A kinetic and pharmacologic analysis of 5-hydroxytryptamine transport by human platelets and platelet storage granules: comparison with central serotonergic neurons. The mechanisms whereby human platelets transport serotonin (5-HT) were explored by determining the initial velocity of 5-HT uptake over a wide range of 5-HT concentrations. Total 5-HT transport could be resolved into a saturable high affinity-low capacity active transport system plus nonsaturable passive diffusion. Previous kinetic analyses of 5-HT transport into platelets and brain slices have been found to be in error and the correct kinetic constants have been recalculated here. The saturable active uptake of 5-HT into human platelets is directly susceptible to inhibition by several pharmacologic agents (ouabain, metabolic inhibitors and tricyclic antidepressants) which do not inhibit the nonsaturable passive diffusion nor the nonsaturable granular transport of 5-HT. On the other hand, granular binding of 5-HT is directly susceptible to inhibition by pharmacologic agents (reserpine, tetrabenazine and N-ethylmaleimide) which do not directly inhibit saturable active uptake nor nonsaturable passive diffusion of 5-HT. Quantitative studies of platelet 5-HT transport have shown that at low concentrations of 5-HT, the pharmacologic and biochemical properties of total 5-HT transport are determined mostly by the saturable high affinity active membrane transport system for 5-HT; at high concentrations of 5-HT, the properties of 5-HT accumulation by platelets are determined mostly by the granular storage mechanism. Detailed comparisons of the kinetic, biochemical and pharmacologic characteristics of 5-HT transport in platelets and brain support the notion that the platelet can serve as a model for 5-HT transport by central nervous system neurons.


Dopamine turnover in the intact rabbit brain: effect of pentobarbital or haloperidol. Turnover of dopamine in the intact brain of the unanesthetized rabbit was estimated from the rate of appearance of endogenous homovanillic acid (HVA) in the cerebrospinal fluid (CSF) compartment. The rate of appearance of the dopamine metabolite was determined by isotope dilution during ventriculocisternal perfusion with artificial CSF containing [3H]HVA. Removal of HVA from the perfusate was concomitantly determined and analyzed in terms of bulk absorption, diffusion and active transport. Studies of the effects of pentobarbital and haloperidol showed that application of either drug resulted in increased HVA levels in the cerebrovascular perfusates. Haloperidol caused a 4-fold increase in the rate of appearance of HVA without affecting the processes for metabolite removal, whereas pentobarbital did not alter the rate of appearance of HVA but induced blockage of its active transport from the perfused CSF compartment. The perfusion method permits simultaneous estimations of the rates of appearance and disappearance of monoamine metabolites in the CSF and is therefore suitable for determining whether a change in the metabolite concentration is causally related to a change in its production or removal or both.


Centrally mediated release by cocaine of endogenous epinephrine and norepinephrine from the sympathoadrenal medullary system of unanesthetized rats. A radioenzymatic-paper chromatographic method for a simultaneous assay of catecholamines was used to study the effect of cocaine on the release of endogenous catecholamines from the sympathoadrenal medullary system into the blood of unanesthetized rats. Twenty-four hours after arterial cannulation, the "basal" levels of norepinephrine (NE) and epinephrine (EPI) in blood obtained through the catheter from conscious, undisturbed rats were 0.48 +/- 0.06 and 0.36 +/- 0.06 ng/ml, respectively. Administration, via the arterial catheter, of cocaine (0.4-10 mg/kg) produced dose-related increases in NE (0.59 +/- 0.03 to 1.58 +/- 0.34 ng/ml) and EPI (1.15 +/- 0.16 to 6.67 +/- 0.46 ng/ml). Inhibition of catechol O-methyltransferase by tropolone (40 mg/kg) enhanced by 5- to 10-fold the maximal response to cocaine without altering significantly the basal plasma levels of EPI or NE. Bilateral splanchnic denervation reduced the cocaine-tropolone-induced release of EPI and NE by 75 and 50%, respectively. Desipramine (10 mg/kg) failed to alter significantly plasma levels of NE or EPI, even after tropolone. Thus, the increment in plasma levels of NE and EPI in conscious rats given cocaine is mainly the result of a centrally mediated adrenal medullary discharge of catecholamines, rather than inhibition of catecholamine uptake.


Responses of heart ornithine decarboxylase and adrenal catecholamines to methadone and sympathetic stimulants in developing and adults rats. Sympathetic stimulation elevates heart ornithine decarboxylase (ODC) activity in adult rats, an effect which is followed by cardiac hypertrophy. In developing animals, adrenergic agonists play a role in cardiac growth and differentiation. Methadone administration to adult rats stimulated heart ODC, and this stimulation could be blocked by the sympatholytic agents chlorisondamine, reserpine or propranolol, suggesting that the effect is mediated via central stimulation of sympathetic nerves. With repeated methadone administration, tolerance developed to the heart ODC stimulation by methadone, eventually resulting in decreased heart ODC accompanied by deficits in heart weight. The sensitivity of the mature heart and adrenal medulla to the sympathetic stimulants insulin, nicotine or isoproterenol was virtually unchanged during long-term methadone administration, indicating that tolerance of the heart ODC response to methadone did not result from subsensitivity of the efferent sympathetic pathway or the heart ODC response system. In normally developing rats, responses to insulin-induced reflex stimulation of sympathetic nerve supplies to the heart and adrenal medulla did not occur until 8 days of postnatal age; however, daily treatment of pups with methadone begun the day after birth accelerated the development of functiona heart and adrenal medullary responses to insulin such that responses were obtained by 4 days of age. The cardiac responses to nicotine developed somewhat differently, with significant ODC stimulation first appearing at 12 days in controls and at 8 days in methadone-treated pups. In the adrenal gland, a tissue in which responses to nicotine do not depend on an intact nerve supply a catecholamine secretory response to nicotine was observed at 4 days of age in controls. These data suggest that methadone treatment accelerates the development of functional sympathetic innervation of heart and adrenal medulla, with resultant abnormalities in cardiac muscle growth and differentiation.


Reserpine-induced supersensitivity to the chronotropic and inotropic effects of calcium in rabbit atria. Supersensitivity to the chronotropic and inotropic effects of calcium was demonstrated in spontaneously beating paired atria from reserpine-pretreated (0.1 mg/kg/day, 7 days) rabbits. Supersensitivity to the inotropic effects of calcium in electrically driven left atria was also demonstrated. Atria were driven at 80, 100 and 120 beats/min. At each frequency the reserpine-pretreated atria were more sensitive than controls. Atria were tested under diastolic tensions of 1,2 and 4 g. As the tension was increased the sensitivity to calcium increased. The sensitivity of reserpine-pretreated atria was greater at each tension than that of control atria. Atria tested at 37 degrees C were less sensitive than those tested at 30 degrees C; however, the reserpine-pretreated atria were more sensitive than control atria at both temperatures. This study demonstrates that reserpine-induced supersensitivity to the inotropic effects of calcium can be obtained and that the ability to demonstrate this phenomenon does not appear to be altered by the frequency, diastolic tension or temperature at which each experiment is performed.


Studies with a new antifolate 2,4-diamino-5-adamantyl-6-methylpyrimidine (DAMP): tissue distribution and disposition of 2,4-diamino-5-adamantyl-6-methylpyrimidine and its metabolite. The pharmacokinetics of a potentially useful antitumor agent, 2,4-diamino-5-adamantyl-6-methylpyrimidine (DAMP) has been studied in rat using 14C-labeled drug. It is reported that DAMP is metabolized rapidly by liver microsomes to an unidentified compound. The metabolite seems to be excreted by liver more rapidly than the unchanged drug, and within 24 hours all radioactivity is eliminated, 80% through kidney and 20% through the bile. Both DAMP, and its metabolite accumulate readily in pancreas and kidney. In contrast, in the brain mostly unchanged DAMP could be detected. The accumulation of the drug in tissues other than liver is much greater after i.v. than after i.p. administration.


Effects of droperidol on depolarization-induced automaticity, maximum upstroke velocity (Vmax) and the kinetics of recovery of Vmax in guinea-pig ventricular myocardium. The neuroleptic drug droperidol has been shown to have clinically useful antiarrhythmic activity. Prior reports have resulted in conflicting conclusions regarding actions on ventricular myocardial fibers. The present study was carried out to determine whether droperidol did in fact affect the electrophysiological properties of guinea-pig papillary muscle fibers. By means of microelectrode recordings from preparations mounted in a single sucrose gap, the effects of concentrations from 10(-6) to 4 X 10(-5) M were studied on depolarization-induced automaticity, and on Vmax and its recovery time under several conditions of membrane potential, stimulation rate and external ion concentration. The results showed that at clinically relevant concentrations, droperidol significantly slows ventricular pacemaker activity, a depression reversible by epinephrine. Furthermore, Vmax was decreased and the time constant for Vmax recovery was significantly prolonged under several conditions which pertain to clinical arrhythmias, i.e., reduced membrane potential, elevated extracellular potassium concentrations and increased stimulation rate.


Lidocaine effects on action potentials of Purkinje fibers from neonatal and adult dogs. We studied the effects of lidocaine (L), 2 to 40 mg/l, on the cellular electrophysiologic properties of Purkinje fibers (PF) from neonatal (0-10 days) and adult dogs. Microelectrode impalements of neonatal and adult PF were selected so that there were no differences between the two groups in control maximum diastolic potential, action potential amplitude and maximum upstroke velocity of phase 0 depolarization (Vmax). However, control action potential duration was significantly shorter in neonates than in adults (P less than .05). At a superfusate [K+] = 4 mmol/1, the threshold concentration for L effects on action potential amplitude in neonates was 40 mg/1 and in adults, 20 mg/1; on Vmax in neonates threshold was 5 mg/1 and in adults was 2 mg/1; on action potential duration in neonates and adults threshold was 2 mg/1. For all variables studied the effect of L on adult PF action potentials was greater than on neonatal PF. The effects of L on action potential duration also suggest that potassium conductance may be greater in neonatal fibers. When superfusate [K+] was increased to 6 mM the effects of L on adult PF were potentiated more than on neonates. These results provide further experimental evidence of the age-related changes in sensitivity of the specialized conducting system to cardioactive drugs.


Effects of locally and systemically infused bradykinin on transvascular fluid and protein transfer in the canine forelimb. Local intra-arterial infusions of bradykinin into canine forelimbs perfused either naturally or at constant inflow markedly increase skin lymph protein concentration promoting edema formation. However, prolonged systemic infusions of this agent either intravenously or into the left ventricular chamber, in blood concentrations calculated to exceed those that produce massive protein and fluid efflux on local administration, causes only minimal increases in lymph protein concentration, and in naturally perfused forelimbs promotes extravascular fluid reabsorption rather than net fluid filtration. Local infusions of bradykinin fail to alter aortic pressure whereas systemic infusions produce a profound but transient decrease in this variable. Moreover, the local intra-arterial infusion of bradykinin into forelimbs perfused at constant inflow fails to increase skin lymph protein concentration after 60 minutes of systemic hypotension. In contrast to bradykinin alone, the simultaneous infusion of bradykinin and norepinephrine or bradykinin and isoproterenol fails to increase skin lymph protein concentration. The antagonism of the bradykinin protein efflux by both norepinephrine and isoproterenol can be prevented by prior treatment with propranolol. These data suggest that the liberation of catecholamines may account, in part, for the minimal increases in forelimb protein efflux during systemic infusions of bradykinin relative to that produced by local intra-arterial infusions of this agent.


Effects of 1,10-phenanthroline and a zinc complex of 1,10-phenanthroline on nucleic acid synthesis in mouse liver and spleen. The effects of 1,10-phenanthroline and a zinc complex of 1,10-phenanthroline on nucleic acid synthesis were examined by noting the capcity of these agents to incorporate [methyl-3H]thymidine, or [5-3H]uridine into hepatic and splenic DNA and RNA. Within 32 hours after the intraperitoneal injection of 1,10-phenanthroline in mice, a decrease of [methyl-3H]thymidine incorporation into hepatic DNA was observed. The administration of the zinc complex of 1,10-phenanthroline decreased the incorporation of [5-3H] uridine into hepatic RNA within 24 hours and decreased the formation of [3H]DNA from [methyl-3H]thymidine in the liver within 24 and 32 hours. An increase of the isotopic incorporation into hepatic RNA and of the pool size of ATP within 2 hours after the administration of the complex was also noted. In the splenic studies, the zinc complex significantly inhibited the formation of labeled DNA and RNA at 2, 8, 24, and 32 and 2, 8 and 24 hours postinjection, respectively. A relationship exists between the results obtained from sequential treatment (zinc chloride after 1,10-phenanthroline) and those derived from the zinc complex of 1,10-phenanthroline pertaining to an inhibition of isotopic incorporation into hepatic and splenic nucleic acid.


Kinetic analysis of the renal handling of 2,2-bis(p-chlorophenyl) acetic acid by the rat. The kinetics of uptake and efflux of organic acids in rat renal cortical slices were used to examine the affinity of 2,2-bis(p-chlorophenyl)acetic acid (DDA) for the organic acid transport system and to assess intracellular binding of this polar 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) metabolite. As judged by its ability to inhibit p-aminohippuric acid transport, DDA was a potent competitive inhibitor, almost as strong as probenecid, the classical inhibitor of this system. Efflux of DDA from slices demonstrated that the bulk (85%) of the DDA within the slice was reversibly bound to proteins or other macromolecules. Cortical slices incubated 60 minutes with 10 micron DDA contained a total concentration of 160 micron DDA within the tubular cells, but the actual free concentration in the cells was only 20 to 30 micron. Thus, although DDA was accumulated against a concentration gradient by the kidney, the gradient was much smaller than the measured tissue/medium ratio. Potential consequences of DDA exposure through its interaction with the organic acid system and roles of DDA binding sites in the toxicity and transport of DDA are discussed.


Changes in the composition of the mammary secretion of women after abrupt termination of breast feeding. 1. The composition of mammary secretion has been followed in seven women before and after abrupt termination of breast feeding. The period of full lactation was 39 days for 1 woman and a mean of 332 days (range 251--443 days) for the six others. Small samples of mammary secretion (0.5--5.00 ml.) were collected by manual expression from three women at monthly intervals throughout 12 months of lactation and from seven women at frequent intervals for 42 days of involution. 2. During full lactation (12 months, three women) the mean values (+/- S.E. of mean) for lactose, total protein, alpha-lactalbumin, Na, K and Cl were 7.03 +/- 0.13 g/100 ml., 1.68 +/- 0.08 g/100 ml., 163 +/- 6.39 mg/100 ml., 8.5 +/- 0.90 mM, 13.4 +/- 0.34 mM and 11.93 +/- 0.53 mM, respectively. 3. After termination of breast feeding, the concentrations of lactose and K decreased while Na, Cl, fat and total protein increased progressively over 42 days. The increase in the protein content was contributed to by increases in the concentration of lactoferrin, IgA, IgG, IgM, albumin, alpha-lactalbumin and casein. There was no significant difference in the concentration of the milk constituents between the right and left breast throughout full lactation and after its termination. 4. These observations indicated that the secretory capability of the mammary gland of women changed dramatically after complete cessation of breast feeding but that the involuting gland remained partially functional for a long period.


The synaptic connexions to intercostal motoneurones as revealed by the average common excitation potential. 1. The hypothesis is advanced that the joint occurrence of unitary e.p.s.p.s evoked in motoneurones by branches of common stem presynaptic fibres causes, on average, transient depolarization in one motoneurone at the time of discharge in another motoneurone of the same pool. 2. The hypothesis was tested in anaesthetized, paralysed cats by averaging the naturally occurring synpatic noise of thoracic inspiratory motoneurones with an averager triggered by spikes from other inspiratory motoneurones. These spikes were obtained as efferent discharges in nerve filaments supplying the proximal regions of the external intercostal muscles. 3. A transient depolarization centred around the time of the trigger spikes was consistently observed and was designated the average common excitation (a.c.e.) potential. 4. The peak depolarization lay between -1.0 and +4.6 msec (mean +0.7 msec) with respect to the trigger spikes and the rise times of its most prominent component ranged from 4 to 16 msec (mean 8.4 msec). 5. The amplitudes of the a.c.e. potentials ranged from 6 to 104 muV (mean 32 muV) when the trigger spikes were derived from a filament in the same segment as the relevant motoneurones, and from 3 to 42 muV (mean 19 muV) when the filament was two segments rostral to the motoneurone. 6. Cells innervating the proximal region of the intercostal space gave larger a.c.e. potentials than those innervating more distal regions and also showed larger central respiratory drive potentials. 7. A.c.e. potentials were observed for either alpha or gamma spikes as triggers. The potentials were usually smaller for the gamma than for the alpha spikes, the mean ration being about 0.6. The presence of the a.c.e. potentials from the gamma spikes was taken as evidence for alpha-gamma coactivation by common presynaptic axons. 8. A theory is developed which quantitatively accounts for the main features of both the a.c.e. potential and the short term synchrony observed by Sears & Stagg (1976). 9. The theory includes the proposition that the raised probability of firing of a motoneurone due to a unitary e.p.s.p. has a time course which may be described by the sum of the e.p.s.p. time course and its time differential. Thus, via the measurements, the theory predicts at least to a first approximation the expected probability of firing due to e.p.s.p.s of various shapes and sizes.


Absorptive and secretory functions of the perfused rat cauda epididymidis. 1. A microperfusion technique has been developed to study transport processes in the rat cauda epididymidis in vivo. 2. Na+ and water were found to be reabsorbed by the perfused rat cauda epididymidis at the rates of 3.000 +/- 0.25 n-equiv cm-1 min-1 (mean +/- S.E., n = 14) and 20.7 +/- 1.7 nl. cm-1 min-1 (mean +/- S.E., n = 14) respectively. Reabsorption of Na+ was isotonic. 3. K+ was found to be secreted into the ductal lumen at the rate of 0.124 +/- 0.016 n-equiv cm-1 min-1 (mean +/- S.E., n = 14). 4. Na+ reabsorption and water reabsorption were abolished by removing Na+ ions from the perfusion medium. The dependence of rate of net Na+ reabsorption on the intraluminal Na+ ion concentration showed saturation kinetics, with the apparent Km values of about 20 mM Na+. The dependence of water reabsorption on the intraluminal Na+ ion concentration also followed closely that of Na+. 5. Application of amiloride 10(-4) M) to the perfusion fluid abolished both Na+ and water reabsorption by the rat cauda epididymidis. 6. Removal of chloride from the perfusion fluid had no effect on Na+ and water reabsorption but increased the K+ secretion rate by threefold. 7. Proteins were also found to be secreted by the rat cauda epididymidis at a rate of 11.7 +/- 1.8 ng cm-1 min-1 (mean +/- S.E., n = 11). The secretory rate was not dependent on the intraluminal Na+ ion concentration. 8. Castration in rats abolished the reabsorption of Na+ and water and secretion of K+ and proteins by the rate cauda epididymidis. These effects could be reversed by injecting testosterone propionate into castrated rats. 9. The possible role of these transport processes in sperm maturation is discussed.


Field potentials, inhibition and the effect of pentobarbitone in the rat olfactory cortex slice. 1. Field potentials were evoked in slices of rat olfactory cortex by stimulating the lateral olfactory tract. In addition to previously described components of the wave-form, a further distinct surface-negative potential of low amplitude and long duration (I-wave) has been described. 2. Pentobarbitone, at concentrations of 10(-5) M and above, markedly enhanced enhanced the amplitude and duration of the I-wave with only minimal effect on other components of the field potential. 3. The I-wave was reversibly reduced by the GABA antagonists bicuculline and picrotoxin and was also attenuated at rapid rates of stimulation. Low chloride medium usually caused a transient increase in amplitude of the I-wave followed by a gradual reduction, suggesting that a chloride-mediated depolarization was involved. 4. Evoked inhibition, which was most probably post-synaptic, occurred in parallel with the I-wave. This was monitored as a suppression of, or increase in latency of the population spike evoked by a second stimulus at appropriate intervals after the first. Pentobarbitone substantially increased the duration of the post-synpatic inhibition, without obvious changes in the presynaptic inhibitory phenomenon associated with antidromic firing in the lateral olfactory tract. 5. It is proposed that the I-wave is the field potential representation of a population depolarizing i.p.s.p. and that the main action of pentobarbitone is to enhance this inhibition.


Uptake of [14C]urea by the in vivo choroid plexus--cerebrospinal fluid--brain system: identification of sites of molecular sieving. 1. The time course of the uptake of [(14)C]urea by the lateral ventricular choroid plexus of the adult rat in vivo was analysed to delineate further the permeability characteristics of the epithelial membrane of this secretory tissue.2. Eight hours after I.P. injection, [(14)C]urea attained a steady-state distribution in 78% of the tissue water of lateral ventricular choroid plexus; similarly, approximately 8 hr was required for radiourea to reach a steady-state concentration in both the cerebral cortex and cerebrospinal fluid (c.s.f.).3. Results obtained for compartment analysis were used to calculate the concentration of [(14)C]urea in the epithelium of the lateral ventricular plexus during the approach to and at steady-state distribution. Even after 1 hr of distribution, the [(14)C]urea concentration in choroid cell water was less than 15% of that in plasma water.4. Although the concentration of radiourea in choroid cell water continually increased after 3 hr, it remained in equilibrium with the concentration of [(14)C]urea in c.s.f. water. At the steady state (i.e., 8 hr), the distribution of [(14)C]urea between the water of plasma and that of the choroidal epithelium was considerably away from equilibrium (i.e., by 25-30%).5. An analysis of the concentration gradients for [(14)C]urea across both the apical (c.s.f.-facing) and basolateral (plasma-facing) membranes of the epithelium of the lateral ventricular plexus suggests that the movement of urea is hindered to a greater extent by the basolateral membrane than by the apical membrane.6. Only a single half-time component (1.3 hr) can be resolved from analysis of the curve describing the time course of uptake of radiourea by the choroid epithelial cell compartment.7. The concentration gradient data suggest that urea penetrates from blood to c.s.f. via the choroid plexus by a transcellular pathway; however, it is not possible to rule out a paracellular pathway for urea movement.8. At the steady state, radiourea distributes into 88% of the water of cerebral cortex. This observation, together with the finding of a steady-state concentration gradient for [(14)C]urea from cortical tissue to c.s.f., constitutes evidence that urea movement is hindered at the blood-brain barrier as well as at the blood-c.s.f. barrier.


Exchange of 5-hydroxyindoleacetic acid between the spinal cord and lumbar cerebrospinal fluid. 1. After inhibition of 5-hydroxyindoleacetic acid (5-HIAA) transport by repeated administration of probenecid in cats, this acid accumulates linearly in the lumbosacral cord, lumbar cerebrospinal fluid (c.s.f.) and cisternal fluid during 5 hr of experiment. 2. A simple mathematical analysis of these results shows that (a) the rates of 5-HIAA accumulation in the lumbar c.s.f. and cisternal c.s.f. are faster than in the cord, (b) about 22% of 5-HIAA formed in the cord diffuses into lumbar c.s.f. and (c) by measuring 5-HIAA in the lumbar c.s.f. the concentration and turnover of 5-HIAA and turnover of serotonin in the lumbosacral cord can be calculated as well as the changes of 5-HIAA in the cisternal c.s.f. predicted. 3. These results suggest that it is possible to calculate the level and turnover of endogenous substances in the central nervous system on the basis of their measurement in the c.s.f.


Characterization and ionic basis of GABA-induced depolarizations recorded in vitro from cat primary afferent neurones. 1. Responses of single cells in the isolated cat spinal ganglion to GABA applied by superfusion or by iontophoresis were recorded using intracellular micro-electrodes. 2. Of the twelve structurally related compounds investigated, GABA was the most effective in its ability to produce a depolarization of the cell membrane. 3. Studies determining concentration-response relationships indicate that two to three molecules of GABA are required to combine with the GABA receptor for activation. 4. Bicuculline and picrotoxin, each act in a non-competitive manner to antagonize the GABA-induced membrane current. 5. The equilibrium potential for iontophoretically induced GABA depolarizations (EGABA) was found to be -23.5 plus or minys 6.1 mV. EGABA was independent upon [cl-]o, but independent of [Na+]o, [K+], or [Ca2+]o. 6. Intracellular injection of twenty antions (Br-, I-, NO2-, NO3-, ClO4-, SCN-, Bf4-, HS-, OCN-, ClO3-, BrO3-, F-, HCO2-, HSO3-, HCO3-, CH3CO2-, SO42-, C6H5O73-) indicated that the activated GABA receptor membrane was permeable to those anions whose hydrated diameter is no larger than that of ClO-3. 7. Restoration of the GABA depolarization to its control level after augmentation by Cl- injection had a mean time constant of 27.8 plus or minus 2.6 min. Picrotoxin did not alter this value. 8. When foreign anions were exchanged for Cl- in the perfusion solution, the ten anaions smaller or equal to ClO3-, decreased the GABA depolarization by 50-90% and increased its time course 1.5-2.0 x control. The only exception having a small radius was Br- which augmented the amplitude 10-30%. 9. The ten anions larger than ClO3- produced a biphasic effect, i.e. an initial augmentation followed by a marked (up to 100%) depression of the response. Experiments with CH3COO-, CH3SO4-, or HOCH2CH2SO3-, indicated that this depression was non-competitive.


Action of fatty acids on the exocrine pancreatic secretion of the conscious rat: further evidence for a protein pancreatic inhibitory factor. The existence of a delayed inhibition of the secretion of protein by the rat pancreas after intraduodenal injection of oleic acid has been confirmed. 1. This phenomenon is not dependent on the presence or absence of bile or pancreatic juice in the intestine. 2. The action of oleic acid is not a pathological phenomenon due to lesions of the gut mucosa because isotonic solutions of Na oleate dispersed into polysorbate 80 or olive oil (rich in oleic acid) plus pancreatic juice have the same effect. 3. Fatty acids must be free or saponified but not esterified in the form of triglycerides. Triglycerides are only effective if pancreatic juice is simultaneously reintroduced into the duodenum. 4. Oleic acid (C18 monoéne) is more efficient than caprylic acid (C8) and butyric acid (C4) is ineffective. The effect of chain length in releasing the inhibitory factor is therefore approximately the same as in CCK-PZ release. 5. Intraduodenal infusion of hypertonic glucose solution does not inhibit pancreatic protein secretion indicating that release of enteroglucagon is probably not responsible for the inhibition. The inhibitory action of hypertonic NaCl solution is not explained.


Afterhyperpolarization mechanism in the dorsal spinocerebellar tract cells of the cat. 1. The longlasting afterhyperpolarization (a.h.p.) following single or short trains of spikes in dorsal spinocerebellar tract (DSCT) neurons of the cat has been studied with intracellular recording techniques. 2. The a.h.p. amplitude was found to be potential dependent, increasing with depolarization and decreasing with hyperpolarization of the membrane. With large membrane hyperpolarization, the a.h.p. could be reversed in direction, the estimated reversal level being around 30 mV more negative than the threshold potential for spike initiation. The a.h.p. amplitude was also little affected by Cl- ions injected into the cell. 3. The a.h.p. was associated with an increase in the membrane conductance, as measured with short current pulses. The major part of the conductance change was related to the a.h.p. itself and not secondary to the hyperpolarization, i.e. to an anomalous rectification. A conductance change was also found when the membrane potential was polarized close to the a.h.p. reversal level. There was a clear correlation between the a.h.p. amplitude and the measured conductance changes. 4. It is concluded that the a.h.p. in DSCT neurones, as in spinal motoneurones, is caused primarily by an increase in membrane conductance to potassium ions. 5. The time course of the conductance change underlying the a.h.p. was calculated from the a.h.p. voltage and a mathematical expression describing this time course is given. The properties of the a.h.p. in DSCT cells are compared with those in spinal motoneurones and the functional significance of the differences is discussed briefly.


Effect of repetitive activation on the afterhyperpolarization in dorsal spinocerebellar tract neurones. 1. The changes in the afterhyperpolarization (a.h.p.) with repetitive activation have been studied in dorsal spinocerebellar tract cells of the cat using intracellular recording techniques. 2. The a.h.p. following a single spike was conditioned at different interspike intervals by a single preceding spike. In the majority of neurones the a.h.p. following a spike added approximately linearly with that generated by a preceding spike. 3. In other cells the a.h.p. following a spike was instead depressed by a preceding spike. THis depression was approximately constant at interspike intervals less than the a.h.p. duration (50-100 msec). Thereafter the a.h.p. slowly recovered during the next 100-300 msec. There was no associated decrease in the initial brief hyperpolarizing undershoot. 4. With shortlasting repetitive activation at high frequency (greater than 100 impulses/sec) the a.h.p, peak amplitude increased progressively with successive spikes (5-15 spikes). No change in the time constant of decay was observed. A good correspondence was found between the observed increase in peak amplitude of the a.h.p.s and that given by a theoretical linear superposition of the successive a.h.p.s. 5. Changes in the brief hyperpolarizing undershoot with repetitive activation is also described.


Firing behaviour of dorsal spinocerebellar tract neurones. 1. The repetitive discharge evoked by constant current injection from an intracellular micropipette has been studied in dorsal spinocerebellar tract cells of the cat. 2. The discharge frequency decreased with time, the decrease being more pronounced at high current intensities. Most of the frequency change occurred during the first ten intervals but the decrease continued slowly for several seconds. In some cells the frequency rose initially, the first interspike interval being larger than immediately succeeding ones. 3. The frequency-current (f/I) curves for the first interspike intervals were S-shaped, as found in spinal motoneurones. With successive intervals the lower leg of the f/I curve extended to higher frequencies, giving a progressive linearization of the f/I curves. In almost all cells this linearization was completed at 200 msec after current onset. 4. The experimental f/I curves were compared with the f/I curves obtained with a simple neurone model based on the properties of the postspike afterhyperpolarization. For the first interspike interval there was a good agreement between the experimental and calculated f/I curves of individual neurones up to frequencies of several hundred impulses per second. In the high frequency range, it was necessary to compensate for changes in initial postspike voltage trajectories caused by the injected current. Other aspects of the firing of real neurones, such as the progressive linearization of the f/I curves, the negative adaptation and the changes in the interspike voltage trajectories with increasing current were also reproduced by the neurone model. 5. It is concluded that the conductance process underlying the postspike afterhyperpolarization is a major factor in the regulation of repetitive firing in dorsal spinocerebellar tract neurones.


Ionic effects on the membrane potential of hyperpolarizing photoreceptors in scallop retina. 1. The effects of different external ionic conditions and of metabolic inhibitors on the membrane potential of hyperpolarizing photoreceptors in the retina of the scallop Pecten irradians were examined in the presence and absence of light.2. Changes in extracellular K(+) have a greater effect on membrane potential in the light than in darkness. The receptor potential is increased in amplitude when [K](o) is reduced and decreased when [K](o) is elevated. It is hyperpolarizing when [K](o) is less than the estimated value for [K](i) and depolarizing when this condition is reversed.3. The complete replacement of [Na](o) causes a significant hyperpolarization of membrane potential in darkness, whereas it has a much smaller hyperpolarizing effect on the peak of the receptor potential.4. The ratio of Na(+) to K(+) permeabilities (P(Na)/P(K)) decreases during bright illumination. Our results suggest that P(K) is seven times that for P(Na) in the dark but is 57 times greater than P(Na) in light.5. The metabolic inhibitors DNP and NaCN cause membrane potential in the dark to hyperpolarize. This hyperpolarization is associated with a decrease in the P(Na)/P(K) ratio similar to that found during illumination.6. High [Ca(+)](o) also causes membrane potential in the dark to hyperpolarize. This hyperpolarization is associated with an increase in membrane conductance.7. The results indicate that the hyperpolarizing receptor potential of the distal photoreceptor is produced by a light-evoked increase in K(+) permeability.


Changes in the intracellular concentration of free calcium ions in a pace-maker neurone, measured with the metallochromic indicator dye arsenazo III. 1. The bursting pace-maker R-15 cell of Aplysia was injected with the Ca2+ sensitive dye arsenazo III. Changes in absorbance were measured with a differential spectrophotometer to monitor changes in free intracellular Ca2+, [Ca-a], during activity. 2. Dye absorbance increased during each pace-maker-induced burst of action potentials and decreased during the hyperpolarizing phase of the pace-maker cycle. 3. The increase in dye absorbance was, at least in part, dependent upon action potential discharge and was greater when action potential duration was prolonged by treatment with tetraethylammonium chloride. 4. Changes in dye absorbance occurred under voltage clamp conditions when the membrance was depolarized 5-15 mV from a holding potential near the resting potential and were larger with greater step depolarizations. 5. These changes were completely blocked by the addition of 3mM-La3+ to normal ASW. 6. The ratio of the absorbance change between two pairs of wave-lengths during the pace-maker cycle was compared with the ratio observed following injection of Ca2+, Mg2+ and H+ ions. The ratio for the pace-maker cycle was well matched by that for Ca2+ injection, but not by that for injection of Mg2+ or H+. 7. Intracellular Ca2+ injections which increased [Ca]1 to the same amount as occurred during the pace-maker cycle also produced an outward current of sufficient magnitude to account for the post-burst hyperpolarization. 8. Depolarization of the cell membrane by extrinsic current during the burst increased and prolonged the change in dye absorbance as well as the post-burst hyperpolarization. 9 It is suggested that Ca2+ enters during the pace-maker cycle, thereby increasing [Ca]i, and that this increase is sufficient to activate an outward current carried by K+ ions which causes or contributes to the post-burst hyperpolarization.


Biphasic effects of insulin and ouabain on fluid transport across rabbit corneal endothelium. 1. Low levels of insuling stimulate transendothelial fluid transport from preswollen stroma to aqueous in rabbit corneal preparations. The rate of stromal thinning at the end of the first hour averages 30% faster with insulin, 3.5 x 10(-22) M (4.8 micromicron/ml.), than that of the paired control. This concentration is about the physiological level in rabbit aqueous. 2. The stimulation with insulin is transient. Rates of thinning average higher but not significantly different from control rates by the second hour. 3. High levels of insulin between 3.5 x 10(-9) M (480 micromicron/ml.) and 2.0 x 10(-6) M (2.75 X 10(5) micromicron/ml.) inhibit fluid transport. The inhibition at the low end of this range of concentrations becomes more pronounced with longer perfusion times but appears not to exceed ca. 50% of the control rate. 4. Ouabain also induces a biphasic effect on fluid transport which is characteristically different from that with insulin. The maximal stimulation observed at all times occurred with a fixed concentration of 10(-10) M. The stimulation is not transient but increases throughout the duration of the perfusion; the average rate is elevated 50% above the control rate by the third hour. 5. The transition from a stimulatory to an inhibitory effect occurs consistently at ca. 10(-8) M with ouabain, while a similar transition with insulin occurs at ca. 10(-9) M and appears to shift towards slightly higher concentrations during a 3 hr perfusion period. 6. Inhibition of fluid transport with ouabain, 3 x 10(-7) M, is increased from ca. 50% after 1 hr to more than 70% at the end of the third hour of perfusion. 7. The combined presence of stimulatory concentrations of ouabain and insulin affects tromal thinning in a manner resembling the effect of ouabain alone more than that of insulin; additive effects could not be discriminated. Progressively raising the concentration of insulin to a level (10(-8) M) that alone inhibits stromal thinning, ultimately abolishes the stimulatory effect of ouabain. Based on other evidence and current models of drug/hormone-membrane interaction, these results can be interpreted to indicate a concentration-dependent interaction between receptor complexes of ouabain and insulin with (Na+ + K+)-ATPase.


Sodium and water metabolism under the influence of prolactin, aldosterone, and antidiuretic hormone. 1. Rabbits were placed in metabolism cages in order to measure their intakes of food, water, and sodium chloride (as 1% saline solution), and to measure urinary and faecal excretion of sodium, potassium, and water. 2. Antidiuretic hormone (0.2 i.u./day) caused a reduction in urine volume and no change in sodium excretion. There was full compensatory reduction in water intake so that no accumulation of water occurred. 3. Aldosterone (4 mg/da) caused a reduction in renal sodium excretion for 1--2 days. The saline intake was reduced, though this was insufficient to prevent some sodium accumulation. 4. Renal mineralocorticoid 'escape' resulted in a large increase in sodium excretion at the end of the aldosterone treatment period. This was fully compensated through increased saline intake, and balance was maintained. 5. Prolactin (200 i.u./day) caused a reduction in urine volume and in renal sodium excretion and since there were no compensatory changes in water and sodium intake, this led to substantial accumulation of both water and sodium. 6. The effects of smaller doses of both aldosterone and prolactin were investigated and found to be similar but smaller. 7. It is suggested that whereas prolactin may have little or no role to play in the sodium homoeostasis of the normal animal, the hormone may well be responsible for the substantial increase in body fluids in pregnancy.


Autonomic thermoregulation after intermittent cooling of the spinal cord and cold exposure in the rat. 1. O2 consumption, rectal and several skin temperatures were studied, at various ambient temperatures, in unanaesthetized rats that had been thermally stressed for an average of 290 h either by prolonged and intermittent cooling of the spinal cord or by prolonged and intermittent exposure to an ambient temperature which induced the same increase in O2 consumption as did the thermal stimulation of the spinal cord. 2. At all the test ambient temperatures, both groups of thermally stressed animals maintained a metabolic level higher than that of the controls. In the animals previously exposed to cold the extent by which the metabolic rate was greater than that of the control animals was independent of ambient temperature; in those previously subjected to cooling of the spinal cord, however, it increased as the ambient temperature was lowered. Rectal and average skin temperatures were essentially unaffected by the treatments. 3. It is concluded that prolonged and intermittent cooling of the spinal cord increases the gain of the temperature control system, whereas prolonged and intermittent cold exposure has no effect on it, and that these forms of thermal stimulation are therefore not equivalent.


A comparison of the action of glutamate, ibotenate and other related amino acids on feline spinal interneurones. 1. The effects of microiontophoretically applied glutamate, ibotenate and other related amino acids on the spike activity of feline spinal interneurones were investigated. 2. Unlike the other amino acids, which evoked excitatory responses only, ibotenate evoked slow biphasic responses (excitation-depression) from the majority of these neurones. The depressant action was associated with an increase in spike height and was reversible. 3. The ibotenate depression could be observed as a temporary reduction in background firing rate, a loss of sensitivity to other amino acids, a progressive decrease in the excitatory responses to repetitive ibotenate applications or a fading of excitation following a prolonged administration of ibotenate. 4. The onset of the excitatory effects of glutamate, quisqualate and ibotenate was relatively well fitted by diffusion equations for a continuous point source. However, radial distances for diffusion in the case of ibotenate responses were comparatively greater than those for glutamate and quisqualate. 5. The depressant action of ibotenate was not antagonized by strychnine, picrotoxin or bicuculline. 6. Some methods of quantifying the responses to excitatory amino acids are described. The excitatory potency of quisqualate and N-methyl-D-aspartate was several times greater than that of glutamate. Aspartate and ibotenate were equipotent, while alpha-aminopimelate and alpha-methyl-DL-aspartate were much weaker. 7. It is suggested that the biphasic action of ibotenate on spinal interneurones might be the result of activation of excitatory and inhibitory sites fairly remote from the cell somata where extracellular recordings were probably made.


Effects of phlorizin on glucose, water and sodium handling by the rat kidney. 1. The effect of phlorizin on glucose, water and sodium handling by the kidney in anaesthetized rats was investigated, using clearance techniques, during infusion of saline (200 microliter min-1) or saline to which either low (0.1 mumole kg body weight-1 ml.-1) doses of phlorizin had been added. 2. Phlorizin increased the absolute and fractional excretion of glucose, urine osmolality and negative free water clearance; and reduced urine flow rate, glomerular filtration rate (GFR), absolute and fractional excretion of sodium, absolute excretion of sodium, absolute excretion of potassium and absolute and fractional rates of glucose reabsorption. 3. The data indicate that phlorizin has sites of action and effects additional to those on glucose transport in the proximal tubule. 4. Within each series there was a positive correlation between sodium and glucose reabsorption; but the rate of glucose reabsorption was different between each series even though the sodium reabsorption was not. 5. It is suggested that since both sodium and glucose reabsorption correlate with GFR, they may be related via GFR. 6. The data indicate that for the whole kidney any effect of glucose on sodium transport is small relative to total renal handling of sodium.


Effects of glucose on water and sodium reabsorption in the proximal convoluted tubule of rat kidney. 1. The effects of glucose on sodium and water reabsorption by rat renal proximal tubules was investigated by in situ microperfusion of segments of proximal tubules with solutions containing glucose or no glucose, with and without phlorizin. 2. Absence of glucose did not significantly alter net water flux. Sodium flux was reduced by about 10% but this was not statistically significant. 3. In the absence of glucose in the perfusion fluid net secretion of glucose occurred. 4. Phlorizin reduced either net reabsorption or net secretion of glucose; and net water flux. 5. The data suggest that in later parts of the proximal convoluted tubule some sodium may be co-transported with glucose, but that this represents only a small fraction of the total sodium reabsorption. 6. It is suggested that the glucose carrier is reversible and in appropriate circumstances could cause glucose secretion. 7. Although phlorizin alters net water flux the underlying mechanisms are not clear. 8. The calculated osmolality of the reabsorbate was significantly greater than the perfusate osmolality and greater than plasma osmolality although this was not quite significant statistically.


Electrical coupling and dye transfer between acinar cells in rat salivary glands. 1. Adjacent acinar cells in isolated rat parotid and submaxillary glands were found to be electrically coupled in greater than 90% of the pairs tested. 2. Cells injected with fluorescein or procion yellow showed transfer of the dyes to their coupled neighbours. While not all coupled cells exchanged dye, exchange occurred only between coupled cells. 3. In experiments using three micro-electrodes, coupled acinar cells from parotid gland were found to have a mean coupling coefficient of 0.69 +/- 0.04. This value is higher than those reported for most other vertebrate epithelial systems. 4. Membrane damage sufficient to reduce the occurrence of coupling between cells by 97% lowered the transmembrane potential by only 13%. This would indicate that in this system membrane potential may not be the most sensitive indicator of cell damage. 5. The significance of the presence of electrical coupling and cell-to-cell transfer of small tracer molecules is discussed in relation to salivary gland structure and possible functional consequences.


Membrane potential, resistance, and intercellular communication in the lacrimal gland: effects of acetylcholine and adrenaline. 1. Intracellular micro-electrode recordings were made from surface acini of mouse exorbital lacrimal glands placed in a Perspex bath through which oxygenated physiological saline solutions were circulated. Two micro-electrodes were inserted into neighbouring communicating cells. Through one of the electrodes, current pulses could be injected. The cells impaled were stimulated by iontophoresis of acetylcholine (ACh), adrenaline or isoprenaline from an extracellular micropipette. 2. During exposure to standard Krebs solution the resting membrane potential was -42.5 mV +/- 1.2 and the resting input resistance 3.3 Momega +/- 0.3. When the tips of the two intracellular micro-electrodes were more than 100 micrometer apart no electrical coupling between two impaled cells could be detected. At intertip distances below about 80 micrometer coupling was frequently observed. In all such cases the coupling ratio was 1. The resting current-voltage relation was almost linear within the membrane potential range of -30 to -80 mV. 3. During exposure to standard Krebs solution the resting membrane potential was -42.5 mV +/- 1.2 and the resting input resistance 3.3 Momega +/- 0.3. When the tips of the two intracellular micro-electrodes were more than 100 micrometer apart no electrical coupling between two impaled cells could be detected. At intertip distances below about 80 micrometer coupling was frequently observed. In all such cases the coupling ratio was 1. The resting current-voltage relation was almost linear within the membrane potential range of -30 to -80mV. 3. During exposure to standard Krebs solution short iontophoretic pulses of ACh or adrenaline caused fully reversible hyperpolarizations accompanied by marked reduction of surface cell membrane resistance and membrane time constant. The effects of ACh were blocked by atropine (1.4 x 10(-6)M). Iontophoresis of isoprenaline never had any detectable effect on membrane potential or resistance. 4. Applying de- or hyperpolarizing direct currents through one of the two intracellular micro-electrodes the effect of ACh or adrenaline could be observed at different lvels of resting potential. Depolarizing the acinar cell membrane resulted in an enhanced stimulant-evoked hyperpolarization whereas hyperpolarizing the acinar cell membrane resulted in a reduction, and at potentials more negative than -60 mV in a reversal of the stimulant-evoked potential change. The ACh equilibrium potential (EACh) under control conditions was -56.6 mV +/- 1.1 and EAdrenaline was -61.4 mV +/- 1.0. 5. Replacing the control superfusion solution by a Clfree sulphate solution resulted in an immediate shift of EACh towards more negative values. At steady state in the Cl-free solution the resting input resistance was 6.8 Momega +/- 1.3 EACh was -95.9 mV +/- 3.4. 6. Reducing [K]o from the usual 4.7 to 1.0 mM resulted in an immediate marked increase in the amplitude of ACh-evoked hyperpolarization whereas increasing [K]o to 10 mM almost abolished the ACh-evoked potential, but not resistance change. 7...


Chloride/bicarbonate exchange in human erythrocytes. 1. The exchange of chloride and bicarbonate across the human erythrocyte membrane has been followed by measuring the changes in extracellular pH which occur when chloride-rich erythrocytes are added to chloride-free media containing varying concentrations of bicarbonate and carbonic anhydrase. 2. The dependence of the rate of chloride/bicarbonate exchange on the extracellular concentration of bicarbonate was consistent with the existence of a saturable membrane anion transporter exhibiting Michaelis--Menten kinetics. In a medium containing sodium gluconate buffered to pH 7.0 with imidazole--malate the Km for bicarbonate activation of transport was 0.39 (+/- 0.03) mM and the Vmax was 2033 (+/- 80 m-mole anions exchanged/3 X 10(13) cells. min, at 10 degrees C. 3. Chloride/bicarbonate exchange was temperature-dependent with an Arrhenius activation energy of 19.4 kcal/mole in the temperature range 2--10 degrees C. 4. Exchange of intracellular chloride for extracellular bicarbonate was inhibited by the presence of extracellular halides. Inhibition by chloride, bromide and fluoride was competitive and the affinity of the transport system decreased in the order HCO-3 greater than Cl- greater than Br- greater than F-. The kinetics of inhibition by iodide were complex, but inhibitory effects of low concentrations of iodide were less than those of chloride and bromide.


Effect of amiloride on the renal response to saline expansion in new-born dogs. 1. The renal effects of amiloride were studied in twenty-six new-born and nine adult dogs, with and without saline expansion. 2. Without saline expansion, amiloride inhibited more sodium reabsorption (normalized to GFR) in puppies than in adults (5.95 vs. 2.18 muequiv/ml. GFR, P less than 0.01). Amiloride inhibited sodium reabsorption more in saline expanded than in nonexpanded puppies (9.39 vs. 5.95 muequiv/ml. GFR, P less than 0.01) but there was no difference between expanded and non-expanded adults. 3. Saline expansion by itself increased fractional sodium excretion (CNa/GFR) more in the adult than in the puppy (0.071 vs. 0.019, P less than 0.01). During amiloride inhibition, saline expansion increased CNa/GFR to 0.045 in the puppy (compared to 0.019 in the nonamiloride inhibited puppy) but saline expansion increased CNa/GFR to the same degree in the amiloride as in the non-amiloride inhibited adult. 4. In all puppies amiloride inhibited more sodium reabsorption than potassium secretion and there was poor correlation between the degree of inhibition of sodium reabsorption and potassium secretion for both the puppy (r = 0.14) and the adult (r = 0.05). 5. Assuming that amiloride acts by inhibiting sodium reabsorption and potassium secretion in the late distal and cortical collecting tubules, these results support the conclusion that in these regions of the nephron of the new-born dog (a) a greater fraction of the filtered sodium is reabsorbed than in the adult and (b) increased fractional sodium reabsorption is responsible, in part, for the attenuated natriuretic response to saline expansion.


Electrical properties of neurones in the olfactory cortex slice in vitro. 1. Slices of guinea-pig olfactory cortex were maintained in vitro. Electrical properties of neurones in the prepyriform region were studied using single high resistance glass micro-electrodes filled with potassium acetate, connected to a resistance-compensating circuit to allow passage of current through the electrode. 2. Neurones showed a high, stable resting membrane potential (75.4 +/- 2.7 mV, mean +/- S.D.; n = 47). Input resistance measured with small depolarizing currents varied over a range of 9-280 Momega. The time constant for decay of depolarizing potentials was 19.4 +/- 7.5 msec (mean +/- S.D.).. 4. Depolarization produced repetitive action potentials (maximum frequency of 85 Hz) having peak amplitudes of +16 to +47 mV. The action potential was followed by a depolarizing after potential of about 20 mV positive to the membrane potential. 5. In these and other respects, the prepyriform neurones appear to behave like most other neurones in the mammalian brain, after allowing for the more stable recording conditions in this preparation.


A depolarizing inhibitory potential in neurones of the olfactory cortex in vitro. 1. Stable intracellular recordings were obtained from neurones in slices of the guinea-pig olfactory cortex maintained in vitro. 2. Single stimuli applied to the lateral olfactory tract (l.o.t.) produced an excitatory post-synaptic potential (e.p.s.p.) usually generating a single spike. 3. The e.p.s.p. was followed by a long (200-500 msec) after-depolarization (l.a.d.) of peak amplitude 5-16 mV. This was accompanied by a very large conductance increase and was associated with an inhibition of the intracellularly recorded e.p.s.p. and of spike generation. 4. The l.a.d. was more susceptible than the e.p.s.p. to depression by (i) repetitive l.o.t. stimulation and (ii) raising external [Mg2+]. The l.a.d. could be generated without a preceding spike. 5. At an average resting membrane potential of -74 mV the average reversal potential for the l.a.d. (El.a.d.) was -63 mV.El.a.d. became more positive on reducing [Cl-]out or on using KCl-filled electrodes. 6. It is concluded that the l.a.d. represents a Cl- -mediated inhibitory post-synaptic potential, generated through deep-lying recurrent inhibitory loops.


A barbiturate induced intensification of the inhibitory potential in slices of guinea-pig olfactory cortex. 1. A study has been made of the effect of barbiturates on membrane constants and synaptic potentials of neurones in the isolated guinea-pig olfactory cortex slice. 2. Normally, a long depolarizing i.p.s.p. follows the e.p.s.p. Pentobarbitone (0.1 mM) produced a tenfold increase in the duration of the high conductance phase of this i.p.s.p. 3. The i.p.s.p. was potentiated increasingly with higher barbiturate concentrations from 0.02 to 1.0 mM-pentobarbitone and 0.2 to 5 mM-phenobarbitone. 4. The resting membrane conductance, the initial phase of the e.p.s.p. and the threshold for the action potential were unaffected at lower concentrations. 5. The highest barbiturate doses increased the resting membrane conductance. This was associated with a depolarization of about 14 mV maximally and resulted in smaller synaptic potentials. The effect was probably generated by the same mechanism as the i.p.s.p. 6. This fortifies the idea that barbiturates have a primary action on prolonging inhibition rather than a depression in the excitatory potential.


Calcium-induced increase in membrane permeability in the guinea-pig taenia coli: evidence for involvement of a sodium-calcium exchange mechanism. 1. High-Na tissues exposed to a Na-free solution with dimethyldiethanol ammonium chloride (DDA) or sucrose replacing Na, develop an increase in membrane permeability to small ions and molecules such as Na, K, sucrose and CoEDTA. 2. The increase in permeability only occurs when the Na gradient across the cell membrane is reversed, and is not due to damaging effects of the Na-free solution. It does not occur in normal or high-K tissues, and 15 mM-[Na]0 is enough to prevent the permeability change in high-Na tissues. 3. Tissues with increased permeability maintain high levels of Ca and the increased permeability does not occur in Ca-free solutions, or in solutions containing 5 mM-La3+. The rate of development of membrane leakiness depends on the level of extracellular Ca. 4. Tissues exposed to iodoacetic acid (IAA) and dinitrophenol (DNP) also develop a membrane leakiness, dependent on extracellular Ca and blocked by La3+. 5. The time taken for development of the increase in membrane permeability in metabolically inhibited tissues can be affected by the Na gradient. With no gradient, or a slightly reversed gradient the membrane break-down occurs more rapidly. 6. It is concluded that the increase in permeability is caused by an increase in internal Ca ions, and that the Na gradient as well as the levels of ATP are important in controlling Ca movements. 7. Tension recordings also support the some form of Na--Ca exchange mechanism operating in the taenia, and this mechanism is not completely blocked by La3+ ions, although they suppress the break-down in membrane permeability.


Mechanical properties of smooth muscle cells in the walls of arterial resistance vessels. 1. Methods have been developed for measuring the dynamic mechanical response of arterial resistance vessels (i.d. 83--235 micrometer) with a time resolution of about 4 msec. 2. Observations of the microscope image of the smooth muscle cells in the walls of these vessels indicate that there is little intercellular compliance in this preparation, and that the mechanical properties of the activated preparation are a reflexion of the mechanical properties of the individual smooth muscle cells. 3. Under isometric conditions the force developed per unit cell area was about 350 mN/mm2. Under isotonic conditions the cells had a maximum velocity for shortening at 37 degrees C of about 0.17 lengths/sec. 4. Quick releases of activated vessels indicate that the instantaneous elastic characteristic of smooth muscle cells is approximately exponential. 5. The wall tension response to small (0.3%) square wave changes in circumference was proportional to the logarithm of the time following the start of each circumference change. 6. Active wall tension, deltaT, was varied by varying the Ca2+ concentration of the activating solution. Under these conditions the active dynamic stiffness, k, was proportional to deltaT, and was not temperature dependent. The active half response time, tau (the time, taken to recover half the tension change caused by a small change in circumference) was also proportional to deltaT, but here the constant of proportionality had a Q10 of about 1.8. 7. It is concluded that the quick release response and the square wave response are in part a function of the mechanical properties of the crossbridges between the contractile filaments. Calculations show that both these responses can be explained if it is assumed that there is a relatively compliant passive component in series with the crossbridges.


Uptake and fate of ferritin in the uterine epithelium of the rat during early pregnancy. The ingestion of ferritin injected into the uterine lumen for 20 min was followed by light and electron microscopy. Uptake occurred on Days 4 to 6, with a distinct peak of activity on Day 5 when blastocysts are present in the uterine lumen. At this time, the antimesometrial cells took up more tracer than those on the mesometrial side. The ferritin was located in various types of organelles which contained acid phosphatase, indicating that the tracer entered the lysosomal system. Ferritin-containing lysosomes were essentially all located in the apical half of the cells at 1 h after the injection, but thereafter were distributed throughout the cell. There appeared to be some digestion of ferritin by 48 h, but no evidence for exocytosis of the tracer at the base of the cells was found with light or electron microscopy.


The organization of testicular interstitial tissue and changes in the fine structure of the Leydig cells of European moles (Talpa europaea) throughout the year. Seasonal changes of the testicular interstitial tissue were studied by electron microscopy. During the breeding season in spring, clusters of Leydig cells are surrounded by wide lymphatic sinusoids. In sexually quiescent moles, these sinusoids collapse, and the abundant Leydig cells become closely packed and occupy most of the testis. During sexual activity, the Leydig cells contain abundant smooth endoplasmic reticulum (SER), mitochondria with tubular cristae, and lipid droplets. Some areas of the cytoplasm are occupied exclusively by tubular SER, arranged in parallel. During regression the SER appears tortuous, and large lipid droplets are found in the cytoplasm, although these gradually become smaller. During the long period of sexual quiescence, the size and abundance of Leydig cells and the appearance of SER, lipid droplets and mitochondria were similar to those observed during sexual activity.


Seasonal changes in testosterone levels and androgen-dependent organs in male moles (Talpa europaea). Seasonal changes in testicular and plasma testosterone levels and in androgen-dependent organs were determined in moles breeding at 53 degrees N. Although the testes contain up to 30 times more testosterone during spermatogenesis than during sexual quiescence, appreciable quantities of this hormone are present during late summer and early autumn. Annual spermatogenesis lasts for only 2 months, but in some moles spermatozoa remain in the epididymis for up  to 3 months after the testes have begun to involute, and may therefore be available to inseminate females coming into a second oestrus.


Progesterone secretion by the corpus luteum of the early pregnant pig during superfusion in vitro with PGF-2alpha, LH and oestradiol. Corpora lutea obtained from pregnant sows (Days 18-22) were superfused in vitro for 2-4 h with PGF-2alpha and for 3 h with LH or oestradiol or combinations of PGF-2alpha with LH or oestradiol. LH but not oestradiol stimulated progesterone secretion while superfusion for a minimum of 3 h with PGF-2alpha caused an irreversible decrease in progesterone secretion. LH and PGF-2alpha were mutually antagonistic while oestradiol did not inhibit the luteolytic action of PGF-2alpha.


Adrenergic innervation and contractile activity of the mesotubarium superius of the rabbit oviduct. Various patterns of spontaneous contractile activity were observed in the mesotubarium in vitro, but generally the frequency was lower and the amplitude was higher in the contractions than in those of the spontaneously motile oviduct. Contractile responses to norepinephrine occurred at concentrations higher than 10(-8) M. Twitch-like contractile responses were produced by field stimulation of 1 msec, 1-30 HZ and 100 V for 10sec. Responses to norepinephrine and electrical stimulation were inhibited by phentolamine or phenoxybenzamine, but were not affected by propranolol. Spontaneous contractile activity of the mesotubarium was diminished but the tonus was not affected by isoproterenol. These results suggest that the responses of the mesotubarium to norepinephrine and electrical stimulation are mainly related to the alpha-receptor rather than to the beta-receptor component.


Role of the granulosa cells of the postovulatory follicle of the domestic fowl in oviposition. Surgical removal of the granulosa cells, leaving the remainder of the postovulatory follicle (POF) intact (including the thecal interstitial cells), resulted in delays of oviposition of about 19 h; similar delays were obtained when the granulosa was left in situ but was damaged by the insertion of a silicone disc into the POF. The insertion of wax balls resulted in delays of 3-4 h but the granulosa appeared to be normal. It is concluded that the integrity of the granulosa is important for normal oviposition.


The source of progesterone in rabbit blastocysts. High levels of progesterone were found in the blastocysts, uterine fluid and sera of normal pregnant rabbits on Days 6 and 7 of pregnancy. Very little progesterone (less than 2% of control) was present in bilaterally ovariectomized rabbits in which pregnancy was maintained by the administration of medroxyprogesterone acetate. The results demonstrate that the rabbit blastocyst is provided with large amounts of progesterone derived from the maternal ovaries.


Changes in concanavalin A agglutinability during development of the inner cell mass and trophoblast of mouse blastocysts in vitro. Mouse blastocyst cultures were analysed for Concanavalin A (Con A) agglutinability by microhaemadsorption methods and for Con A binding capacity with Rhodamine-Con A stain. The inner cell mass, which was not agglutinable in the early culture stages, became agglutinable when it started to develop. The trophoblast, which was initially agglutinable, lost this property as the cells matured. There was no apparent correlation between changes in agglutinability and capacity to bind Rhodamine-Con A. The pattern of change in Con A agglutinability which characterized development of the inner cell mass and trophoblast is consistent with an interpretation that agglutinability was related to the migratory activities of these cells. The loss of agglutinability associated with trophoblast maturation may have been due to alterations in Con A receptor accessibility.


Effect of fetal hypophysectomy on the initiation of parturition in the goat. Fetal hypophysectomy performed between 97 and 130 days of gestation caused a significant (P is less than 0.005) prolongation of pregnancy in 5 goats in which every fetus was treated. Three of these goats gave birth spontaneously. Sham surgery or hypophysectomy of one fetus of twins had no effect on gestation length. Hypophysectomized kids, delivered after prolonged pregnancy, were significantly heavier than normal term kids (P is less than 0.005) and had lighter adrenals (P is less than 0.025). Measurements of maternal peripheral plasma concentrations of progesterone and total unconjugated oestrogens showed that the changes in goats carrying hypophysectomized fetuses were similar to those of normal pregnancy except that the prepartum oestrogen peak was absent, whether or not parturition occurred spontaneously.


The maintenance of pregnancy in hypophysectomized goats. Pregnancy in goats is maintained after hypophysectomy at about Day 90 of gestation by injection of 20 mg progesterone or 1 mg LH/day, but not by 5 mg prolactin/day.


Effects of epsilon-aminocaproic acid on fertility in the rabbit. Administration of epsilon-aminocaproic acid, a fibrinolytic inhibitor, either orally or from an impregnated IUD, had no effect on numbers of implanted embryos, their viability, or their diameters at Day 10 of pregnancy.


Testicular blood flow and testosterone concentration in spermatic venous blood of anaesthetized rats. Testicular blood flow was measured by a radioactive microsphere technique. A significant correlation, rs equal to 0.82, was found between testicular blood flow and testosterone outflow in the spermatic venous blood, indicating that factors which affect the testicular circulation may influence testicular endocrine function.


Treatment of pregnant gilts with a prostaglandin analogue, Cloprostenol, to control oestrus and fertility. Oestrus was induced 4-7 days after treatment with Cloprostenol (ICI 80,996) in gilts between 12 and 40 days pregnant. Fertility at this synchronized oestrus was good (85%).


Pregnancy in the domestic cat after artificial insemination with previously frozen spermatozoa. Methods for collection, freeze preservation and artificial insemination of domestic cat semen were developed. Total sperm count and pre-freeze and post-thaw percent motility were significantly greater (P is less than 0.05) for samples collected by an artificial vagina method than for those collected by electroejaculation. Although conception rate was low (10.6%), 6 pregnancies were achieved, 2 after hormonal induction of oestrus.


Cyclic variation in concentrations of protein and hexose in human uterine flushings collected by an improved technique. Uterine flushings were obtained from fertile women at various stages of the menstrual cycle. A technique was used which excluded contamination with cervical mucus and significantly lowered contamination with blood in comparison with an established technique. Contamination of the uterine flushings with seminal plasma and tubal fluid was also prevented. The concentrations of protein and hexose in the uterine flushings, corrected for contamination with plasma, were significantly lower in the secretory stages than in the proliferative stages of the cycle. It is concluded that proteins and carbohydrates are present within the uterine lumen not only after ovulation but also during the preovulatory period.


The effects of a sudden decrease or increase in daylength on prolactin secretion in the ram. Six adult Soay rams were preconditioned to an artificial lighting regimen of alternating 4-month periods of long (16L:8D) and short days (8L:16D) for at least 10 months before blood samples were collected at hourly intervals for 24 h at various times. The abrupt change from long to short days resulted in a progressive decrease in plasma levels of prolactin, while that from short to long days had the reverse effect; the first response to the light changes was rapid, beginning within 6 days. During the periods of high secretion there was a 24-h cycle in plasma prolactin concentrations, with a peak in both the early dark and early light phases of each day. Changes in the relative magnitude of these peaks were observed in relation to the long-term alteration in prolactin secretion. Plasma levels of FSH were also measured and a close inverse relationship between gonadotrophin and prolactin secretion was observed.


Factors in mouse uterine fluid that inhibit the incorporation of [3H]uridine by blastocysts in vitro. Fluid flushed from the uteri of "delayed implanting" and "implanting" mice was fractionated by gel-filtration. The fractions were freeze-dried, individually resuspended in culture medium containing [3H]uridine, and used for incubating "implanting" blastocysts. Several factors were found that reduced incorporation of [3H]uridine by the blastocysts. The amount of inhibitory activity in corresponding factors was generally similar in flushings from both types of uteri, but there was significantly more inhibitory activity in the void volume fractions of flushings from "delayed implanting" animals and it is suggested that this factor may be responsible for the metabolic dormancy of embryos during the diapause associated with delayed implantation.


The appearance of oestrone sulphate in the peripheral plasma of the pig early in pregnancy. Detectable concentrations of oestrone sulphate were present in 50% of the plasma samples collected from pregnant animals by Day 17. No oestrone sulphate was detected in plasma from cyclic nonpregnant pigs.


Scanning electron microscopy of the vitelline membrane of the hen ovum. Manual removal of the perivitelline layer overlying the animal pole (AP) reveals three morphologically distinct regions of the vitelline membrane (VM). (1) The central germinal region is 600-800 micron in diameter and is densely populated with pleomorphic microvillous projections. (2) The periblastic region, which also exhibits microvillous projections, is 250-550 micron wide and consists of numerous (80-120) lacunae that are 10-60 micron in diameter and up to 20 micron in depth. (3) At the outer periblastic region, the microvillous projections are less numerous. In the vegetal hemisphere, the VM has few projections and occasionally is discontinuous.


Androgenic effects of the antiprogestagen RMI 12,936. RMI 12,936 (7alpha-methyl-17beta-hydroxy-androst-5-en-one) was tested for androgenic activity in mouse kidney and for antiprogestational activity in guinea-pig uterus. RMI 12,936 stimulated an increase in kidney weight and in the activity of the androgen-responsive renal enzymes, beta-glucuronidase, alcohol dehydrogenase and arginase. RMI 12,936 was bound by the renal androgen receptor with a relative affinity approximately one-third that of testosterone. Although RMI 12,936 did not stimulate glycogen accumulation in guinea-pig endometrium in vivo, it was active in endometrial organ culture. When RMI 12,936 was combined with progesterone, glycogen accumulation in vitro was partly inhibited. RMI 12,936 was bound by the guinea-pig uterine progesterone receptor with a relative affinity of less than 1%. It is concluded that RMI 12,936 is an androgenic steroid with antifertility actions and in-vitro antiglycogenic activity.


Further investigation of the antifertility effects in the rat of the antiprogestational steroid, RMI 12,936, and related compounds. The antifertility activities of RMI 12,936 and 7alpha-methyltestosterone may be reversed by progesterone implants in ovariectomized, but not in intact, rats on Day 8 of pregnancy. The presence of the ovary for 48 h after administration of RMI 12,936 is necessary for irreversible antifertility activity to be developed, and it is concluded that this activity is due to a metabolite other than 7alpha-methyltestosterone. 7alpha-Methylandrostenedione was significantly less potent than RMI 12,936 in antifertility tests, while the uterotrophic activity of RMI 12,936 was not inhibited by aromatization inhibitors, suggesting that the active metabolite is not produced by dehydrogenation or aromatization of 7alpha-methyltestosterone.


Age-related changes in responsiveness of rat Leydig cells to hCG. The responsiveness of decapsulated testes and isolated Leydig cell preparations from rats (30-80 days of age) to a constant dose of 3 ng hCG/2 ml was assessed by comparison of the production of testosterone and "total 17beta-hydroxy androgen" (17beta-HA). When testosterone secretion was used as the index of response, there was a marked increase in the production with age by decapsulated testes and also by equal numbers of Leydig cells. When 17beta-HA was taken as the response parameter this increase was only marginal for the decapsulated testes and there was an age-dependent decrease when expressed per 10(6) cells. These differences probably reflect changes in the metabolism of testosterone to 5alpha-reduced products with increasing age because 80% of androgen secreted at 30 days is 3alpha-androstanediol and 86% is secreted as testosterone at 80 days. We conclude that for studies on hCG responsiveness and the steroidogenic capacity of immature rat Leydig cells (a) testosterone is an inappropriate response parameter and (b) this response undergoes a decrease rather than an increase during prepubertal development.


Assessment by microflow fluorometry of the purity of interstitial cell suspensions from the rat testis. The technique of microflow fluorometry (MFF) was used to identify the proportion of haploid cells (from the tubules) in interstitial cell suspensions. The MFF estimates of the degree of contamination by tubular elements correlated well with the numbers of cells with Leydig cell morphology and those staining positively for 3beta-hydroxysteroid dehydrogenase.


The viability of deep-frozen cow embryos. Day 7 cow embryos were frozen in 1.5 M-DMSO in PBS at 0.3 degrees C/min to -36 degrees C and at 0.1 degrees C/min between -36 and -60 degrees C before being plunged directly into liquid nitrogen. They were subsequently thawed (rapidly to -50 degrees C, at 4 degrees C/min from -50 to -10 degrees C, and rapidly again) to room temperature. Embryonic viability was tested by four different transfer techniques. Maximum pregnancy rate (8/12) was obtained with surgical transfer immediately after thawing and dilution of DMSO.


Comparison of the fetal survival rate in heifers after the transfer of a embryo surgically to one uterine horn and non-surgically to the other. When transfer of Day 7 embryos was surgically to the horn ipsilateral to the CL and non-surgically to the contralateral horn, fetal survival rate was 85 and 35% respectively. After non-surgical transfer to the ipsilateral and surgical transfer to the contralateral horn, fetal survival rate was 20 and 30% respectively.


Reproduction in young sheep: some genetic and environmental sources of variation. "The extent of genetic and environmental variation" in the development of reproduction in sheep is illustrated by examples with particular reference to variation among breeds and to the effects of photoperiod. The interactions between genetic and environmental effects are introduced; these may be so great that genetic groups may reverse their ranking for rate of development in different environments. The "physiology of puberty" is then discussed. The difficulty of separating puberty from seasonal variation is stressed, and a possible contrast is drawn between the physiological characteristics of genetic variation and those of environmental variation in reproductive development. Finally the physiological factors associated with sterility in young females are discussed; most studies, however, have been conducted during the time of year when adult females would also be expected to be sterile, so that conclusions are difficult and a "missing link" cannot be identified.


The HLA system and immunological defence against cancer: a review. In nonmalignant disease, there have been two mechanisms implicated in the association of HLA antigens with disease. In ankylosing spondylitis, evidence is accumulating for cross tolerance between a bacterial antigen and the HLA-B27 antigen; while in the autoimmune diseases, the involvement of an abnormal immune response gene, associated with A1/B8 haplotype, is strongly suspected. The same haplotype has also been associated with recovery from hepatitis B infection and survival of patients with Hodgkin's disease and acute myeloid leukaemia. At present, there are no techniques to study directly immune response genes in man and so these observations are still strictly academic. However, with increasing interest in the use of immunotherapy in cancer and the demonstration in mice that the major histocompatibility system may be the site of action of soluble mediators of immune memory, understanding the mechanisms of action of the HLA associated resistance factors may enable a more rational approach to immunotherapy in man.


The treatment of perianal and anal condylomata acuminata: a new operative technique. Seventy-five patients have been treated for condylomata acuminata by means of a new operative approach which results in the preservation of the maximum amount of normal tissue. The technique has proved to be simple to perform, it has minimal complications and causes the patient little in the way of discomfort. Three out of 4 patients treated have no significant recurrent wart formation.


Cure or care in everyday practice.

Cure or care in everyday practice. Two cases of carcinoma of the stomach presenting during the same month and dying within four weeks of one another less than one year later are presented. One was treated symptomatically and the other received radical surgery. The care they received depended on decisions about diagnosis and treatment; the outcomes of these and the difficulties involved in evaluating monetary costs and quality of care are discussed in the light of recent interest in medical audit.


Sterilisation: the Aberdeen experience, and some broader implications. In her paper, Sue Teper outlines the various methods of contraception or fertility control and their relationship to sterilisation. She also considers a particular group of women in Aberdeen as a mini case-study. From these two aspects of sterilization develops a third--that of broader medical and economic issues. Sterilisation usually concerns patients who are free from illness, therefore the attitudes of medical personnel are much more relevant to whether or not the operation is performed on request purely as a means of fertility control, rather than for medical reasons where the patient may be at risk were a pregnancy to occur. Ms Teper calls for medical staff in this instance to clarify their own attitudes in decisions which involve surgical skills and healthy patients.


Recent and possible future trends in abortion. The regularly published abortion statistics are insufficiently detailed to make it easy to assess the significance of increases or decreases in the annual number of abortions. Numbers of abortions are related only to a few broad age groups of the women at risk, the size of those age groups is not normally stated, and the age and marital status groupings employed differ from those used for comparable data about trends in child bearing. By matching demographic data on trends in pregnancies which are deliberately terminated (abortion) and those which are not (fertility), this note attempts a) to assess the true impact of abortion among women living in England and Wales during 1973-76, and b) to consider whether the annual volume of abortions may increase over the next decade and what such an increase might signify.


Fetal survival--who decides?

Fetal survival--who decides? In this paper Iain McFadyen highlights a modern ethical dilemma. In each case the fetus was recognised to be in danger, but in both cases the advice given in the fetal interest was refused by the mothers. Both the mother and the physician were concerned for the fetus, but their differing actions and reasons pose the dilemma--who decides?


The teaching of medical ethics: University College, Cork, Ireland. Dolores Dooley Clarke describes how the course in medical ethics at University College, Cork is structured, how it has changed and how it is likely to change as time goes on. Originally, the students seemed to view it as an intrusion 'to be tolerated' in their programme of 'strictly medical' studies. However, having moved on from that and away from the lecturer always being a Roman Catholic priest as well as a member of the Philosophy Department, the students now appear to view it as producing a stimulus for a new interest in the area of ethics for physicians. This seems to have come about through the more extensive participation of students in researching and presenting issues of medical ethics.


Risk of coeliac disease in children of patients and effect of HLA genotype. Among 73 offspring of parents with coeliac disease, 4 were affected, including 1 in whom the diagnosis was made as a result of the study. The coeliac parents of all 4 were HLA-B8 positive, but 1 affected child had failed to inherit his affected parent's B antigen. The findings are consistent with the hypothesis that an allele affecting liability to coeliac disease is in linkage disequilibrium with HLA-B8.


Popliteal pterygium syndrome: a phenotypic and genetic analysis. Two additional families with popliteal pterygium syndrome are presented. Using previously published pedigrees, as well as the ones reported here, evidence is presented that supports an autosomal dominant mode of inheritance for this syndrome. Analysis of previous familial cases showed a large degree of between and within-family variation. The segregation analysis supports the dominant hypothesis (P=0.5).


Trisomy 8 syndrome.

Trisomy 8 syndrome. Clinical and dermatoglyphic data on a male patient with complete trisomy 8 are reported and compared with those of other known cases of trisomy 8. The more discriminating findings for this condition are skeletal anomalies, restricted articular function, and speech problems.


Trisomy 18 syndrome with an unusual karyotype: possible double isochromosome. Chromosome analysis of an infant with characteristic features of trisomy 18 is presented. The chromosome complement contained a modal count of 47 but there was only one No. 18. In addition, there were two metacentric chromosomes of different sizes. The two metacentric chromosomes were identified by G- and C-banding to be possible isochromosomes of the long and short arms of a No. 18 chromosome.


Partial 18 trisomy (with 47 chromosomes) resulting from a familial maternal translocation. A newborn female infant presented with the classical picture of 18 trisomy syndrome. Her karyotyping was 47,XX,+der(18)t(12;18)(q24;q21)mat. The mother was a balanced reciprocal translocation carrier and so too was one of the two maternal uncles of the proposita, indicating that the translocation was already present in one of the grandparents who were not available for examination. This family suggests that triplication of the distal part of the long arm of chromosome 18 is not necessary to produce Edwards' syndrome.


Participation of house staff in group practice: experience at a tertiary care center. In order to improve patient care, provide better teaching in an ambulatory setting, and establish research opportunities for faculty staff, the medical clinic of the Children's Hospital of Philadelphia has been developed into a group practice. The entire house staff is involved in this project, and it appears that the endeavor has resulted in improved patient care and house officers who are better prepared for outpatient problems. Some of the difficulties are discussed.


The nurse practitioner as a teacher of physical examination skills. The service role of nurse practitioners has been widely recognized (1). However, their potential as clinical instructors of physical examination skills has not been appreciated. This article details a new first-year medical school course in physical examination in which nurse practitioners are key members of the instructional team.


Physician's orders, use of nursing resources, and subsequent clinical events. Orders written by medical residents to be carried out on newly hospitalized patients were reviewed to determine the frequency of vital signs orders. Subsequent clinical events requiring the nurse to contact the house officer were then determined by daily follow-up. No relationship was found between the frequency of initial vital signs and the probability of a subsequent vital-sign event. However, the probability of a subsequent non-vital-sign event was 3.8 times greater among patients with frequent initial vital signs than among all others. Since orders requesting the frequent determination of vital signs appear to predict clinical events other than vital-signs events, such orders may be wasteful of nursing resources. In addition, other skilled observations may be neglected. These data suggest that physicians should request nurses to use more efficient and appropriate methods of clinical observation.


The effects of monitoring the use of gentamicin in a community hospital. This report describes the effect of a combined education and monitoring program on the use of gentamicin in a community hospital. The use of gentamicin was evaluated in 82 patients prior to an education program and in 80 patients after the education program. The results indicate that the attention focused on gentamicin by the study significantly improved the valid indications for treatment from 75% to 87% (p less than .05), increased the pretreatment use of bacteriologic cultures from 85% to 97% (p less than .05), increased the use of alternative less toxic antibiotics from 36% to 75% (p less than .05), and increased the frequency with which serum gentamicin concentrations were requested during therapy from 28% to 56% (p less than .001). Thus, the data support the tenet that the ways antibiotics are employed in community hospitals can be altered.


External examinations for internal evaluation: the National Board Part I Test as a case. The appropriateness of the Part I examination of the National Board of Medical Examiners to evaluate second-year curricular performance of students at Case Western Reserve School of Medicine was examined. Review of the June 1974 examination by 37 faculty members revealed that 85% of the items reflected the content of the second-year curriculum and that 60% could be answered from information provided in the second-year teaching. Two-thirds of the items were related to the content of the first-year curriculum, and half could be answered on the basis of first-year material. The school's faculty used the study data in making policy-changing decisions.


Results of the NIRMP for 1977.

Results of the NIRMP for 1977. The results of the National Intern and Resident Matching Program for the past four years show a steadily increasing number of positions offered and filled in the primary care specialties. The number of percentage of unmatched U.S. students decreased. The number of foreign medical graduates matched remained constant. Marked differences in the numbers of positions offered and filled were found among the various regions of the country.


Measuring the medical school learning environment. Medical educators' growing concern over the high level of student stress has been accompanied by a shift in their conceptualization of the problem. Student stress is increasingly seen as a problem resulting from the individual's interaction with the learning environment and not as an indication of personal deficiency. This shift has made evident the need for an instrument capable of assessing the significant dimensions of the medical school learning environment. This report describes how the Medical School Learning Environment Survey (MSLES) was developed to measure aspects of the learning environment relevant to student stress. Results of the first administration and plans for future projects using the survey are discussed.


One strategy for controlling costs in university teaching hospitals. Major teaching hospitals, because they treat a more complex mix of patients than do nonteaching hospitals, usually show higher costs per patient day or per case. As a result, teaching hospitals are particularly vulnerable to the decisions of those cost control and planning agencies that are unable or unwilling to treat the problem of case mix. Research at Yale University reported here demonstrates the effect of case mix on costs. A methodology is outlined that can be used by teaching hospitals in determining their costs of treating patients with a complex mix of diagnoses. It is not held that case mix alone explains all of the cost differences between teaching and nonteaching hospitals; but until that factor is isolated and identified, the other contributors to cost variation cannot be examined.


Primary and specialized care: implications for learning situations. Existing data suggest that there are differences between primary and specialized (consultant) care in clinical practice and in clinical decision-making. In addition, there are distinctions attributable to the nature of the two functions, the clinical settings, and the use of knowledge and technique. The most important difference, however, centers around the varying prevalence of disease between primary and specialized care and the practitioner's relative use of disease frequency in decision-making. Because of these differences, medical schools should develop primary care situations which are equally as valued as specialty care situations. Although the impact of substantial and attractive primary care curricula is unknown, their potential value in guiding appropriate students to enter primary or specialized care careers could be considerable.


Terminating the doctor-patient relationship. This paper addresses a neglected area of medical student education--terminating the doctor-patient relationship. Rich clinical teaching opportunities are lost when educators fail to illustrate the significant emotional aspects of ending this highly personal affect-laden experience. The author explores these teaching opportunities through examination of elements of doctor-patient relationships, professional development, unresolved doctor-patient conflicts, role underevaluation, patient gifts, and referral procedures.


Behavioral scientists as clinical educators of primary care practitioners. Behavioral scientists on the faculty of the Johns Hopkins University Health Associate Program work in teams with medical preceptors in the clinical education and supervision of students during their first year of training. The rationale, objectives, and methods of implementation for this aspect of the program are discussed. This approach answers current concerns that relevant behavioral science content must be integrated into clinical training, and it appears to be useful at all levels of medical education.


Studies on isolated subcellular components of cat pancreas. III. Alanine-sodium cotransport in isolated plasma membrane vesicles. Transport of alanine was studied in isolated plasma membrane vesicles from cat pancreas using a rapid filtration technique. The uptake is osmotically sensitive and the kinetics of L-alanine transport are biphasic showing a saturable and a nonsaturable component. The saturable component is seen only when a sodium gradient directed from the medium to the vesicular space is present. Under this condition an overshooting uptake of L-but not of D-alanine occurs. The Na+ gradient stimulated uptake of L-alanine is inhibited by L-serine and L-leucine and stimulated when the membrane vesicles had been preloaded with L-alanine, L-serine or L-leucine. The ionophore monensin inhibits stimulation of uptake caused by a sodium gradient. In the presence of valinomycin or carbonyl cyanide p-trifluoromethoxyphenylhydrazone (CFCCP), the sodium-dependent transport is augmented in vesicles preloaded with K2SO4 or H+ ions (intravesicular pH 5.5), respectively. In the presence of different anions, the Na+-dependent transport is stimulated according to increasing anionic penetration through membrane (lipid solubility). We conclude that a sodium dedpendent electrogenic amino acid transport system is present in pancreatic plasma membranes.


Oscillation of membrane potential in L cells: III K + current-voltage curves. Cultured L cells were found previously to have an oscillating membrane potential. Current-voltage (I--V) curves were measured during these oscillations. Two I--V curves were recorded, one at the maximum and one at the minimum of oscillations. Each curve is nonlinear, and when they are subtracted from one another, the result gives the I--V curve for the K+ current producing oscillations. This Ik--V curve is zero for -85 to -90 mV and saturates for positive and high negative membrane potentials. When the external K+ is increased the I--V curve is shifted and its zero current potential is reduced. The K+ zero current potential follows a Nernst relation when plotted against the external K+ concentration. The Ik--V curves all have a similar shape at different K+ concentrations, showing a saturation on each side of the zero current potential. The results can be explained satisfactorily in term of a carrier model for K+ ions.