more important for low levels of force. This may be one of the mechanisms by which the summation of the twitches leads to a stable contraction. 3. At each level of force, the diverse MUs fire at the same mean frequency, except during the "catching up phase" which follows the start of the 'MUS activity. 4. The force generated by the muscle varies linearly with the number of active MUs, i.e. the MU recruitment has a constant contribution to the increase of force. 5. The comparison between firing rate and MU recruitment suggests that the first mechanism is more important f or low levels of force, while MU recruitment becomes more important at higher force levels.


The effect of altering self-descriptive behavior on self-concept and classroom behavior.

This research examined the impact of operant reinforcement of positive self-descriptive behavior on the self-concepts and classroom behavior of 60 fifth-grade students. Three groups of 10 male and 10 female low self-concept students wrote a series of eight essays describing their school performance. The first group (P) received written reinforcement for positive self-descriptions of their school performance. The second group (G) received an equal number of reinforcements for general statements. The third group (C) received no reinforcement for written statements. Three areas of self-concept were measured with the Primary Self-Concept Inventory: personal-self, social-self, and intellectual-self. A frequency count was also made of nine classroom behaviors thought to be influenced by self-concept. The P group displayed increases in the frequency of positive self-descriptive statement and in intellectual self-concept but no changes in personal self-concept, social self-concept, or the nine classroom behaviors. The G and C groups showed no change in self-description, self-concept, or the nine classroom behaviors.


Relationships between psychological differentiation and Cattell's personality traits.

It was hypothesized that individuals who are field-dependent are discriminated from those who are field-independent by Cattell's personality factor A, F, and Q2. A sample of adults (N=68 male and female graduate students) was tested by means of Oltman's Portable Rod-and-Frame Test, field-dependence groups thus being established. Cattell's Sixteen Personality Factor Questionnaire was then administered to the sample. Discriminant analysis of the data resulted in the research hypothesis being supported. Thus, the hypothesized theoretical link between Witkin's psychological differentiation personality dimension and certain Cattellian personality factors was supported empirically. An exploratory stepwise analysis indicated that the Cattellian factors A, L, O, and M may also form a discriminant function which distinguishes between the two groups.


Verbal aggression as a function of sex of subject and sex of target.

This experiment raised the question of whether previously reported sex differences in physical aggression also hold for verbal aggression. It was hypothesized that verbal aggression would be a function of sex of the object of aggression but not of the sex of the aggressor. Eighty male and female American college students gave messages which varied in degree of hostile content to either a male or female confederate (C). As predicted, verbral aggression was a function of sex of target but not of S. Verbal aggression was inhibited only toward the female C when the S was not provoked by the C; when provoked, however, Ss displayed the same level of verbal aggression toward female and male targets.


Social dysfunction and anxiety.

A sample of 44 male and female adults, newly admitted to outpatient clinics at a large community mental health center, was given the Denver Community Mental HEALTH Questionnaire on social functioning, the abbreviated version of the Minnesota Multiphasic Personality Inventory, the Social Readjustment Rating Scale, and the Taylor Manifest Anxiety Scale. The results indicate that impairment of social functioning, as well as personality disturbance and excessive change, is strongly associated with anxiety. The outcome implies that effective treatment must include social and vocational training in addition to psychotherapy.


Eye-movement asymmetry and hemispheric function: an examination of individual differences.

The relationship between lateral eye movements and selected individual characteristics was examined in a group of 81 right-handed adult males. Ss answered 20 verbal and 20 visuospatial questions in one of three experimental conditions while their eye movements were being recorded electrically. Multiple regression analyses were used to predict the proportion of eye movements to the right on the basis of spatial and verbal test scores, questionnaire responses concerning imagery and verbal processes, a self-report measure of values and interests, and choice of academic major. No significant relationships were found. Even the most consistent "left movers" and "right movers" did not differ in the manner suggested by a model of eye-movement asymmetry based upon individual differences in cerebral function.


Academic achievement as a function of specific and global measures of self-concept.

This study examined the correlations between academic achievement and factor specific, as well as global, measures of self-concept for 314 fourth and sixth grade boys and girls divided into grade level groups with and without Spanish surnames. The Primary Self-Concept Inventory was used to measure self-concept on six scales: physical size, emotional state, peer acceptance, helpfulness, success, and student-self. A global self-concept score was derived by totaling the scores on the six scales. Achievement was measured as total score on the Comprehensive Tests of Basic Skills. The two specific measures of self-concept that were most reflective of school performance, success and student-self, tended to show low positive correlations with achievement. The remaining specific measures, as well as the global measure, tended to show no relationship to achievement. These results suggest that an area specific model of self-concept is more useful than a global or undifferentiated model. Further, the low correlations between school related self-concept and achievement suggest that, as a group, students frequently have rather inaccurate academic self-concepts.


Enhancement of leader power after election or appointment to undersirable leader roles.

Sixteen groups of male and female university students (N= 129) were tested in a 2 by 2 design which varied mode of leader selection (election vs. appointment) and desirability of leader role (desirable vs. undersiable). Desirable leader roles were created by offering $5.00 and extra experimental credit for extra work to be completed on the leader's own time. Leaders in undersirable roles had to complete the extra work without pay or experimental credit. After a warm-up task, a confederate was either elected or appointed leader. On two subsequent tasks the leader made three influence attempts on (a) the task structure, (b) the task content, and (c) the members' willingness to volunteer to help the leader with the extra work. Results indicated that on all influence measures individuals elected to the undersirable leader role had significantly greater social power than individuals elected to the desirable role. Desirability of the leader role did not significantly affect the social power of appointed leaders.


Self-concept of psychopaths.

The purpose of the present investigation was to study the self-concept of psychopaths. The sample consisted of 56 adult males: 28 psychopaths and 28 nonpsychopaths. The MMPI was used to select the sample. The Tennessee Self Concept Scale was administered to all Ss. The two groups differed significantly on 18 of the 28 scales used for the study. Sixteen of these differences were in the direction of greater deviance for psychopaths. Several inconsistencies were also observed in the self-concept of psychopaths. The results confirmed those previously obtained in other studies.


The conceptual structure of aphasic and schizophrenic patients in a nonverbal sorting task.

Hierarchical and overlapping cluster methods were applied to the sortings of aphasic, nonaphasic brain-damaged, schizophrenic, and normal subjects presented with 30 pictures of animals. The hierarchical structure solutions were most diffuse for the groups of the schizophrenics and the fluent aphasics'. The structure for the nonfluent aphasics showed more clarity, but was also deviant from the structures of the normals and the brain-damaged without aphasia. Fluent aphasics but not nonfluent aphasics tended to sort pictures which they could not name into smaller groups. For the nonfluent aphasics, there was a significant correlation between the commonality of the sortings and the severity of aphasic disturbances as measured by the Token Test. The relationship between conceptual disorganization and language impairment seems to be functionally different for fluent and nonfluent aphasics.


Nonverbal measurement of affect: the graphic differential.

The measurement of affective meaning (Osgood's three universal factors) is easily accomplished via the semantic differential. However, the verbal nature of this instrument prevents its use with many subject groups in which the measurement of affective meaning would be the most interesting: members of illiterate cultures, verbally damaged individuals such as anomic aphasics and thought-disordered schizophrenics, and children younger than 6 years. For these purposes, the present study describes the development of a nonverbal alternative to the semantic differential and assesses the statistical comparability of scores resulting from the use of the two instruments.


Early diagnosis of pregnancy in general practice.

The value of the signs and symptoms of pregnancy and of the pregnancy diagnostic test as predictors of pregnancy was estimated for 1,592 women seen in general practice. The presence of a sign or symptom alone is a poor pointer to a diagnosis of pregnancy. The combination of pairs of features improves the value, the best being breast signs combined with either the presence of signs of pregnancy on vaginal examination or a palpable fundus, both giving predictive values of 0.89. The pregnancy diagnostic test alone, however, had a predictive value of 0.91, a value of 1.00 indicating 100 per cent reliability.


The care of oral contraceptive users by general practitioners in Oxfordshire.

A questionnaire was circulated to a sample of general practitioners in Oxfordshire enquiring about the supervision of women taking oral contraceptives. A high standard of care was being offered and the doctors believed that there was a wide range of conditions that should influence the prescription of oral contraceptives. We conclude that while suitably trained paramedical staff could provide the same standard of care as the general practitioners, this could not be achieved through the use of a package insert listing possible contraindications.


The incidence and management of female breast disease in a general practice.

A retrospective study is reported of 180 women with breast symptoms consulting at a group practice during a 27-month period. The management policies of the general practitioners are discussed in the light of the observed short-term outcomes and of proposals to introduce screening clinics for breast cancer.


Too old to teach?

The scores obtained by 71 generalpractitioner trainers on a 100-question multiple choice question paper were analyzed in relation to the number of years since the trainer qualified. No evidence was found that older trainers had poorer recall of clinical facts.


Doctors' attitudes to women in medicine.

There is only moderate enthusiasm in the medical profession for an increase in the number of women doctors. The profession has been slow to recognize the problems of combining home life with a career, but it is encouraging that there appears to be little discrimination against women.Women doctors are capable of and may wish to rise to the intellectual challenges of full-time medicine. Unfortunately, too often the attempt at combining domestic life with a professional career is poorly organized and minimally supported leading to an unsatisfactory compromise. Until a more positive attitude develops within the profession women doctors will not feel accepted as equals.


An analysis of 3,199 patients booked for delivery in general-practitioner obstetric units.

The outcome of 3,199 women booked for delivery in six general-practitioner obstetric units in one year was analyzed.Five per cent cancelled their bookings, 26 per cent were transferred to a consultant unit after referral for routine problems of pregnancy (mainly postmaturity), and 14 per cent were transferred for problems arising in labour (principally uterine inertia). One per cent were transferred after confinement.Fifty-four per cent were delivered successfully in the general-practitioner units.There were 3,037 live births, 27 stillbirths and 22 neonatal deaths. Nine stillbirths and nine neonatal deaths resulted from congenital abnormalities, while two stillbirths and 11 neonatal deaths were due to immaturity. There were 25 sets of twins and one set of triplets. Seventy-five babies were abnormal, 105 weighed less than 2,500g, and 198 over 4,000g.In this series almost 60 per cent of eventual perinatal deaths were transferred during pregnancy, and over 85 per cent before delivery.The perinatal mortality of all women initially booked for a general-practitioner unit who delivered was 15.. The perinatal mortality of the 1,795 births in the six general-practitioner obstetric units was 3.9.


Patients transferred in labour from general-practitioner maternity units.

Two hundred and one patients transferred in labour from general-practitioner maternity units to the consultant unit in West Berkshire are analyzed. Ways in which such transfers at a critical stage in pregnancy may be reduced are discussed.


The severity of depression in patients treated in general practice.

The severity of depression, the presence and intensity of suicidal feelings, and the outcome of depressive illness treated in general practice were studied. The results suggest that a consideration of the relatively good outcome at 16 to 18 weeks alone is misleading. At least one in six new patients is suffering from a depression of moderately severe intensity and a similar proportion experience suicidal ideas that are persistent and require active rejection. A sample of patients with chronic depression had only a slightly smaller morbidity. The presence of moderately severe symptoms of depression in both groups of patients has important implications for treatment.


Depression in rheumatoid arthritis.

We have examined 144 patients with rheumatoid arthritis and found a high prevalence of depression, which has not previously been reported.It is probable that good practitioners who see patients at home acquire a better understanding of the social and psychological aspects of such an illness. The presence of depression was statistically significant when associated with the articular index, the degree of functional impairment, and with dependence on others, but not with many other medical and social factors.


Pre-school development screening in a health centre--the problem of non-attendance.

Poor attendance at a health centre pre-school child screening clinic (total default rate 41.2 per cent) raises the question of whether selective screening would be a more realistic alternative to comprehensive screening. Furthermore, an analysis of the outcome of screening over one year has shown a low prevalence of abnormalities and underlines the need to justify such programmes as worthwhile screening tests.The most efficient method of detecting child-hood abnormalities at an early a stage as possible remains an open question, but with present financial restrictions and staff shortages, whatever programmes are used, rigorous continuing evaluation is essential.


Consumers, family physicians, allied health workers, and sociomedical problems.

Patients and doctors have differing opinions about the role of family physicians. These opinions were sampled by two questionnaires and the results suggest that family physicians have, for example, high expectations of themselves and their psychiatric colleagues whereas patients expect other allied health professionals to play a significant role in providing care.


Pyometra complicating radiation therapy of uterine malignancy.

This report concerns our experience with the clinical management of pyometra in 12 patients receiving radiation therapy at the University of Iowa Hospitals and Clinics for uterine epithelial malignancy. The effect of pyometra on radiation therapy is discussed. Adequate drainage is imperative, and appropriate cultures should be obtained. External radiation therapy may be continued as planned; however, intracavitary radium applications should be deferred.


Evaluation of Monistat cream (miconazole nitrate 2%) in a reduced regimen for the treatment of vulvovaginal candidiasis.

A carefully conducted study with reduced regimens of Monistat cream (miconazole nitrate 2%) was undertaken to compare the therapeutic cure rates in patients with vulvovaginal candidiasis on Monistat cream for 7, 10 and 14 days. Five clinical investigators participated in the study and randomly assigned 139 patients, who met criteria outlined in the protocol, to either the 7-, 10, or 14-day regimen. Case records of 108 patients were used in evaluating the results. Thirty-one records were classified as invalid and were eliminated from the final analysis. Analysis of the data revealed no statistically significant difference in cure rates between the three regimens. It can be concluded, therefore, that Monistat cream used in a regimen consisting of 7 or 10 days of therapy has a cure rate equivalent to the currently recommended 14-day regimen.


The hazard of cryosurgery for treatment of cervical dysplasia.

Cryosurgery was used to treat patients with cervical dysplasia and cervicitis during a 44-month period. The course of dysplasia following cryosurgery in these patients has been evaluated and compared to the course of dysplasia in similar patients who were untreated or treated with biopsy only. When the groups with moderate and severe dysplasia are combined, a significantly greater number of patients treated with cryosurgery had progression of dysplasia in comparison to those patients in the untreated group. The disadvantages of cryosurgery are discussed, and criteria for evaluation of dysplasia prior to cryosurgery are outlined.


Antibiotic prophylaxis for puerperal endometritis following premature rupture of the membranes.

The incidence of intrauterine infections following premature rupture of the membranes is high in indigent populations. In 1970 a prospective study was carried out to determine the value of prophylactic antibiotics in preventing puerperal endometritis in such patients. Penicillin and kanamycin were administered when the patients went into labor or when a move was made toward delivery by induction of labor or cesarean section. Antibiotics were continued for two days postpartum. Puerperal endometritis was significantly decreased. Six-year follow-up has shown no problems with masked infections, superinfections or changes in the antibiotic resistance patterns of cultured pathogens.


Psychiatric aspects of voluntary sterilization in young, childless women.

An increasing number of young, childless women currently seek tubal ligation for fertility control. They state that they have no maternal aspirations and that available contraceptive methods are not safe enough. This aspect of voluntary sterilization has received little attention by psychiatrists in the past. This paper presents a psychological picture of seven women with a particular focus on some psychodynamic considerations underlying their wish to remain childless and the role of the psychiatrist in the decision-making process for this procedure.


Medical equipment costs: those you see and those you pay.

A review of life cycle and operation support costestimating capabilities in the health care industry shows few models that discuss total ownership costs for major items, let alone for some expensive minor ones. As yet, no data collection system exists wthat will provide total costs of acquisitions. There is a clear need for the health industry to focus greater attention on life cycle costs of medical equipment. This is particularly pertinent to those physicians responsible for medical equipment acquisition programs. The industry must evaluate the impact of life cycle costs and make such evaluations available to decision makers. The purpose of this paper is to improve the visibility and accuracy of cost estimating by examining the elements of life cycle costs.


Membrane stripping to induce labor.

A group of 91 pregnant women at term were studied randomly to see the effect of digital stripping of the membranes from the lower uterine segment upon the onset of labor. The women with unfavorable cervices (Bishop score 0 to 5) demonstrated a significant increase in the onset of labor within 48 hours as compared to controls. When the cervix was favorable (Bishop score 6 to 10), there was no significant effect. The overall success rate for induction of labor was not significantly altered (43.5% in membrane-stripped patients, 22.2% in controls). There were no major complications of the procedure.


A selective approach to outpatient breast biopsy under local anesthesia.

Outpatient breast biopsy was recommended for women who had a clinically benign, relatively small, accessible breast mass and for a few women with clinical cancer who would not consent to biopsy and possible mastectomy under general anesthesia. Inpatient biopsy under general anesthesia, with possible immediate mastectomy, was recommended for women who had clinical cancer, a large mass or a mass deep within a large breast, and to a few women psychologically unfit for local anesthesia. The incidence of malignancy was 8% in the 153 outpatients and 45% in the 114 inpatients. The incidence of complications between the two groups was not significantly different. The total cost of inpatient biopsy under general anesthesia was over five times higher than that of outpatient biopsy under local anesthesia. Outpatient breast biopsy is a satisfactory approach for appropriately selected patients.


The unwed pregnant teenager and her male relationship.

A group of 100 primiparas, 17 years of age and younger, were interviewed one to three days postpartum. From these interviews, the quality of the relationship between the patient and the father of the newborn child was scored in three categories. Contrary to popular opinion about illegitimacy, it was found that in the majority of cases a good, continuing relationship was maintained throughout the pregnancy, despite the fact that 97% of the patients were unmarried. Fully 84% of the fathers of the unborn children has ongoing contacts with the patients; 68% of the fathers reported that they liked the idea of having the baby, whereas only 9% disliked the pregnancies. The relationship scores were compared with the occurrence of complications in the patient's labor and delivery. Statistical analyses revealed that the relationship between the teenage obstetric patient and the father of her child was not associated with the occurrence of complications in the patient's labor and delivery. However, trends indicate a possible association between these two variables.


Tracheobronchial epithelial multinucleation, viral inclusion bodies and malignant disease.

Patients with malignant disease are known to have an increased incidence of multinucleation in their tracheobronchial ciliated epithelial cells as compared with controls matched by age, sex and smoking habit. A seasonal relationship of viral inclusion bodies in the cilated epithelium of asymptomatic subjects has also been shown and is not related to age, sex and smoking habit. We have conducted an epidemiologic study to determine the possible relationships between these factors. Smears from 4,150 patients with a wide variety of pathologic conditions were examined for the presence of viral inclusions and multinucleated, ciliated epithelial cells. High degress of multinucleation were observed least frequenctly in the summer both in patients with and without known malignancy. Cytoplasmic inclusion bodies were also seen least frequently in the summer and autumn both in patients with and without know malignancy. In the presence of cancer, multinucleated epithelial cells and inclusion bodies were seen more frequently regardless of the season. When the seasonal incidence of multinucleated cells in 155 smears containing viral inclusion bodies was analyzed, it was found that patients without cancer had the lowest levels of multinucleation in the summer, whereas cancer patients had a depressed incidence of multinucleation in the winter and spring. Respiratory viruses may have a specific effect on the ciliated epithelium of cancer patients.


Unilateral tuboovarian autoamputation.

Six cases of unilateral tuboovarian absence are reviewed. In four, the peritoneal cavity contained a separate ovoid structure. In two of these, the pathologist could identify the remnant as a phagocytized ovary. In a third patient, the ovoid body was seen fixed to the contralateral ovary during laparoscopy. Subsequently, it was identified radiologically as a calcific density. In the fourth case, an intact ovary was separated from the uterus and engulfed by omentum. If a total embryogenic error or selective dysgenesis of the urogenital fold occurs, ipsilateral anomalies usually involve adjacent structures of both the urinary and genital systems. Howerver, no anomalies of the uterus and urinary structures appeared evident in any reviewed case. Therefore, adnexal torsion with subsequent infarction necrosis and autoamputation represents the most likely explanation for this phenomenon.


The merits of extraperitoneal cesarean section: a continuing experience.

The continuing experience with extraperitoneal cesarean section at this institution is reviewed. The first 50 cases performed are reviewed and compared with equal numbers from two control groups as previously presented. A persistent advantage in the use of the procedure is demonstrated. Earlier optimism about the use of the procedure in selected patients is vindicated.


Induction of ovulation with combined glucocorticoid and clomiphene citrate therapy in a minimally hirsute woman.

A very minimally hirsute anovulatory woman uho had failed to ovulate with 200 mg clomiphene citrate for five days had a successful ovulation and pregnancy with 150 mg clomiphene citrate plus glococorticoids for five days.


Design, synthesis, and correlation analysis of 7-substituted 4-hydroxyquinoline-3-carboxylic acids as inhibitors of cellular respiration.

Fifteen 7-substituted 4-hydroxyquinoline-3-carboxylic acids have been designed to minimize covariance between the physicochemical substituent parameters: pi, MR, and sigmap. The molecules have been synthesized and evaluated for their ability to inhibit the respiration of Ehrlich ascites cells as a whole cell model and for their ability to inhibit malate dehydrogenase as an intracellular target enzyme model. Correlation analysis indicates that ascites cell inhibition is linearly related to pi and that malate dehydrogenase inhibition is linearly related to MR.


Prostaglandins and congeners. 14. Synthesis and bronchodilator activity of dl-16,16-trimethyleneprostaglandins.

The interesting bronchodilator activity of novel dl-16,16-trimethyleneprostaglandin congeners and their preparation via the conjugate addition of the appropriate vinyl lithiocuprate reagent to several cyclopentenones are described. Also discussed is the preparation of the key intermediate vinyl iodine 7.


Hypolipidemic arylthioalkanoic acids.

A series of arylthioalkanoic acids related to probucol was studied for hypolipidemic activity. Homologation of the alkyl side chain led to marked changes in the serum cholesterol and serum triglyceride lowering activity in rats with the best combination of properties appearing in compound 7, 2-[3,5-di-tert-butyl-4-hydroxyphenyl)thio]hexanoic acid. Modification of the ring substitution failed to improve the activity despite the empirical observation that lipophilic substitution was necessary. Removal of the phenolic hydroxyl produced compound 23 with properties similar to 7 but of somewhat lower activity. Replacement of the sulfur by oxygen increased the toxicity of the series. Resolution of racemic 7 did not change the activity of the compound. The LD50 in mice of 7 was between 5000 and 10 000 mg/kg and compound 7 has been submitted for human clinical evaluation.


Cholecystokinin (pancreozymin). 3. Synthesis and properties of an analogue of the C-terminal heptapeptide with serine sulfate replacing tyrosine sulfate.

The influence of tyrosine O-sulfate, the 27th residue in the sequence of cholecystokinin (pancreozymin) (CCK-PZ) on calcium outflux in isolated pancreatic cells of guinea pigs, was studied by replacing this residue in the biologically active C-terminal heptapeptide, CCK-PZ-(27--33) (I), with L-serine O-sulfate. The synthetic analogue Ser(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2 (IV), produced the half-maximal outflux observed with I, if applied at about 250 times higher concentration. The unsulfated form of IV was about ten times less potent than unsulfated I. Thus, in the effect on the calcium outflux, serince cannot replace tyrosine without a major loss in potency; a sulfate ester group in position 27 is important but in itself not sufficient for full potency. Interestingly, if the terminal amino group of the heptapeptide is left protected by a tert-butyloxycarbonyl group, the potencies of the derivatives of both I and IV were slightly, but significantly, higher than those of the free peptides.


Synthesis and antiallergic activity of 2-hydroxy-3-nitro-1,4-naphthoquinones.

A selection of novel 2-hydroxy-3-nitro-1,4-naphthoquinones are shown to be potent inhibitors of rat passive cutaneous anaphylaxis (PCA) and to have highest potency with alkyl substitution at both C-6 and C-7. The most potent compounds were 7c and 7e which produced a 50% inhibition in the rat PCA test at doses of about 10 micrometerM/kg following subcutaneous administration and showed activity after oral administration. Related 4-hydroxy-3-nitro-2(1H)-naphthalenones had no effect on rat PCA in doses up to 500 micrometerM/kg.