Surfactant solutions as test liquids for measurement of critical surface tension.

Contact angles of various liquids and surfactant solutions on polytef and paraffin were measured. Critical surface tension values were obtained by extrapolation of plots of cosine of the contact angles versus corresponding surface tension values. Contact angles measured using polyoxyethylene octylphenols produced linear Zisman plots and yielded critical surface tensions that agreed with accepted values. This liquid series provides a reasonable approach to the measurement of critical surface tension for solid drugs that are soluble in organic liquids but relatively insoluble in water.


Critical surface tensions of pharmaceutical solids.

Advancing contact angles measured on compacts of several drugs by the sessile drop method and also by penetration through a column of drug granules were used to find the critical surface tension of the drugs. After liquid was delivered at a very slow rate, the contact angle of sessile drops decreased with time, but use of a consistent method of timing always led to the same value for critical surface tension. Results from penetration studies and work on compacts were in agreement, provided that the surfaces of the compacts were smooth and highly reflective. Critical surface tension of the six drugs, three analgesics and three sulfonamides, ranged from 31 to 33 dynes/cm. The critical surface tension of mixtures of phenacetin and microcrystalline cellulose was not a linear function of the relative surface fractions of the two materials. If the surface contained 25% or more of phenacetin, the critical surface tension barely differed from that of pure phenacetin.


Stability-indicating assay for vidarabine.

A physicochemical procedure for the analysis of vidarabine in aqueous parenteral formulations was needed to assure potency and to define stability. Concurrent with the development of this method, its decomposition products and route in aqueous solution were determined. A quantitative procedure was developed to determine intact drug in the presence of decomposition products, and the results obtained were validated by microbial assay. Spectral (UV and polarimetric) and TLC evidence indicated that, in aqueous solution, hydrolysis without racemization occurs, yielding adenine and arabinose. The sensitivity of the method to decomposition is improved by ion-exchange separation of adenine and drug before UV measurement. Analysis of partially decomposed solutions of the drug by both ion-exchange and microbiological methods gave comparable results.


GLC determination of trihexyphenidyl hydrochloride dosage forms.

A rapid, sensitive, and specific GLC method for the quantitation of trihexyphenidyl hydrochloride in various pharmaceutical dosage forms is described. The procedure involves chloroform extraction of the active ingredient from a weakly acidic solution, followed by GLC determination using a 3% methyl silicone column. The specificity of the system in relation to several compendial drug analogs also is reported.


Simultaneous GLC determination of methyl salicylate and menthol in a topical analgesic formulation.

A simultaneous GLC determination for methyl salicylate and menthol in a topical analgesic formulation is reported. n-Nonadecane is used as the internal standard. The method is rapid, accurate, precise, and selective in the presence of salicylic acid and ethyl salicylate.


Analysis of dienestrol and its dosage forms by high-performance liquid chromatography.

A high-performance liquid chromatographic (HPLC) analysis is described for dienestrol as a drug substance and in cream, foam, and tablet dosage forms. After incorporation of the drug or dosage form into a solvent mixture containing an internal standard, biphenyl, an aliquot was chromatographed using a reversed-phase medium, followed by UV spectrophotometric detection at 254 nm. The response of the chromatographic system was linear over a concentration range corresponding to 50-200% of the labeled amount of dienestrol. Satisfactory accuracy and precision were confirmed by analyzing cream by the standard addition method. The advantages of the HPLC method are its simplicity, speed, and sensitivity, which permit direct analysis of single-dose quantities of dienestrol.


Improved electron-capture GLC determination of alprenolol and oxprenolol in serum using a wall-coated open tubular column.

An accurate, rapid, and sensitive GLC determination of alprenolol and oxprenolol in serum is described. This method combines an electron-capture detector with a wall-coated open tubular column. The lowest detectable amount of the halogenated (heptafluoroacyl) derivatives of alprenolol and oxprenolol is 2 pg. The high resolving power and the rapid elution time of the wall-coated open tubular column dramatically improve the performance (accuracy and sensitivity) of the conventional electron-capture detector and packed column system in these determinations. This method allows the use of small volumes of sample (100-200 microliter), does not require redistilled reagents, and has a simplified extraction procedure.


New spectrophotometric determination of inorganic bromide and chloride salts in aqueous solutions.

A new method for the determination of inorganic salts of chloride and bromide is described. The method is based on the facts that iodine forms complexes with the anions and that these complexes absorb strongly in the UV region. The molar absorptivities of I2Br- at 265 nm and I2Cl- at 245 nm were calculated to be 3.27 X 10(4) and 2.3 X 10(4) M-1 cm-1, respectively.


Stability of 10-acetylphenothiazine.

The degradation kinetics of 10-acetylphenothiazine were studied after isolation and identification of its degradation products, phenothiazine, phenothiazine-5-oxide, 3H-phenothiazine-3-one, and 7-(10'-phenothiazinyl)-3H-phenothiazine-3-one. The acetyl group was not present in any degradation product. The degradation rate was independent of oxygen but highly pH dependent, indicating a specific hydrogen-ion-catalyzed hydrolysis of 10-acetylphenothiazine to give phenothiazine, which was oxidized. The experimental values for the phenothiazine concentration were in good agreement with values calculated on the basis of this assumption, both in the presence and absence of oxygen.


Drug absorption from in situ rat small intestine during metoclopramide administration.

The effect of metoclopramide on the absorption of drugs in solution in the small intestinal lumen of rats in situ was studied. Metoclopramide in doses up to 50 mg/kg sc did not significantly modify the disappearance of isoniazid and quinidine from the small intestinal lumen. At the end of the absorption experiments, quinidine in the whole blood of the experimental animals was increased after metoclopramide. The blood level did not correlate to the drug disappearance from the intestinal lumen. The results probably differ from those obtained when drugs are given orally to subjects treated with metoclopramide.


Synthesis of 3-hydroxy-3-phenacyloxindole analogs.

Substituted isatins and substituted acetophenones were condensed to give analogs of 3-hydroxy-3-phenacyloxindole. These alcohols were dehydrated, and the alkene was reduced. None of the products had the level of anticonvulsant activity exhibited by the parent compound.


Synthesis of methyl 1-(3,4-dichlorobenzyl)-hexahydro-2,3-dioxo-4-pyridinecarboxylate.

Methyl 1-(3,4-dichlorobenzyl)-hexahydro-2,3-dioxo-4-pyridinecarboxylate was prepared by alkylation of methyl hexahydro-2,3-dioxo-4-pyridinecarboxylate with alpha,3,4-trichlorotoluene. The compound showed significant antifungal activity when challenged by a spectrum of pathogenic yeast species in a minimum inhibitory concentration test. It was active against some dermatophytic fungi and Aspergillus niger.


Rapid, stability-indicating, high-pressure liquid chromatographic determination of theophylline, guaifenesin, and benzoic acid in liquid and solid pharmaceutical dosage forms.

Theophylline, guaifenesin, and benzoic acid were determined by reversed-phase high-pressure liquid chromatography without interference from active and/or vehicle decomposition. A degradation product of sucrose, 5-hydroxymethylfurfural, can be identified and quantified in liquid samples simultaneously.


Influence of neuronal activity levels on the cytotoxic effects of guanethidine.

Reduction of activity levels in the noradrenergic innervation of the iris of the rat by decentralization of the superior cervical ganglion resulted in a marked increase in sensitivity of these fibers to damage by chronic guanethidine treatment (15 mg/kg/day) as shown by fluorescence histochemistry. Guanethidine also had an increased cytotoxic effect on the decentralized nerve cell bodies. These results suggest that the relative inactivity of male "short" noradrenergic neurons may contribute to their sensitivity to damage by guanethidine. The nature of the damage produced in other tissues by this dose of guanethidine indicates that levels of neuronal activity are not the only factor determining sensitivity to the cytotoxic effects of this drug.


Effect of acute smoke exposure on hepatic protein synthesis.

In vivo hepatic protein synthesis was monitored in female rats under control and smoke-exposed conditions. During the 15 min period after i.v. administration of [3H]proline protein synthesis was 206 +/- 35 nmol of proline per mg of DNA for sham-control animals. When animals were subjected to acute exposure to cigarette smoke, protein synthesis was inhibited and the extent of inhibition was positively correlated with the dosage of smoke (32%, 15 puffs; 66%, 60 puffs). The inhibitory effect of whole smoke on protein synthesis was unaltered by passing the smoke through either charcoal or cambridge filters. Carbon monoxide in smoke is not removed by either type of filter. At a level comparable to that in cigarette smoke carbon monoxide depressed hepatic protein synthesis to the same extent as did whole or filtered smoke.


Effects of nonsteroidal anti-inflammatory drugs (NSAID) on renal excretion of sodium and water, and on body fluid volume in rats.

Effects of nonsteroidal anti-inflammatory drugs (NSAID) on urine volume and urinary sodium excretion, and on plasma volume and extracellular fluid volume were examined in conscious rats. The basal urine volume and urinary sodium excretion were decreased and the increased urine volume and urinary sodium excretion elicited by saline load (25 ml/kg) and by hydrochlorothiazide (10 mg/kg) were inhibited after oral administration of NSAID in doses which inhibited the rat carrageenin-induced hind paw edema (indomethacin, 1--10 mg/kg; tolmetin, 3--30 mg/kg; phenylbutazone, 3--30 mg/kg; aspirin, 30--300 mg/kg), but aminopyrine (30--300 mg/kg) did not show such an effect. The inhibitory activity on renal function was diminished gradually with repeated administration of NSAID. NSAID (indomethacin, 3 mg/kg; tolmetin, 10 mg/kg; phenoxybenzamin, 10 mg/kg; aspirin, 100 mg/kg) increased plasma volume and extracellular fluid volume of rats after repeated medication for 3 or 5 days, but the body fluid volume expansion disappeared with further repeated administration of NSAID. These results suggest that NSAID may inhibit the intrarenal role of prostaglandins and decrease sodium and water excretion in urine with resulting increased body fluid volume. Tolerance to these actions of NSAID developed after repeated administration.


Gallamine and pancuronium inhibit pre- and postjunctional muscarine receptors in canine saphenous veins.

The influence of gallamine, pancuronium, suxamethonium and d-tubocurarine on adrenergic neurotransmission was studied in the isolated saphenous vein of the dog. Pancuronium but not the other muscle relaxants increased significantly the response to sympathetic stimulation and to exogenous norepipephrine; these increases were abolished after blockade of neuronal uptake by cocaine. Pancuronium and gallamine inhibited both the relaxation produced by lower doses of acetylcholine added during sympathetic stimulation (prejunctional effect) and the direct contractions evoked by high doses of the amine (postjunctional effect). In strips previously incubated with [3H]norepinephrine, gallamine had no effect on [3H]norepinephrine efflux in basal conditions and during sympathetic stimulation; it increased markedly the efflux evoked by sympathetic stimulation in the presence of acetylcholine confirming that gallamine inhibits the prejunctional effect of the latter on adrenergic transmission. When extrapolated to the intact organism, the present experiments indicate that gallamine and pancuronium augment the release of norepinephrine in vascular tissue under vagal control, which explains in part the cardiovascular effects of these muscle relaxants.


Urinary excretion of meperidine by the fetal lamb.

The renal excretion of meperidine by the fetus was determined in five chronic, unanesthesized fetal lamb preparations. Chronic indwelling catheters were implanted in the maternal aorta and vena cava, the fetal aorta, amniotic sac and allantoic sac. Via laparotomy, two catheters were implanted in the fetal bladder; the urachus and urethra were ligated. After intravenous administration of 2.5 mg/kg to the mother, meperidine rapidly appears in fetal urine. Approximately 0.02 to 0.05% of the maternal dose was excreted into fetal urine as unchanged meperidine in 300 min. The elimination half-life of meperidine in the fetus is 32.6 +/- 3.7 min when calculated from the urinary excretion rates, and 28.6 +/- 3.9 min when estimated from the plasma decay curve. The renal clearance of meperidine by the fetus ranged from 2.8 to 16.7 ml/min. Although the urachus and urethra were ligated, meperidine is found in samples of amniotic and allantoic fluid, indicating that the drug can diffuse across the placental membranes from the mother into these fluids. We have demonstrated that renal elimination of meperidine is a route of drug elimination by the fetus. These data support a pharmacokinetic model that describes the disposition of meperidine in the maternal-fetal unit by use of a two-compartment open model with elimination from both maternal and fetal compartments.


A new extracorporeal reactor-dialyzer for enzyme therapy using immobilized L-asparaginase.

Depletion of circulating L-asparagine has proved beneficial in the treatment of some acute lymphoyctic leukemias. To avoid the immunologic sequelae of administering L-asparaginase parenterally, we have covalently attached the enzyme to the outside of the fibers of a conventional hollow fiber hemodialyzer. This provides ready access of the substrate to the enzyme, while simultaneously isolating the foreign protein from the immune system. Such reactor-dialyzers perform well, both in vitro and in vivo. Circulating L-asparagine in the healthy dog is reduced from about 50 micrometer to less than 2 micrometer within 30 min of connecting the reactor-dialyzer and the reduction persists for at least 4 hr after cessation of treatment.


Influence of epinephrine and propranolol on transmembrane K transfer in anuric dogs with hyperkalemia.

In anuric dogs K loaded by infusion of 2 mEq of KCl per kg per hr the quantity of K transferred to intracellular fluid in ureter-ligated animals is considerably less than in nephrectomized ones; the combination of ureter ligation and hyperkalemia seems to suppress transmembrane K transfer. In the present investigation we found that treatment of K loaded ureter-ligated dogs with epinephrine markedly increased the animals' ability to transfer K to intracellular fluid, and that administration of propranolol (with and without epinephrine) reduced K transfer capacity below the control level. Further, we found that propranolol treatment of K-loaded nephrectomized dogs produced a striking diminution of K transfer ability. The data suggest that beta adrenergic receptors are importantly involved in the transmembrane K transfer of K-loaded anuric dogs, and that ureter ligation and hyperkalemia suppress K transfer capacity by blocking beta receptors.


The effects of perhexiline on the sympathetic nervous system.

The effects of perhexiline on sympathetic nervous system function were studied in vitro and in vivo. Perhexiline decreased the field stimulation-induced contractile response of the isolated vas deferens and significantly decreased the quantity of norepinephrine released during stimulation of this preparation. In vivo studies in dogs showed that perhexiline reduced the heart rate response to cardiac accelerator nerve stimulation, an effect not associated with an increase in cholinergic tone or beta adrenergic blockade. Measurements of norepinephrine released from the heart during cardiac nerve stimulation showed that perhexiline (3 mg/kg) decreased norepinephrine release by approximately 35%. These results suggest that a presynatpic effect of perhexiline, which results in a decrease in norepinephrine release, contributes significantly to the attenuated heart rate response which occurs after administration of this drug. A decrease in transmitter release during sympathetic stimulation could play an important role in the mechanism for the protective effects of perhexiline in myocardial ischemic damage.


Steady-state disposition of propranolol and its total metabolites in the spontaneously hypertensive rat: chronic subcutaneous vs. intracerebroventricular infusion with osmotic minipumps.

The steady-state disposition of propranolol and its total metabolites was measured after 6 day continuous subcutaneous (1 mg/kg/day) or intracerebroventricular (i.c.v., 0.01 and 1 mg/kg/day) infusion of dl-[3H]propranolol with osmotic minipumps in spontaneously hypertensive rats. After 2 days daily excretion of total radioactivity was 70% or more of the total dose infused each day. Steady-state plasma concentrations (day 3 and 6) of propranolol and its total metabolites did not differ significantly during subcutaneous or i.c.v. infusion of 1 mg/kg/day. During i.c.v. infusion with 0.01 mg/kg/day these concentrations were only 0.01 to 0.02 times as high. Propranolol and its total metabolite concentrations did not differ significantly in peripheral tissues during subcutaneous or i.c.v. infusion of 1 mg/kg/day, whereas brain propranolol concentrations were 40- to 600-fold higher during i.c.v. infusion. During i.c.v. infusion with 0.001 mg/kg/day, peripheral propranolol and total metabolite concentrations were only 0.003 to 0.02 times those following 1 mg/kg/day. Brain propranolol concentrations after 0.01 mg/kg/day i.c.v. were in the same range as those following 1 mg/kg/day subcutaneously. The data suggest that the osmotic minipump is a useful tool for creating and maintaining a steady-state for propranolol in spontaneously hypertensive rats. Moreover, by i.c.v. placement of the pump outlet the brain can be selectively perfused with this agent for a prolonged period of time.


Intestinal absorption of S-adenosyl-L-methionine.

The gastrointestinal absorption of S-adenosyl-L-methionine (SAMe) is demonstrated by evaluating plasma levels and gastrointestinal content of the unmodified molecule after oral administration. When [methyl-14C]SAMe is given orally, the radioactivity found in the liver is associated both with SAMe and phosphatidylcholine, a compound known to be derived from the methylation of phosphatidylethanolamine with SAMe as a methyl donor. These results and low plasma levels after the oral administration may be suggestive of a first-pass effect of SAMe characterized by an extensive uptake of the drug by the liver where it is rapidly metabolized.


The effect of water deprivation on lithium clearance and lithium excretion fraction in lithium-polyuric rats.

The effect of water deprivation on lithium clearance was studied in rats with lithium-induced polyuria. During a 3-hr period of water deprivation, the rats lost water in amounts corresponding to about 10% of body weight. Lithium clearance fell to about 25% of the level observed in rats which were not water deprived. During shorter periods of water deprivation, the fall of lithium clearance was less. The decrease of lithium clearance was partly due to a fall of inulin clearance and partly due to a fall of fractional excretion of lithium. The decrease of the two variables contributed to the same extent to the decrease of lithium clearance. The findings support the suggestion that insufficient intake of water in patients with lithium-induced polyuria may lead to a rapid lowering of lithium clearance and, hence, to a rise of the serum lithium concentration and development of intoxication.


Comparison of the activity of the cis and trans isomer of vitamin K1 in vitamin K-deficient and coumarin anticoagulant-pretreated rats.

The cis and trans isomers of vitamin K1 have been prepared at a purity of better than 99.5% and tested for effect on plasma level of factor VII in coumarin anticoagulant-pretreated and vitamin K-deficient rats. Both isomers show activity, but in coumarin anticoagulant-pretreated animals the cis isomer has approximately 10% and in vitamin K-deficient approximately 1% of the activity of the trans isomer. The cis isomer also shows slower onset and rate of increase of the response. Reduction of the 2',3'-double bond of the phytyl side chain of either isomer to the same 2',3'-dihydro derivative of vitamin K1 leaves the activity of the trans isomer unchanged but increases the activity of the cis isomer to that of the trans isomer. The results suggest that the phytyl side chain not only serves to increase lipid solubility, but may play a more direct functional role.


Transmural distribution of metabolites and blood flow in the canine left ventricle following isoproterenol infusions.

The effects of intravenous infusions of isoproterenol (0.1, 1.0 or 2.5 micrograms/kg/min for 1 hr) on the transmural distribution of myocardial high-energy phosphates and glycolytic intermediates were determined in anesthetized, open chested dogs. The transmural distribution of blood flow across the left ventricular wall was determined after serial injections of 15 mu radioactively labeled microspheres. A biopsy of the posterolateral wall was frozen in liquid nitrogen, divided into epicardial, midmyocardial and endocardial thirds, and assayed for metabolites. The remainder of the heart was processed for light and electron microscopy. At the infusion rate of 2.5 micrograms/kg/min, isoproterenol caused nonuniform reductions in ATP, phosphocreatine, total adenine nucleotides and glycogen, which were particularly depleted in the endocardium. Isoproterenol also caused nonuniform increases above baseline in blood flow (epicardial, 492%; midmyocardial, 197%; and endocardial, 131%). The endocardial/epicardial blood flow ratios, however, were reduced. Evidence of cellular damage was demonstrated by the presence of numerous contraction band lesions along with mitochondrial swelling and the appearance of electron-dense deposits. It is concluded that necrogenic infusions of isoproterenol impair myocardial energy production in all myocardial layers despite an overall increase in blood flow. There appears to be a link between the gradients in metabolites and the distribution of blood flow such that the endocardium becomes more vulnerable to injury.


Systemic administration of prostaglandin E1 produces hypothermic effects in unanesthetized rats.

The effects of intraperitoneal administration of prostaglandin E1 (PGE1) on thermoregulatory responses were assessed in unanesthetized rats at ambient temperatures (Ta) of 8, 22 and 29 degrees C. The body temperatures, metabolic rate, respiratory evaporative heat loss and vasomotor activity in response to PGE1 were observed. Intraperitoneal administration of PGE1 produced dose-dependent hypothermia at Ta's of both 8 and 22 degrees C. The PGE1 hypothermia was due to both the decreased metabolic rate and the cutaneous vasodilation. However, at a Ta of 29 degrees C, intraperitoneal administration of PGE1 produced no changes in rectal temperature, since the thermoregulatory responses were not affected by PGE1 application at this Ta. The data indicate that peripheral administration of PGE1 decreases metabolic heat production and increases heat loss, which leads to hypothermia in rats, in contrast to hyperthermia seen after central administration.


Effects of imipramine on cellular electrophysiological properties of cardiac Purkinje fibers.

The electrophysiological effects of imipramine (Tofranil) on cardiac Purkinje fibers were studied in vitro. Imipramine has a direct membrane action. It reduces excitatory inward current in Purkinje fibers, at least as measured by Vmax and conduction velocity. The mechanism of action of imipramine is probably by both reduction in gNa and marked slowing of the time constants of recovery of the rapid inward sodium current. Imipramine also reduces the action protential duration, decreasing the absolute refractory period. This effect is not seen with antiarrhythmic agents of the local anesthetic class, but it is similar to lidocaine. This effect may be a result of the decrease in steady-state gNa, but effects of the drug on other ionic conductances could play a role.


Denervation-like supersensitivity in the rat vas deferens induced by local application of colchicine to the hypogastric plexus.

In an attempt to induce denervation-like supersensitivity in the smooth muscle of the vas deferens without depriving the tissue of its innervation, a small amount of colchicine was locally applied to the hypogastric plexus of the rat. Colchicine produced supersensitivity and a partial depletion of the tissue norepinephrine. These effects were dose-dependent. The supersensitivity produced by colchicine was qualitatively and quantitatively similar to that induced by denervation. Following application of 20 micrograms of colchicine, the supersensitivity was fully developed by the 4th day. The supersensitivity began to decline by the 6th day but was measurable even after 16 days. Functional neuromuscular transmission was maintained even on the 4th day after colchicine application, although it was significantly less than the control. The time course of the development of supersensitivity was dependent on the length of the adrenergic nerve between the colchicine-applied site and the effector cells. The results indicate that supersensitivity is independent of an irreversible degeneration of the adrenergic nerves. The possible mechanisms of action of colchicine are discussed in relation to the known effects of colchicine on axoplasmic transport.


Effects of verapamil on rapid Na channel-dependent action potentials of K+-depolarized ventricular fibers.

We studied the effects of 1 to 3 micrograms/ml of verapamil on Vmax and plateau duration in guinea-pig papillary muscles depolarized from -90 to -55 mV by increasing extracellular potassium from 5.4 to 20 mM. Under the conditions of our experiments, we found that verapamil did not influence the steady-state or recovery characteristics of Vmax at any of the studied K levels even when Vmax was less than 20 V/sec. Thus in the absence of rapid sodium channel blockade, the value of Vmax cannot be used to identify slow channel-dependent action potentials. Verapamil caused no shortening of plateau or total action potential duration when potassium was less than 7.5 mM. Above this level, verapamil caused progressive shortening of plateau and total action potential duration, due to the increase in potassium and not the associated decrease in resting membrane potential. Increasing extracellular calcium shortened plateau duration at all levels of potassium before verapamil but lengthened plateau duration in the high K, verapamil-treated fibers. These results, which can be explained by known effect of verapamil on the slow outward as well as slow inward currents, provide a mechanism whereby verapamil may increase Vmax of K-depolarized but rapid sodium current-dependent premature action potentials.


Effect of antrum exclusion on endocrine cells of rat stomach.

1. Following antrum exclusion the serum gastrin concentration was raised and independent of the prandial state. The antral gastrin concentration and number of gastrin cells were greatly lowered. 2. The histamine content and the number of histamine-storing endocrine ('entero-chromaffin-like') cells in the oxyntic mucosa was almost doubled and the mucosal histidine decarboxylase activity was greatly elevated following antrum exclusion. 3. At the ultrastructural level both types of histamine-storing endocrine cells (ECL and A-like) were found to be enlarged and to have a reduced number of granules per unit cytoplasm. These changes are compatible with an increased secretory activity. The G (gastrin) cells were not increased in size but their granule volume density was lowered. 4. We propose that antrum exclusion results in uninhibited gastrin release causing profound changes in the histamine-storing endocrine cells of the oxyntic mucosa. The cells respond to the hypergastrinemia by an increase in functional activity (activation of histidine decarboxylase and reduction of granule volume density) as well as by an increase in number and size.


Immobilization of intramembrane charge in Myxicola giant axons.

1. Immobilization of gating charge was examined in Myxicola giant axons dialysed with Cs+. 2. With increasing pulse durations the ratio QOFF/QON decreases to as little as 0.25 with a time constant of 3.2 msec determined from composite data. Na inactivation time constants measured in the same axons ranged from 0.8 to 1.5 msec. A slow component of QOFF tends to appear as QOFF/QON decreases. 3. Both QON and QOFF may be decreased by a prepulse with no change in their time course. In this case the time course of the decrease is similar to that observed for INA. 4. The normalized steady-state charge immobilization curve is shifted in the depolarized direction by 15--20 mV from the normalized Na inactivation curve.


Carotid and cardiopulmonary baroreceptor control of splanchnic and forearm vascular resistance during venous pooling in man.

1. This study evaluated the contribution of carotid and cardiopulmonary baroreceptors to reflex splanchnic and forearm vascular adjustments during venous pooling in man. We compared (a) responses to lower body suction which produces venous pooling with (b) responses to lower body suction plus simultaneous application of neck suction. The rationale was that simultaneous application of neck suction, which stretches carotid baroreceptors, would minimize the contribution of carotid baroreceptors to circulatory adjustments produced by lower body suction.2. Lower body suction at 40 mmHg decreased central venous pressure and arterial pulse pressure and increased forearm vascular resistance (plethysmography), splanchnic vascular resistance (indocyanine green dye clearance), and heart rate. Simultaneous application of neck suction prevented the tachycardia and most of the splanchnic vasoconstriction during lower body suction, but did not significantly attenuate the forearm vasoconstriction.3. The major findings in this study are first, that the splanchnic vasoconstrictor response during venous pooling is mediated primarily through carotid baroreceptors, and secondly, that carotid and cardiopulmonary baroreceptors produce strikingly contrasting and non-uniform regional vascular responses during venous pooling. Cardiopulmonary baroreceptors exert the predominant influence on forearm vascular resistance, but appear to have only a minor influence on splanchnic vascular resistance. Carotid baroreceptors produce most of the splanchnic vasoconstriction during venous pooling. but have a minor role in the forearm vasoconstriction.


Relation of potassium transport to oxidative metabolism in isolated brain capillaries.

1. The uptake of K by a capillary suspension isolated from rat brain was studied with the radioactive analogue (86)Rb.2. Rb uptake was dependent upon the presence of oxygen and could be markedly inhibited with ouabain.3. The ouabain sensitive Rb uptake was measured at varying external concentrations of K. Uptake of K (as (86)Rb) was half-maximal when the K concentration was 3.0 mM. This in vitro affinity of the transport carrier for K is similar to that found in previous in vivo studies of K efflux from brain to blood.4. I propose that the ouabain sensitive K pump is located on the antiluminal plasma membrane of brain capillary endothelial cells and that this pump contributes to the maintenance of a constant concentration (i.e. 3 mM) of K in brain interstitial fluid.5. Glucose and palmitate were tested as possible energy substrates for the support of active Rb uptake by isolated brain capillaries. The rate of Rb uptake increased 40% when 0.25 mM-palmitate was added to a capillary suspension containing 5 mM-glucose. This stimulation of Rb uptake could be blocked by 1 mM-4-pentenoic acid, an inhibitor of fatty acid oxidation. In contrast, the fraction of Rb uptake supported by glucose was not altered by 4-pentenoic acid.6. The rates of [U-(14)C]glucose and [U-(14)C]palmitate oxidation to CO(2) were measured in isolated brain capillaries and compared to their oxidation by brain slices and synaptosomes. Palmitate was the source of 28% of the (14)CO(2) produced by the capillaries but only 0.5% of the (14)CO(2) produced by the brain slices and synaptosomes.7. It is concluded that brain capillaries are similar to renal tubules in their polar distribution of ouabain sensitive K transport carriers, dependence on oxidative metabolism for active ion transport, and use of fatty acids as energy substrates. These features may underlie the vulnerability of brain capillaries in several metabolic diseases that cause brain oedema.


Natural selective cooling of the human brain: evidence of its occurrence and magnitude.

1. The technique of perceptual rating of thermal stimuli was used, in eight human subjects immersed in warm water, in order to appreciate whether they were hypo-, normo- or hyperthermic. Oesophageal, tympanic and forehead skin temperatures were recorded, as also was the temperature of the skin above the angularis oculi vein. Once the subjects gave clearly hyperthermic ratings, one arm was exposed to a 6 m/s wind. After 5--10 min the arm was re-immersed and the face was fanned. 2. Fanning of the arm resulted in lowering of body core temperature. However ratings of thermal stimuli remained hyperthermic. 3. Face fanning decreased forehead skin, angularis oculi vein and tympanic temperatures. Hyperthermic ratings were replaced by normothermic ratings, although oesophageal temperature continued to rise. 4. The upper limit of oesophageal temperature for normothermic ratings was 37.o6 +/- 0.09 degrees C during the control period without fanning. This temperature rose to 37.91 +/- 0.09 degrees C during facial ventilation. 5. These results suggest a selective cerebral cooling due to venous blood returning from facial skin via the ophthalmic vein to the cavernous sinus, where a cooling of arterial blood ascending to the brain can take place.


Tactile sensibility in the human hand: relative and absolute densities of four types of mechanoreceptive units in glabrous skin.

1. Single unit impulses were recorded with percutaneously inserted tungsten needle electrodes from the median nerve in conscious human subjects. 2. A sample of 334 low threshold mechanoreceptive units innervating the glabrous skin area of the hand were studied. In accordance with earlier investigations, the units were separated into four groups on the basis of their adaptation and receptive field properties: RA, PC, SA I and SA II units. 3. The locations of the receptive fields of individual units were determined and the relative unit densities within various skin regions were calculated. The over-all density was found to increase in the proximo-distal direction. There was a slight increase from the palm to the main part of the finger and an abrupt increase from the main part of the finger to the finger tip. The relative densities in these three regions were 1, 1.6, 4.2. 4. The differences in over-all density were essentially accounted for by the two types of units characterized by small and well defined receptive fields, the RA and SA I units, whereas the PC and SA II units were almost evenly distributed over the whole glabrous skin area. 5. The spatial distribution of densities supports the idea that the RA and SA I units account for spatial acuity in psychophysical tests. This capacity is known to increase in distal direction along the hand. 6. On the basis of histological data regarding the number of myelinated fibres in the median nerve, a model of the absolute unit density was proposed. It was estimated that the density of low threshold mechanoreceptive units at the finger tip is as high as 241 u./cm2, whereas in the palm it is only 58 u./cm2.


The excitation of mammalian central neurones by amino acids.

1. The relative potencies of a number of analogues of L-glutamate as excitants of thalamic neurones in the rat have been compared. The most powerful compounds were kainate, ibotenate and (+/-)cis-1-amino-1,3-dicarboxycyclopentane. The D- and L-isomers of glutamate and aspartate were also compared. Whereas D-glutamate is approximately one-half as active as the L-form, D-aspartate is more potent than L-aspartate. 2. Computer analysis has indicated that ibotenate and cis-1-amino-1,3-dicarboxy-cyclopentane have relatively fixed and similar C alpha-N, Comega-N and C alpha-Comega interatomic distances which can also be achieved by glutamate in certain conformations of the molecule, but not by aspartate. 3. Parallel examination of the antagonists glutamate diethylester and D-alpha-aminoadipate has shown that the former preferentially reduces L-glutamate effects while the latter blocks the actions of other amino acid excitants more readily than those of L-glutamate. 4. The evidence is consistent with the hypothesis that at least two populations of neuronal receptors for the excitatory amino acids exist.


Efferent control of stimulus access to the hamster vomeronasal organ.

Previous workers had identified the vomeronasal organ, on anatomical evidence, as an accessory olfactory organ, present in most terrestrial vertebrates. Lesion experiments had demonstrated its importance in sexual behaviour in the hamster. Howevever, the sequestered position of the vomeronasal receptor epithelium within the organ raised questions concerning the access of olfactory stimuli. Using electrophysiological and pharmacological methods we have now demonstrated the following. 1. A pumping mechanism exists, powered by vasomotor movements, which can suck stimulus substances into the vonmeronasal organ. 2. A mechanism also exists for the active expulsion of the contents of the vomeronasal organ. 3. These mechanisms are activated by fibres running in the nasopalatine nerve. 4. The suction mechanism is controlled by sympathetic, probably adrenergic, fibres from the superior cervical sympathetic ganglion. Control of the expulsion mechanism has not been definitely established but does not appear to be sympathetic. 5. The vomeronasal organ can be adequately stimulated by activation of the pumping mechanism in the presence of odour. 6. Odour responses of single units in the accessory olfactory bulb have been recorded for the first time. 7. The time course of neuronal response in the accessory olfactory bulb is more rapid than predicted by many authors. The response is sufficiently fast that the vomeronasal system cannot be ruled out as a possible sensory pathway in many odour related behaviours. Possible modes of action of the pumping mechanism in awake animals are discussed.


The transport of the lead cation across the intestinal membrane.

1. The transport of the lead cation has been investigated using the everted sac preparation of Wilson & Wiseman (1954).2. Only a small percentage of lead was transported into the serosal compartment but there was a rapid and massive uptake onto the tissue. There was no significant difference in the amount of lead cations transported across different regions of the small intestine.3. Both the rate of transport into the serosal compartment and the tissue uptake increased linearly with increasing concentration of the lead cation, from 10(-7)M to 5 x 10(-5)M. Little evidence for saturation of serosal transport or tissue uptake was found.4. Lead transport into the serosal compartment appeared to be related to water movement, but was little affected by changes in glucose concentration and temperature.5. It is concluded that lead is transported into the serosal space by a process of passive diffusion linked to water transport.6. The interaction between lead ions and the intestinal tissue was extremely tenacious and displayed characteristics of covalent bonding.7. It is suggested that the lead cation interacts with tissue phosphate ions thus removing lead ions from the transport pool. Chelation of lead to form a neutral species reduces this interaction and also promotes transport.


Noradrenaline as a possible mediator of the actions of angiotensin on fluid transport by rat jejunum in vivo.

1. Net fluid absorption and transmural potential difference were measured in the rat jejunum in vivo.2. Increased rates of net fluid transport were observed following infusions of angiotensin or noradrenaline. There was a small, but significant, fall in transmural p.d. associated with noradrenaline but not with angiotensin infusions.3. The alpha-adrenergic antagonists phentolamine and dihydroergotamine abolished both the angiotensin and the noradrenaline stimulations of transport and the noradrenaline-induced fall in p.d., whereas the beta-adrenergic antagonist propranolol did not significantly affect these responses.4. Phentolamine did not alter the rise in p.d. following administration of the cholinergic agonist pilocarpine.5. The protein synthesis inhibitor cycloheximide abolished both the angiotensin and the noradrenaline-induced stimulation of fluid transport.6. Neither angiotensin nor noradrenaline significantly altered jejunal cyclic AMP levels.7. Bilateral nephrectomy had no apparent effect upon the increase in fluid transport following noradrenaline infusions.8. The noradrenaline-induced stimulation of transport was unaffected, and the fall in p.d. potentiated in rats pre-treated with reserpine, but a marked inhibition of transport was observed following angiotensin infusions.9. The results are consistent with the view that noradrenaline may mediate the actions of angiotensin upon intestinal fluid absorption in the rat.


Non-electrolyte permeability of trout gills: effect of temperature and adrenaline.

1. The gill permeability to various non-electrolytes (P(s)) was measured in fresh-water and sea-water adapted trout (Salmo gairdneri). This study was performed in vitro using a ;head-perfused' preparation. The influence of temperature and adrenaline (10(-6)M) on permeability to non-electrolytes was also investigated.2. During salt adaptation P(butanol) and P(water) decrease, P(mannitol) rises and P(dextran) stays constant. In view of recently acquired morphological data these results back up the hypothesis of different pathways across the gill epithelium (transcellular, vesicular and paracellular) according to the physico-chemical characteristics of the molecules. The low selectivity of the gill epithelium as a function of the liposolubility of the molecules used testifies to the hydrophilic nature of diffusion across this epithelium, a feature becoming more pronounced during salt adaptation.3. The activation energies are about 4 kcal/mol, an energy comparable to diffusion in water for most of the substances tested, exceptions being butanol for fresh-water adapted gills and water for fresh-water and sea-water adapted gills. Arrhenius plots for butanol in fresh water gills show a transition temperature at 15 degrees C, suggesting an increased membrane lipid fluidity above this temperature.4. Adrenaline has no effect on P(mannitol) and P(dextran), but increases P(butanol) and P(water) selectively according to the adaptation medium (+ 160% and + 100% in fresh water and + 25% and + 20% in sea water respectively). These results point to an effect of this catecholamine on the membrane lipid fluidity.


Serotonergic innervation of the locus coeruleus from the dorsal raphe and its action on responses to noxious stimuli.

The connexions between the dorsal raphe nucleus and the nucleus locus coeruleus were studied in urethane anaesthetized rats. 1. Cells in the locus coeruleus gave an excitatory response to a noxious stimulus, e.g. leg pinch. 2. This excitatory response was blocked by either a parenteral or an ionophoretic injection of morphine and recovered after an injection of naloxone. 3. Electrical stimulation in the region of the dorsal raphe blocked excitatory locus coeruleus responses to noxious stimuli. 4. While naloxone did not antagonize the effects of the dorsal raphe stimulation towards locus coeruleus activity, these effects were absent in rats pretreated with a serotonin synthesis inhibitor, PCPA or with 5,7-DHT which destroys serotonin-containing terminals, and were reduced by the serotonin antagonist methysergide. 5. A serotonin-containing inhibitory pathway between the dorsal raphe and the locus coeruleus is proposed to account for these results.


Calcium current in molluscan neurones: measurement under conditions which maximize its visibility.

1. Membrane currents were studied in isolated somata of molluscan neurones from Archidoris monteryensis and Anisodoris nobilis. Under voltage clamp, inward current displayed a two phase time course, and in some cases a clear reversal potential difference could be shown for the fast and slow phases. The slower phase was carried predominantly by calcium ions. 2. The apparent magnitude of the slower phase was greatly influenced by conditions which altered potassium current flow. Blocking voltage-dependent potassium conductances, either by appropriate conditioning polarizations or by tetraethyl-ammonium (TEA) ion, enhanced the magnitude, while conditions which augmented potassium current made the slow phase disappear. 3. A fraction of the membrane potassium conductance was TEA insensitive. This fraction could be blocked by procedures which prevented internal levels of calcium from increasing during the voltage clamp pulse. Three such procedures were demonstrated; replacement of external calcium by magnesium, internal buffering by EGTA, and replacement of calcium by permeant barium. 4. Internal EGTA buffering or external barium in combination with external TEA produced an extreme change in membrane current as compared with the normal time course. Membrane current, when activated by pulses up to +50 mV, was net inward and showed only fractional inactivation over time courses running to several seconds. Pulses to voltages greater than +60 mV resulted in outward current. 5. It is concluded that under normal conditions the calcium conductance has the extended time course clearly evident under the modified conditions of paragraph 4 but that the calcium flux component is easily missed. 6. In agreement with several prior studies it is also concluded that a rise in internal calcium is causally related to a rise in potassium conductance. A transmembrane flux of calcium can be uncoupled from the gK increase by appropriate buffering of internal calcium. 7. The transient potassium current, IA, which bears a resemblance to calcium-dependent potassium transients in some muscle cells did not depend upon internal calcium but instead is a voltage-activated mechanism.


Diffusional inhomogeneity: gas mixing efficiency in the new-born lung.

1. The results of 105 nitrogen washouts on seventy-six new-born babies are presented; the mean lung volume (functional residual capacity, FRC) of the seventy-six babies measured at more than 1 hr of age was 77.5 +/- 2.9 (S.E. of mean; S.D. = 25.4). 2. The mean gas mixing efficiency was 0.466 +/- 0.0097 (S. E. of mean; S.D. = 0.096). The reasons for the difference between this figure and the normal for adults of 0.66--0.76 are discussed, and it is suggested that the very much greater turnover rate of gas within the lungs is responsible for diffusion inefficiency. 3. Calculations indicate that there is a tenfold fall in diffusion inefficiency for every 9.8 sec turnover time (the time for VE to equal VFRC). In the baby the turnover time is 5--6 sec on average but with a very wide spread; in the adult it is of the order of 30 sec, so that diffusion inefficiency of gas in the lung would be only 0.001 or 0.1%. 4. The significance of this is that the effective alveolar ventilation of the average neonate is less than half the total ventilation (as opposed to two-thirds if deadspace only is considered), becoming a smaller fraction of VE on hyperventilation. This would explain discrepancies in the calculation of alveolar carbon dioxide levels from the output of that gas and the non-deadspace ventilation.


Prolonged changes in excitability of pyramidal tract neurones in the cat: a post-synaptic mechanism.

1. Prolonged changes in the excitability of cortical neurones can be produced by altering their firing rates for brief periods. In the anaesthetized cat, increased firing of pyramidal tract cells induced by trains of antidromic conditioning shocks led to increases in cell excitability, as measured by the size of the mass response at the medullary pyramid to test shocks applied to the cortical surface. We have shown in two ways that post-synaptic mechanisms could be responsible. 2. In one experimental design, MgCl2 solution (1 mole/l.) was applied to the cortical surface in order to block synaptic activity throughout the cortical depth. Following antidromic conditioning trains, cell excitability was increased; the size of the mass response was up to 30% larger than the control values. This persisted undiminished for up to 3 hr. 3. In the second experimental design, synaptic activity was not blocked, but we compared the effects of antidromic plus synaptic activation of pyramidal tract cells with the effects of synaptic activation alone. Antidromic plus synaptic activation was obtained by applying conditioning trains to the pyramidal tract at the medulla ipsilateral to the cortical test shock; prolonged increases in the ipsilateral response to the test shock were produced. Synaptic activation alone was obtained by the same conditioning trains, but in those cells whose axons projected into the contralateral pyramidal tract; prolonged increases in the contralateral response to the cortical test shock were never seen. In many instances prolonged decreases in excitability were found. 4. We conclude that prolonged increases in excitability of pyramidal tract cells can occur in the absence of any synaptic input, demonstrating that the underlying mechanism is post-synaptic; this does not preclude the action of synaptic mechanisms when synaptic transmission is not blocked.


Different mechanisms for neutral amino acid uptake by new-born pig colon.

1. Mucosal amino acid uptake by pig proximal colon, measured independently for fourteen different amino acids each used at a concentration of 1 mM, ranged from 0.6 to 8.6 n-mole. cm(-2). min(-1) in the new-born to 0 to 0.3 n-mole. cm(-2). min(-1) in the 2-day-old animal. Long chain amino acids entered the mucosa of new-born pig proximal colon much more readily than did short chain amino acids.2. Glycine was used extensively to inhibit the uptake of other neutral amino acids. The degree of maximal inhibition produced depended on the amino acid used. The relative inability of glycine to inhibit the uptake of long chain amino acids suggested that these compounds could cross the brush border on a carrier inaccessible to glycine. The glycine-sensitive uptake remained more or less constant for all amino acids tested (1-2 n-mole.cm(-2).min(-1)); the glycine-insensitive uptake varied from 0 to 7 n-mole.cm(-2).min(-1) (glycine and methionine respectively).3. It is suggested that at least two mechanisms exist for the entry of neutral amino acids into pig proximal colon, one showing specificity for hydrophobic amino acids and the other having broad specificity. The mechanism responsible for the uptake of long chain essential amino acids predominates over the less specific mechanism.4. These results are discussed in relation to previous work carried out on the rabbit ileum where two similar systems for neutral amino acid entry have been shown to be present. Both tissues transport hydrophobic amino acids on their own specific carrier at approximately the same rate; the ability of the pig colon to transport amino acids on the broad specificity carrier is eight times less than in the rabbit ileum. The possibility is raised that this system is subject to regulation.


The effects of background illumination on the photoresponses of red and green cones.

1. The photoresponses of light- and dark-adapted red and green cone photoreceptors were recorded intracellularly in the retina of the turtle, Pseduemys scripta elegans. Background illumination produced similar effects on both types of cones. 2. In response to the onset of a prolonged, steady background illumination the cone initially hyperpolarized to a peak which then sagged back to a steady-state polarization that was typically about one half the initial peak amplitude. This sag was observed for all backgrounds studied (dim as well as bright). 3. A resensitization was observed concomitantly with this sag; both the maximum increment and decrement responses grew in amplitude as light-adaptation proceeded. After about 2--3 min of background illumination, the amplitudes of these responses stabilized. 4. The dark-adapted cone produced graded responses to test pulses over a range of intensities spanning about 3.5 log units. The amplitudes of these responses were well fit by the relationship V = I.Vm/(I + sigma). 5. After 2--3 min of background illumination, 500 msec test pulses either brighter or dimmer than the background intensity were substituted for the background. The light-adapted intensity-response curves constructed from this data were similar to the dark-adapted curve but were shifted horizontally and slightly vertically, so that they still spanned about 3.5 log units of intensity. Thus, in the light-adapted cone, graded responses were elicited by a range of bright test pulses which would have produced saturated responses when delivered to the dark-adapted cone. 6. The 'off response' observed at the offset of the background became faster as the background intensity was increased. It also became faster with time following the onset of any particular background intensity. 7. It was concluded that cone sensitivity during any state of light-adaptation is determined by two mechanisms; response compression resulting from the instantaneous non-linearity between 'internal transmitter' concentration and membrane potential and a more active 'cellular adaptation' mechanism which is manifest as a shift in the intensity-response curve. In the steady-state condition of light-adaptation, most of the sensitivity changes are a result of the cellular adaptation mechanism. 8. Photopigment bleaching caused by the backgrounds, negative feed-back from horizontal cells and voltage dependent mechanisms in the cones could not account for this cellular adaptation. These effects of background illumination were interpreted in terms of the 'internal transmitter' hypothesis of phototransduction.


Electrolyte secretion by the isolated cat pancreas during replacement of extracellular bicarbonate by organic anions and chloride by inorganic anions.

1. The effect of replacing extracellular bicarbonate and chloride by other anions on the volume and composition of secretin-stimulated pancreatic juice has been analysed in the isolated, perfused cat pancreas. 2. The anions of some aliphatic carboxylic acids were able partially to substitute for bicarbonate in sustaining pancreatic secretion. The order of effectiveness was: acetate greater than proprionate greater than butyrate greater than formate. 3. The rate of secretion in the presence of 25 mM-acetate was 42% of that achieved with 25 mM-bicarbonate. The concentration of acetate in the secretion varied with flow rate, reaching a maximum of 120 mM at high flow rates and declining at lower flow rates, with reciprocal changes in chloride concentration. Bicarbonate was always present in the secretion at a concentration of 5--7 mM. 4. Inorganic anions were able totally or partially to substitute for chloride in sustaining secretion. In relation to chloride, their degree of effectiveness was: chloride = bromide = or greater than nitrate greater than iodide greater than sulphate greater than methyl sulphate greater than isethionate. Those anions which had no effect on secretion rate (i.e. bromide and nitrate) also had no effect on the bicarbonate concentration of the secretion and themselves appeared in the secretion in place of chloride. Those anions which inhibited secretion increased the bicarbonate concentration in the secretion in proportion to the degree of inhibition they caused (i.e. the increase was greatest with isethionate). 5. When perfusate chloride was only partially replaced by bromide or iodide the ratios of chloride: bromide and chloride: iodide in the secretion were approximately equal to those in the perfusate. 6. The carbonic anhydrase inhibitor acetazolamide reduced secretory rate and bicarbonate concentration when added to normal perfusion fluid or chloride-substituted fluids, but had no effect following replacement of perfusate bicarbonate by acetate. 7. These observations illustrate that an extracellular source of permeant anions is required for optimal pancreatic bicarbonate secretion to occur. This may indicate the participation of an anion exchange carrier in the transport events responsible for this secretory process.


Mechanics of the trachea and behaviour of its slowly adapting stretch receptors.

1. The trachea is constructed by a series of U-shaped cartilaginous rings supporting a membranous posterior wall. We have studied separately the pressure-volume relationships of the two components. 2. The motion of the membranous posterior wall contributes most to the tracheal volume change caused by any given transmural pressure change; the cartilaginous rings provide a semi-rigid support to the posterior wall and have a far greater compliance with negative than positive transmural pressure. 3. The response of tracheal stretch receptors to transmural pressure can be explained by the mechanical coupling between cartilages and posterior wall. They respond both to positive and negative transmural pressure, they are active at zero transmural pressure and have a point of least activity with small negative transmural pressures. 4. The stress-strain relationship of the posterior wall has been studied in static and dynamic conditions in control situations and after removal of either the tunica fibrosa or the trachealis muscle. Each of these two components contributes to the stiffness of the posterior wall, with the trachealis muscle providing most of its viscosity. 5. The response of tracheal stretch receptors to transverse traction of the posterior membranous wall has been studied in both static and dynamic conditions before and after removal of the tunica fibrosa. The behaviour of these receptors reflects the visco-elastic properties of the trachealis muscle in which they have been localized.


Measurement of calcium influx under voltage clamp in molluscan neurones using the metallochromic dye arsenazo III.

1. The metallochromic indicator dye, arsenazo III, was injected into somata of molluscan neurones from Archidoris monteryensis. Membrane current and dye absorbance change were simultaneously monitored under voltage clamp. 2. Absorbance measured at 660 nm increased during positive-going voltage steps large enough to activate membrane conductances. In situ idifference spectra were qualitatively similar to dye, dye-calcium difference spectra recorded in vitro. The absorbance change was abolished by either a thorough removal of external calcium or internal chelation of calcium by EGTA. It was concluded that the absorbance increase primarily reflected changing internal calcium concentration and that the calcium entered from the outside. 3. Dye absorbance increased in a nearly linear fashion during voltage clamp pulses of 100--300 msec duration. This is in qualitative agreement with electrical stuidies which demonstrated only fractional inactivation of calcium conductance during such periods. Plots of absorbance change vs. Vm peaked at +30 to +40 mV and fell off sharply until approximately +70 mV where the slope became less steep. A null or reversal of the absorbance change was generally observed aroung +110 mV. Evidence is presented that calcium influx was in some cases sufficient to cause sizeable changes in its equilibrium potential. 4. During multisecond voltage clamps the slope of the absorbance change showed a large decline. Where barium substituted for calcium as the influx species in identical clamps, the absorbance at 660 nm also increased but in a much more linear fashion. Except for a slight effect on the initial few pulses, the absorbance signal did not recover after a period of barium influx. These results suggest that part of the slope decline might result from processes related to calcium uptake and not to membrane conductance decrease. 5. Dye absorbance changes during normal and TEA action potentials were measured. Comparison of these changes with voltage clamp records indicated that calcium influx during a spike was capable of raising concentration by roughly 2 X 10(-7) M if the cell were considered to be a uniform sphere with no buffering capacity. Calcium influx during action potentials was increased dramatically by TEA, primarily as a result of a prolonged plateau phase. The existence and duration of the plateau was controlled mainly by potassium conductance systems, however. There was no evidence found for facilitation of the calcium conductance. 6. Following a moderate influx of calcium it required 20--60 sec, depending on the neurone, for the dye absorbance to return to base line (at 9 degrees C). The recovery time course showed a marked difference when examined at different wavelengths. For lambda = 660 nm there was an initial period in which the absorbance decreased rapidly, followed by a slower phase which generally carried the absorbance below the initial (prepulse) value...


Metabolism of boar spermatozoa before, during preparation for, and after storage in liquid nitrogen.

Boar spermatozoa incorporated more [14C]glycerol into lipid when incubated with 200 mM- than with 25 mM-glycerol. Measurements were made of the metabolism of spermatozoa while they were being prepared for frozen storage. [14C]-Glucose was converted to CO2 and lipid while the cells were cooling to 15 degrees C. Glycerol was added at 15 degrees C and during further cooling to 5 degrees C glucose metabolism was greatly reduced but [14C]glycerol was converted to CO2 and lipid. Under aerobic conditions spermatozoa accumulated lactate while cooling from 30 to 15 degrees C and from 15 to 5 degrees C. With essentially anaerobic conditions, although more lactate was accumulated this occurred only while the cells were cooling from 30 to 15 degrees C, and no further accumulation could be detected during cooling from 15 to 5 degrees C. When boar spermatozoa were incubated at 37 degrees C after storage in liquid nitrogen, metabolism of glycerol was greater than metabolism of glucose. It is suggested that this preferential use of glycerol during cooling and after storage may be one facet of its cryoprotective function. After storage, boar spermatozoa incorporated relatively less [14C]stearic and [14C]palmitic acids into phospholipids (especially phosphatidyl choline) than did freshly collected cells. Caffeine stimulated the oxygen uptake of freshly collected and thawed cells.


Effects of osmolality, bicarbonate and buffer on the metabolism and motility of testicular, epididymal and ejaculated spermatozoa of boars.

Spermatozoa were collected from the rete testis of conscious boars, from the cauda epididymidis by retro-flushing, and by ejaculation. Testicular spermatozoa showed no progressive motility, and that of ejaculated was greater than that of epididymal spermatozoa. Glycolysis and respiration of testicular spermatozoa, while lower than that of the more mature cells, were only slightly affected by the incubation conditions. Epididymal spermatozoa converted 83% of the glucose they utilized to CO2 or lactate, but testicular cells converted only 35% to these metabolites. Synthesis of lipid was greatest by testicular spermatozoa. With the more mature cells hyperosmolar conditions depressed CO2 production, but increased lactate production, and these changes were greater for ejaculated than for epididymal spermatozoa. Glycolysis plus respiration of these cells was related to their motility. These results were interpreted as showing increasing motility, glycolysis and respiration with maturation, but also decreased synthetic capacity and increased sensitivity to the environment.


Effects of urine from pregnant and lactating female house mice on oestrous cycles of adult females.

It was demonstrated that mice treated with urine from pregnant or lactating females experienced longer periods of oestrus than did mice treated with water or urine from singly caged females. Application of urine by means of perforated capsules placed in the cage of the test mouse showed that the factor(s) responsible for the longer periods of oestrus was an airborne pheromone. The females experiencing longer oestrous periods ovulated (ova in oviducts), became pregnant and gave birth.


Measurement of thymus weight, lumbar node weight and progesterone levels in syngeneically pregnant, allogeneically pregnant, and pseudopregnant mice.

Female CBA mice were mated to fertile CBA males, to vasectomized CBA males, to fertile C57BL males or to vasectomized C57BL males. After allogeneic or syngeneic mating the extent of thymic involution on the 10th day of pregnancy and pseudopregnancy was similar. Lumbar lymph node weight was not affected by pseudopregnancy but increased similarly in allogeneic and syngeneic pregnancies. Serum progesterone levels on the 10th day of pseudopregnancy were similar to those of non-pregnant females, and significantly lower than those of pregnant females. On the 4th to 7th days progesterone levels in pseudopregnant animals were equal to those in pregnant animals. Progesterone levels and thymic involution were similar in syngeneically and allogeneically pregnant females. Progesterone levels were negatively correlated with thymus weight but reached significance only when the mating was allogeneic. It is suggested that there is an interaction between progesterone concentrations and the degree of thymic involution during pregnancy.


Effects of vasectomy on the blood-testis barrier of the hamster.

The effects of vasectomy on the blood-testis and blood-epididymal barriers to 3H2O, [3H]inulin, and [14C]urea were examined by study of the radioactivity appearing in micropuncture samples of fluids from the seminiferous tubules and cauda epididymidis. By 4 months after vasectomy, there were changes in the blood-seminiferous tubule barrier to [3H]water and [14C]urea (increased entry) and in the blood-epididymal barrier to [3H]water and [3H]inulin (increased entry) and to [14C]urea (decreased entry). These subtle changes could have an impact on spermatogenesis and/or sperm maturation after vasectomy.


Differential transport of embryos and degenerating ova by the oviducts of the long-tongued bat, Glossophaga soricina.

Female long-tongued bats which had been maintained in sexually segregated groups in captivity for more than 8 months were bred and killed at various intervals between Days 1 and 25 post coitum. Their reproductive tracts were then examined histologically. In 20 of the 28 bats carrying tubal embryos the remnants of 1-4 other ova were also observed in the oviductal ampullae. These remnants consisted of intact zonae pellucidae containing cellular debris, empty zonae, and/or zona fragments. Since long-tongued bats are monovular, the remnants had apparently been retained in the oviducts from previous, non-fertile reproductive cycles. In 27 of the 31 bats carrying implanting blastocysts, zonae pellucidae probably shed by the embryos had been retained in the oviducts. The remnants of 1-3 ova were also observed in the oviductal ampullae of 22 of the 31 bats carrying uterine blastocysts. In at least 14 of these bats the embryos had by-passed ovum remnants in the oviducts on their way to the uterus. No evidence of such remnants was found in the oviducts of 17 animals with tubal or uterine embryos, although old, as well as new, CL were present in the ovaries.


Effect of underfeeding on the inhibition of gonadotrophin secretion by testosterone propionate in rats.

Single (0 . 25 mg/100 g body wt) or multiple (5 x 20 microgram/100 g) injections of testosterone propionate were given to castrated male rats fed normally or restricted to a 50% intake. Serum FSH and LH levels were higher in the underfed rats and the effectiveness of testosterone propionate in suppressing serum levels of gonadotrophins was increased by underfeeding.


Radioimmunoassay for PMSG and its application to in-vivo studies.

A double-antibody radioimmunoassay for PMSG, especially for meauring PMSG in cattle blood after exogenous application, has been developed. A rabbit antiserum against PMSG and pure PMSG for radioiodination were used. There was a strong cross-reaction against equine LH and FSH, but the slight cross-reaction against bovine LH and FSH could be eliminated by adding bovine LH to each tube during the assay. Unspecific, interfering influences of equine or cow serum could be eliminated by adding a constant amount of PMSG-free serum to each tube. PMSG added to 200 microliter of serum could be recovered by this method with a mean of 90 . 5 +/- 9 . 9%. Inhibition curves obtained with pregnant mare serum or cow serum after administration of PMSG were parallel to those obtained with the PMSG standard preparation. The intra-assay coefficient of variation (CV) was 6 . 9%. The inter-assay CV was 12 . 6%. Sensitivity of the assay was 1 mi.u. PMSG/tube. Values of PMSG measured in the serum of pregnant mares by this assay were comparable with those obtained by a bioassay on the same samples. PMSG was still measurable in blood serum about 10 days after injection of 1500-3000 i.u. PMSG. After infusion of 12,000 i.u. PMSG for 3 h (2 heifers), the half-life of PMSG was found to have two components, one of 51 or 40 h and a slower one of 123 or 118 h.


Selective oocyte degeneration and impaired fertility in rats treated with the aliphatic monoterpene, Citral.

Mature female rats treated with Citral (3-7-dimethyl-2,6-octadienal) either topically for 60 or 100 days or by 6 i.p. injections (at 4-5 day day intervals) showed a marked decrease in the number of normal follicles per section, because oocytes tended to degenerate although the follicular cells remained normal. The reproductive performance after Citral treatment was impaired: there was a reduction in implantation number and litter size and an increased post-implantation fetal wastage. None of the young survived after 100 days of topical Citral treatment. It is suggested that Citral directly affects the oocytes.


Plasma levels of progesterone, provera, oestradiol-17beta, and 13,14-dihydro-15-keto-prostaglandin F in cows treated with provera-impregnated intravaginal sponges.

Plasma concentrations of progesterone and Provera were measured daily in 3 cows during 21 days of treatment with Provera-impregnated intravaginal sponges. Plasma concentrations of oestradiol-17beta and 13,14-dihydro-15-keto-prostaglandin F (PGFM) were measured hourly from 5 h before until 62 h after sponge removal. The profile of progesterone concentrations indicated that luteolysis occurred at the expected time (Days 19 to 23 of the cycle), even though plasma Provera concentrations were 150-250 pg/ml. The occurrence of peaks of PGFM after sponge withdrawal suggests that PGF-2alpha release is stimulated by falling levels of progestagen.


Gonadotrophin-induced accumulation of 'interstitial fluid' in the rat testis.

'Interstitial fluid' containing high levels of testosterone (60-250 ng/ml) was recovered from the testes of rats, the amounts increasing with increase in age and testis weight. Injection of 170 i.u. hCG/kg resulted 20 h later in significant increases in interstitial fluid and its testosterone content (300-800 ng/ml). In immature rats this effect of hCG was dose-dependent and time-related and the accumulated fluid contained high levels of potassium and phosphate; levels of sodium, calcium and protein were similar to those in serum. At 20 h after injection of hCG, other testicular changes were (1) increased 'adhesiveness', (2) reduced in-vitro binding of 125I-labelled hCG, and (3) an hCG-induced increase in the testis:blood ratio of hCG in vivo.


The occurrence of non-tubal ectopic pregnancies in women with an intrauterine device.

The occurrence of intra-ovarian gestation in 2 women and an abdominal pregnancy in a third, all bearing IUDs, is described.


The effects of vasectomy on testicular metabolism in the guinea-pig.

The effects of vasectomy on testicular DNA production were studied in guinea-pigs at 2 weeks and 2 and 6 months after surgery. By 6 months, vasectomy had resulted in lower testicular weight and absolute DNA, RNA and protein contents, although RNA and DNA concentrations/protein were unchanged. Incorporation of thymidine into the testis had decreased by 2 weeks after vasectomy, and continued to do so unless the ductal system subsequently ruptured and formed a granuloma when thymidine incorporation returned to normal control levels. It is suggested that in the guinea=pig vasectomy alters spermatogenesis by reducing testicular DNA synthesis.


Incidence of polyspermy in mouse eggs fertilized in vivo and in vitro after administration of progesterone and oestradiol.

Female mice, induced to superovulate, were injected subcutaneously with progesterone or oestradiol near the time when hCG was given. The incidence of polyspermy in first-cleavage embryos following mating or in-vitro fertilization was then determined. There were no detectable differences in the incidence or degree of polyspermy between treated and control in either the in-vitro or in-vivo groups, although the mean incidence of polyspermy was higher in vitro than in vivo. Furthermore, there was no detectable acceleration of egg transport after administration of either hormone.


Sperm head length as a predictor of fecundity in the sandhill crane, Grus canadensis.

Semen samples from 14 sandhill cranes were collected for 15 weeks. Mean sperm head length which did not vary significantly over weeks was found to be significantly correlated with fertility (P less than 0 . 04; r = 0 . 54, n = 14).


Effect of hypophysectomy on mouse oocyte maturation in vitro.

There was no difference in frequency of maturation of oocytes obtained from mice hypophysectomized for 2 weeks compared to those from sham-operated or untreated (control) animals of the same age. By 7 weeks, and also at 12 and 17 weeks, the incidence of polar body formation in vitro was significantly reduced. The number of oocytes which remained meiotically inactive in culture was increased at 7, 12 and 17 weeks after hypophysectomy. This decrease in spontaneous oocyte maturation in vitro could be partly overcome by administering exogenous PMSG, oestradiol-17beta or PMSG + oestradiol-17beta, but not progesteron or hCG, to hypophysectomized mice.


The effect of LH on the fertilizability and developmental capacity of rat oocytes matured in vitro.

The effect of adding LH (10 microgram NIH-LH-B8/ml) to the medium in which oocytes were undergoing maturation in vitro was studied. The fertilizability of the oocytes was evaluated in the sterile oviduct of a unilaterally ovariectomized, mated recipient. Freshly ovulated oocytes, used as a control of the method, were fertilized at a rate of 72%. Only 14% of oocytes matured in culture (without LH) were penetrated by spermatozoa, and 11% were fertilized normally. Addition of LH to the medium increased these proportions to 43 and 33% respectively. Oocytes matured in the presence of LH were able to develop into apparently normal rats. It is concluded that, although oocytes can mature in vitro spontaneously, and that these matured oocytes can be fertilized, addition of LH increases the numbers 3-fold. LH therefore has a direct maturation-promoting action on the rat oocyte-cumulus complex in vitro.


The state of the device and copper levels in the products of conception in women becoming pregnant with a copper-bearing IUD in situ.

Of the 8 pregnancies studied, 2 were of small gestational sacs with blighted ova and were associated with devices in which the copper wire had very high detectable X-ray emissions for copper (greater than 90%). In 2 other pregnancies intrauterine deaths had occurred by the time of termination at 13 and 17 weeks and copper levels in the products of conception were variable. There was no abnormality of the fetus in the term pregnancy but it seems possible that copper can affect the early growth and development of the embryo. On only 1 of the 8 devices was any great amount of calcium deposited and it is therefore considered unlikely that calcium deposition increases the risk of pregnancy by preventing the release of copper.


Inhibition of in-vitro fertilization of intact and denuded hamster eggs by univalent anti-sperm antibodies.

Univalent (Fab) rabbit anti-hamster sperm antibodies added to an in-vitro fertilization system did not interfere with the sperm acrosome reaction or motility, but inhibited cumulus dispersion by the spermatozoa, sperm binding to and passage through the zona pellucida as well as sperm-egg fusion. Addition of the Fab preparations to the capacitated spermatozoa at various times before or up to 40-45 min after the sperm-egg mixing prevented penetration of spermatozoa through the zona pellucida. Detachment of the spermatozoa already bound as well as those partly inside the zona pellucida was achieved by a late addition of antibodies. In experiments with zona-free hamster eggs, addition of the Fab antibodies to the spermatozoa 10 min to 5 h before the introduction of unfertilized eggs reduced the rate of adhesion and fertilization to very low levels. These antibodies were not absorbed on hamster ovary, liver or kidney and had no direct effect on the fertilizability of zona-intact or zona-free eggs.


The effect of reserpine, oestradiol and in-vitro perfusion on oviduct calcium levels in the mouse during egg transport.

Mouse oviduct calcium content, determined by atomic absorbance after ashing of the tissue, showed a significant fall on Day 2 of pregnancy followed by a significant rise on Day 3. This pattern was altered by administration of reserpine and oestradiol in doses which were shown to alter the rate of egg transport. In-vitro perfusion of the oviduct, capable of maintaining muscular activity and back and forth movement of eggs for 24 h, was associated with lack of forward progressive motion of eggs and by a more rapid increase in tissue calcium levels during incubation than occurred in vivo.


Complete and partial vaginal agenesis.

The proper diagnosis and treatment of a patient with vaginal agenesis demands a thorough knowledge of the relevant embryology, anatomy and physiology as well as sensitivity to the potentially emotionally devastating effects of the condition. Ten patients with vaginal agenesis were evaluated and treated at Wilford Hall USAF Medical Center over a three-year period. The patients fell into three groups, those with: (1) Müllerian atresia, complete or partial; (2) maldevelopment of the lower one-third of the vagina; and (3) testicular ferminization. Other congenital anomalies existed in many of these patients. Most of the patients were treated with the Frank method of vaginal development with good results. Some underwent surgical correction.


A preliminary report of "subclinical varicocele": diagnosis by Doppler ultrasonic stethoscope. Examination and initial results of surgical therapy.

Two hundred sixteen consecutive infertility patients were examined with the Doppler ultrasonic stethoscope to detect incompetence of the gonadal vein valves, the precursor of frank varicocele. All 75 men with clinically palpable varicoceles had positive Doppler findings. In 33 cases varicocele could not be definitely excluded because of unsatisfactory physical examinations; the Doppler findings were negative in 13, positive in 13 and equivocal in 7 of these men. Eighty-nine men had no evidence of varicocele on physical examination and negative Doppler findings. However, 19, patients with no palpable varicocele had positive Doppler examinations. With respect to testicular size and semen quality, this subclinical varicocele group could not be clearly distinguished from patients with idiopathic semen quality depression. Nevertheless, five men with subclinical varicocele and oligoasthenospermia underwent internal spermatic vein ligation. Postoperatively, four had negative Doppler examinations. Two patients showed a significant improvement in semen quality, and both men fathered children after several months. We believe that these preliminary results justify further investigation of "subclinical varicocele".


Ovarian hemorrhage in patients receiving anticoagulant therapy.

During a 10-year period, five laparotomies were performed on three patients for hemorrhage from nonneoplastic ovarian lesions that occurred while the patients were on anticoagulant therapy. The patients were stabilized with blood transfusions, given medication to reverse the anticoagulants and underwent immediate surgery. Nineteen similar patients have been reported on previously. During the brief follow-up a 31% incidence of recurrent hemorrhage was observed in those patients continued on anticoagulants postoperatively. All physicians caring for women on anticoagulants should be on the alert for this life-threatening complication.


Ectopic pregnancy. An eight-year review.

Ruptured ectopic pregnancy constitutes a major gynecologic emergency that may result in death. From January 1968 through December 1975, 313 patients with ectopic pregnancy were treated at Chicago Lying-In Hospital. The historical and physical findings, diagnostic procedures, causative factors and patient management are reviewed and discussed. The most common symptoms were abdominal pain and amenorrhea. More than half the patients were misdiagnosed prior to admission. Only 30% had distinct adnexal masses. The treatment of choice was salpingectomy unless the opposite tube was absent or damaged. Three deaths occurred in this series. Only 31% of the patients gave histopathologic evidence of pelvic inflammatory disease.


Verrucous carcinoma of the vulva.

A case of invasive verrucous carcinoma of the vulva is reported. The English literature is reviewed and the mode of therapy discussed.


Urinary nitrogen excretion as related to dietary protein in pregnant women.

The amount of urea in the urine acutely decreases when dietary protein is restricted. This change in urinary urea nitrogen can be represented satisfactorily by the urea nitrogen/total nitrogen (UN/TN) ratio or the UN/creatinine nitrogen (UN/CN) ratio. These determinations are apparently effective tools for simply and objectively describing the recent protein intake of pregnant women.


Ovarian surface papillomatosis of borderline malignancy.

Bilateral ovarian surface papillomatosis of borderline malignancy is a rare condition. In our case it was associated with benign serous cystadenofibroma. The histologic diagnosis and the clinical aspects are discussed.


Reliability factors of delivery due dates.

This study attempted to identify the factors that are most important in establishing accurate pregnancy due dates. It quantitated the influence of many factors that affect the duration of pregnancy, as calculated from the last menstrual period, with data from a large prospective study. To limit the influence of maternal constitutional factors, analyses were conducted on the differences between the durations of repeat pregnancies in the same mothers. The mean difference between the calculated durations of successive pregnancies in 4,599 mothers was 18 days. This difference was reduced to 10 days when the pregnancies had been planned and the dates of the last menstrual period had been recorded in the first trimester of pregnancy. Many other factors, including maternal and fetal disorders, significantly altered the length of individual pregnancies but had no significant influence on the overall duration of pregnancies in the study.


Utilization of gyniatricians as primary health care providers for women.

The role, functions, activities, educational preparation and relationship with other health professionals of a new type of primary health care provider is described. The name gyniatrician has been applied to this kind of physician, who will be qualified to provide overall primary health care for women from the onset of puberty through adult life.


An unusual cause of postoperative fever: a case report.

A typical gynecologic approach to postoperative fever and its theoretical as well as practical shortcomings is discussed. Difficulties in establishing a specific diagnosis in the gynecologic patient with postoperative fever are explored. A case of exacerbation of dermatomyositis in the immediate postoperative period illustrates the failings of our current approach to postoperative fever.


Congenital incompetence of the cervical os: reduction of bulging membranes with a modified Foley catheter.

A case is described of congenital incompetence of the cervix associated with pronounced bulging of the fetal membranes through the cervical os. The patient, a primigravida, presented at 25 weeks' gestation without any evidence of uterine activity. She had no past history of cervical surgery or disease. The tip beyond the bulb of a size 22 Foley catheter was removed. We inflated the bulb progressively while applying sustained, gentle pressure to the bag of forewaters. Upon reducing the membranes to within the uterine cavity, we inflated the bulb of the catheter further with saline to a total volume of 25 cc. This procedure maintained the catheter within the uterine cavity and facilitated the insertion of a MacDonald cerclage in the region of the internal cervical os.


Spontaneous rupture of a primigravid uterus.

The spontaneous rupture of the primigravid uterus is an obstetric rarity prior to the onset of labor. Invariably there is a history of antecedent scarring. A case of uterine rupture is reported on where the only antecedent history was damage by the second trocar during laparoscopy. The use of electrocautery and the immediacy of subsequent conception are probably implicated in the pathogenesis. It is recommended that should the fundus be damaged during laparoscopy as part of a subfertility investigation, barrier contraception should be advised for a two-month period.


Systemic Herpesvirus hominis in pregnancy.

Primary genital herpesvirus infection occurring in late gestation may provide the portal of entry for systemic infection. This report describes the clinical events and pathologic findings of lethal disseminated herpetic infection after a primary genital lesion in late gestation and reviews the physiologic changes of pregnancy that may cause the failure of normal defenses against the systemic spread of the virus.


A rapid, sensitive technique to assay penicillamine levels in blood and urine.

We have used a rapid, sensitive technique to assay penicillamine and its disulphide metabolites in body fluids. Penicillamine in serum is rapidly oxidized and the serum levels of the reduced material found in a pilot study of 10 patients ranged between 0.07 to 0.28 mg%. This technique may prove useful in allowing closer monitoring of therapy with this agent.


An assessment of penicillamine therapy in rheumatoid arthritis and the influence of previous gold therapy.

One hundred and fourteen patients with rheumatoid arthritis who had received treatment with penicillamine are reviewed. Side effects occurred in 50 patients. Sixty patients were considered to be improved with the drug. Low and high maintenance regimes were compared. There was no significant difference in the incidence of side effects or clinical improvement. Previous gold therapy did not influence the therapeutic response or total incidence of side effects observed with penicillamine. Rashes were, however, more common if patients had previously had treatment with gold.


Cytotoxicity in progressive systemic sclerosis: no evidence for increased cytotoxicity against fibroblasts of different origin.

Peripheral blood mononuclear cells from 13 patients with progressive systemic sclerosis and 10 normal controls were tested in a cytotoxicity assay against fibroblasts derived from normal adult skin, scleroderma-involved skin and fetal skin. No differences between controls and patients were demonstrated. Sera from patients and controls revealed no differences in cytotoxic effect on scleroderma fibroblast cultures, and patients' sera did not induce antibody-dependent cell-mediated cytotoxicity when added in combination with control peripheral blood mononuclear cells.


Chronic active hepatitis in a patient presenting with clinical and serological evidence of SLE.

A patient with clinical and serological manifestations of systemic lupus erythematosus (SLE) without renal or neurological manifestations was managed conservatively for 4 1/2 years. At this time she developed ascites and abnormal liver function tests, and was found to have severe chronic active hepatitis (CAH) with cirrhosis and portal hypertension. No clinical or biochemical evidence of liver disease was documented over the first 3 1/2 years of her illness, though no tests were performed in the 12 months before diagnosis. This case emphasizes the value of monitoring liver function tests over extended periods in such patients, since appropriate immunosuppressive therapy may benefit CAH, and as in this case, systemic manifestations of CAH may simulate SLE and precede clinical liver disease.


Systemic lupus erythematosus, partial lipodystrophy and hypocomplementemia.

A patient with partial lipodystrophy, increased susceptibility to infection and a clinical picture compatible with systemic lupus erythematosus is described. This patient had persistently low serum C3 levels and a C3-cleaving factor similar to the C3 nephritic factor (C3NeF). During periods of disease inactivity, serum levels of the other components of the classical and alternative pathways of complement measured were normal; heat labile opsonic capacity was low, suggesting functional depletion of factors of the alternative pathway of complement activation.


Osteomalacia complicating a blind loop syndrome from congenital megaesophagus-megaduodenum.

A young female with osteomalacia complicating a blind loop syndrome associated with congenital megaduodenum is described. In this case, the correction of vitamin D malabsorption by administration of antibiotics highlights the role of massive intraluminal bacterial overgrowth from destruction of vitamin D, or decreased unicellar solubilization due to deconjugation of biliary acids. The importance of cutaneous vitamin D synthesis in patients with osteomalacia of gastrointestinal origin is emphasized. The detection of megaduodenum and megaesophagus in the patient's father may be the first report of a familial association of these gastrointestinal abnormalities.


Osteomalacia and weakness complicating jejunoileal bypass.

Five years following jejunoileal intestinal bypass surgery for obesity, a patient developed debilitating weakness and muscle pain. Osteomalacia was suspected clinically by radiographic and laboratory abnormalities and confirmed by bone biopsy. Malabsorption was documented as well as secondary hyperparathyroidism. Successful treatment of this syndrome with vitamin D and calcium identified a medically reversible disorder which obviated the need for surgical reanastomosis.


The development of membranous glomerulonephritis in a patient with rheumatoid arthritis and Sjögren's syndrome.

A case of classical rheumatoid arthritis and Sjögren's syndrome complicated by the development of membranous glomerulopathy is presented. Circulating immune complexes were demonstrated. The possible relationship between glomerulitis and rheumatoid arthritis is discussed and the literature is reviewed. Chrysotherapy was instituted because of persistent synovitis. The patient responded and her proteinuria did not increase.


Electron microscopic study of depot corticosteroid crystals with clinical studies after intra-articular injection.

Depot corticosteroid crystals and their in vivo handling after intra-articular injection have not been studied by electron microscope (EM). We therefore injected 20 mg of either prednisolone tebuate or triamcinolone hexacetonide into knee joints of 7 patients with osteoarthritis and painful effusions. Six patients had a rise in the synovial fluid leukocyte counts, but only 1 patient had clinical evidence of a post-injection flare. Scanning and transmission EM revealed intra- and extracellular crystals 24 hours and 1 week after the initial injection. These combined EM studies provide an adjunct to compensated polarized microscopy in differentiation of depot steroid from other crystals.


Vasculitis of the gallbladder in a 70-year-old man with giant cell (temporal) arteritis.

A patient with giant cell (temporal) arteritis developed acute cholecystitis related to vasculitis. Histopathologically, the vasculitic lesions in the gallbladder resembled polyarteritis nodosa. In addition to demonstrating the rare occurrence of vasculitis of the gallbladder in a patient with giant cell arteritis, this case points out the inadequacies of currently used criteria to separate the various forms of arteritis.


Psycho-social adjustment of rheumatoid arthritis patients from two alternative treatment settings.

Fifty rheumatoid arthritis (RA) patients are compared with a control sample of 72 non-patients on five attitude scales which measure psychol-social adjustment. Patients generally indicate more negative attitudes toward self, which are significantly related to variables such as severity of condition and socio-economic status. The adjustment of patients who are being treated by registered nurses (physician extenders) is not significantly different from that of patients who are being treated by physicians.


University center and community hospital: problems in integration.

This study of health care in Chicago and its suburbs deals with a dilemma faced by many university hospitals located in our nation's metropolitan areas. Because of a massive displacement of population from the city to its suburban ring, some of the major medical centers in Chicago's inner zone have experienced a leveling-off of inpatient admissions. In contrast, outer zone and suburban community hospitals are in need of referral sources with specialized personnel and equipment to accommodate growing admissions. This imbalance would be corrected in a regional network based on an exchange of clients and services. A case study of the University of Chicago Medical Center highlights the tensions, strains, and resistances which inhibit the development of such a system and thus raises questions about the role of the research and teaching hospital in regional health care planning.


Hospitals and medical schools as factors in the selection of location of practice.

A study analyzing the relationship between the state in which a physician practices and the location of residency training was conducted using as subjects 467 individuals who entered graduate medical training programs at the University of Texas Southwestern Medical School at Dallas. The study population included physicians who were graduated from medical schools between 1955 and 1969 and who entered a phase of graduate training (internship/residency) at one of Southwestern Medical School's affiliated teaching hospitals. Results of the study support the conclusions of an earlier report that stressed the influence of the location of residency training in retaining physicians in Texas. The statistical findings indicate that if all other factors are equal, additional residency positions filled by graduates of medical schools in the same state might aid in increasing the retention rate of medical practitioners there.


A teaching hospital medical clinic: secondary rather than primary care.

Although medical clinics in teaching hospitals are said to dispense primary care, the assertion has not been established by formal descriptions of care in such clinics. In this paper the authors describe 287 patient visits to a medical polyclinic (where generalists and subspecialists of internal medicine practice together) over a one-year period. The prevalence of disease was much higher than in existing descriptions of office-based primary care. The majority of visits to subspecialists involved medical problems relevant to the subspecialty, but both subspecialists and generalists dealt with medical problems across subspecialty lines because most patients had multiple problems. Although the data indicate these patients' need for accessibility, comprehensiveness, coordination, and continuity is at least as great as that of patients receiving primary care, this clinic is most appropriately described as a secondary-care facility.


Histocompatibility antigens in paraplegic or quadriplegic patients with sacroiliac joint changes.

HLA typing for the A and B loci and radiographic examination of the sacroiliac joints were performed in 54 randomly selected patients with paraplegia or quadriplegia of more than 3 years' duration. The sacroiliac joints were abnormal in 24 patients. No association was found between any of the HLA antigens of the A and B loci and the sacroiliac joint changes. There was, however, an increased incidnece of sacroiliac joint changes in quadriplegic as compared to paraplegic patients.