Methadone-induced respiratory depression in the dog: comparison of steady-state and rebreathing techniques and correlation with serum drug concentration.

The respiratory effect of di-methadone administered subcutaneously was examined in awake, unsedated female Labrador retrievers in which a chronic tracheostomy had been established. Respiratory depression was determined from the change in ventilatory response to carbon dioxide. Two methods for assessing the response were evaluated and compared, namely the classical steady-state and rebreathing techniques. Maximal methadone-induced respiratory depression after administration of 2 mg/kg of dl-methadone occurred by 1 hr as detected by both methods, but the magnitude of the response as detected by the steady-state technique was significantly greater. At 8 hr significant respiratory depression was still detectable by the steady-state but not by the rebreathing technique. At comparable serum drug levels, the rebreathing method consistently detected a smaller degree of drug-induced respiratory depression. Methadone administration produced a decrease in slope of the ventilation-response curve which was significant at 1 and 2 hr for both methods. Slopes of the response curves obtained at pretreatment control measurements were markedly different for the two techniques, being significantly greater for the rebreathing method. Serum dl-methadone concentration was measured by radioimmunoassay. The mean serum half-life of methadone was 4.7 hr. There was excellent correlation between the logarithm of serum drug concentration and drug-induced respiratory depression as measured by either technique.


Interaction of methadone and ethanol metabolism.

To determine whether there might be a physiologic basis for the abuse of ethanol by methadone maintenance patients, studies of methadone metabolism were conducted in vivo and in vitro after acute and chronic ethanol administration to rats. Acute administration of ethanol resulted in increased brain and liver concentrations of methadone at two time periods and decreased biliary output of pharmacologically active methadone measured by radioactive tracer technique with [3H]methadone. In vitro, ethanol inhibited N-demethylation of methadone by microsomes from livers of naive rats, with a Ki averaging 32 mM (146 mg/kl). Also, methadone metabolism was inhibited by carbon monoxide indicating cytochrome P-450 dependence as is the case for ethanol. Chronic administration of ethanol to rats led to decreased levels of unmetabolized methadone in brain and liver, in vivo, and to increased microsomal N-demethylation of methadone, in vitro, compared to pair-fed controls. Therefore, acute ethanol administration may enhance cerebral effects of methadone by interfering with degradation of methadone at liver microsomal sites. Chronic ethanol administration increases methadone metabolism by stimulating degradation in liver microsomes.


The effect of delta9-tetrahydrocannabinol on the conversion of [3H]trypotphan to 5-[3H] hydroxytryptamine in the mouse brain.

The effects of a 30-min pretreatment with varying doses of delta9-tetrahydrocannibinol (delta9-THC) on the synthesis of 5-[3H]hydroxytryptamine (5-[3H]HT) from an intravenous 10-min pulse of L-[3H]tryptophan ([3H]try) were measured in the mouse brain. We also determined the effects of delta9-THC on several parameters believed to influence the synthesis of brain 5-HT, including total and free plasma tryptophan and the high-affinity synaptosomal uptake of tryptophan. Delta9-THC was found to increase the amount of [3H]try accumulated by the brain as well as the amount of 5-[3H]HT synthesized. This effect was greater at intermediate doses than at the highest dose tested. However, delta9-THC was determined to have no effect on the actual rate of conversion of [3H]try into 5-[3H]HT at any dose tested. Delta9-THC had no effect on either plasma tyrosine ot free tryptophan levels. However, delta9-THC decreased total plasma tryptophan at low and intermediate doses, but had no effect at the highest dose tested. Synaptosomal uptake of [3H]try was unaffected by pretreatment with delta9-THC at any dose tested. These data suggest that delta9-THC increases the synthesis of 5-HT, not by altering the actual rate of conversion of tryptophan to 5-HT, but by altering, via an unknown mechanism, the quantity of tryptophan available for conversion to 5-HT.


N,N-Di-n-propyl dopamine: a qualitatively different dopamine vascular agonist.

N,N-di-n-propyl dopamine (DPDA) dilates the renal vascular bed by action on dopamine (DA) vascular receptors. In phenoxybenzamine-treated dogs DPDA caused dose-related increments in renal blood flow with an ED50 approximately 15 to 30 times greater than DA. The renal vasodilation was not antagonized by propranolol, antihistamines, atropine or hexamethonium, but was attenuated specifically by the DA antagonists metoclopramide and haloperidol. DPDA lacked beta adrenergic activity. In doses up to 480 microgram/kg i.v. DPDA had no effect on cardiac contractile force, whereas the minimal effective dose of DA is usually less than 8 microgram/kg. Increments in femoral or renal blood flow produced by DPDA were not antagonized by propranolol. DPDA and DA also differed in their effects on the femoral vascular bed. Before administration of phenoxybenzamine DPDA caused vasodilation while DA typically produced dose-related vasoconstriction. DPDA-induced femoral vasodilation was markedly attenuated by phenoxybenzamine and hexamethonium in contrast to renal vasodilation which was not affected by these drugs. DPDA was also a weaker vasoconstrictor than DA. These findings demonstrate that it is possible to synthesize DA vascular agonists with qualitatively different pharmacological profile than DA.


Structure-activity relationships of natural and synthetic cannabinoids in suppression of humoral and cell-mediated immunity.

Delta-9-Tetrahydrocannabinol (delta-9-THC) a psychoactive constituent of marihuana, has been shown in previous studies to suppress humoral and cell-mediated immunity. The objective of this study was to determine whether structural modification of delta-9-THC would result in a more potent immunosuppressant agent devoid of central nervous system activity. The ED50 for reduction of the humoral immune response to sheep erythrocytes as measured by spleen plaque forming cells/10(6) spleen cells was 70 mg/kg for delta-9-THC. Delta-8-THC, 1-methyl delta-8-THC and abnormal delta-8-THC were more potent with ED50 values of 14, 13 and 8 mg/kg, respectively. Cell-mediated immunity was evaluated by a delayed-type hypersensitivity response to sheep erythrocytes. At doses of 100 mg/kg s.c. for 4 days, the cannabinoids suppressed the delayed-type hypersensitivity response from 35 to 64%. These data show that the cannabinoids can cause immunosuppression which is not related to central nervous system activity since 1-methyl delta-8-THC and abnormal delta-8-THC have minimal central nervous system activity.


Kinetics of metabolite formation and elimination in the perfused rat liver preparation: differences between the elimination of preformed acetaminophen and acetaminophen formed from phenacetin.

Both [14C]phenacetin and [3H]acetaminophen in tracer concentrations were perfused simultaneously once through the rat liver preparation at a constant perfusate flow rate (10 ml/min), and the rates of appearance of [14C]acetaminophen and [3H]acetaminophen in the effluent were compared. The data indicated that the extraction ratio of [14C]acetaminophen derived from [14C]phenacetin was smaller than that of the preformed [3H]acetaminophen added to the input perfusate (exogenously), i.e., the availability of the metabolite formed in situ was higher than the availability obtained when the metabolite was presented in the input blood. The observed availability of the acetaminophen derived from phenacetin was usually greater than that predicted by a "well-stirred" model and less than that predicted by a "parallel tube" model of hepatic drug clearance; the former model describes the liver as a well-stirred compartment with the drug in liver in equilibrium with that in the hepatic venous blood, and the latter model describes the liver as a group of identical and parallel uints with enzymes distributed evenly in hepatocytes lining the tubes. We conclude that the liver may be viewed as an imperfectly mixed compartment with regard to the availability of the metabolite which is generated from a precursor.


Disposition of clonidine in rats as determined by radioimmunoassay.

The disposition of the potent antihypertensive drug clonidine has been poorly understood through the lack of a convenient and sensitive assay. A radioimmunoassay for clonidine has been developed and is capable of detecting as little as 10 pg of clonidine. 2,6-Dichlorophenyl-guanidine, a known metabolite of clonidine, did not cross-react with the antiserum whereas another metabolite, 4-hydroxyclonidine, was as potent as clonidine in displacing labeled clonidine from the antibody. However, a simple solvent extraction step before the radioimmunoassay selectively extracted clonidine from a mixture of clonidine and 4-hydroxyclonidine in alkaline plasma and this procedure permitted a specific assay for clonidine. The plasma levels of clonidine in rats after the administration of a hypotensive dose (100 microgram/kg i.v.) were determined by radioimmunoassay and these data indicated that the disposition of clonidine conforms to an open two-compartment, pharmacokinetic model. Clonidine rapidly accumulated in the brain as shown by the attainment of peak concentrations within 2 min of i.v. injection.


Spin-label study of phenothiazine interactions with erythrocyte ghost membranes: a possible membrane-mediated antisickling action.

Erythrocyte membrane alterations by 11 phenothiazine derivatives known to inhibit the sickling phenomenon in vitro have been evaluated in ghosts by the spin-labeling technique. Four sulfydryl-reactive spin labels were employed: 4-maleimido-2,2,6,6-tetramethylpiperidinooxyl; 4-(2-iodoacetamido)-2,2,6,6-tetramethylpiperidinooxyl; 3-[(2-iodoacetamido)methyl]-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl; and 3-(maleimidomethyl)-2,2,5,5-tetramethyl-1-pyrrolidiny-loxyl. The latter spin label was judged most useful since its spectrum was sensitive to subtle perturbations by drugs spanning a considerable potency range. An increase in spin-probe immobilization was induced by each drug with approximate relative potencies given by the order: desmethylchlorpromazine congruent to thioridazine congruent to fluphenazine congruent to prochlorperazine congruent to trifluoperazine greater than acetophenazine congruent to triflupromazine congruent to chlorpromazine greater than promazine greater than promethazine greater than perphenazine. This order correlates (P less than .01) with their antisickling potency in vitro.


Renal effects of bumetanide.

Effects of bumetanide (2.5, 25 and 250 microgram/kg i.v.) on renal hemodynamics and function were investigated in anesthetized dogs using clearance methods, stop-flow analysis and radioactive microsphere. Under conditions of mild isotonic saline loading, significant diuresis was observed within 5 min after the injection of 25 and 250 microgram/kg of the drug, and with the higher dose, a maximal fractional sodium excretion of 34% was observed. The dose of 250 microgram/kg of bumetanide caused a significant 44% increase in blood flow 5 min after the injection. In a hydropenic condition, the reabsorption of free water was significantly reduced, thus suggesting an inhibitory effect on the ascending limb of Henle's loop. In stop-flow experiments, inhibition of sodium reabsorption at the distal tubule was evident. Bumetanide increased blood flow in the juxtamedullary more so than in the superficial area. The increased blood flow in the juxtamedullary area also may contribute to the diuretic action of bumetanide through enhancement of the countercurrent exchange system in the renal medulla.


Pharmacological analysis of the action of diuretics in the newborn pig.

The effects of furosemide, ethacrynic acid, hydrochlorothiazide and amiloride on renal function of newborn piglets, 5 to 10 days old, were evaluated. Furosemide and ethacrynic acid were the most effective diuretics. Furosemide infusion at 0.5 mg/kg/hr inhibited reabsorption of 21% filtered sodium and ethacrynic acid, 1 mg/kg/hr, increased fractional sodium excretion to 29%. Hydrochlorothiazide infusion produced a milder natriuresis than furosemide or ethacrynic acid. Infusion of hydrochlorothiazide at 1.0 mg/kg/hr increased fractional sodium excretion from 0.3% during the control period to 7.2%. Furosemide, ethacrynic acid and hydrochlorothiazide each increased potassium excretion to near 20 microEq/min. amiloride (1.0 mg/kg/hr) increased fractional sodium excretion from 0.2% during control period to 2.8% during drug infusion but did not affect potassium excretion. When infused in combination with furosemide and hydrochlorothiazide, amiloride increased the natriuresis and decreased the kaliuresis of both diuretics. It is concluded that the unanesthetized piglet is a good model for renal function of immature mammals and responds to diuretics in a manner qualitatively similar to adults.


Cyclophosphamide. I. Effects of survival and colony-forming cells in BDF1 L-1210-bearing mice.

A new technique is described in which L-1210 colony-forming cells and myelopoietic colony-forming cells can be assessed simultaneously from hemopoietic organs of L-1210-bearing mice. This technique was utilized to evaluate the effects of cyclophosphamide on the recovery of myelopoietic function in tumor-bearing mice. In general, changes in L-1210 colony-forming cells in bone marrows and spleens of cyclophosphamide-treated L-1210-bearing mice correlated with their mean survival time. Injection of L-1210 cells alone enhanced myelopoiesis in the spleen and injection of both cyclophosphamide and L-1210 cells resulted in a synergistic enhancement of myelopoiesis in the spleen. The results in this paper are also compatible with the hypothesis that the host defense system does regulate the growth of L-1210 cells in BDF mice.


Interaction of hydralazine with tension development and mechanisms of calcium accumulation in K+-stimulated rabbit aortic strips.

A study was made of the effects of hydralazine on K+ contractures in rabbit aortic strips. Measurements were made of effects on tension generation, Ca++ accumulation measured using 45Ca++ (lanthanum method) and 45Ca++ efflux. Hydralazine relaxed established K+ contractures and inhibited tension development when tissue exposure to hydralazine preceded K+ depolarization. Both the threshold and the maximum tension responses of strips to Ca++ (K+-depolarized tissues) were altered by hydralazine in a dose-dependent manner. The Ca++ uptake associated with K+ depolarization was inhibited by relaxant doses of hydralazine; however, hydralazine did not significantly affect the rate of 45Ca++ efflux. Hydralazine also raised the threshold to the inhibitory (relaxant) effects of higher (greater than 2.5 mM) bath concentrations of Ca++. It is suggested that hydralazine inhibits K+ contractures in aortic strips by interference with the entry of Ca++ into the cell, reflecting an effect of hydralazine at the cell surface membrane.


The voltage- and time-dependent effects of (-)-verapamil on the slow inward current in isolated cat ventricular myocardium.

The effects of (-)-verapamil on the slow inward current in cat papillary muscle were investigated under voltage clamp conditions. The following results, which correlate significantly with the negative inotropic effect of the drug, were obtained: (-)-verapamil reduced the slow inward current in a highly frequency dependent manner, with greater reduction at higher frequency; at cycle intervals longer than 10 sec, the inhibition practically disappeared. As an associated phenomenon there was a stepwise decrease of slow inward current subsequent to an increase in frequency. This "staircase" of the current was facilitated with lowering the holding potential and was diminished by hyperpolarization. Possible mechanisms underlying the membrane action of (-)-verapamil are discussed.


A mechanism to explain the antihypertensive action of propranolol.

The present experiments were designed to measure the direct effects of propranolol on carotid sinus pressoreceptor nerve activity in the semi-isolated, superfused sinus of the cat. Propranolol (5 microgram/ml) significantly enhanced carotid sinus nerve activity at perfusion pressures of 100, 150 and 250 mm Hg. The enhancement was due primarily to the recruitment of new fibers. In similar preparations, perfused at constant flow, propranolol increased sinus resistance in parallel with the increase in sinus discharge. These effects were rapidly dissipated by rinsing with drug-free perfusion solution. The evidence suggests that propranolol may produce a change in either the elastic or autoregulatory modalities of sinus smooth muscle. This may produce a functional "resetting" of the sinus and provide a mechanism to explain the antihypertensive effect of propranolol.


A novel vascular relaxing agent, N-(6--aminohexyl)-5-chloro-1-naphthalensulfonamide which affects vascular smooth muscle actomyosin.

The relaxing effect and possible mechanism of N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) on isolated rabbit artery were investigated. The addition of W-7 in concentrations ranging from 1 X 10(-6) to 3 X 10(-4) M caused a significant relaxation of isolated rabbit vascular strips contracted by KCl, prostaglandin F2alpha, norepinephrine, histamine, CaCl2, serotonin or angiotensin II. W-7 also caused a shift to the right of the dose-response curves for all agonists tested. Propranolol and atropine did not affect W-7 induced relaxation, suggesting that this drug does not act through beta adrenergic or cholinergic receptors. Superprecipitation of actomyosin from bovine aorta smooth muscle was inhibited by the addition of W-7 in a dose-dependent fashion. The concentration of W-7 which inhibited superprecipitation of bovine aorta smooth muscle actomyosin was in good agreement with the dose producing relaxation of isolated vascular strips. These facts suggest that W-7 produces relaxation of isolated vascular strips by inhibiting actin and myosin interaction.


A bilateral antidiuresis to renal artery infusion of prostaglandin E1 in dogs treated with phenylbutazone.

1. In acute experiments, high levels of endogenous prostaglandins, provoked by operative stress, could obscure or alter the actions of infused prostaglandins on the kidney. For this reason we decided to compare the effects of infusing prostaglandin E(1) into the renal artery of the dog before and after the administration of phenylbutazone, a prostaglandin synthetase inhibitor.2. Infusion of prostaglandin E(1) into the left renal artery of the pre-phenylbutazone treated dog undergoing a mannitol diuresis increased renal plasma flow, glomerular filtration rate and the excretion of salt and water. The findings are in general agreement with those reported by others.3. Following phenylbutazone administration the vascular and saluretic actions of prostaglandin E(1) were unchanged but a reduced diuretic effect was observed. The response to a low dose of prostaglandin E(1) (0.05 mug/min) was reduced from 1.46 +/- 0.15 to 0.96 +/- 0.16 ml./min (P < 0.001) and the response to a high dose (0.5 mug/min) from 1.82 +/- 0.19 to 0.99 +/- 0.31 ml./min (P < 0.002).4. A significantly less dilute urine was excreted during prostaglandin infusion in the dog after phenylbutazone treatment than before. The reduction in the diuretic response was of the same order as the decrease in the free water clearance response, while the increase in osmolar clearance was unchanged.5. In water-loaded dogs treated with phenylbutazone, infusion of prostaglandin E(1) into the left renal artery had a biphasic effect on urine output from the left kidney. An initial diuretic response to a low dose of prostaglandin E(1) disappeared with the infusion of higher doses, and antidiuresis developed in the immediate post-infusion period.6. As prostaglandin was infused into the left kidney progressive antidiuresis was seen in the non-infused right kidney.7. It is concluded that endogenous prostaglandins do not obscure or alter the vascular and saluretic actions of intrarenal prostaglandin E(1). The findings question the proposed link between the vascular and saluretic actions of this compound.8. It is suggested that the reduced diuretic effect of prostaglandin E(1) in series no. 1, and the antidiuresis in the water-loaded dogs, are caused by the release of endogenous ADH. It is further suggested that phenylbutazone unmasks this release by removing the endogenous prostaglandins. If these deductions are correct, the findings support the anti-ADH role assigned to endogenous prostaglandins by Anderson, Berl, McDonald & Schrier (1975).


Tactile sensibility in the human hand: receptive field characteristics of mechanoreceptive units in the glabrous skin area.

1. Impulses in tactile units innervating the glabrous skin of the hand recorded from the median nerve of adult human subjects. The recording electrodes which were made of tungsten were inserted percutaneously in the upper arm. 2. The units were classified on the basis of their sensitivity to sustained identation and to remote stimuli. Two types of rapidly adapting  units and two types of slowly adapting units were found. In accordance with earlier reports they were denoted RA and PC units, and SA I and SA II units. 3. The sensitivity profiles of the receptive fields were analysed by measuring the extent of the receptive field as a function of the identation amplitude. 4. The RA and SA I units had receptive fields with several zones of maximal sensitivity distributed over an approximately circular or oval area typically covering five to ten papillary ridges. Within this area the sensitivity was high, whereas the sensitivity diminished steeply with increasing distance from this area. 5. The PC and SA II units had receptive fields with a single zone of maximal sensitivity and gentle continuous threshold increase outside this zone. 6. The relation between the identation amplitude and the receptive field size of a unit was described by a power function. The power exponent for the RA and SA I units was well below unity, whereas the PC and SA II units had exponenets greater than unity. The variation in exponent was very small among the RA and among the SA I units. Their average exponents were therefore regarded as characteristics of the unit type. 7. The SA II units were qualitatively studied with regard to their sensitivity to lateral skin stretch. Three different types of SA II units were described with regard to the directional pattern of this sensitivity. 8. The relation of the present findings to the problem of correlation between morphological structures of nerve end-organs and physiologically defined unit types is considered. 9. Moreover, the findings, indicate that the RA and SA I units are well suited for the analysis of mechanical events on the skin surface with a high degree of spatial selectivity, whereas the PC and SA II units are suited for analysis of other mechanical events, e.g. vibration and various forms of tension in the skin and related tissues.


Influences of cones upon chromatic- and luminosity-type horizontal cells in pikeperch retinas.

1. The spectral sensitivity and spatial organization of cones and horizontal cells have been analysed by intracellular recording in pikeperch retinas. 2. The vast majority of cone recordings were obtained from orange-sensitive cones. They have an action spectrum which peaks at about 605 nm. Recordings from several green-sensitive cones have also been obtained. 3. The results of action spectrum measurements and spectral screening tests indicate that the vast majority of luminosity-type horizontal cells receive predominant input from the orange-sensitive cones. 4. Chromatic-type horizontal cells were recorded at more proximal levels of the retina than luminosity-type cells and were the classic red-depolarizing, green hyperpolarizing (R/G) type. 5. The action spectra of the depolarizing and hyperpolarizing responses of chromatic horizontal cells peak at about 650 and 530 nm, respectively. When the depolarizing mechanism is selectively depressed by a red background field, the action spectrum of the hyperpolarizing mechanism shows an enhanced sensitivity, peaks at 530--540 nm, and may approximate the action spectrum of the green-sensitive cones. 6. Small red fields evoke depolarizing responses from chromatic-type horizontal cells but do not seem to significantly activate the depolarizing surround mechanism of cones. 7. These and other results suggest that the colour-opponent properties of the chromatic-type horizontal cells are not fundamentally dependent upon feed-back to cones but rather originate from antagonistic interactions generated in post-receptor networks.


Localization of the effect of acetylcholine in regulating intestinal ion transport.

1. The location of the site involved in the secretory response of rat jejunum and colon to ACh was investigated by selectively damaging either the villi of the jejunum and the surface epithelium of the colon or the crypts. 2. The secretory response induced by ACh was measured both in terms of changes in electrical activity and chloride fluxes. 3. Exposure of the mucosa to 2 M-Na2SO4 for 30 min selectively damaged the jejunal villi and colonic surface epithelium but did not reduce the increased potential difference and current generated by ACh. 4. When resistance changes were taken into account the colonic response was markedly increased after Na2SO4 treatment although the jejunal response was unchanged. Under control conditions ACh reduced net Na absorption and stimulated Cl secretion by the colon. After exposure to Na2SO4 only the Cl secretory component of the ACh response remained, thus accounting for the enhanced effect. 5. Cycloheximide, administered I.V. at a dose of 12 mg/kg, damaged the crypts after 2 hr without affecting the villi of the jejunum or the surface epithelium of the colon. After cycloheximide treatment the increased potential difference, current and net Cl secretion induced by ACh were significantly reduced. 6. The crypts therefore appear to be the site primarily involved in the secretory response of rat jejunum and colon to ACh, although in the colon an inhibitory effect on the Na transport process located in the surface epithelium was observed.


Role of calcium ions in transient inward currents and aftercontractions induced by strophanthidin in cardiac Purkinje fibres.

1. Under the influence of strophantidin, Purkinje fibres exhibit transient inward current (TI) which contributes to arrhythmogenic activity. Voltage-clamp experiments were carried out to study the role of Ca ions in this phenomenon. 2. The amplitude of TI varied directly with the extracellular Ca concentration, CaO. Magnesium ions had an antagonistic effect. 3. TI was closely associated with a phasic increase in force ("aftercontraction"). Like TI, the aftercontraction was evoked by a preceding action potential or by the break of a strong depolarizing pulse. 4. TI and the aftercontraction displayed similar wave forms although peak current preceded peak force by 50--100 msec. Both transients were enhanced by increasing the strength or duration of the preceding depolarization pulse. Both events were slowed as the potential level following the pulse was displaced in the negative direction. 5. TI and the aftercontraction could be evoked in the absence of cardiotonic steroids by strongly elevating CaO. 6. Additional experiments were carried out to test the hypothesis the TI reflects an influx of Ca2+ ions. Moninhibited TI but the developed and removal of the inbibition lagged far behind the effects on the slow inward current. 7. TI could be suppressed and eventually inverted by varying the membrane potential in the positive direction. The inversion potential averaged -5mV and was not consistent with a Ca-specific pathway. The aftercontraction was more closely related to the phasic conductance change underlying the current than to thecurrent flow itself. 8. The results are consistent with the idea that an oscillatory release of Ca from an intracellular store is the primary event underlying both the aftercontraction and the conductance change which generates TI. Digitalis intoxication or very high CaO may promote such events by elevating intracellular Ca levels.


Ionic basis of transient inward current induced by strophanthidin in cardiac Purkinje fibres.

1. Voltage clamp experiements studied the ionic basis of the strophathidin-induced transient inward current (TI) in cardiac Purkinje fibres. 2. The reversal potential of TI (Erev) was determined in the presence of various bathing solutions. Erev averaged --5 m V in the standard modified Tyrode solution (Kass, Lederer, Tsien & Weingart, 1978). Erev was displaced toward more negative potentials when the external Na concentration (NaO) was reduced by replacement of NaCl with Tris Cl, choline Cl or sucrose. 3. A sudden reduction of NaO evoked a temporary increase in TI, followed after a few minutes by a sustained diminution. The initial increase was closely paralleled by an enhanced aftercontraction and could be explained by an indirect effect of NaO on internal Ca. The subsequent fall in TI amplitude could be accounted for by the reduced driving force, E--Erev. 4. Erev was not significantly changed by replacing extracellular Cl with methyl-sulphate, or by limited variations in external Ca (2.7--16.2 mM) or external K (1--8 MM). 5. These results are consistent with an increase in membrane permeability to Na and perhaps K. 6. TI was not directly affected by TTX, which blocks excitatory Na channels, or by Cs, which inhibits inwardly rectifying K channels.  TI may be distinguished from the slow inward current by its kinetic, pharmacological and ionic properties. 7. TI might be carried by a pre-existing ionic pathway such as the 'leak' channel which provides inward current underlying normal pace-maker depolarization. Another possibility is that TI reflects Ca extrusion by an electrogenic Ca--Na exchange.


Ocular dominance in layer IV of the cat's visual cortex and the effects of monocular deprivation.

1. The relation between the physiological pattern of ocular dominance and the anatomical distribution of geniculocortical afferents serving each eye was studied in layer IV of the primary visual cortex of normal and monocularly deprived cats. 2. One eye was injected with radioactive label. After allowing sufficient time for transeuronal transport, micro-electrode recordings were made, and the geniculocoritcal afferents serving the injected eye were located autoradiographically. 3. In layer IV of normal cats, cell were clustered according to eye preference, and fewer cells were binocularly driven than in other layers. Points of transition between groups of cells dominated by one eye and those dominated by the other were marked with electrolytic lesions. A good correspondence was found between the location of cells dominated by the injected eye and the patches of radioactively labelled geniculocortical afferents. 4. Following prolonged early monocular deprivation, the patches of geniculocortical afferents in layer IV serving the deprived eye were smaller, and those serving the non-deprived eye larger, than normal. Again there was a coincidence between the patches of radioactively labelled afferents and the location of cells dominated by the injected eye. 5. The deprived eye was found to dominate a substantial fraction (22%) of cortical cells in the fourth layer. In other cortical layers, only 7% of the cells were dominated by the deprived eye. 6. These findings suggest that the thalamocortical projection is physically rearranged as a consequence of monocular deprivation, as has been demonstrated for layer IVc of the monkey's visual cortex (Hubel, Wiesel & Le Vay, 1977).


A morphological study of the axons and recurrent axon collaterals of cat alpha-motoneurones supplying different hind-limb muscles.

1. Intracellular injections with horseradish peroxidasewere performed in cat alpha-motoneurones supplying various hind-limb muscles. 2. Ten alpha-motoneurones from each of the quadriceps, posterior biceps, gastrocnemius-soleus and anterior tibial pools as well as from the pool supplying the short plantar muscles were collected for morphological analysis of the intramedullary axonal systems including the recurrent axon collaterals. 3. The diameter of the alpha-motor axons showed considerable variation within each motoneurone pool, the total range being from 4.6 to 9.0 micrometer. No significant difference in mean axon diameter was obtained between the different pools. 4. All alpha-motoneurones supplying the short plantar muscles and one single alpha-motoneurone supplying the quadriceps muscle lacked collaterals completely, while the remaining motoneurones gave off one to five collaterals. 5. The number of axon collateral outbulgings, interpreted as synaptic boutons, wihch originated from a single alpha-motoneurone showed large variation within each pool that possessed axon collaterals, the total range being from seventeen of 158. The mean number varied from forty-four (quadriceps) to eighty-two (anterior tibial). 6. The axon collateral outbulgings were distributed not only in the Renshaw cell area ventromedial to the main motor nuclei but also in those parts of the motor nuclei which were located in the vicinity of the parent cell bodies. In the rostrocaudal direction, the outbulgings were distributed within a distances of less than 1 mm around the position of the parent cell bodies. 7. Some physiological implications of the lack of axon collaterals from alpha-motoneurones supplying the short plantar muscles were discussed in relation to the functional characteristics of plantar muscles and motor units.


A morphological study of the axons and recurrent axon collaterals of cat alpha-motoneurones supplying different functional types of muscle unit.

1. Cat alpha-motoneurones supplying muscle units of the soleus S type and gastrocnemius S, FR and FF types were injected intracellularly with horseradish peroxidase. 2. Ten alpha-motoneurones of each motor unit type were collected for morphological analysis of the intramedullary parts of their axonal systems including the recurrent axon collaterals. 3. The alpha-motor axon diameters in the spinal cord white matter were significantly smaller for the soleus motor units (mean = 5.2 micrometer) than for the gastrocnemius S units (mean = 6.4 micrometer), which in turn differed significantly from those of the gastrocnemius FR (mean 7.4 micrometer) and FF (mean = 7.3 micrometer types. 4. The number of axon collateral outbulgings, interpreted as synaptic terminals, which originated from the soleus motor axons (mean = 27.8) was significantly smaller, white that of the gastrocnemius FF motor axons (mean = 98.1) was significantly larger, than the number of outbulgings from the gastrocnemius S (mean = 44.4) and FR (mean = 53.8) motor axons. The latter two types were not significantly different. 5. In transverse sections the axon collateral outbulgings were found not only in the classical Renshaw cell area ventromedial to the main motor nuclei but also within the homonymous motor nucleus. However, only some of the neurones projected to the latter area. Rostrocaudally, the outbulgings were distributed within a distance of less than 1 mm around the position of the parent cell bodies. 6. Some physiological implications of the observed differences between axon collateral systems of various functional types of alpha-motoneurones were discussed in relation to the present knowledge of the effects of the recurrent axon collaterals during different types of involuntary and voluntary activation of the alpha-motoneurones.


Vascular and metabolic responses to adrenergic stimulation in isolated canine subcutaneous adipose tissue at normal and reduced temperature.

1. The circulatory and metabolic effects of temperature reduction were studied in autoperfused canine subcutaneous adipose tissue in situ. 2. Cooling the adipose tissue sufficiently to reduce venous effluent temperature by 5--6 degrees C decreased blood flow from an average of 6.4--4.1 ml. min-1 . 100g-1. 3. Vasoconstrictor responses to sympathetic nerve stimulation (4 HZ) and injected noradrenaline (5 n-mole) were potentiated by cooling while vasodilator components of the vascular responses, such as autoregulatory escape and post-stimulatory hyperaemia, were virtually abolished by this treatment. 4. Oxygen uptake was reduced by cooling without signs of tissue hypoxia. This reduced oxygen demand may partly cause the decrease in adipose tissue blood flow. 5. Cooling inhibited glycerol mobilization from the adipose tissue during sympathetic nerve stimulation. Post-stimulatory lipolysis was, however, not inhibited. In vitro studies with 'perifused' rat fat cells suggest that this may be due to impaired inactivation of the lipolytic process, rather than to changes in transmitter removal, following stimulation at low temperature. 6. Cooling inhibited the mobilization of fatty acids more than that of glycerol, suggesting increased re-esterification of fatty acids within the tissue at low temperature. 7. It is concluded that cooling increases the sensitivity to vasoconstrictor stimuli and that inhibition of metabolic vasodilator mechanisms play a role for this effect. The stimultaneous inhibition of activating and inactivating mechanisms could explain the unchanged vascular and lipolytic responses to brief stimuli. Some possible implications of the present findings for the physiology of adipose tissue during cooling are discussed.


The generation of resting membrane potentials in an inner ear hair cell system.

1. The macula sacculi in the mudpuppy is an inner ear sensory area accessible for intracellular recordings in vitro and in vivo. 2. The resting potentials recorded in vitro can be explained by the electrodiffusion theory assuming a uniform ionic selective in the membranes of the neuroepithelial cells. 3. The resting potentials recorded in vivo are significantly larger than predicted by the electrodiffusion theory, probably because of an electrogenic metabolic process present in the neuroepithelial cells. 4. An equivalent circuit is proposed to explain the resting electrogenesis in the neuroepithelial cells present in the sensory area.


Specificity of initial synaptic contacts made on guinea-pig superior cervical ganglion cells during regeneration of the cervical sympathetic trunk.

1. Largely appropriate synaptic connexions are formed with neurones in the superior cervical ganglion at long intervals after interruption of the preganglionic nerve. In the present study we have assessed the accuracy of connexions during the early stages of re-innervation by observing end-organ responses to ventral root stimulation in vivo, and by recording intracellularly from ganglion cells during ventral root stimulation in isolated preparations. 2. Appropriate, but weak, end-organ responses were elicited by stimulation of the first and fourth thoracic ventral roots (T1 and T4) 15--30 days after freezing the cervical sympathetic trunk. 3. Intracellular recordings from ganglion cells during stimulation of the ventral roots C8--T7 in vitro showed that synaptic contacts are first re-established 8--11 days after freezing the preganglionic nerve. The proportion of re-innervated cells, and the strength of innervation of individual neurones, increased rapidly for up to about 3 months after nerve injury, but showed little change thereafter. Innervation remained weaker than normal even after 6 months. 4. Patterns of segmental innervation recorded intracellularly during the early stages of regeneration were similar to, but more restricted than normal. Even 13--19 days after interruption of the preganglionic nerve, neurones re-innervated by more than one spinal cord segment tended to be innervated by a contiguous subset of the spinal segments which contribute innervation to the ganglion. The incidence of neurones receiving innervation from a discontinuous segmental subset was about the same at early and late stages or re-innervation. 5. Throughout the course of nerve regeneration, re-innervated neurones tended to receive dominant synaptic input from axons arising at a particular spinal level, as do normal cells, with adjacent segments contributing a synaptic influence that diminished as a function of distance from the dominant segment. 6. The results of these experiments argue against the initial formation of imprecise connexions with subsequent retention of appropriate contacts and a loss of inappropriate ones. Rather our findings suggest that the re-innervation of ganglion cells proceeds by a gradual accumulation of synaptic connexions which are, from the outset, appropriate.


The role of the cat choroid plexus in regulating cerebrospinal fluid magnesium.

1. The regulation of c.s.f. Mg concentration was studied using the cat choroid plexus isolated in a chamber in situ. 2. An increase in plasma Mg concentration was accompanied by the usual reciprocal decrease in plasma Ca concentration. Chamber fluid Ca concentration was unaffected. 3. Hypermagnesemia (plasma Mg concentration greater than 6 m-equiv/1.) caused relatively small increases in c.s.f. Mg concentration (delta plasma [Mg]/ delta c.s.f. [Mg] = 4). 4. Various chamber fluid Mg concentrations (0, 2.4 or 4.8 m-equiv/1.) were rapidly (within 30--60 min) returned to near the control value of 1.83 m-equiv/1. 5. When plasma and chamber fluid Mg concentrations were altered simultaneously, the final chamber fluid Mg concentration was returned towards normal with or against a concentration gradient. 6. The data indicate that the choroid plexus is involved in maintaining the constancy of the c.s.f. Mg concentration by sensing changes in the normal c.s.f. Mg concentration and altering approximately its rate of active secretion of Mg.


Regulation of glycolysis in intermittent exercise in man.

1. Seven healthy male volunteers performed intermittent exercise (15 sec work--15 sec rest) at a high work load for 60 min and six subjects performed continuous exercise at an equally high load to exhaustion, which occurred after 4--6 min. 2. Muscle biopsies were obtained from the lateral portion of the quadriceps muscle before intermittent exercise and after the end of a work period and the end of the subsequent rest period at 5, 15, 30 and 60 min of exercise, as well as before, immediately after and about 15, 30, 60 and 180 sec after continuous exercise. 3. The reduction in glycogen content was smaller and glucose-6-phosphate, glycerol-1-phosphate, lactate and malate contents were lower after both work and rest periods in intermittent compared with continuous exercise, indicating a lower rate of glycolysis. 4. ATP and CP levels had decreased at the end of work periods in intermittent exercise but increased to slightly below basal in the subsequent rest periods. A still larger decrease in ATP and CP levels was found after continuous exercise to exhaustion and a progressive increase occurred over the 3 min of recovery. 5. In each rest period during intermittent exercise citrate levels increased to reach above basal. They increased also in the recovery phase after continuous exercise, although more slowly. 6. The findings support the assumption that ATP, CP and citrate act as regulatory factors of glycolysis in human muscle by retarding certain rate limiting steps. The increase in G-6-P/F-1-6-P2 ratio in rest periods of intermittent intense exercise and in the recovery phase of continuous intense exercise suggests that glycolysis is retarded at the phosphofructokinase reaction. 7. The factors mentioned may therefore contribute to the relative increase in lipid utilization during intense intermittent compared to continuous exercise.


Propagating calcium spikes in an axon of Aplysia.

1. Intracellular recordings were obtained from the axon of the giant neurone R2 of Aplysia in order to study the ionic dependency of action potentials. 2. The overshoot potential of the axon spike increases with Na concentration in the manner predicted for a Na electrode. The maximum rate of rise (Vm) is linearly related to Na concentration. The overshoot potential is insensitive to Ca concentration at Na concentrations as low as 250 mM. 3. Tetrodotoxin (TTX) or replacement of Na with Tris abolishes action potentials in the axon but not soma of R2. Addition of 4-aminopyridine to a Na-free solution permits axon spikes to be generated. These action potentials are blocked by 30 mM-Co2+, but not by TTX. The overshoot potential and Vm of these action potentials increase monotonically with Ca concentration. 4. Axonal action potentials can be generated when an equimolar concentration of Sr is substituted for all of the Ca and Mg in Na-free medium. These action potentials are abolished by 30 mM-Ca2+ or mM-Co2+, and increase with Sr concentration. 5. TTX-resistant Ba spikes can similarly be elicited in R2 axon. These action potentials are reduced by Ca, Co, or Cd, and enhanced by raising the Ba concentration. 6. The Vm of Na spikes in the absence of Ca is greater in the axon than in the soma of R2, whereas the Vm of divalent spikes is greater in the soma. 7. During repetitive stimulation the axon spikes incrase in duration. This broadening is inhibited by replacing Ca in the bath with Mn or by the addition of 30 mM-CoCl2, and is enhanced by raising the Ca concentration by 30 mM. 8. The action potention of R2 axon has a mixed Na/Ca dependency. The density of Ca current may be greater in the some than in the axon of this cell.


[Studies on the excitation-metabolism coupling mechanism in brown adipose tissues, 2; Effects of K+ and norepinephrine on the lipolysis in brown adipose tissues (author's transl)].

This investigation was undertaken to clarify the lipolytic response caused by K+ and norepinephrine in brown adipose tissues. 1. Lipolytic response was obviously observed at the concentration of 50 mM in the K+-induced stimulation, and at 1.0 microgram/ml in the norepinephrine-induced stimulation, respectively. 2. K+- and norepinephrine-stimulated lipolysis were inhibited in the Ca2+-deficient tissues, and were inhibited by the addition of Mg2+, Mn2+ and La3+. 3. In the K+-stimulated lipolysis Ca2+ could be substituted only by Sr2+, while in the norepinephrine-stimulated lipolysis the substitution was possible with both Sr2+ and Ba2+. 4. K+- and norepinephrine-stimulated lipolysis were inhibited by the addition of propranolol and procaine. Accordingly, these positive results suggest that K+- and norepinephrine-stimulated lipolysis are dependent on the presence of Ca2+, and are related to the movements of Ca2+ and cyclic AMP system in the cells.


Financial support for research in general practice.

I have tried to identify all the main sources of financial support for general-practice research and to classify the work and the sources of support.The Department of Health is the biggest single source and the total sums involved exceed pound1 million.About a quarter of the money is spent by academic departments of general practice, about a quarter by research units directed by practising general practitioners, and the remaining half is spent by other academic departments such as social research, medical sociology, or community health.


Confidentiality and medical records.

Protecting confidential information disclosed to doctors has been one of the most important ethical traditions of the medical profession. However, the patient's right to such confidentiality is threatened because it is legally unclear how far ownership by Government of the paper on which NHS records are kept or of the computer system in which they are stored confers right of access.We hope the medical profession will examine this problem urgently and offer some suggestions as to how patients' confidences can continue to be protected in the future.


Referral letters--the enclosure of the general practitioner's computerized record.

The computerization of general practice records in group practices often makes it possible for a print-out of the record to be sent to hospital specialists on referral. I examined the assessments made by consultants of the value of this. While general practitioners and consultants do not agree on the content of the ideal referral letter, the addition of a computer print-out would aid about a third of consultants.


Unusual presentations of thyroid disease in general practice.

We report nine cases of unusual presentations of thyroid disease seen in our practice during a period of about two years. We discuss the implications and management of these cases in general practice.


General practice in New Zealand and the UK.

The morbidity and referrals in a New Zealand and an English practice are described and compared, and the results analysed and discussed.


Manipulation for locked knee.

There is a type of locked knee in which the last 10 to 40 degrees of extension are lost. The manipulation used in the treatment of six patients is described. Manipulation in this instance should primarily be regarded as a first aid procedure to restore function and to stop the pain. The condition is usually caused by an abnormality of the lateral meniscus and meniscectomy may be required later.


Pulled elbow.

Pulled elbow (distal subluxation of the radial head) is a common, painful condition in young children. Although it has been well documented it is often missed, often mistreated, and generally over-investigated. Treatment is simple and effective. Without treatment the condition can continue for several days.


General practice in remote areas: attractions, expectations, and experiences.

Interviews with a sample of general practitioners in remote areas of Scotland revealed a strong commitment to a wide family counsellor role as well as a wish to use clinical skills more fully. While many urban doctors express similar orientations we believe that rural practitioners feel better able to implement their preferred style of work which combines personal and professional elements.


Early infant feeding and weight gain.

Three hundred and one babies were surveyed for one year in an infant welfare clinic in North London. There was no significant difference at six months and one year of age in the mean weights of babies breast-fed for more than one month and those not breast-fed at all.At six months, the mean weight of those babies given solid food before three months of age was significantly higher than the mean weight of those babies given solids only after three months of age. This difference had disappeared by one year of age.


The reliability and validity of the age-sex register as a population denominator in general practice.

I report evidence which raises doubts about the reliability and validity of age-sex registers as true population denominators in general practice in the UK. These have potentially disturbing implications for the interpretation of data based on the presumed precision of age-sex registers. I am undertaking a prospective study to identify and quantify sources of inaccuracy to try to establish a method of estimating the true population at risk and its true age-sex characteristics. This would greatly enhance the utility of the age-sex register as the most valuable tool in general-practice research.


The operation of a health centre after a catastrophe in Finland.

In April 1976 the most disastrous peace-time accident in Finland took place in the town of Lapua, where a cartridge-filling station in an ammunition factory exploded and 40 people were killed. I was in charge of the local health centre activities, and describe what happened.


Tolerating uncertainty in family medicine.

In family practice, early undifferentiated signs and symptoms dominate many consultations. A physician must learn to tolerate uncertainty in addition to managing well-defined pathological processes. A series of steps are presented on how to approach the uncertain. I hope these will stimulate further comment and help to develop a body of organized and testable knowledge on the skills of managing the uncertain problems in family practice.


The Department of General Practice at the Erasmus University of Rotterdam.

The philosophy which provides the framework for looking after patients, teaching, and research at the University Department of General Practice in Rotterdam is described and the need stressed that this philosophy should be discussed continually with other departments and with local general practitioners.In particular I believe that young doctors need to be trained in the skill of deciding whether patients in general practice need any treatment at all and who is the most appropriate adviser. Analysis of the doctor-patient relationship is essential in order to train young doctors to develop supportive rather than authoritarian relationships with patients.


Training practices in the Oxford region.

Considerably more time for training has been made available by trainers in the Oxford region since July 1976, with regular tutorials being held in all training practices. However, in spite of this by January 1978 nearly half the trainees still received training which was largely unplanned, and some of the reasons for this are briefly discussed.


Evaluation of structured and unstructured training for general practice.

Twenty-four general-practice trainees were assessed at the beginning and end of their training year. They improved significantly in their factual recall and problem-solving ability. Sixteen young principals who had had an unstructured training for general practice were assessed at the same time and were initially of the same standard but their results showed no difference over the same year.


General-practice teaching in Australia.

There have been several important changes in the aims and organization of general-practice teaching in Australia in recent years. During a visit to Australia I had the opportunity to see many of these and to discuss others. This report describes the features I found of most interest.


The aetiology of consultation: a threefold classification.

A threefold classification of aetiological factors in consultation is suggested, for use in day-to-day clinical general practice.


The primary prevention of atherosclerosis in general practice.

The prevention of atherosclerosis, especially ischaemic heart disease, in general practice is important. The evidence for and against the various risk factors is reviewed, and the rationale for screening and health education is examined. I conclude that health education and screening for risk factors are likely to be more successful in decreasing morbidity and mortality than treating established disease.There are arguments for and against screening and health education and about the effectiveness of various schemes. Much of the routine work of health education and screening can be carried out by suitably trained health visitors, practice nurses, or community nurses.


Talking out of alcoholism: results from a survey of Alcoholics Anonymous in England and Wales.

A national survey of Alcoholics Anonymous (AA) produced data on the way AA members talk about their experiences and the role this plays in achieving and maintaining sobriety. The survey was based on self-completion questionnaires given to one in four members attending meetings of a one in ten random sample of AA groups operating in England and Wales. Only 1.8 per cent of current members had never spoken at a meeting, while 62.5 per cent spoke regularly. Hearing other people's personal stories was felt by members to be the most useful part of AA meetings. At some time 81.9 per cent of members had told their own story and there was some relationship between dropping out and not telling personal stories. The great majority of those who had told stories reported changes in their content over time; 58.0 per cent of these changes involved a shift of emphasis from drinking to recovery. The results suggest that AA enables people to change the way they perceive and evaluate themselves. It enables them to talk themselves out of alcoholism.


Screening the aged in general practice.

We describe a comprehensive screening project in a general practice in which patients over the age of 65 were assessed both socially and medically. We conclude from our results that there was little treatable but previously undiagnosed illness within the community studied.


The benefits to an elderly population of continuing geriatric assessment.

There is currently great interest in the care of the elderly in general practice and discussion about the role of surveillance programmes. We report a comparison between two surveys of an elderly population carried out with a view to determining the difference in findings between two surveys of the same population.Each patient had an average of 4.8 problems at the time of the second assessment. The number of active and unknown problems fell from 6.4 per patient at the initial assessment.The greatest improvements were found in such topics as clothing, bedding, heating, dentition, diet, vision, and hearing, and the least in such aspects as dependency, home hazards, and problems with a caring relative.We remain convinced that a continuing programme of geriatric assessment is valuable in general practice.


Integration of general-practitioner and specialist antenatal care.

Despite the growing role of specialist obstetricians in intranatal care the importance of the general practitioner's role, especially in antenatal and postnatal care, is being increasingly recognized. We describe a new way of sharing care which involves the consultant obstetrician attending antenatal sessions at fortnightly intervals in the practice. In addition the antenatal record is retained by the patient herself who brings it to all attendances, both in the practice and at the hospital.We analysed the results of this arrangement and compared them with a controlled series of hospital patients and found some advantages for shared care arrangements including, in particular, a reduction in the number of different doctors seen by patients, a big reduction in the number of patients who were seen by more than three doctors, and an increase in the breast feeding rate at the time of discharge from hospital.


Home and hospital: a comparison of the experiences of mothers having home and hospital confinements.

A survey of women delivered in 24 different districts compared the patients' reports of their experiences of delivery in hospital with delivery at home.Among the findings were that labour lasted a significantly shorter time at home, significantly fewer women were left alone at home, and significantly fewer had episiotomies at home.Husbands played much more of a role at home and 76 per cent were present at the birth compared with 30 per cent in hospital.Of the mothers at home 57 per cent held their baby "as long as they wanted" compared with 29 per cent in hospital.These and other factors suggest that more needs to be done to improve the qualitative aspects of delivery in hospital and especially to promote warmer human relationships within the patient's family.


Survey of a Royal Air Force practice in Germany.

Throughout 1974 records were kept of all patients seen by the medical staff at Royal Air Force Bruggen, an RAF Station in Germany. Full details of patients and diagnoses were recorded and an analysis was made of the patterns of consultation and morbidity. The method of storing and analysis the information on punched cards is discussed, and the results are compared with service and civilian general practice in the UK and abroad.


Altitude sickness.

Ten climbers were studied trekking from 1,950 to 4,650 m (6,500 ft to 15,500 ft) in the Nanda Devi Sanctuary of the Garwhal Himalaya. All developed altitude sickness, one seriously. Pulse, blood pressure, and peak flow rate were monitored daily in an attempt to predict the onset of altitude sickness. Prediction was uncertain though the one climber who became seriously cyanosed at 4,200 m (14,000 ft) had a consistently higher blood pressure than his colleagues.


The vital role of the cottage-community hospital.

The history of general-practitioner hospitals is reviewed and a case made for their retention and extension. Among the advantages they provide are: a local service for patients, less expensive hospital care than is possible in a district general hospital, less travelling expenses for patients, valuable postgraduate education for doctors, and improvement of general-practitioner morale.


Symptom prevalence in the community.

The prevalence of physical symptoms among a sample of patients registered at a health centre is described as recorded from home interviews. The number of physical symptoms per person is then correlated with personal characteristics and environmental factors, using computer programmes.


The future of the College.

THE COLLEGE SHOULD NOW PLAN ITS FUTURE POLICIES ACCORDING TO THE FOLLOWING SIX PRINCIPLES: (1) Preventive and therapeutic services must be integrated. (2) Such action falls naturally to neighbourhood doctors. (3) A positive practical approach to health should replace the traditional disease dominated emphasis in medical training. (4) There are important manpower implications for general practice, both for doctors and their staff. (5) The need to alter the life-style of patients means that practical preventive medicine increasingly means achieving change in human behaviour. (6) The Royal College of General Practitioners should increasingly emerge as the voice of progress by publicizing successful developments in general practices and by campaigning for public support for these principles.


Nonspecific inflammatory bowel disease in two general hospitals.

During 1976, 50 patients were admitted to two general hospitals for the investigation or treatment of nonspecific inflammatory bowel disease. There were more patients admitted with Crohn's disease (23) than proctocolitis (11). Half of those patients admitted with Crohn's disease required surgical treatment, the majority for small bowel obstruction. Five patients were admitted for the treatment of an acute attack of proctocolitis; these patients were all previously undiagnosed, were all admitted urgently and all responded to medical treatment.


Radioactive oxygen 15O studies in cerebral neoplasms.

Methods of diagnosis and anatomical localization of cerebral neoplasms have reached a high level of efficiency. A new method of studying cerebral circulation and metabolism by a simple noninvasive technique of steady-state imaging during the inhalation of radioactive oxygen and radioactive oxygen-labelled CO2 is described. The results of preliminary studies of a group of cerebral neoplasms of various histological types are presented and the implications discussed.


Do we overtreat patients undergoing transurethral resection of the prostate?

Two hundred unselected patients undergoing transurethral resection of the prostate have been surveyed. The routine use of endotracheal intubation, muscle relaxants, intermittent positive pressure respiration, intravenous fluids and postoperative sedation was avoided whereever possible. The results of this survey are presented and indicate that such measures can be omitted from the management of patients undergoing transurethral resection of the prostate with no significant increase in morbidity or mortality and, indeed, morbidity and mortality may be decreased by their exclusion.


The recognition of depressive disorder in children.

A study of 547 children aged between 3 and 17 years, attending a child psychiatric clinic, showed that 23% were rated as having the symptom of morbid depression present. This group was compared with a control group from the same clinic without depression. The depressed children had a number of symptoms which were significantly associated with depression and formed a characteristic pattern of symptoms that could be defined as a specific depressive disorder.


Hydradenitis suppurativa.

The surgical treatment of a group of 24 patients with hydradenitis suppurativa is described and the clinical features, aetiological factors and other methods of treatment are reviewed. An abnormally high incidence of atopy is noted within the group.


Kikuyu grass poisoning of cattle in Natal.

The clinical findings in six natural and two experimental cases of Kikuyu grass poisoning in Natal, South Africa, are described and compared with findings in cases of toxicity reported elsewhere. The toxic factor has not been identified but a mycotoxin is suspected.


Geeldikkop: preservation of toxic material.

Wilted Tribulus terrestris plants were harvested from a camp in which geeldikkop had just previously broken out. The plants were treated in various ways in an attempt to preserve their toxicity. The only successful method of preservation found was rapid freezing of harvested material. Three kg of plants were kept frozen for six weeks and then dosed via rumen fistula to a sheep which subsequently developed characteristic symptoms and lesions of geeldikkop.


An outbreak of "kikuyu poisoning" in Western Transvaal.

An outbreak of mortality in cattle grazing kikuyu (Pennisetum clandestinum) pastures on a farm in the western Transvaal is described. These pastures had been heavily infested with army worm (Spodoptera exempta) two weeks preceding the onset of deaths. The main symptoms were excessive salivation, paresis of the tongue and pharynx, localized fine muscular tremors, ruminal tympany and stasis and congested or cyanotic mucous membranes. Significant clinical pathological findings were leukocytosis, elevated blood sugar levels and lowered serum magnesium and sodium levels. Autopsy findings of interest were patchy or diffuse hyperaemia of the rumen and abomasum and small haemorrhages in especially the lymph nodes, heart and tracheal mucosa. The most important histopathological finding was superficial or deep necrosis of the ruminal epithelium with marked neutrophile infiltration. All forms of treatment, including intravenous administration of magnesium sulphate, were of no avail. The condition closely resembles so-called "Kikuyu poisoning" in New Zealand.


Field observations on the occurrence of rabies in cattle in the magisterial districts of Soutpansberg and Messina.

The field manifestation of rabies in cattle is discussed. The observations cover the period 1974--1977 with emphasis on the geographical spread, vectors, symptoms and immunization of cattle with the Flury H.E.P. (high egg passage) rabies vaccine as prepared by the Onderstepoort Veterinary Research Institute.


Porcine arthritis and meat hygiene in South Africa.

The incidence, economic implications, aetiology and possible public health significance or porcine arthritis in South African slaughter pigs is discussed. An investigation into the aetiology and pathology of porcine arthritis as found at a South African abbattoir revealed that Erysipelothrix rhusiopathiae was present in 48% of the affected joints and Streptococcus spp., Corynebacterium spp. and Staphylococcus spp. in 20%, 4% and 2% respectively. The joints showed various degress of subacute to chronic proliferative sero-fibrinous to fibrinopurulent arthritis regardless of whether bacteria were isolated. It is essential that the Lnn. axillares primae costae which drain the forelimb joints also be examined routinely during meat inspection.


Evaluation of neurological examination of sheep.

One hundred clinically negative Merino sheep were examined neurologically in an attempt to establish normal responses. Dependable results were obtained regarding eye muscle integrity, corneal sensitivity, the optic papilla and righting reflexes and to some extent the knee jerk reflex. The elicitation of other reflexes was inconsistent and unreliable except the placing reflex as shown by raising and lowering the forequarters.


Biochemical mechanisms causing tick resistance.

Three general biochemical mechanisms can cause ticks to be resistant to acaricides: an alteration in the properties of the site of action, a change in the rate of transportation and a change in the rate of metabolism. The first mechanism enables increased concentrations of acaricide at the site of action to be tolerated, while the last two mechanisms result in a decreased concentration and/or persistence of the acaricide at the site of action. These mechanisms are discussed in detail with reference to a range or acaricides, particular emphasis being given to blue tick strains occurring in Southern Africa.


Health and disease in intensive aquaculture.

The paper deals with the increasing importance of aquaculture in South Africa and with the possible importance of disease problems following intensification and importation. It deals specifically with some infectious, parasitic and metabolic diseases found in South African eels. Attention is drawn to the role of fish as a public health hazard and to the need for increased attention to the provision of fish as food.


Fatal parasitism among free living bushbabies (galago crassicaudatus).

Four cases of severe parasitism due to Primasubulura otolicini in adult bush babies (Galago crassicaudatus) are described.


Embryo transfer in cattle: an evaluation of the current situation.

A technique for the transcervical recovery of ova in cattle is described. The donors recipient pool consisted of 122 cows of different ages and 4 different breeds. Of these 102 cows were superovulated. For recovery of ova an apparatus consisting of a metal catheter glued to the inside of a 3-way Foley catheter was used. The technique used for embryo transfer was basically the same as for collecting the embryos. The 102 donors yielded at slaughter a total of 956 corpora lutea i.e. an average of 9,4 per cow. Of the ova released 294 or 30% were recovered on transcervical flushing of the uterus. 40% of the inovulated cows conceived. The future development of inovulation in cattle is discussed on the basis of the results recorded and on those previously documented.


Some effects of trinitrocresolate and valinomycin on Na and K transport across thin lipid bilayer membranes: a steady-state analysis with simultaneous tracer and electrical measurements.

This paper describes the effect of trinitrocresolate anions (TNC-) on the electrical conductance (Gm), and tracer-measured unidirectional Na and K fluxes (MNa and MK) across bilayers formed from sheep red cell lipids dissolved in decane. In the absence of TNC-, typical low conductances were observed, while the cation fluxes were too low to measure by our techniques (less than 10(-12) moles cm-2 sec-1). In the presence of TNC- (10(-2) M), Gm increased and TNC- was the main charge carrier in the system. The cationic fluxes were also much increased, but the membranes showed no significant selectivity between K and Na. Furthermore, the Na and K fluxes were at least two orders of magnitude larger than the ionic fluxes calculated from Gm. Thus, almost all of the K and Na transport across the membrane in the presence of TNC- is electrically silent and is probably carried out as KTNC and NaTNC ion pairs. In the presence of valinomycin (10(-6) M) and no TNC-, both the ion fluxes and Gm were 10(3) times larger in KCl than in NaCl, thus exhibiting the characteristic high selectivity of valinomycin for K over Na. In the presence of both valinomycin (10(-6) M) and TNC- (10(-2) M), this selectivity disappeared in that both Gm and MNa in the NaCl system were similar to the respective values in the KCl system. Even under these conditions, most of the Na is still transported by a process which does not carry charge. Both Gm and Mx increased alike and monotonically with increasing temperature over the range 7 to 30 degrees C. In the absence of TNC- the enthalpies of activation were invariably higher in KCl than in NaCl. Addition of TNC- produced equal enthalpies of activation for both Na and K containing systems suggesting a common, temperature-dependent, rate-determining step in charge transfer and the electrically silent cation fluxes.


Amiloride and calcium effect on the outer barrier of the frog skin.

Amiloride (0.1 mM) as well as Ca++ (10 mM) inhibit Na+ transport across frog skin by blocking Na+ entrance across the outer barrier of the epithelium. The inhibition produced by amiloride consists of an "early" and a "late" phase which together account for almost a total inhibition of the short-circuit current (SCC). The analysis of the time course indicates that the two phases are due to the inhibition of superficially and deeply located Na sites, respectively, Ca++, instead, only blocks a fraction of the SCC, and this fraction seems to correspond to the inhibition of the same population of Na sites blocked by the "late" phase of amiloride effect. The location of the two populations of Na sites as well as the possible relationship between them are discussed in terms of maturation of the outermost cell layer.


Studies on chloride permeability of the skin of Leptodactylus ocellatus: I. Na+ and Cl- effect on passive movements of Cl-.

The outflux of chloride through the isolated skin (JCl31) of the South American frog Leptodactylus ocellatus (L.) is carried by a mechanism that saturates at high concentration of chloride on the inside, and is stimulated by the presence of Cl- in the outer solution (trans side). The presence of Na+ on the outside, by itself, does not increase JCl31. However, when JCl31 is already increased by chloride on the trans side, the addition of Na+ produces a significant further increase. At low concentration of Cl- on the outside JCl31 is carried by an exchange diffusion mechanism. At high concentrations of Cl- outside, JCl31 proceeds through a route which involves changes in electrical parameters. The results suggest that both mechanisms are located on the cell membranes and, therefore, that the fluxes would cross through the cytoplasm of the cells. Na+ stimulates the second mechanism only.


Studies on chloride permeability of the skin of Leptodactylus ocellatus: II. Na+ and Cl- effect of inward movements of Cl-.

At low concentration (1 mM) of Cl- in the outer solution, the influx of chloride through the isolated skin (JCl13) of the South American frog Leptodactylus ocellatus (L.) seems to be carried by two mechanisms: (i) a passive one that exhibits the characteristics of an exchange diffusion process, and (ii) an active penetration. Studies of the influx and efflux of chloride (JCl13 and JCl31) indicate that the presence of a high (107 mM) concentration of Cl- in the outer solution activates the translocation of this ion through the cells. Studies of the unidirectional flux of Cl- across the outer barrier (JCl12) indicate that Na+ out stimulates the penetration of Cl- at this level. Cl- out, in turn, stimulates the JNa12, but this effect is only detected at low concentrations of Na+ out.


Studies on chloride permeability of the skin of Leptodactylus ocellatus: III. Na+ and Cl- effect on electrical phenomena.

During their flux through the skin of the frog Leptodactylus ocellatus, Na+ and Cl- interact with each other. This interaction gives rise to electrical phenomena which are studied in the present paper. The skin is mounted in Na2SO4 Ringer's with 115 mM Na+ on the inside, and a variety of outer solutions. The osmolarity of all solutions is kept constant at 237.8 mosmol by adding sucrose. When the main anion used on the outside is SO=4 the electrical potential difference (deltapsi) rises steadily with the concentration of sodium (Na+)0 up to 87 mV, which is reached at about 20 mM. Thereafter deltapsi remains constant. When the main anion is Cl- it is observed that deltapsi rises steadily with (NaCl)0 with a slope similar to the curve obtained with SO=4 (37 mV per decade), but with a lower intercept attributed to an inward Cl pumping which is characteristic of this frog species. At 2--9 mM (NaCl)0 a Cl-specific channel is activated. Further increases of (NaCl)0 produce a decrease of deltapsi. The specificity of the activation of this site by monovalent cations and its use by monovalent anions is also studied.


Sodium uptake across the apical border of the isolated turtle colon: confirmation of the two-barrier model.

The initial rate of Na uptake by the turtle colon from the mucosal bathing solution consists of two operationally distinct components. One component is a linear function of mucosal Na concentration, is unaffected by amiloride, and appears to represent Na uptake into the paracellular shunt path. The major component of Na uptake is abolished by amiloride and is virtually equal to the short-circuit current over a wide range of mucosal Na concentrations, suggesting that this portion of Na uptake represents Na movement into Na-transporting cells of the colon. The amiloride-sensitive component of Na uptake, at low mucosal Na concentrations, was unaffected if net Na transport was abolished by ouabain. Similarly, at low mucosal Na concentrations the amiloride-sensitive conductance of the colon was identical in the presence and in the absence of net Na transport. These results show that the isolated turtle colon behaves as two distinct barriers to transmural Na transport, an apical barrier blocked by amiloride and a more basal-lying barrier where active, transmural Na transport is blocked by ouabain. In addition, these experiments appear to provide the first unambiguous demonstration that the initial-rate isotope uptake technique can provide a direct measure of the properties of the amiloride-sensitive barrier to transmural Na movement, presumably the apical membranes of the Na-transporting cells. The results are consistent with the notion that the rate of transmural active Na transport and the conductance of the active Na-transport path are determined by the properties of the apical membrane.


Water exchange across red cell membranes: II. Measurements by nuclear magnetic resonance T1, T2, and T12 hybrid relaxation. The effects of osmolarity, cell volume, and medium.

We have used the nuclear magnetic relaxation of water protons to measure the diffusional permeability (Pw) of human red blood cells to water as a function of concentration of nonpermeable and permeable solutes. Measurements of T1, T2, and a hybrid of the two were made and yielded the same Pw. In the presence of the nonpermeable electrolyte NaCl, membrane permeability is constant between the volumes of 70 and 105 micron3 and increases both as the cells swell and shrink beyond these limits. Changes in both the internal and external osmolarity, using the permeable solutes urea and ammonium chloride, do not affect membrane permeability. The composition of the suspending medium also has a significant effect on membrane permeability. Cells suspended in plasma have a cell water lifetime about 30% longer than cells of the same volume suspended in serum, or isotonic saline with human serum albumin. Addition of a crude preparation of fibrinogen in physiological amounts to isotonic saline and human serum albumin restores the cell water lifetime to a value similar to that observed in plasma.


Effects of insulin on the adenylyl cyclase activity of isolated fat cell membranes.

Insulin decreased markedly the adenylyl cyclase activity associated with fat cell membranes purified by centrifugation in sucrose gradients. The hormone effect was not readily evident in crude membrane preparations. The kinetics of this effect indicate that some time was required for the onset of the insulin-induced inactivation. This lag period decreased when the insulin concentration was increased. The hormone dose dependence for adenylyl cyclase inactivation measured at a fixed time (3 min) showed a 10 to 15% decrease in activity at 1 to 30 muU per ml insulin; 30 to 40% at 100 to 1000 muU per ml; and 75% at 0.1 U per ml. The insulin effect was completely abolished by 0.1 mM GMP-P(NH)P, 10mM fluoride, or 50 ng per ml glucagon, or by increasing the Mn++ concentration to 4 mM. In addition, it was partially reversed by the addition of a fraction from the sucrose gradient, which contained soluble factors. The kinetics of the adenyl cyclase-catalyzed reaction were studied using ATP or AMP-P(NH)P as adenylyl donor, and Mn++ or Mg++ as divalent cation, in the absence or presence of insulin. With ATP and Mg++ there was a striking reduction of the transient reaction rates after 1.5 min of incubation. Under these conditions the insulin effect was not evident. On the contrary, with ATP and Mn++ this spontaneous reduction of activity was less evident; however, in the presence of insulin there was a clear and marked reduction of the transient reaction rate measured after 1.5 min of incubation. With AMP-P(NH)P the kinetic data were qualitatively similar to those observed with ATP. It is concluded that under certain assay conditions adenylyl cyclase may be converted to an inactive enzyme form, and that such a conversion is more evident in the presence of Mg++ than with Mn++. In the latter case, insulin appears to enhance the rate of this conversion.


Kinetic studies of adenylyl cyclase of fat cell membranes. I. Comparisons of activities measured in the presence of Mg++-ATP and Mn++-ATP. Effects of insulin, GMP-P(NH)P, isoproterenol, and fluoride.

The kinetic behavior of the adenylyl cyclase activity associated with fat cell membranes purified by centrifugation on sucrose gradients was studied. Under most of the conditions explored, with either Mn++ or Mg++ as the divalent cation in the assay mixtures, the time courses of the reaction were not linear. In the absence of modifiers (i.e., basal activity) or in the presence of insulin, the rate tended to decrease with time; on the other hand, with fluoride or GMP-P(NH)P the curves were concave upwards. To simplify analysis of the results, two kinetic components were defined: an "initial component" corresponding to the transient rate measured between zero time and 1.5 min of assay and a "final component" corresponding to the transient rate determined between 3 and 5 min. Over the entire range of Mn++ concentration explored (0.5 to 6.0 mM), the basal initial rates were slightly higher than the final ones. With Mg++ in the range between 1.5 and 2.5 mM, the final rates were fourfold lower than the initial ones. Higher or lower Mg++ concentrations gave velocity ratios equivalent to those observed with Mn++. Insulin clearly decreased the final rates at Mn++ concentrations up to 2.5 mM. With higher concentrations the effects were completely reversed. The effects of insulin on initial rates measured with Mn++, or the initial or final rates measured with Mg++, were less evident. Stimulation of adenylyl cyclase activity by fluoride was most pronounced on the final rates. In addition, this stimulation was higher with Mg++ than with Mn++. Isoproterenol stimulation of adenylyl cyclase was negligible in the presence of Mn++ (0.5 to 6.0 mM). With Mg++ (0.5 to 6.0 mM), stimulation was more evident on the final rates. GMP-P(NH)P inhibited the initial but activated the final components of the reaction. The extent of this inhibition or activation was more pronounced with Mg++ than with Mn++. Under conditions which lead to maximal inactivation of the final component, adenylyl cyclase activity was tenfold or more higher with Mn++ than with Mg++. Similar effects were observed with GMP-P(NH)P on the initial component. However, insulin, isoproterenol and fluoride decreased the Mn++ dependence of the final component. With fluoride, the final rates measured with Mg++ were almost equivalent to those found in assays containing Mn++. Under the conditions used for measurements of adenylyl cyclase activity, the enzyme system slowly interconverts between active and inactive forms.


Kinetic studies of adenylyl cyclase of fat cell membranes. II. Comparison of activities measured in the presence of Mn++-AMP-P(NH)P and Mg++-AMP-P(NH)P. Effects of insulin, fluoride, isoproterenol, and GMP-P(NH)P.

The kinetics of fat cell adenylyl cyclase were studied, with AMP-P(NH)P and Mn++ or Mg++ as the divalent cation. In general, the reaction times were not linear. In the presence of fluoride or GMP-P(NH)P, the time curves were concave upwards; in other cases (i.e., basal activity, insulin, or isoproterenol), transient rates tended to decrease with time during the assay. Kinetic data were analyzed according to a previously described procedures (Torres et al., 1978b) which isolates two kinetic components: initial and final. With AMP-P(NH)P, kinetic activities were about ten times lower than those for ATP. With Mn++, activities were at least two-times higher than for Mg++. Spontaneous inactivation of adenylyl cyclase was higher in assays containing Mg++ than in those supplemented with Mn++. In the latter case, insulin was able to increase the inactivation rate. Fluoride and isoproterenol both activated adenylyl cyclase in both the initial and final kinetic components; under most of the conditions explored, their effects on the final component appeared to be more dramatic. Assays with GMP-P(NH)P showed inhibited activity in the initial component and increased activity in the final one. When the results obtained with AMP-P(NH)P are compared with those of ATP (Torres et al., 1978b. J. Membrane Biol. 43:000), the following differences were found: (i) in the presence of insulin and Mn++, cyclase inactivation was higher with AMP-P(NH)P than with ATP; (ii) fluoride stimulation of the final component was more marked with ATP than with AMP-P(NH)P; (iii) cyclase stimulation by isoproterenol was slightly higher with the nucleotide analog; and (iv) GMP-P(NH)P stimulation of the final component resulted in higher activity with ATP than with AMP-P(NH)P.


The fate mapping of the eleventh and twelfth day mouse otocyst: an in vitro study of the sites of origin of the embryonic inner ear sensory structures.

An experiment was undertaken to determine which sensory structures of the mouse embryo inner ear developed from what portion of the mouse otocyst. Otocysts of gestation days 10, 11, 12, and 13 were divided by surgical dissection into six anatomical groups: dorsal, ventral, anterior, posterior, medial and lateral halves. They were organ cultured separately. After a period of ten days, the explanted tissues were harvested and processed histologically for microscopic analysis. The surgical control specimens fixed at the time of explantation were composed of undifferentiated ectodermal cells for tissues of gestation days 10, 11, and 12. Otocysts of gestation days 11, and 12 showed, during the course of their subsequent growth, that the three semicircular ducts and their associated cristae developed from the dorsal and lateral halves. Only the anterior and posterior canals and cristae originated from the medial portion. The posterior half gave rise to the posterior crista and the anterior half provided for the development of the anterior and lateral cristae. The cochlear duct and its sensory epithelium developed in all the anatomical groups except the dorsal half. The utricle developed in the dorsal section of the middle third of the otocyst, while the utricular macula developed in the anterior half of the same section of the otocyst. The saccule and its macula differentiated from the ventral section of the middle third of the anterior half.


Re-regeneration of lower jaws and the dental lamina in adult urodeles.

Transverse amputations were carried out through one-third fully regenerated jaw segments and through normal tissue of the mandible on the same and opposite sides of the jaw in adults of Notophthalmus viridescens. Collectively the results suggest that, in adult urodeles, the mandible and the dental lamina can be replaced in an identical manner more than one time. Although the major histological events are the same in jaw regeneration and re-regeneration, regrowth is more rapid in re-regeneration. It appears that recently differentiated tissues of the regenerate have a higher capacity for regeneration than normal tissues amputated for the first time. Re-regeneration of the jaw occurs by growth of the original regenerate cartilage which has undergone reorganization. In re-regeneration, the skeletal elements exhibit no polarity and regrowth occurs in both directions, while the dental lamina possesses an anterior-posterior polarity and can regrow in an anterior direction only. Information concerning the mechanisms involved in the regenerative events remain to be determined.


Associations of cancer mortality with halomethanes in drinking water.

Associations between site- and sex-specific county cancer mortality rates and levels of trihalomethanes (THM's) in drinking water were examined after adjustment of rates for the influence of multiple socioeconomic, industrial, and demographic factors. U.S. counties with sampled supplies were grouped by percent of the county population receiving water from the supply, as well as by region of the country. For two sites (bladder and lung), county rates were also adjusted for the activity level in specific high-risk industries. Positive correlations with THM levels were observed for several cancers, including bladder and brain cancers in both sexes, and non-Hodgkin's lymphoma and kidney cancer in males. Stomach cancer in females showed a negative association. Bladder cancer mortality rates showed the strongest and most consistent association with a THM exposure index, after control for differences in social class, ethnic group, urban versus rural residence, region of the United States, and industrialization of the county. These ecologic associations suggested that further evaluation in analytic investigations is warranted.


Study of irreversibly sickled cells in an animal model.

Erythrocytes (RBCs) from six patients with sickle cell anemia were transfused to laboratory rats in order to study the intravascular survival of irreversibly sickled cells (ISCs). Fifteen minutes after transfusion, a mean of 48.8 percent (range 23-95 percent) of the ICSs injected were present in the rats' blood, a value that was significantly lower than that for the total population of sickle cell anemia erythrocytes transfused (mean 82.4 percent, range 36-114 percent). The intravascular half-life of ISCs was also lower (mean 0.83 hours ± 0.18 SD) than that observed for the total sickle cell anemia erythrocytes (mean 1.62 hours ± 0.19 SD) during the initial two hours of the transfusion experiments. The irreversibly sickled cells that remained in the rats' blood thereafter survived as well as those cells that were not irreversibly sickled. Severe hypoxia in the recipient animals did not appear to selectively remove ISCs from circulation. These data are consistent with heterogeneity of ISCs in terms of their intravascular viability. Some ISCs may have adapted to the stress of circulation despite their abnormal shape.


Health policy and the underserved.

Historically, the provision of health benefits and health services has been wedded to the needs of an industrial society to maintain a productive labor force. The casual observer will note that since the late 19th century the role of government as a participant either in the provision for health services or the delivery of health services has been strongly tied to the labor movement in Western Europe. Overtime benefits, initially procured for the worker, were expanded to include the dependents of the worker and, finally, to include the former worker who was no longer able to work due to age or infirmity. The provision of health care to the poor was considered an act of charity and was never liberal enough to reward poverty nor was it essentially humane, for poverty was a condition to be punished. The rise of "alms houses" and public hospitals for the poor provided constant physical reassurance to the worker that he was, indeed, successful. Such institutions were also warnings to the worker lest he slip into the numbers of the poor.


Race-related differences in HLA association with ankylosing spondylitis and Reiter's disease in American blacks and whites.

Ankylosing spondylitis is three times less common in American blacks than in whites. It is extremely rare in African blacks of unmixed ancestry. A histocompatibility antigen HLA-B27, which does not exist in African blacks of unmixed ancestry, and is present in eight percent of white and two to four percent of the American black population, is strongly associated with ankylosing spondylitis and Reiter's disease. B27 is present in more than 80 percent of white patients with ankylosing spondylitis or Reiter's disease but in less than 60 percent of American black patients. Other genetic and environmental factors may be of major importance in the genesis of these diseases in American blacks. For diagnostic purposes the absence of B27 is of less importance in excluding these diseases in blacks than in whites.


Ventilation corrected oxygen tension in lethal pulmonary embolism.

Lethal pulmonary embolism is associated with hypoxemia and hypocapnia in the vast majority of cases. The easily calculated ventilation corrected oxygen tension was a very sensitive test in patients breathing air. It yielded no normals, four percent mild hypoxemia, and 96 percent moderate to extreme hypoxemia. The alveolar-arterial oxygen tension difference and oxygen ratio were equally sensitive during air breathing. During oxygen inhalation, alveolar-arterial oxygen difference was most sensitive; oxygen ratio was second best; and oxygen saturation was the least sensitive test.


The anastomotic leak syndrome.

To evaluate the mechanisms, diagnosis, treatment, and prevention of the anastomotic complex, 151 anastomotic disruptions (representing a 20-year-study) were analyzed from records of St. Frances General Hospital, Pittsburgh. These leaks are serious postoperative problems which require individualized treatment. Prevention should be the main approach to controlling the syndrome.


Remote afterloading for intracavitary irradiation of cervix carcinoma.

The technique of remote afterloading for intracavitary radiotherapy was developed by Henschke et al 15 years ago, and since then the technique has received wide acceptance, both abroad and in the United States. Here at Howard University, it plays an integral part in the intracavitary portion of the treatment of cervix carcinoma. Most applications are done on an outpatient basis without anesthesia or sedation. This has become possible by dilating the cervical canal painlessly with thin laminaria rods. Spread of the lateral colpostats is accomplished by inflating a Foley balloon secured to the applicator with contrast medias, instead of using the customary gauze packing for increased rectal distance.A single cobalt-60 source of 1 mm diameter and 3 to 7 Curies is used, which can be moved during the treatment to simulate linear sources of different lengths and loading. Our present treatment policy calls for 4,000 rad given to the whole pelvis in 20 fractions of 200 rad three times per week plus eight fractions of 400 rad by the remote afterloading technique given one fraction per week concomtant with the external irradiation. Only 18 patients have been treated to date with minimal adverse tissue reactions. There is only an 18-month maximum follow-up, so survival figures are still pending but all patients so treated are currently living without recurrence.


Value of radiotherapy in superior vena cava syndrome.

The superior vena cava syndrome is among the most important radiotherapeutic emergencies currently known. It is almost always due to malignant disease and therefore no time should be wasted in establishing the histological diagnosis of the malignant tumor which causes the superior vena cava obstruction. The conventional slow, low-dose irradiation is a safe method of treatment. High-dose irradiation in this condition might further compromise the respiratory distress already present thus leading to sudden death.


Abdominal tuberculosis: observations in three cases.

Although pulmonary tuberculosis has decreased, extra pulmonary tuberculosis has shown a relative increase in frequency during the past decade. This paper discusses three cases of extrapulmonary tuberculosis which presented with abdominal signs. The patients were completely evaluated and surgery was done, followed by antituberculosis therapy with survival and rehabilitation of all three patients.


The placenta: a diagnostic tool in sickle cell disorders.

Examination of the placenta for the presence of sickling is an accurate, simple, inexpensive, and readily available technique for determining the presence of sickle cell disorders. There were 24 placental specimens out of 904 which showed evidence of sickling. The importance of this confirming procedure can be seen in the uncovering of two cases of false negative reports from conventional testing.


Racism, narcissism, and integrity.

Recently there has been much literature pertaining to the psychodynamics of narcissism and its relation to psychopathological and normal psychic functions. While these models of the mind are primarily aimed at understanding individual behavior in the therapeutic relationship, they are also useful in clarifying one's thinking about racism, which can be approached both from an individual and social viewpoint.The author demonstrates that the racist individual suffers from a defect in narcissistic personality development, which precludes the subsequent development of such qualities as creativity, empathy, and integrity.


Gallbladder polyp mimicking an obstructive calculus.

The second documented case of obstructing polyp of the gallbladder-an extremely rare lesion-is presented. Symptoms were indistinguishable from those of acute obstructive cholecystitis. The mechanism of obstruction is hypothesized.


Postmortem examination of an x-ray tube.

During rapid sequence radiographics in a special procedure room, unexplained random loss of contrast was observed. The effective focal-spot size, output, and the half-value layer of the tube was measured. The focal-spot size was within the +50 percent established by the National Electrical Manufacturer's Association (NEMA). The half-value layer was within the limits suggested in Table 6 of the National Council on Radiation Protection and Measurement (NCRP) Report Number 33, but the output was half the suggested value.