Electronic monitoring of events within dynamic particulate beds: conductance and capacitance measurements. Methods for monitoring mechanical events occurring within particulate solids systems in a dynamic state are described. The electrical conductance and capacitance characteristics of such systems, as they relate to the degree of bed dilation or expansion, extent of interparticulate contact, and intensity of particle motion, were studied and are discussed. To establish the potential of this approach, harmonically vibrated beds of monodispersed conducting spheres were used. A technique, based on the frequency modulation of standard FM broadcast frequency carrier signals, was developed to measure low and high frequency fluctuations in bed capacitance. The electrical conductance of these systems also was determined by both voltage drop and current flow methods. The experimental techniques developed are broadly applicable to various materials and modes of agitation or flow. They permit the evaluation of the time courses of both bed dilation and particle motion which, in turn, are known to determine of modify critically powder flow and mixing behavior.


Oxidative degradation of pharmaceutically important phenothiazines I: Isolation and identification of oxidation products of promethazine. The thermal degradation of promethazine in water in the presence of oxygen was studied. After degradation, the products were isolated by TLC. Identification was carried out by comparison of the isolated compounds with reference compounds. Melting points, spectral data, and polarographic and chromatographic behavior were compared. The following products were identified: 10-methylphenothiazine, phenothiazine, 3H-phenothiazine-3-one, phenothiazine 5-oxide, promethazine 5-oxide, 7-hydroxy-3H-phenothiazine-3-one, acetaldehyde, formaldehyde, and dimethylamine.


Oxidative degradation pharmaceutically important phenothiazines II: Quantitative determination of promethazine and some degradation products. Methods for the determination of promethazine and several degradation products, which can be used in kinetic studies, were developed. All determinations were carried out after isolation of the compounds by TLC. Promethazine was determined by oxidation with vanadyl sulfate in an acidic medium. The method was suitable for approximately 3 mg of the compound. 3H-Phenothiazine-3-one was determined spectrophotometrically at 492 nm in acetone. The compound could be determined in amounts of 30-40 microgram. Promethazine 5-oxide was determined spectrophotometrically using the acid dye method; 100-200 microgram could be determined. 7-Hydroxy-3H-phenothiazine-3-one could be determined spectrophotometrically at 600 nm after extraction of the other compounds from the solution. The medium had to be alkaline and contain water in a fixed ratio. The method was suitable for 15-30 microgram of the compound.


Determination of ethinyl estradiol in human urine by radiochemical GLC. A radiochemical GLC analysis was developed for 3H-labeled ethinyl estradiol in human urine. The technique was applied to the unconjugated and aglycone fractions of urine collected from women who were dosed orally with: (a) single capsules containing 2.0 mg of 3H-quinestrol (900 muCi) and 2.5 mg of unlabeled quingestanol acetate dissolved in sesame oil and (b) single tablets containing 100 microgram of 3H-quinestrol (86 muCi). Unconjugated ethinyl estradiol in Day 1 urine collections represented means of 0.02% of the high quinestrol dose and 0.12% of the low dose. Ethinyl estradiol glucuronide in the same collections represented means of 0.55% of the high drug dose and 1.35% of the low dose. The method could detect 1-ng quantities of 3H-ethinyl estradiol and 3H-quinestrol.


Spectrophotofluorometric analysis of 3',4',7-tris[O-(beta-hydroxyethyl)]rutoside in urine. A sensitive procedure was developed for 3',4',7-tris[O(beta-hydroxyethyl)]rutoside (I) in urine. The method is based on the fluoresence behavior of the I-aluminum complex in absolute methanol. This complex has activation and emission wavelengths of 420 and 480 nm, respectively. Optimum conditions for the reaction were investigated. The fluorescence was linear (r = 0.998) in the range of 0.1-4.0 microgram of I/ml. At concentrations below 0.1 microgram/ml, a shift in the emission wavelength was observed. Replicate studies (n = 9) of spiked urine samples, each containing 0.4 microgram of I/ml, showed good precision with a relative standard deviation of 0.009. Overall percent recovery (+/- SEM) from five urine samples was 99.5 +/- 1.34%. Following a single 500-mg po dose of I to individuals, only traces of I were found in the urine. However, beta-glucuronidase treatment of urine resulted in a total cumulative urine excretion of 26.53 mg of I after 78.6 hr.


Hepatic disposition and biliary excretion of the organic cations thiazinamium and thiazinamium sulfoxide in rats. The disappearance from plasma and the excretion in bile of the monoquaternary thiazinamium (administered as the iodide) and one of its polar metabolites, thiazinamium sulfoxide (also administered as the iodide), were studied in the rat after intravenous injection to obtain more information on hepatic transport mechanisms for organic cations. Both compounds exhibited an extremely rapid plasma disappearance, partly due to a rapid liver uptake. After injection of thiazinamium iodide and thiazinamium sulfoxide iodide, 36 and 47%, respectively, of the administered dose were excreted in bile during 1 hr. TLC analysis of the bile showed at least two unidentified polar metabolites in addition to thiazinamium sulfoxide and only 3.8% unchanged thiazinamium after administration of thiazinamium iodide. The same metabolites were found after injection of thiazinamium sulfoxide iodide. Urinary excretion and intestinal secretion were 18 and 12%, respectively, for thiazinamium sulfoxide iodide and 27 and 9%, respectively, of the dose for thiazinamium iodide. It is concluded that, in spite of unequal physicochemical features, thiazinamium iodide and thiazinamium sulfoxide iodide differ only slightly in hepatic uptake and metabolism.


Structure-toxicity relationships of iodinated aromatic carbonates and related compounds. Structure-toxicity relationships of iodinated aromatic carbonates, carbamates, and esters are presented. The approximate lethal dose of intraperitoneal injections in mice was used for toxicity determinations. Increasing the alkyl portion of the molecules reduced toxicity. m-Amino and m-acetamido groups also reduced toxicity. Carbonates were preferred X-ray contrast because of their low viscosity and more rapid elimination.


Quantitative GLC analysis of sterols in biological samples. A GLC method for the quantitative analysis of cholesterol, beta-sitosterol, stigmasterol, campesterol, 7-dehydrocholesterol, and dihydrocholesterol in biological samples was developed to screen serum and lipid extracts of heart and liver tissue for these sterols precisely. The addition of the internal standard, cholestane, at the beginning of the procedure led to a reduction in the required sample size and the elimination of several steps. The only critical measurements are those of the biological samples and internal standard.


Differential plus polarographic determination of submicrogram quantities of carmustine and related compounds in biological samples. A polarographic method was developed to determine the antineoplastic agent carmustine and other nitrosoureas, such as N-methyl-N-nitrosourea and N-cyclohexyl-N-nitrosourea, in biological fluids at levels well below 1 microgram/ml or g. The stability of carmustine in different media was investigated to prevent losses during administration or assay. Examples of nitrosourea determination in biological samples are given.


Synthesis of dextroamphetamine sulfate and methamphetamine hydrochloride from D-phenylalanine. Starting from D-phenylalanine, dextroamphetamine sulfate and methamphetamine hydrochloride were synthesized. The reaction sequence proceeds through three intermediates, in which the absolute configuration of the asymmetric carbon atom is changed but the relative configuration remains the same. Either product can be obtained from a common intermediate by altering the reductive conditions employed for the removal of a carbamate protecting group.


Solasodine stability under conditions of saponin hydrolysis. The extent of formation of solasodiene from solasodine upon treatment with hydrochloric acid under various conditions was determined. The diene formed was assayed by using the characteristic extinction at 236 nm. Diene formation was effected by the acid concentration and the boiling point of the solvent used. Optimal conditions for the hydrolysis of solasodine glycosides are suggested.


Analysis of cefazolin in serum or urine. A method was developed to determine cefazolin in serum or urine. The drug is extracted from serum or urine with ethyl acetate, separated by TLC, and determined by fluorescence quenching densitometry. The method was developed to study the pharmacokinetics of the compound in humans.


Inhibitors of polyamine biosynthesis VI: 2,5-Diamino-2-(cyanomethyl) pentanoic acid, a potential irreversible inhibitor of ornithine decarboxylase. (+/-)-2,5-Diamino-2-)cyanomethyl)pentanoic acid was obtained by the reaction of chloracetonitrile with the anion obtained by treatment of 3-(benzylideneamino)-2-piperidinone with sodium hydride, followed by hydrolysis in the presence of trifluoroacetic anhydride. The target compound was isolated as the monohydrochloride salt of the lactam. The compound was synthesized as a potential irreversible inhibitor of the enzyme L-ornithine decarboxylase by the mechanism generally known as suicide or Kcat inhibition. The synthesized compound produced no inhibition of the enzyme ornithine decarboxylase obtained from rat prostate gland. The inactivity of the target compound is attributed to the hydrophilicity of the cyanomethyl group.


Formation of thermally stable derivatives of chlordiazepoxide and its desmethyl metabolite for GLC. A derivatization procedure is described for the GLC determination of subnanogram amounts of chlordiazepoxide and nanogram amounts of N-desmethylchlordiazepoxide. Treatment with acetic anhydride at elevated temperature eliminates the highly polar and unstable nitrone group of these compounds by rearrangement and acetylation. The mass spectrometric fragmentation pattern of the acetyl derivatives is recorded and interpreted.


Effect of changes in intercompartment rate constants on drug removal during hemoperfusion. A computer simulation of the effect of changing intercompartment clearance rates on drug removal during hemoperfusion was undertaken. As intercompartment clearance slowed, the fall in plasma levels increased and postperfusion rebound increased, but the total drug removed decreased.


Factors affecting homogeneous precipitation of aluminum hydroxide gel. The variables affecting homogeneous precipitation in the hydrolysis of aluminum nitrate by sodium carbonate were studied. Increased temperature, decreased concentration of reactants, and decreased rate of addition of titrant favor conditions that achieve homogeneous precipitation. During acid hydrolysis, the nitrate anion was the major anion associated with the gel and only small amounts of carbonate were observed. It is recommended that homogeneous conditions be achieved during the precipitation of aluminum hydroxide gel to improve reporducibility.


Synthesis and antiulcerogenic evaluation of 2-(substituted phenylimino)-2H-quinolizines. The synthesis and antiulcerogenic evaluation of a series of 2-(substituted phenylimino)-2H-quinolizines are described. The most active compound, the 4-chlorophenylimido derivative, inhibited ulcer formation by 98%.


Assignment by 13-C-NMR spectroscopy of configuration at C-5 in 17 alpha-ethylestran-17 beta-ol, an impurity in the anabolic steroid ethylestrenol. The stereochemistry at C-5 in 17 alpha-ethylestran-17 beta-ol, found as an impurity in ethylesterenol, was assigned by 13C-NMR spectroscopy. The hydrogen atom attached to C-5 is in the alpha-configuration. Resonance assignments were confirmed by partial deuteration, off-resonance 13C-(1H)-decoupling, and comparison with model compounds.


Glycine fluxes in squid giant axons.

Glycine fluxes in squid giant axons. 1. The influx of a number of amino acids into squid giant axons has been studied. Particular emphasis has been placed on glycine and to a lesser extent glutamate. 2. To facilitate the study of the uptake of 14C-labelled amino acids a technique was devised in which the 14C taken up was measured directly in the intact axon with a glass scintillator fibre. This technique gave results similar to the usual technique in which the axoplasm was extruded for the assay of radioactivity. 3. The changes in glycine influx with extracellular glycine concentration suggests that two saturating components are present, one with high affinity and one with low affinity. 4. The glycine influx does not seem normally to be sensitive to the removal of extracellular sodium by replacement with choline. A Na-sensitive component appeared, however, after a period of immersion in artificial sea water. There was also some depression of glycine influx if Na were replaced by Li. 5. Glutamate uptake was greatly reduced by removal of extracellular Na in confirmation of work by Baker & Potashner (1973). Orthophosphate uptake was also greatly reduced by removal of extracellular Na. 6. CN reversibly inhibited glycine uptake after a delay, indicating that part of the uptake mechanism may require ATP. 7. 14C-labelled glycine injected into squid axons was found not to exchange to any serious extent with other compounds over periods of a few hours. The glycine efflux could therefore be studied. This was found to be markedly increased by extracellular glycine and by certain other neutral amino acids applied extracellularly in the artificial sea water. 8. The enhanced glycine efflux in extracellular glycine was not affected by ouabain and CN. 9. It is suggested that glycine uptake in squid axons involves two components. One is sensitive to CN and ouabain and probably derives energy from ATP break-down. The other is probably an ATP independent exchange diffusion system in which other amino acids as well as glycine can exchange for glycine. Both these systems are independent of extracellular Na concentration. A third Na-dependent system may appear under certain conditions.


The properties of surround antagonism elicited by spinning windmill patterns in the mudpuppy retina. 1. A truncated spinning  windmill pattern, illuminating only the receptive field surround, shown previously to activate amacrine cells, was used to elicit activity at the inner plexiform layer and to reduce the response of ganglion cells to test flashes at the receptive field centre. 2. The spinning windmill pattern reduced the ganglion cell response over its entire graded range by a fixed amount, and reduced the domain of test intensities required for graded activity. 3. The windmill effect was graded for windmill intensities over a domain of about 1000 to 1. The effect was constant for windmill velocities from about 0.05 to 0.5 rev/sec, and diminished beyond these velocities. 4. The windmill effect varied with windmill area as though each retinal point contributed to the reduction of ganglion cell response with a weighting which fell exponentially from the receptive field centre. The space constant was 0.35 mm. 5. The graded reduction in ganglion cell response was closely correlated with the graded increase in amacrine cell activity when the windmill intensity, area, and velocity were varied. It is inferred that amacrine cells, activated by the windmill, act to reduce the response range of the ganglion cells, primarily through a feed-forward pathway.


Kinetics of bleaching and regeneration of rhodopsin in abnormal (RCS) and normal albino rats in vivo. 1. Rhodopsin concentration has been measured by the method of densitometry in retinae of rats with inherited retinal dystrophy (RCS) raised in darkness and compared with that of normal rats similarly reared. 2. In both RCS and normal rats the fraction of rhodopsin bleached is always directly proportional to the photon content of the light, I.t, where I is the light intensity in effective quanta (500 nm) cm-2 sec-1 and t is the duration of the bleaching exposure in seconds. 3. Rhodopsin photosensitivity for bleaching is slightly higher in RCS rats than in normals (2.3 (10)-16 cm2 chromophore-1 compared with 1.3 (10)-16 cm2 chromophore-1). 4. Rhodopsin regeneration in the dark in both RCS and normal rats cannot be described by the kinetics of a simple monomolecular chemical reaction. 5. Following 5 min bleaches, the regeneration rate becomes slower as the preceding bleach is made stronger. Regeneration in the dark is significantly faster in the RCS rats than in the normal ones. 6. In normal rats, after a full bleach, rhodopsin regenerates back to the dark-adapted level within 3--4 hr. In RCS rats rhodopsin regenerates to reach a plateau level, below the previous dark-adapted level, that lasts for several hours. 7. The faction of total rhodopsin that can regenerate gradually declines with age until in 70 days old RCS rats no rhodopsin regeneration can be measured by the ensitometer. However, total rhodopsin density (fully bleached-dark-adapted) is still close to normal.


Dark-adaptation in abnormal (RCS) rats studied electroretinographically. 1. Electroretinogram (e.r.g.) responses recorded from dark-reared rats with inherited retinal dystrophy (RCS) showed progressive decline in b-wave ampliture and prolongation of the time to the peak of the b-wave with age when compared with records obtained from dark-reared normal albino rats. 2. Dark-adaptation was followed in RCS and normal rats by recording the light intensity needed to evoke a criterion e.r.g. response at different time intervals after bleaching and 90% of the rhodopsin. 3. In normal rats, dark-adaptation was governed by two mechanisms. The first 25--35 min of recovery was determined by cones. The second branch, determined by the recovery of rods, lasted for about 3 hr and proceeded along an exponential time course with time constant of 41.4 +/- 2.4 min (S.E. of mean). 4. In RCS rats, the time course of the dark-adaptation after a 90% bleach depended on age. In 25--30 day old rats the recovery curve had at least three breaks separating three different mechanisms. Rats, 35--40 days old, exhibited double exponential recovery curves, while 45--70 day old rats recovered along a single exponential curve similar in time course to the cone branch of dark-adaptation found in normal rats. 5. Action spectra obtained from RCS rats at different time intervals of the recovery curve showed that in young rats, 25--30 days old, small e.r.g. responses recorded before bleaching and at the end of the recovery period were determined by rhodopsin while those recorded during the first part of the recovery from 90% bleach were determined by a combination of rods and cones. In RCS rats of advanced age (45--70 days old), rhodopsin was the major contributor to the e.r.g. responses recorded either before bleaching or at the end of the recovery period. 6. The gradual deterioration with age of the e.r.g. in RCS rats cannot be explained by either the decrease in quantum catch due to the decrease in rhodopsin content or by the linear relationship between log e.r.g. threshold and pigment concentration. 7. Using estimates of rhodopsin density within surviving rods obtained from retinal densitometry, it was shown that in RCS rats where more than 30% of normal levels of rhodopsin was located within the functioning rods, the log intensity needed for a criterion e.r.g. response measured at the end of the recovery period from a 90% bleach was linearly related to the fraction of 'functional' rhodopsin. 8. No simple relationship between log e.r.g. threshold and rhodopsin concentration could be found during the course of recovery in the dark from a strong bleaching exposure in RCS rats of all ages.


Life time and elementary conductance of the channels mediating the excitatory effects of acetylcholine in Aplysia neurones. 1. The excitatory effects of acetylcholine (ACh) on an identified group of Aplysia neurones have been studied under voltage clamp in an attempt to measure the average life time. tau, of the channels opened by ACh and the elementary current, iel, flowing through these channels. The value of tau was determined both from spectral noise analysis and from current relaxations after voltage steps. Both methods lead to similar values. iel was calculated from the ratio of the variance of the ACh induced noise to the mean ACh induced current. 2. tau is increased by hyperpolarization, or by lowering the temperature. At 12 degrees C, tau = 27 msec AT -80 MV, tau = 17 msec at mV. tau is about 5 times smaller at 21 degrees C than at 12 degrees C. 3. iel increases linearly with hyperpolarization. At -80 mV, in Tris-buffered sea water, the mean value of iel was 0.8 X 10)-12) A at 12 degrees C. At 21 degrees C, this value was multiplied by 1.8. 4. The estimate of the ACh reversal potential Erev obtained by extrapolation of the relation between iel and the membrane potential V was + 30 mV. The estimate obtained from the analysis of the instantaneous current changes produced by voltage steps was + 15 mV. The difference between the two values appears to be due to the development of a K curent activated by the entry of Ca into the cell during the ACh response. This current introduces an error in opposite directions into the two estimates of Erev, which can therefore be assumed to be intermediate between + 15 and + 30 mV. An assumed value of + 20 mV yields an elementary conductance of 8 X 10(-12) omega-1 at 12 degrees C in Tris-buffered sea water. 5. The total ACh induced current measured in steady-state conditions increases more with hyperpolarization than does iel. The difference can be entirely accounted for by the fact that hyperpolarization increases tau. 6. When carbachol or tetramethylammonium is applied instead of ACh, the value of iel is identical to that found with ACh, but tau is slightly shorter (about 75%). 7. Inward ACh induced currents can still be observed in solutions where all Na has been replaced by Cs, Mg, or Ca. 8. iel increases when Na is replaced by Cs; it decreases when Na is replaced by Mg or Ca. In all Na-free solutions, tau is larger than in Na sea water: the lengthening of tau is largest for Ca sea water, smallest for Cs sea water. An interpretation of these changes of gamma is proposed. This interpretation may also account for the voltage sensitivity of gamma in normal sea water. 9. Partial replacement of NaCl by TrisCl strikingly reduces the ACh induced current. gamma is not modified by Tris substitution, and the reduction of the total current is entirely accounted for by a steep decrease of iel. Tris does not seem to affect the pore opening and closing processes, but to block the ACh controlled channel.


The mode of action of antagonists of the excitatory response to acetylcholine in Aplysia neurones. 1. The mode of action of various antagonists of acetylcholine (ACh) excitatory effects on Aplysia neurones was studied under voltage clamp. ACh was applied by iontophoresis whereas antagonists were applied in the bath. Tubocurarine and hexamethonium were the most thoroughly studied compounds. 2. The 'elementary current', calculated as the ratio of the variance of the ACh noise to the mean ACh induced current, was not modified by any of the antagonists tested. 3. The evolution of the ACh induced current after a voltage jump, which is normally described by a single exponential, was modified by all the antagonists tested. A common feature of the modified relaxations was the appearance, over a certain concentration range of the antagonist, of two successive and opposite exponential components. 4. The characteristics of the composite relaxations depend on the antagonist. For a given antagonist they vary with membrane potential, ACh concentration, and antagonist concentration. 5. The noise power spectra of the ACh induced current showed changes consistent with those of the relaxations. 6. In the absence of antagonists, the current induced by a steady application of ACh increases linearly with hyperpolarization. In the presence of antagonists, the I-V curve shows a marked curvature, indicating a proportionally larger reduction of the ACh response at more negative membrane potentials. 7. The voltage sensitivity of the blocking action of hexamethonium and decamethonium is noticeably stronger than that of monovalent antagonists. 8. A model is proposed which accounts for the observed effects. It assumes that the antagonists studied bind perferentially to the 'activated' ACh-receptor complex, and convert it to a non-conducting state. Kinetic constants can be calculated for this reaction; e.g. for curare, at 12 degrees C and -80 mV, the dissociation and association constants were estimated at 0.1 sec-1 and 4 X 10(5) M-1 sec-1. 9. Partial replacement of the extracellular Na by Tris modifies the relaxations observed in the presence of hexamethonium. Hexamethonium appears less effective in the presence of Tris, which supports the hypothesis that the binding site of the antagonists is linked to the ionic channel.


Noise and relaxation studies of acetylcholine induced currents in the presence of procaine. 1. The effects of procaine on the excitatory effects of acetylcholine (ACh) on Aplysia neurones were studied by analysing the current relaxations induced by voltage steps. Procaine was applied by perfusion and ACh was applied iontophoretically under two sets of experimental conditions designed to produce very different ACh concentrations at the membrane. 2. When ACh was applied at high concentration, the current relaxation following a hyperpolarizing step showed two components at procaine concentrations of about 2 X 10(-5) M; a fast increase was followed by a slow decrease. At high procaine concentrations (greater than 10(-4) M), the relaxation has only one component, corresponding to an exponential current decrease. 3. When ACh was applied at low concentrations, the current relaxation usually showed two components. At low procaine concentrations a fast increase was followed by a slower one; at higher procaine concentrations, a fast decrease preceded the slow increase. 4. All the results can be accounted for by assuming that procaine binds preferentially to the activated receptor-channel complex and converts it into a non-conducting complex. The association and dissociation constants were calculated to be (at 12 degrees C, -80 mV) 1.3 X 10(6) M-1 sec-1 and 10 sec-1.


Ionic currents in cultured mouse neuroblastoma cells under voltage-clamp conditions. 1. Ionic currents in differentiated cells of mouse neuroblastoma clone N1E-115 have been studied under voltage-clamp conditions. 2. Depolarizing voltage steps from a holding potential of -85 mV to levels more positive than -40 mV produced fast transient inward currents followed by delayed outward currents. 3. The fast inward current is carried by Na+: it is blocked by tetrodotoxin and is absent in Na+-free solutions. Its kinetic behaviour resembles that of the Na+ current in squid giant axon. A mean value of 85 mmho/cm2 was found for the maximum Na+ conductance (GNa).4. The delayed outward current is carried primarily by K+: it is blocked by externally applied tetraethylammonium (TEA, 15 mM) and has a reversal potential (mean -71 mV) close to the theoretical K+ equilibrium potential. Its instantaneous I--V curve is linear. By analogy with the formulation of Hodgkin & Huxley (1952c), the outward current can be described by IK = -GKn2(V--EK) where GK = 12 mmho/mc2. 5. During prolonged depolarizations the delayed outward current declines. This decline, which occurs in two phases, represents a partial inactivation of the K+ conductance. 6. A weak inward current with slow activation and inactivation kinetics appears in Na+-free solution containing 10 mM-Ca2+. It is activated at a membrane potential of -55 mV and reaches its maximum at -20 mV with a time to peak of about 10 msec. This current is tetrodotoxin-resistant, reversibly blocked by Co2+ (5mM) and is suggested to be carried by Ca2+. 7. An increase in the external divalent cation concentration results in a parallel shift of the steady-state I--V curve along the voltage axis in positive direction. The activation of delayed outward currents is suggested not to depend on Ca2+ influx. 8. It is concluded that separate voltage-dependent Na+, K+ and Ca2+ channels exist in the differentiated neuroblastoma membrane with kinetic and pharmacological properties similar to those observed in non-mammalian preparations.


Early development of visual cortical cells in normal and dark-reared kittens: relationship between orientation selectivity and ocular dominance. 1. 535 units were recorded in the primary visual cortex in twelve normally reared and fifteen dark-reared kittens aged between 8 and 50 days. These results were pooled with a previous study of 582 units recorded from thirty-five kittens reared in similar conditions. 2. These 1117 cells were classified into four functional classes of neurones: (a) visually unresponsive cells, (b) non-specific cells which were sensitive to spots or slits of light moving in any direction, (c) immature cells which were preferentially activated by a rectilinear stimulus but unselective regarding its precise orientation and (d) specific cells that appeared to be as selective for orientation as the simple or complex cells in the adult cat. 3. The results confirm that cells having the same orientation-specific response properties as adult cortical visual neurones are present in the earliest stages of post-natal development, independently of visual experience. However, to maintain and develop these specific cells after the third week of post-natal life, visual experience is necessary. 4. The ocular dominance of visual cells is not constant from the earliest stages of development. A significant increase in binocularly driven neurones occurs with age. 5. Before 3 weeks of age, whatever the rearing conditions, there are more specific cells coding horizontal and vertical orientations than those coding oblique orientations. These 'horizontal and vertical detectors' are preferentially driven by the contralateral eye. 5. After 4 weeks of age, specific neurones are found at all orientations in normally reared kittens. At this stage of development the ocular dominance is independent of orientation preference, of the functional class of neurones considered and of the rearing conditions. The proportion of binocularly driven cells is slightly below adult standard. 7. A hypothesis of differential plasticity is proposed: contralateral, monocular 'horizontal and vertical detectors' are supposed to be stable; they would remain so until they become binocular. Binocular cells, for which competition between two inputs occurs, are the labile units which can be despecified or specified under the control of visual experience.


Changes in plasma dopamine beta-hydroxylase activity induced by stimulation of the complete sympathetic outflow in the pithed rat. 1. Plasma dopamine beta-hydroxylase (DBH) activity, noradrenaline tissue levels and blood pressure were monitored in the pithed rat following electrical stimulation of the complete sympathetic outflow of the spinal cord. Stimulation at 10 or 30 Hz evoked marked increases in mean blood pressure which averaged 121 mmHg and were abolished by phenoxybenzamine. 2. Stimulation for 1 hr at 10 or 30 Hz did not change the noradrenaline content of the spleen nor the catecholamine content of the adrenals, but the heart noradrenaline content was doubled. 3. Plasma DBH activity was increased by 27% after 1 hr stimulation at 30 Hz, but remained unchanged after stimulation at 10 Hz, or at 30 Hz in phenoxybenzamine-treated rats. 4. We conclude that the pressor responses evoked by sympathetic nerve stimulation are due to the release of noradrenaline probably from adrenergic nerve terminals supplying the entire vasculature, and that acute alterations of circulating DBH activity are not dependent on the rate of catecholamine release evoked by direct electrical stimulation of sympathetic nerves in the whole pithed rat. The rat seems not to be a good model to study circulating noradrenaline and DBH levels as an index of exocytotic noradrenaline release from adrenergic neurones, and therefore of sympathetic activity.


Combined voltage-clamp and dialysis of Myxicola axons: behaviour of membrane asymmetry currents. 4. A new technique for the simultaneous internal dialysis and voltage-clamp of Myxicola axons is described and shown to control the internal composition of the axon adequately. 2. The permeability ratio (PNa/PK) of the sodium channel is 15.5 in axons dialysed with sodium-free solutions, somewhat higher than observed in perfused axons. 3. Asymmetry currents are easily recorded in dialysed Myxicola axons. At 4--5 degrees C for pulse durations sufficiently short Qon = Qoff with a maximum charge displacement of 10 nC/cm2 and half the charge being displaced by a step to -32 mV. Maximum slope of the Q(V) curve is 15 mV/e-fold change in charge displaced. The time constant tau on reaches a maximum of 325 microseconds at a potential of -23 mV. 4. The time course of sodium activation cannot be adequately accounted for by (Q/Q infinity) X using any single value of X for potentials between -40 and 40 MV. 5. Both asymmetry currents and INa are inactivated by the same amount when Myxicola axons are repetitively depolarized at frequencies from 0.1 to 50 Hz.


Sprouting and regression of neuromuscular synapses in partially denervated mammalian muscles. 1. The capacity of motor units to sprout after partial denervation and the ability of regenerating axons to suppress newly formed sprouts was examined in mouse skeletal muscle. Most experiments were performed on the peroneus tertius muscle which has 300 muscle fibres and eleven motor units ranging in strength from 1 to 35% of the total muscle tension. 2. Individual units, regardless of starting size, were able to sprout by up to 5 times their normal size following interruption of one of the two spinal roots innervating the muscle. In practive this resulted in muscles which had three or more units left intact becoming completely innervated again within 12 days. The majority of the sprouts probably innervated the old denervated end-plate sites. In the absence of re-innervation by the severed motor axons the sprouts persisted. In peroneus tertius about 60% of the sprouts giving rise to end-plates arose terminally and 40% collaterally. In soleus almost all the sprouts were terminal. 3. Re-innervation of the muscle by the severed motor axons occurred, starting from 14 days onwards after a crush injury, 19 days onwards after a cut. Re-innervation occurred even in muscles which presumably had no remaining denervated muscle fibres at the time regenerating axons reached the muscle. The re-innervating fibres grew to the original end-plate sites. 4. Following re-innervation the size of sprouted motor units apparently decreased. Thus, after re-innervation of muscles with three or more sprouted motor units, the sprouted units no longer caused contraction of all the muscle. However, the normal state of the muscle was not restored and the sprouted units continued to innervate more muscle fibres than normal, returning axons less than normal, and a small percentage of muscle fibres (ca. 10%) remained functionally innervated by axons of both sorts. 5. It is concluded that (i) in the mouse, axonal sprouting is a rapid and efficient process for restoring innervation; (ii) re-innervation of already innervated fibres can occur if the regenerating axons can return to existing end-plate sites; (iii) some of the redundant innervation is removed or repressed. 6. Possible mechanisms of competition between axon terminals are considered.


Influence of intermittent breathing on ventricular depolarization patterns in chelonian reptiles. 1. Alterations between two quite distinct patterns of epicardial depolarization are associated with the normal occurrence of intermittent lung ventilation in both lightly anaesthetized and unrestrained, conscious turtles (Pseudemys scripta) and tortoises (Testudo graeca). 2. During apnoea depolarization sweeps from the left to the right over the ventricular surface at a conduction velocity of 0.15 m/sec. With the onset of lung ventilation the direction of depolarization propagation over the ventricle is reversed, and conduction velocity in the epicardium falls to 0.09 m/sec. 3. Vagal stimulation and acetylcholine produce a shift from the apnoea to the breathing pattern of depolarization in intact animals, while vagal sectioning and atropine abolish all shifts. Acetylcholine reduces conduction velocity but has no effect on the strength of contraction of isolated cardiac muscle strips from turtle hearts. Changes between the two patterns of ventricle depolarization are likely produced by vagal innervation of the rudimentary conduction system of the chelonian heart. 4. Experimental induction of the depolarization pattern of the ventricle normally evident during lung ventilation produces an improved separation of oxygenated and deoxygenated blood within the anatomically undivided chelonian ventricle. It is suggested that changes in ventricle depolarization patterns during intermittent lung ventilation may be an active component of the cardiovascular responses controlling intracardiac blood shunting in reptiles.


Neurones in cat gracile nucleus with both local and widefield inputs. 1. Forty-three neurones were isolated in the cat gracile nucleus that could be driven by electrical stimulation of the ipsilateral forefoot or the contralateral hind food as well as having a normal low threshold localized receptive field on the ipsilateral hind limb. 2. Twenty-five (58%) of the cells were found to have axons projecting to the contralateral ventrobasal thalamus. 3. Most of the cells could only be driven from the 'widefield' receptive field on the forefoot or contralateral hindfoot by percutaneous electrical stimulation. 4. These results are discussed in the context of a model of the gracile nucleus in whick these occasional 'widefield' connexions are considered to be errors in connectivity which are not normally effective due to the patterns of excitation and inhibition in the normally functioning nucleus. 5. In this model, electrical stimulation is an abnormal type of stimulation that can drive cells through these erroneous connexions.


Asymmetry of the hexose transfer system in human erythrocytes. Experiments with non-transportable inhibitors. 1. The asymmetrical nature of sugar affinity for the hexose transfer system in human red cells has been demonstrated using purified 4,6-O-ethylidene-alpha-D-glucopyranose (ethylidene glucose) to inhibit the exchange of glucose, 3-O-methyl glucose and galactose. 2. The half-saturation concentration for ethylidene glucose inside the cell is estimated at ca. 110 mM whereas on the outside the value for exchange inhibition is ca 11mM. 3. The asymmetrics of affinities of two related non-transportable inhibitors 1,2-O-isopropylidene-D-glucofuranose and methyl-2,3-di-O-methyl-alpha-D-glucopyranoside have also been studied. 4. From experiments at varying concentrations and on theoretical grounds the half-saturation concentration for non-transportable inhibitors on the outside surface is shown to be over-estimated by measuring inhibition of exchange. In consequence the actual asymmetry of affinities may be greater than observed. 5. Experiments with ethylidene glucose also suggest that conformational changes redistributing components of the hexose transfer system between inward and outward facing modes may occur.


Asymmetry of the hexose transfer system in human erythrocytes. Comparison of the effects of cytochalasin B, phloretin and maltose as competitive inhibitors. 1. Cytochalasin B inhibits glucose transfer in human red cells. With glucose exit the inhibition is typically non-competitive, but hexose exchange is competitively inhibited. 2. At 16 degrees C the inhibitory constant for inhibition of 3-O-methyl glucose exchange is estimated at 1.1 X 10(-7) M while that for inhibition of glucose exit is 5.0 X 10(-7) M. 3. Uptake of labelled Cytochalasin B includes a saturable component which when correlated with the inhibition of exchange corresponds to a maximal binding of ca. 2.4 X 10(5) molecules per cell. 4. The kinetic parameters are compared with those for maltose (a competitive inhibitor acting on the outside only) and phloretin (an inhibitor acting both inside and out). 5. Kinetic evidence suggests that Cytochalasin B reacts with the inside of the hexose transfer system and that the anomalous inhibitory characteristics are due to the chemical asymmetry of the system. Independent evidence in support of this view is discussed.


Ionic currents in mammalian fast skeletal muscle. 1. The double sucrose-gap technique has been applied to rat skeletal muscle fibres to study the ionic currents under voltage-clamp conditions. 2. The iliacus muscle was found to be of 'fast' type according to the characteristics of the twitch generated by an action potential. 3. Micro-electrode measurements have shown that the intracellular potential is under good control even when an inward current develops. 4. The components of an equivalent circuit with two time constants have been estimated from the records of the capacitive current. 5. In rat muscle, between 15 and 21 degrees C, inward and outward currents are similar to sodium and potassium currents found in frog muscle at lower temperature (1--3 degrees C). 6. The inward current which depends on [Na]o and is abolished by tetrodotoxin is carried by sodium ions. Related to the mean value for the holding potential (-90.5 mV) this current reaches its maximum amplitude a +40 and +50 mV, reverses between +130 and +150 mV and its half inactivation occurs between +14 and +22 mV. The effect of low doses of tetrodotoxin suggests that two components participate in the sodium current. 7. The delayed outward current which shows inactivation is divided in two components: (i) the fast has a linear instantaneous current-voltage relation and differs from the fast component of frog muscle in that its equilibrium potential is more negative than the resting potential; (ii) the slow has a linear instantaneous current-voltage relation and the mean value for its equilibrium potential is 26 mV less negative than the resting potential. 8. Inward-going rectification is present in rat muscle.


The effect of ouabain on noradrenaline output from peripheral adrenergic neurones of isolated guinea-pig vas deferens. 1. The effect of ouabain on the noradrenaline output from peripheral adrenergic neurones has been studied using isolated guinea-pig vasa deferentia.2. Exposure to ouabain (10(-4)M) causes a gradual increase in the noradrenaline output. The effect occurs after a delay of 20 min and reaches a maximum during the period from 40-60 min.3. In the absence of external Ca, exposure to ouabain fails to produce an increase in the noradrenaline output. However, the reintroduction of Ca (2.5 mM) after a 1 hr exposure to ouabain in Ca-free media causes a rapid rise in noradrenaline output which reaches a maximum within the first 20 min.4. After a 1 hr exposure to a low concentration of ouabain (10(-5)M) the reintroduction of Ca is almost ineffective in increasing the noradrenaline output. When the concentration of ouabain is increased, the reintroduction of Ca becomes effective and causes a maximum effect with 10(-4)M ouabain. In the presence of a constant amount of ouabain (10(-4)M) the noradrenaline output induced by the reintroduction of Ca increases over the range 0.2-2.5 mM.5. In the presence of ouabain (10(-4)M) the Ca-induced noradrenaline output increases in a linear fashion with increasing Na concentrations from 25 to 143 mM, as long as NaCl is replaced with equimolar choline chloride or isotonic sucrose.6. In the presence of the lowest effective concentration of sodium (25 mM) the noradrenaline output induced by the reintroduction of Ca after a 1 hr exposure to ouabain is potentiated by LiCl. However, in the complete absence of Na(+) ions, there is no Li-dependent increase in the Ca-induced noradrenaline output.7. It is suggested that ouabain may cause an increase in noradrenaline output by an effect on the Na-dependent Ca influx system.


A transient release of potassium mediated by the action of substance P on rat parotid slices. Substance P (a peptide of eleven amino acids) caused a Ca-dependent release of K+ from rat parotid slices. The response to substance P differed from the alpha-adrenergic and the cholinergic responses in that it was transient, of smaller extent, and was not inhibited by phentolamine and atropine. Substance P caused little, if any, amylase secretion. Successive additions of the peptide to the slice system maintained the effect of C+ release indicating that the transient response to a single addition of the peptide was due to inactivation of substance P and not due to a decline in the response of the tissue.


The half-lives of angiotensin II, angiotensin II-amide, angiotensin III, Sar1-Ala8-angiotensin II and renin in the circulatory system of the rat. 1. Methods are described for estimating the half-life of angiotensin analogues and renin in the rat, from the time course of the blood pressure changes they evoke. 2. The following half-life values were measured: angiotensin II, 16 +/- 1 sec; angiotensin III, 14 +/- 1 sec; angiotensin II-amide, 15 +/- 1 sec; Sar1-Ala8-angiotensin II, 6.4 +/- 0.6 min; renin, 3.0 +/- 0.4 min. The distribution volume of angiotensin was found to be 18 ml./kg body wt. 3. It is inferred that the Asp1 residue does not reduce the rate of angiotensin II catabolism, but that substitution of this residue by sarcosine may inhibit catabolism while substitution by asparagine has no effect. 4. Five experimental criteria were identified which indicate that these methods give reliable estimates of the half-life. It is suggested that these results are more accurate than most previous half-life estimates. 5 When tachyphylaxis to angiotensin II-amide occurs, the pressor activity of the plasma is not reduced.


Effect of lower body negative pressure on human muscle nerve sympathetic activity. 1. Recordings of multi-unit sympathetic activity were made from muscle branches of the median nerve in five healthy subjects during application of lower body negative pressure (l.b.n.p.). Simultaneous recordings of arterial blood pressure were made in four subjects. The strength of the neural activity was quantitated by counting the number of pulse synchronous sympathetic bursts and their amplitudes in the mean voltage neurogram.2. The general appearance of the sympathetic activity in pulse synchronous bursts was similar during control periods and during l.b.n.p., but during l.b.n.p. there was always an increase in the number of sympathetic bursts and usually also in the mean voltage amplitude of the bursts.3. The probability of occurrence of a burst was correlated to different blood pressure parameters of individual heart beats and both during control periods and during l.b.n.p. there was regularly a close negative correlation to diastolic, a low correlation to systolic, an intermediate negative correlation to mean and a positive correlation to pulse pressures.4. The changes in arterial blood pressure during l.b.n.p. were small and in most cases statistically insignificant. The observed increases in the number of sympathetic bursts during l.b.n.p. were significantly greater than what could be expected on the basis of the blood pressure changes.5. The findings suggest that the reflex control from the arterial baroreceptors is maintained during l.b.n.p. but, since the increase of sympathetic activity during l.b.n.p. could not be explained by a change in stimulation of the arterial baroreceptors, influence from other receptor groups (presumably intrathoracic volume receptors) must also have occurred.


Factors affecting the utilization of ketone bodies and other substrates by rat jejunum: effects of fasting and of diabetes. 1. The utilization of some metabolic fuels has been measured in vitro in a preparation of rat jejunum to which the substrates were supplied via the perfusate flowing through the vascular bed. 2. In jejunum from 48 hr-fasted rats, the combined rates of utilization of 1 mM-acetoacetate and 2mM-D-3-hydroxybutyrate are similar to that of 7.5 mM-glucose. 3. The utilization of glucose is reduced in jejunum from animals fasted for 48 hr (45--63% reduction) and also from animals after 3--6 days of diabetes induced by streptozotocin (29% reduction). The addition of ketone bodies or of Na-oleate to the vascular perfusate does not reduce the utilization of glucose by the jejunum of either fed or 48 hr fasted rats. 4. Ketone bodies in the vascular perfusate reduce the oxidation of glucose by the jejunum of fed rats. In the jejunum of 48 hr-fasted rats, ketone bodies completely inhibit the oxidation of glucose so that all the glucose utilized by the tissue is converted to lactate. 5. The findings are discussed in relation to other work and it is concluded that substrates for the oxidative metabolism of the jejunum of fasted rats are likely to be ketone bodies, glutamine and fatty acids; at the same time the utilization of glucose is reduced and its oxidation completely abolished.


The response properties of the steady antagonistic surround in the mudpuppy retina. 1. The graded response of bipolar and ganglion cells to test flashes at the receptive field centre, spans only a limited portion of the test intensity domain: more than 90% of the graded response range can be elicited by test flashes differing by less than 100 to 1. 2. In the presence of steady illumination of the receptive field surround, the absolute levels of log test intensities required to elicit 90% of the graded response are increased (reset), but the relation in (1) still applies. 3. Each point in the receptive field surround, when illuminated, contributes to the resetting of the required centre test flash intensities by a weighing that decreases exponentially with distance from the centre. The space constant is 0.25 mm. 4. When the receptive field surround is fully covered with illumination, the centre test flash intensities required to elicit 90% of the response range must be increased by about tenfold for each tenfold increase in surround intensity over a surround intensity domain of about 1000 to 1. 5. The absolute levels of surround and required centre test intensities are inter-related: when the receptive field surround is fully covered, a test flash with intensity equal to that of the surround elicits a half-maximal response. Thus, in the presence of a full field background, the bipolar potential is held near its half-maximum response potential. 6. The graded resetting of the required centre test flash intensities is well correlated with the graded increase in horizontal cell response as the surround intensity and area are varied. It is inferred that units with response and receptive field properties like those of the horizontal cells, when driven by surround illumination, act as interneurones to reset the relationship between required test flash intensity and response in bipolar and ganglion cells.


Reversal of 6-hydroxydopamine-induced hypotension in the rat without activation of the renin-angiotensin system. 1. Male Wistar rats were housed individually in glass metabolic cages for 5 days during which time their food and water intakes reached plateau levels and they developed a significant systolic arterial hypertension. 2. After the initial 5-day period, systolic blood pressure and water and electrolyte balances were measured for 4 days before and 7 days after I.P. injection of 6-hydroxydopamine (100 mg/kg). In a separate experiment, plasma renin activity and glomerular filtration rate were measured 1 and 3 days after injection of 6-hydroxydopamine. Haematocrit, plasma volume, osmolality and plasma concentrations of glucose, sodium, potassium and protein were also measured at intervals after treatment. 3. Systolic blood pressure fell within 24 hr after treatment with 6-hydroxydopamine but was restored to pretreatment levels within 7 days. There was also a transient fall in glomerular filtration rate. 4. Plasma volume was significantly expanded on the first day after treatment and there was a fall in haemotocrit together with changes in plasma constituents indicative of a haemodilution, although plasma glucose levels were elevated. 5. There was a significant water retention on the third, fourth and fifth days after treatment but this was not accompanied by any measurable sodium retention and could not be attributed to renal compensation. Furthermore, plasma renin activity showed no significant change following 6-hydroxydopamine treatment. 6. It is suggested that the return of systolic blood pressure to pre-treatment levels was chiefly due to the return of vasoconstrictor function. The changes in plasma composition and volume were probably due to a fall in capillary hydrostatic pressure and an increase in the osmolality of extracellular fluid due to the elevated glucose levels.


The febrile responses in rabbits and rats to leucocyte pyrogens of different species. 1. We have investigated the effects on body temperature of rats and rabbits of leucocyte pyrogen derived from the blood of rat, rabbit, ox, pig and baboon. 2. In the rabbit intravenous injections (3.5 ml.) of solutions containing leucocyte pyrogen derived from ox, pig and rabbit blood produced fevers with short latencies; no fevers resulted from injections of similar solutions derived from rat or baboon blood. 3. In the rat intraperitoneal injections (2.0 ml.) of solutions containing leucocyte pyrogen derived from ox blood caused a fever, while pig leucocyte pyrogen produced a marked hypothermia. Neither rabbit, baboon, nor rat leucocyte pyrogen had any significant effect on rectal temperature of the rats. 4. Our results show that there is a variability of response in the rat and the rabbit to injection of leucocyte pyrogen of different species; leucocyte pyrogen may be species specific.


Effects of vasoactive intestinal polypeptide on intestinal absorption and blood flow. 1. Intestinal absorption and blood flow in anaesthetized dogs was determined after I.V. infusion of vasoactive intestinal polypeptide (VIP) (1.75-175 ng/min) to determine the contribution of the cardiovascular changes to transport. 2. 22Na and 3H2O were utilized to determine the unidirectional fluxes of Na and H2O from saline perfused through the ileal lumen and the clearances of 3H2O were used to determine total and absorptive site blood flow. 3. Net Na and H2O absorption were reversed to secretion by VIP at 175 ng/min due to a significant decrease in unidirectional absorptive fluxes and smaller increases in secretory fluxes. 4. Arterial pressure and absorptive site blood flow were reduced in proportion to the changes in Na and H2O fluxes. 5. Total and absorptive site blood flow decreased and the blood flow resistances increased. 6. Prior treatment with guanethidine to suppress sympathetic effects did not greatly affect the responses to VIP. Prior treatment with atropine to suppress cholinergic effects inhibited most of the effects of VIP. 7. Absorptive site blood flow was linearly related to absorptive fluxes of Na and H2O but with different slopes for results from atropinized dogs as compared to those from dogs given VIP alone or VIP plus guanethidine. 8. It was concluded that VIP reduces gut absorption through a generalized cardiovascular effect and also through a mechanism which depends on the release of ACh by the gut.


Antidipsogenic effect of intracranial injections of substance P in rats. 1. The effect on water intake of intracranial injections of Substance P was studied in the rat. 2. Substance P strongly inhibited drinking elicited by Angiotensin II, Carbachol water deprivation or sodium chloride load, in that order. 3. The peptide was particularly effective when water intake was induced by injections of Angiotensin II into the preoptic area. In these experiments, drinking was inhibited by doses of Substance P as low as 1 ng. 4. The results suggest that in the rat Substance P may play a role in the brain in the regulation of water intake, acting as a thirst inhibitor.


Sensitization and habituation of dorsal horn cells in cats. 1. Extracellular recordings were obtained from spinal dorsal horn cells in acutely spinalized cats anaesthetized with sodium pentobarbitone. The dorsal horn cells studied responded to ipsilateral tactile stimulation of the central pad of the hind foot. Eleven short latency dorsal horn cells driven by electrical stimulation of the foot pad were studied intensively; these short latency dorsal horn cells all discharged within 1.5 msec of the arrival of an afferent volley at the dorsal root entry zone. Electrode tip sites were histologically verified to lie near the medial border of the dorsal horn in the seventh lumbar segment, in Rexed's laminae III and IV. 2. Electrical stimulation of the foot pad not only activated the dorsal horn cells studied, but also produced a reflex discharge which was monitored by recording from the ipsilateral first sacral ventral root, which had been sectioned intradurally and mounted on bipolar recording electrodes. Repeated stimulation of the foot pad at moderate intensities and frequencies (e.g. three times threshold for the ventral root response at 5 Hz) typically produced a transitory increase in the magnitude of the reflex discharge (sensitization) followed by a marked waning of the reflex magnitude (habituation). Within a few minutes following cessation of stimulation, the reflex magnitude returned to its prestimulation value. During repeated bouts of five hundred stimuli each, at frequencies from 1.0 to 10.0 Hz, and intensities 1.5-10.0 times reflex threshold, the firing pattern of a short latency dorsal horn cell was monitored along with the magnitude of the ventral root response. Changes in response patterns of the dorsal horn cells were compared to those of the reflex discharges. 3. The short latency dorsal horn cells fell into two distinct patterns of response. The firing pattern of six dorsal horn cells paralleled the response pattern of the reflex discharge; when the reflex increased in magnitude, each of these dorsal horn cells increased in number of responses per stimulus; when the reflex discharge decreased in magnitude, each of these dorsal horn cells decreased the number of responses per stimulus. These dorsal horn cells were characterized by the following: intermediate thresholds to tactile stimulation, comparable to that of the reflex discharge itself; relatively low numbers of responses per stimulus (mean: 1.3/stimulus); low spontaneous activity rates (once per 10 sec or less). 4. The firing patterns of the other class of short latency dorsal horn cells did not parallel the response pattern of the reflex discharge; these showed only a rather rapid, though moderate, decrease in responses per stimulus over the entire range of intensities and frequencies tested. These five dorsal horn cells were characterized by the following: thresholds of tactile stimulation considerably below that of the reflex discharge itself; bursts of responses following each stimulation (mean: 7...


The pattern of stimulated breathing in man during non-elastic expiratory loading. 1. The pattern of breathing expressed as the relationship between tidal volume and the components of breath interval was studied in normal subjects during CO2 rebreathing, both under unloaded conditions and following the introduction of a non-elastic expiratory resistance. 2. Under unloaded conditions end-expiratory thoracic gas volume (FRC) measured plethysmographically did not alter during the course of the rebreathing experiment. Maximum tidal volume attained (VT, max.) was equal to or just less than the inspiratory capacity of the subject measured at rest. Expiratory reserve volume was not encroached upon even at the highest levels of ventilation. 3. Under loaded conditions the pattern of breathing was altered. VT, max. was diminished in all subjects and FRC showed a progressive rise during rebreathing which was proportional to the resistive load afforded by the artificial resistance. There were no consistent differences in the components of breath duration either at rest or on maximal ventilatory stimulation between the loaded and unloaded states. 4. It is suggested that the pattern of breathing adopted under conditions of expiratory non-elastic loading is influenced more by the secondary effects of breathing at an elevated lung volume, than by the effect of the non-elastic load per se.


Conductance increases produced by glycine and gamma-aminobutyric acid in lamprey interneurones. 1. Conductances of individual neurones in the isolated lamprey spinal cord were measured with separate intracellular electrodes for recording potentials and for passing current pulses during application of glycine or GABA (0.1-1.0 MM) in Ca-free bathing fluid. Large, reversible increases in conductance were produced in giant interneurones by both amino acids, but Müller axons and sensory dorsal cells were unaffected. 2. Conductance increases produced by glycine and by GABA were selective for Cl. Both conductance increases were linearly related to external Cl concentrations and repeated exposure to the amino acids in Cl-free fluid progressively reduced the conductance increases to less than 1% of their values in normal Cl. 3. Strychnine was a competitive antagonist of glycine, while GABA was antagonized competitively by bicuculline and non-competitively by picrotoxin. 4. The sensitivity of giant interneurones to glycine and GABA increased at low temperatures, in Na-free fluid, and after repeated exposure to the amino acids. Sensitization may have been produced by inhibition of uptake mechanisms for glycine and GABA in the spinal cord. 5. Discharges of interneurones recorded extracellularly were inhibited by bath-applied glycine and GABA, but directly elicited action potentials of axons were unaffected. Strychnine and Cl-free fluid in the presence of Ca produced seizures in lamprey spinal cord. 6. The conclusions of these experiments are that different receptors for glycine and for GABA are present on giant interneurones, that glycine is the better candidate for an inhibitory transmitter in the lamprey spinal cord, and that GABA produces effects similar to those which have been well studied in arthropod muscle.


Mechanism of slow discharges of sheep carotid artery. 1. Single and double sucrose-gap methods were used to follow changes in membrane potential and conductance of smooth muscle of sheep carotid arteries. 2. K depolarization induced discharges lasting several seconds in various solutions containing Mn, or Mg, or Ca and procaine, sometimes with no other added cations and with only sulphate or ethanesulphonate as anions. 3. Membrane conductance usually rose substantially above resting level in the early part of these discharges, but fell towards resting level during the later part. 4. Large depolarizing currents caused porportionately less voltage displacement than small currents, and reduced voltage displacements induced by superimposed current pulses, even in Cl and HCO3 free solutions, indicating activation of K conductance by depolarization. 5. When procaine was added, or Ca replaced by Mn or Mg, conductance was lower both at rest and on depolarization, and the increase on depolarization often underwent slow inactivation which it never did in simple Ca containing solutions. 6. The results indicate that a slowly inactivated inward current dependent on Ca, Mn or Mg was largely responsible for the slow discharges, and that procaine, Mn or Mg assisted the discharges by reducing the normal rapid outward-rectifying K conductance and allowing it to inactivate on prolonged depolarization.


Intracellular electrical activity of canine and human gastric smooth muscle. 1. Intracellular recordings were obtained from circular smooth muscle fibres of the canine fundus, corpus, antrum and pylorus as well as from the human corpus and antrum. 2. In the canine stomach, all regions of the stomach except the fundus exhibited spontaneous action potentials. 3. The spontaneous action potential consisted of an upstroke potential and a plateau potential. 4. There were regional differences in the configuration of the plateau potential. Corporal and antral smooth muscle did not normally spike during the plateau potential whereas terminal antral and pyloric muscle usually showed spikes on top of the plateau potential. Near the intermediate sphincter, there was a zone of transition in which oscillations in potential of variable amplitude were superimposed on the plateau potential. 5. The configuration of the action potential of the human stomach was similar to the configuration of the canine action potential when the same region of the stomach was compared. 6. The ionic dependence of the plateau potential was studied in canine stomach in an area where neither oscillations nor spikes occurred. 7. In calcium-free solution, all spontaneous activity stopped. D600 selectively suppressed the size of the plateau potential. 8. Sodium-deficient solution reduced the size of the plateau potential. 9. These results suggest that both calcium and sodium may be involved as current carriers in the generation of the plateau potential.


Modulation of canine antral circular smooth muscle by acetylcholine, noradrenaline and pentagastrin. 1. The effects of acetylcholine, noradrenaline and pentagastrin on the action potential of canine antral circular muscle were determined using the intracellular micro-electrode technique. 2. Acetylcholine increased the amplitude and duration of the plateau potential of the action potential. Since these effects were blocked by atropine but not by hexamethonium, the effects of acetylcholine were on muscarinic receptors, probably located on the smooth muscle cell. 3. Pentagastrin 2 x 10(-10) M increased the size of the plateau potential and the frequency of the action potential; pentagastrin 1 x 10(-9) M increased the frequency of the action potential complex and produced a marked diastolic depolarization between action potentials. The effect on the size of the plateau potential was biphasic. The amplitude and half-time duration of the plateau potential increased in the first 3 min, but thereafter, during steady-state conditions, they were the same as or slightly greater than those obtained in Krebs solution. 4. All the effects produced by pentagastrin were due to a direct action on the smooth muscle cell. 5. Noradrenaline decreased the size of the plateau potential but increased its frequency; high concentrations (greater than 10(-5) M) additionally produced a diastolic depolarization between action potentials. These effects were mediated primarily by alpha-adrenoceptors presumably located on the smooth muscle cell. 6. It was concluded that the substances studied primarily alter the size of the plateau potential in antral circular muscle. Since phasic contractions are associated with the plateau potential, it is suggested that agents which increase the size of the plateau potential increase the force of the contraction whereas agents which decrease the size of the plateau potential have the opposite effect.


Ouabain and regulation of cellular volume in freshly prepared slices of rabbit renal cortex. 1. Changes in the water and ion contents of rabbit renal cortical slices, which had been bathed, immediately after slicing, in air-equilibrated media at room temperature ('freshly prepared slices'), were followed during subsequent incubation at 25 degrees C in oxygenated media of the same composition as the initial bathing medium. 2. In comparison with conventional 'equilibrated' slices (slices incubated at 25 degrees C in oxygenated ordinary medium immediately after slicing) these 'freshly prepared' slices had increased tissue water, sodium and chloride contents and low tissue potassium contents. 3. Control freshly prepared slices incubated at 25 degrees C in oxygenated ordinary medium recovered within 4 min to the tissue water content that is usual for rabbit renal cortical slices incubated in oxygenated ordinary medium at 25 degrees C. Freshly prepared slices incubated at 25 degrees C in oxygenated media containing 1 mM-oubain took 75 min or more to recover to this usual tissue water content. Thus the presence of 1 mM-oubain in both bathing and incubation media produced a marked inhibition of the volume recovery observed when freshly prepared slices are incubated in oxygenated media at 25 degrees C. 4. Reduction of the ouabain concentration reduced the inhibition of cell volume recovery. 5. Replacement of medium glucose by 3-O-methylglucose did not inhibit cell volume recovery in the absence of ouabain. 6. The oxygen consumptions of slices that were bathed and incubated in 1 mM-ouabain media were similar to those of slices initially bathed and incubated in ouabain-free media and then incubated in ouabain media. Thus the effect of ouabain in inhibiting cell volume recovery was unlikely to be secondary to inhibition of cellular energy production. 7. The tissue potassium content of slices incubated aerobically in 1 or 10 mM ouabin fell to an apparently stable value of approximately 100 m-mole/kg dry wt., which corresponds to a calculated concentration ratio of 10:1 across the cellular membrane, suggesting that some residual potassium uptake may still have been occurring. 8. These results indicate that in freshly prepared rabbit renal cortical slices ouabain-sensitive mechanisms play a major role in cell volume recovery. They are not in accord with the postulate that renal cortical cells possess a separate ouabain-insensitive mechanism regulating cell volume.


Effects of ouabain and potassium-free media on cellular volume regulation in rat renal cortical slices. 1. Changes in water and ion contents of rat renal cortical slices were followed over 4 hr incubation at 25 degrees C in potassium-free media and media with ouabain. Slices that lost potassium more rapidly swelled earlier. 2. Greater swelling with lower tissue potassium contents was also observed in slices preincubated and leached in potassium-depleting media and in slices incubated in lithium medium with 10 mM-ouabain and in potassium-free lithium medium with 10 mM-ouabain. 3. This swelling associated with potassium depletion was also observed when slices were incuabted in media where the substrate was malate in place of glucose. 4. No distinct fall in the oxygen consumption of potassium-depleted slices was detected during the period in which slices commenced swelling. 5. These results suggest that the swelling observed in potassium-depleted rat renal cortical slices is unlikely to be secondary to inhibition of cellular energy production.


Evidence of active sodium transport in the visceral yolk sac of the rat in vitro. 1. Na transport has been studied in the isolated rat visceral yolk sac from day 17.5 of gestation to term. 2. The transepithelial potential difference (p.d.) and the short circuit current (s.c.c.) in the isolated yolk sac were found to vary with gestational age, with peak values at day 19.5. The maximal p.d. and s.c.c. were 3.85 +/- 0.32 mV (the fetal side positive) and 19.5 +/- 5.3 microamperemeter cm-2 respectively. 3. Simultaneous determination of the two-way Na+ flux and the s.c.c. revealed a preferential active movement of Na in the maternal to fetal direction. The net flux was found to be 50% higher than the s.c.c. 4. Both the p.d. and the s.c.c. were found to be reduced by cooling and by the uncoupling agent 2,4-dinitrophenol. 5. The s.c.c. altered in a curvilinear fashion with the Na+ concentration in the bathing solution, with an apparent Km of about 20 mM-Na+. Removing Cl ions from the bathing solutions had no effect on the p.d. and s.c.c. 6. Addition of amiloride (10(-4) M) to either side of the visceral yolk sac had no effect on the s.c.c. but application of ouabain (10(-5) M) to the fetal side caused a profound fall in the s.c.c. 7. The possible physiological role of this active Na transport by the visceral yolk sac in the formation of amniotic fluid is discussed.


Properties of intraoral mechanoreceptors represented in the mesencephalic nucleus of the fifth nerve in the cat. 1. The activity of neurones in the mesencephalic nucleus of the fifth nerve that respond to forces applied to the teeth were recorded using extracellular microelectrodes; the properties of these neurones have been studied. 2. Electrophysiological evidence consistent with the view that primary afferent intraoral mechanoreceptor fibres have their cell bodies in the trigeminal mesencephalic nucleus is presented. 3. Two groups of intraoral mechanoreceptor neurones were found. The first group, the periodontal mechanoreceptor neurones, which have been described by previous workers, responded to electrical stimulation of the ipsilateral superior or inferior dental nerves and to forces applied to single teeth in the ipsilateral maxilla or mandible respectively. The response characteristics of the mesencephalic periodontal mechanoreceptor neurones differed in two respects from those observed in peripheral nerve studies by previous workers: (a) there were no spontaneously active neurones, and (b) there were no neurones that responded for over 10 sec to a sustained application of a suprathreshold mechanical stimulus to the teeth. The second group, not described before, responded to electrical stimulation of the ipsilateral palatine nerve, and responded to forces applied to all the teeth in the maxillary arch, both contralateral and ipsilateral as well as to forces applied to the nose and hard palate. The site of these receptors is unknown. They have been termed 'Type P' intraoral mechanoreceptors. 4. The recording sites of both the periodontal and Type P mechanoreceptor neurones were all situated in the caudal part of the mesencephalic nucleus of the fifth nerve.


Inhibitory action of dopamine on cat carotid chemoreceptors. 1. The influence of some drugs which affect the dopaminergic system was studied on chemosensory responses to dopamine (DA), acetylcholine (ACh), sodium cyanide NaCN) and hypoxia during experiments on pentobarbitone anaesthetized cats in which chemoreceptor activity was recorded from the peripheral end of a sectioned sinus nerve. 2. Spontaneous chemosensory activity was inhibited in a dose-dependent manner by DA (0.5-5 microgram, I.A.). Higher doses (10-50 microgram) caused a delayed increase in discharge and were associated with inconsistent inhibitory responses. 3. The DA antagonist alpha-flupenthixol (0.2 mg/kg, I.A.) blocked the inhibitory response to DA without affecting either the spontaneous discharge frequency or the response to ACh. The effect of NaCN was potentiated, and during hypoxia chemoreceptor activity increased more rapidly, although the maximum frequency attained was not appreciably different from control values. Similar results were obtained with haloperidol (0.5 and 1.0 mg/kg, I.V.). 4. Higher doses of alpha-flupenthixol (0.5-1.0 mg/kg, I.A.) increased spontaneous chemoreceptor activity, but this was regarded as a non-specific effect of the drug since at these doses the inhibitory effect of 5-hydroxytryptamine (5-HT) was also abolished. 5. The animals were exposed to alternate periods of hypoxia and hyperoxia following administration of the tyrosine hydroxylase inhibitor alpha-methyl p-tyrosine (AMPT, 0.2-10 mg/kg, I.A.). The inhibitory response previously evoked by amphetamine was abolished, and electron microscopic studies showed a great reduction in the number of dense-cored granules, both of which suggested that DA levels in the carotid body had been substantially reduced. Responses to NaCN and hypoxia were slightly potentiated following AMPT, but neither spontaneous activity nor the response to ACh was affected. 6. Apomorphine (0.05-0.2 mg/kg, I.A.) inhibited the chemoreceptor discharge for up to 45 min, an effect which was antagonized by alpha-flupenthixol (0.2 mg/kg, I.A.), implying it resulted from DA receptor stimulation. Although responses to NaCN, hypoxia and higher doses of ACh were reduced following administration of apomorphine, the reduction was not very marked. 7. These results are not compatible with the theory of Osborne & Butler (1975), that in normoxia DA is tonically released in the carotid body and suppresses spontaneous chemosensory activity. 8. It is concluded that DA modulates chemosensory activity by influencing the rate of increase in discharge, without affecting maximum discharge frequency. The mechanism whereby DA is released in response to increased chemosensory activity remains to be established.


On the receptors involved in the nervous control of salivary secretion by Nauphoeta cinerea Olivier. 1. It has been shown that the isolated salivary glands of Nauphoeta cinerea Olivier produce fluid secretion in response to nerve stimulation or bath applications of dopamine, noradrenaline, adrenaline and 5-HT. These catecholamines, of which dopamine is the most potent, evoked maximal responses matching that to nerve stimulation whereas 5-HT was less effective. 2. The receptors combining with 5-HT could be distinguished from those for the catecholamines and the transmitter at this salivary neuroglandular junction. 3. The results of experiments where glands were stimulated by dopamine in the presence of noradrenaline or adrenaline suggested that there are receptors with specific binding sites for dopamine. 4. The effects of several antagonists (Ginsborg, House & Silinsky, 1976) of the hyperpolarizing responses from acinar cells to nerve stimulation and the above agonists have been examined. Phentolamine reversibly suppressed the secretory responses to these stimuli whereas methysergide had no effect and ergometrine elicited fluid secretion in a dose-dependent manner.


Mammary function and its control at the cessation of lactation in the goat. 1. The changes in mammary function following cessation of milking during declining lactation have been studied in conscious goats. 2. No significant changes in the rate of milk secretion, mammary blood flow or metabolism occurred in the first 24 h after cessation of milking. After then, secretory rate, mammary blood flow, oxygen consumption, glucose uptake and acetate uptake decreased markedly over the next 3 days. Up to the time of maximum udder distension on day 3, there were no major changes in milk composition. 3. It was found that the rate of milk secretion declined when the calculated pressure within the alveoli became positive. 4. After 3 days, mammary volume and intramammary pressure decreased, and the composition of milk changed slowly to resemble that of extracellular fluid, i.e. [Na+], [Cl-], [HCO3-] and pH increased while [K+], [lactose] and [citrate] decreased. During this time [lactose] and [K+] were positively correlated, and [lactose] and [Na+], and [lactose] and [Cl-] negatively correlated. 5. It is suggested that the changes in milk composition, the decreases in mammary volume and in intramammary pressure after day 3 are due to the loss of integrity of the mammary epithelium. 6. By about 7 weeks after the cessation of milking the udder volume was less than the empty udder volume before milking was stopped, indicating a loss of mammary tissue as well as the resorption of fluid. 7. When milking of an autotransplanted gland was stopped, while milking of the control gland in situ was continued, the rate of secretion in the transplant fell while that of the control did not change. 8. In goats milked normally but in which a volume of isosmotic lactose equal to the volume of milk removed at that milking was injected into the lumen of one gland at each milking, the rate of secretion of that gland, but not that of the other, decreased.


Branched afferent nerves supplying tooth-pulp in the cat. 1. Recordings have been made from nerve terminals in canine and third incisor teeth of cats. 2. Ninety-three tooth-pulp units in ten cats could be excited either by mechanical or electrical stimulation of adjacent mucous membrane or by electrical stimulation of the pulp of a nearby tooth. 3. Section of the trigeminal nerve centrally did not abolish these responses. 4. Results for twelve out of thirteen units tested with collision techniques indicated that the nerves were branched.


Evoked depolarizing and hyperpolarizing potentials in reticulospinal axons of lamprey. 1. Intracellular recordings were made from reticulospinal axons (Müller axons) in the lamprey spinal cord. Electrical stimuli applied to the spinal cord surface elicited depolarizing and hyperpolarizing 'synaptic-like' potentials in Müller axons. The physiological basis of these evoked potentials was investigated. 2. The depolarizing response was not the result of increased extracellular K, as demonstrated by the constancy of the undershoot of the axonal action potential during the depolarization, by the failure of the response to summate during repetitive stimulation and by the failure of the response amplitude to vary as predicted when the [K] of the saline was varied. 3. When the membrane potential of the axon was varied by passing current through a micro-electrode, the amplitude of the depolarizing evoked potential decreased at membrane potentials positive to the resting potential and increased up to a maximum when the axon was hyperpolarized by about 10 mV. The extrapolated 'reversal potential' for the depolarizing response was about 15 mV positive to the normal -80 mV resting potential of the axon. However, the amplitude of the response did not continue to grow with hyperpolarizations greater than 10 mV, and, thus, the response did not behave as would a normal depolarizing synaptic potential. 4. Müller axons make numerous electrical synapses with spinal motoneurones and interneurones, and this suggested that the depolarizing response might be a coupling potential. In agreement with this idea, quantitative correspondence was found between changes in the input resistance of the axon produced by the depolarizing response and the variation in the depolarizing response amplitude. Thus, although the depolarizing response mimicked in some ways the behaviour of an excitatory synaptic potential, we conclude that it is a coupling potential. 5. The hyperpolarizing response also appeared to be a coupling potential. Its amplitude was not changed by hyperpolarizing the axon up to 30 mV and was decreased by depolarizing the axon sufficiently to decrease the axon's input resistance. 6. It is proposed that both depolarizing and hyperpolarizing evoked potentials in lamprey Müller axons are a result of passive flow of current from cells activated by the spinal cord stimulus and electrically coupled to Müller axons.


An intracellular study of dendrodendritic inhibitory synapses on mitral cells in the rabbit olfactory bulb. 1. In the rabbit olfactory bulb, intracellular potentials were recorded from mitral cells and from neurones in the granule cell layer (g.c.l.) following lateral olfactory tract (l.o.t.) stimulation. 2. Most recordings from mitral cells showed large (5-21 mV) and prolonged (60-650 msec) i.p.s.p.s subseuqent to the antidromic spikes. These i.p.s.p.s decreased in amplitude and then reversed in polarity by progressive increase in hyperpolarizing current applied intracellularly. They were accompanied by a prominent and long lasting (up to 100 msec) conductance increase of the mitral cell membrane. 3. Reversed i.p.s.p.s of mitral cells having quite different time courses from the original hyperpolarizing i.p.s.p.s suggest that the inhibitory synapses are widely distributed on the soma and dendrites. 4. E.p.s.p.s could be recorded from g.c.l. cells whose onset latency was approximately 0.6 msec shorter than that of mitral cell i.p.s.p.s. Comparison of the behaviour of e.p.s.p.s in g.c.l. cells and that of mitral cell i.p.s.p. under various conditions of l.o.t. stimulation suggests that these g.c.l. cells are the inhibitory interneurones mediating mitral cell inhibition. 5. The results support the hypothesis of dendrodentritic pathways for activation of granule cells and subsequent inhibition of mitral cells.


Activation and inhibition of olfactory bulb neurones by anterior commissure volleys in the rabbit. 1. In the rabbit olfactory bulb, analysis has been carried out on intracellular potentials recorded from mitral cells and neurones in the granule cell layer (g.c.l. cells) in addition to the extracellular field potentials in the olfactory bulb elicited by anterior commissure (a.c.) stimulation. 2. Most mitral cell recordings showed i.p.s.p.s with latency of 7-11 msec following a.c. stimulation. These i.p.s.p.s were similar to those evoked by lateral olfactory tract (l.o.t.) stimulation in their sensitivity to internally applied current and showed asymmetrical reversal during application of the hyperpolarizing current. 3. Volleys in the a.c. elicited e.p.s.p.s in type 1 g.c.l. cells whose characteristics were in agreement with those of inhibitory interneurones inferred from the analyses of mitral cell i.p.s.p.s. It has been suggested that these type 1 g.c.l. cells may be the common inhibitory interneurones (presumably granule cells) mediating both a.c.-evoked and l.o.t.-evoked i.p.s.p.s in mitral cells. 4. Conditioning a.c. stimulation depressed the test l.o.t.-evoked i.p.s.p.s in mitral cells and test l.o.t.-evoked e.p.s.p.s in type 1 g.c.l. cells. These observations are in good agreement with the hypothesis that l.o.t.-evoked i.p.s.p.s are mainly mediated by the dendrodendritic reciprocal synapses between mitral cell dendrites and peripheral processes of granule cells. 5. The results are discussed in relation to the inhibitory mechanisms controlling mitral cell activity in the olfactory bulb.


Albumin permeability of the peritubular capillaries in rat renal cortex. 1. Two series of experiments were carried out to determine the permeability of the renal cortical peritubular capillaries to albumin under control conditions in the concentrating kidney and after an infusion of hypo-osmotic fluid amounting to 6% body weight. 2. In the first series of these experiments the turnover of the interstitial albumin pool of the renal cortex was studied. Specifically, the mean transit time of albumin molecules from arterial plasma to renal lymph was measured in nine rats of each group. Mean values of 39.0 +/- 2.8 and 30.6 +/- 2.2 (S.E. of mean) min were found for the control and infused groups, respectively. 3. In the second series of experiments the interstitial distribution volume of plasma albumin in renal cortex was determined in twenty-three control and twenty-two infused rats. Mean values of the extravascular distribution volumes were 1.66 +/- 0.21 and 1.37 +/- 0.18 (S.E. of mean) microliter/100 mg tissue, respectively. 4. The unidirectional clearance of albumin from the capillary to the interstitium in the control and infused groups, respectively, was calculated to be 7.1 +/- 1.0 and 7.5 +/- 0.9 (S.E. of mean) ml. sec-1 10(-4) in 100 g cortical tissue. 5. For the reabsorbing surface of the peritubular capillaries in the renal cortex, a lower bound was calculated for sigma, the reflexion coefficient of albumin. The reflexion coefficient was found to be higher than 0.998 under both experimental conditions.


Effects of acetylcholine and parasympathetic nerve stimulation on membrane potential in quiescent guinea-pig atria. 1. In quiescent preparations of guinea-pig right atria the action of ACh applied in the superfusion medium or released from parasympathetic nerve fibres was investigated by membrane potential measurements. 2. ACh-containing solutions induced hyperpolarizations which did not show desensitization. 3. The relationship between hyperpolarization amplitude (corrected for non-linear summation) and ACh concentration could formally be described by simple saturation kinetics with an apparent dissociation constant KACh = 1.3 x 10(-6) M. 4. Stimulation with impulses subthreshold for myocardial excitation induced a membrane hyperpolarization by releasing ACh from post-ganglionic parasympathetic nerve fibres. 5. The hyperpolarization reached maximum about 1 sec after the onset of stimulation. This slow development of hyperpolarization cannot be accounted for simply by diffusion from the site of release to the receptor site. 6. The hyperpolarization declined exponentially with a time constant of about 3 sec. In the presence of neostigmine (3 x 10(-6) M) the hyperpolarization lasted for 2 min or more. It is concluded that the action of ACh is primarily terminated by enzymic hydrolysis.


Cognitive tempo in educable mentally retarded children. The present study investigated the relationship of time and errors on the Matching Familiar Figures test to the mental age of 40 Caucasian male, educable mentally retarded (EMR) children. The children, who ranged in age from six to 18 years, had intelligence test scores of less than 80, were exhibiting problems in adaptive behavior, and were all receiving special education services. An ANOVA revealed that with increasing mental age, elapsed time to first response increased and errors decreased, thus indicating a mental age developmental decrease in impulsivity. For all subjects, time was inversely related to errors. The data suggest that the development of cognitive tempo in EMR children parallels that of nonhandicapped children.


Perceptions of ugliness in the mentally retarded. Thirty male and female retarded adults were asked to draw a picture of a person and then to draw a picture of an ugly person, in order to determine whether broader facial features are a measure of ugliness (as found by McCullers and Staat). Additionally, measures of broadness of facial outline and body outline of the drawings were taken. Although there were no significant differences, there was a trend to exaggerate the drawing of the ugly person, and the rationale for this was discussed.


Personality correlates of suicidal tendency among Iranian and Turkish students. Personality correlates of S s indicating suicidal intent have been found to be different from those of normals in a direction indicative of possible psychopathology. To test the cross-cultural relevance of this hypothesis, three samples of male and female students were administered Eysenck's extraversion, neuroticism, and psychoticism inventory: 209 Iranian and 128 Turkish university students and 101 Iranian high school students. S s were classified into "suicidal" and "normal" groups in each sample by means of a self-rating scale of suicide intent. Comparison of scores showed that irrespective of nationality and age, suicidals scored higher on neuroticism and psychoticism but lower on extraversion than their normal counterparts. Results suggest that personality correlates of suicidal tendency are rather similar despite differences in age and cultural background.


Wave coherence in the human EEG.

Wave coherence in the human EEG. The investigation is concerned with the phase coherence of human EEG's taken from the median plane of the scalp (N = about 125 male and female undergraduates). Manifestation of coherence was made by using scalp potentials of not less than a fixed value to trigger the sweep of a computer of average transients. Very coherent phase relationships were observed in the occipital region in the form of waves having a period of about 100 msec under a condition of bodily and mental relaxation and eyes closed. With eyes open and under a condition of motivated visual perception, wave coherence disappeared in nearly all S s. Coherence in the alpha frequency diminished as derivation moved toward the frontal region. In some S s, coherence was also noted for waves with a period of 55-60 msec, derived from the occipital region under condition of relaxation. In many individuals, coherent waves of this period were derived from the parietal, central, and frontal areas.


The relationship between fear and death and anxiety. Studies examining fear of death and anxiety have consistently shown these constructs to be positively related. Although several measures of anxiety have been examined, fear of death has always been treated unidimensionally. The present research was an attempt to examine eight types of fear of death in relation to two types of anxiety. Questionnaire data were collected from 375 male and female undergraduates at a Mid-western university. Anxiety was measured by the State-Trait Anxiety Inventory, and fear of death by a factor analytic multidimensional scale. Significant correlations were found between seven of the eight fear of death dimensions and both measures of anxiety. Regression analysis showed fear of premature death and fear of the dead to be the most important death-related fears associated with anxiety.


Reconstructing, recognizing, and reproducing object figures: a fixed order. In this study it is hypothesized that there are three distinct levels of representation and that these levels are hierarchical. The hypothesis was tested by having 100 six-year old boys and girls represent one of the most basic Bender-Gestalt figures. It was demonstrated that a representation of this figure through object reconstruction is prerequisite to recognizing the object figure from a collection of figures which in turn is prerequisite to representing the object figure using a pencil-and-paper reproduction.


Developmental features of speech-sound production in language-impaired children. The speech-sound production of severely language-impaired children was monitored in a longitudinal study. In order to generalize findings, acoustical, phonemic, and clinical observation data were collected from 30 children. Results showed that speech-sound acquisition goes through a hierarchical sequence of development and that speech-sound production will deteriorate in a predictable manner depending on the pathology. The authors hypothesize a speech-sound acquisition model, SSAM, based on the development observed.


Lost intrauterine devices and their localization. With the increasing popularity of intrauterine devices for contraception, an increase in the number of IUD-related complications has been observed. A common clinical problem is loss of marker strings at the external os. It could be due to translocation or unnoticed expulsion, both of which reduce the contraceptive effectiveness of the method. Even with the most scrupulous IUD insertion technics, uterine perforation is a recognized complication. Ectopic devices should be removed because extensive sepsis and adhesions between adjacent organs with subsequent bowel strangulation have been reported. Determining the location of the device is facilitated by flat plate X-rays of the abdomen,  hysterography, ultrasound or hysteroscopy. The best method of IUD removal depends upon its location, extent of adhesions and the experience of the operator.


Observations in perinatal heart rate monitoring. I. A quantitative method of describing baseline variability of the fetal heart rate. Simultaneous magnetic tape recordings of fetal scalp ECG, maternal ECG and uterine contractions were obtained from 23 patients in active labor. Computer-derived distributions of beat-to-beat changes were used to develop a simple numerical and graphical description of the long and short-term variability patterns. The visually observed variability may be described by the R-R interval change (beat-to-beat change), which is greater than 90% of the total number of beat-to-beat changes. Thus, the 90th percentile of R-R interval changes quantitatively describes the baseline variability. The variability may be classified as fixed, minimal, moderate or marked, based on this simple calculation. Graphs of cumulative percentage of R-R interval changes provide additional visual information. The effects of meperidine HCl on the observed variability were easily detected and visualized by these methods.


Educational responsibilities and resources of obstetrics and gynecology departments in 1975. A survey of 108 departments of obstetrics and gynecology in United States medical schools was completed for 1975, and a statistical evaluation of their resources was made. The mean data showed that the student core clerkship had a duration of 6.9 weeks and an enrollment of 17.8 students. The departments had 11.3 full-time faculty members, 69.5 obstetric beds and 56.9 gynecologic beds. There were 3,891 deliveries, 1,846 minor gynecologic operations and 1,418 major gynecologic operations performed. These results should provide a data base upon which to compare the changes in departments in the future.


Aortic stenosis and pregnancy.

Aortic stenosis and pregnancy. Pregnancy in patients with aortic stenosis results in a maternal mortality rate of 17.4% and perinatal mortality rate of 31.6%. Medical treatment, valve replacement and termination of pregnancy are the main modes of therapy. The number of cases reported in the literature is small, and the indications for selecting one method of management over the others have not been established. A case is presented that illustrate some of the difficulties encountered in the management of these patients.


Abnormal Papanicolaou smears found in victims of sexual assault. Four women, at the time of treatment for rape, were concurrently found to have abnormal Papanicolaou (Pap) smears. It is suggested that all women who seek emergency care after sexual assault have Pap smears taken at that time if there is no record of a negative Pap smear within the preceding six months.


Venous stasis retinopathy after long-standing menorrhagia. It is uncommon for visual symptoms to be the initial presentation after long-standing menorrhagia. In this case, menorrhagia secondary to leiomyomata gave rise to a severe iron deficiency anemia. A VSR followed that resolved quickly after transfusion. A hysterectomy was performed for definitive treatment.


Metastasis to the vagina from carcinoma of the breast. Carcinoma of the breast, metastatic to the ovary, is encountered frequently. The potential routes of dissemination include transcoelomic spread, lymphatic spread and vascular (arterial or venous) transportation. A case report of vaginal metastasis secondary to bilateral breast carcinoma is cited and the potential mechanisms for dissemination described.