Depression of drug metabolism in the mouse by a combination of Mycobacterium butyricum and anaesthetics. 1 Subcutaneous injection of Mycobacterium butyricum suspended in mineral oil into the mouse hind paw caused an oedematous local inflammation. Hind paw swelling was maximum 5 days after injection and was still apparent at day 30. 2 Drug metabolism in vivo (as monitored by ketamine- or pentobarbitone-induced sleeping times) was not affected by the inflammatory disease. However, administration of ketamine or pentobarbitone at day 1 led to significantly elevated sleeping times when the mice showing local inflammation were retested at day 5 with the anaesthetics. 3 Indomethacin inhibited hind paw oedema in the mouse but did not affect ketamine-Mycobacterium butyricum-induced depression of drug metabolism. 4 Prolongation of ketamine-induced anaesthesia by combination with Mycobacterium butyricum at day 5 correlated with the degree of hind paw inflammation at this time. 5 The data suggest that anaesthetics (i.e., ketamine and pentobarbitone) may sensitize hepatic membranes to the effect of Mycobacterium butyricum or some toxic compound elaborated during the active phase of inflammation.


Exocytotic release of catecholamines and dopamine-beta-hydroxylase from the perfused adrenal gland of the rabbit and cat. 1 Secretion of catecholamines (CA) and dopamine-beta-hydroxylase (DBH) activity from the perfused rabbit and cat adrenal gland was studied following stimulation by a number of substances, including the physiological transmitter, acetylcholine (ACh), added to the perfusion fluid. 2 Stimulation caused a proportional secretion of DBH and CA from the untreated rabbit adrenal. The ratio of DBH/CA was 11.2 +/- 0.9 (mean +/- s.e.) which was close to that found in the crude granule fraction of the contralateral gland (11.4 +/- 0.7). 3 After treatment with insulin (40 u/kg) for 3 h or with reserpine (0.25 mg/kg) for 24 h, CA and DBH contents decreased in a parallel fashion in the granule fraction, thus resulting in a similar ratio of DBH/CA in the gland. The ratio in the effluents after stimulation was similar to that found in the untreated gland. 4 Higher doses of reserpine (0.7 to 2.5 mg/kg) increased the ratio of DBH/CA in the granule fraction and was dependent on the doses employed. The ratio in the effluents from these glands after stimulation paralleled these increased values. 5 Concomitant secretion of CA and DBH in response to stimulation was also observed in the perfused cat adrenal. However, the ratio of DBH/CA in the effluents tended to be lower than that found in the granule fraction. 6 These results support the concept of exocytotic secretion of CA in the adrenal  medulla.


A centrally mediated prolonged hypotension produced by oxotremorine or pilocarpine. 1 Oxotremorine, methyloxotremorine, pilocarpine or arecoline were given intravenously to anaesthetized cats, dogs or rats, and intraperitoneally to conscious normotensive and spontaneously hypertensive rats, pretreated with doses of methylatropine that completely blocked peripheral muscarinic receptors, to ascertain their effects on blood pressure and heart rate.2 Oxotremorine but not methyloxotremorine produced a prolonged hypotension in cats and dogs but not in rats. Heart rate was not changed. Pilocarpine, although less potent, produced an identical effect, whereas the effect of arecoline was short by comparison. The hypotensive effect of these drugs was reversed by atropine.3 In dogs, oxotremorine produced a prolonged hypotension with no change in heart rate or cardiac output.4 A decrease in spontaneous sympathetic nerve activity accompanied the hypotension in cats. Both effects were reversed by atropine but could be reinvoked by large doses of oxotremorine.5 The oxotremorine-induced hypotension in cats was not altered by decerebration but was abolished by high cervical spinal section.6 The results indicate that the prolonged hypotension elicited by oxotremorine is mediated by an action at muscarinic receptors in the brain stem resulting in a decrease in sympathetic nerve activity and peripheral resistance but not heart rate or cardiac output.


Pharmacological properties of kryptopyrrole and its oxidation products on isolated sciatic nerve of rat and on guinea-pig ileum. 1 Kryptopyrrole (2, 4-dimethyl, 3-ethylpyrrole) inhibited conduction in rat sciatic nerve by a local anaesthetic action. 2 Tone and both spontaneous and electrically-induced contractions of guinea-pig ileum were also inhibited by kryptopyrrole. The concentration of kryptopyrrole required for 50% inhibition of a maximum twitch tension (ID50) was 0.085 mM. 3 Oxidation products of kryptopyrrole with chromatographic properties similar to those of urinary constituents reported in schizophrenia and hepatic porphyrias had little or no effect at similar concentrations. 4 Dose-response curves to exogenous acetylcholine in guinea-pig ileum were shifted to the right by kryptopyrrole, with loss of parallelism and reduction in the maximum contraction. 5 Acetylcholine overflow from ileal segments at rest and during electrical stimulation was reduced by kryptopyrrole. 6 These results on ileal segments are consistent with kryptopyrrole having both a post-junctional site of action, presumably directly on the muscle, and a pre-junctional site reducing the output of acetylcholine from the myenteric plexus. 7 The significance of these findings is discussed in relation to a possible clinical pathological role for these compounds.


The effects of deprivation of prostaglandin precursors on vascular sensitivity to angiotensin II and on the kidney in the pregnant rabbit. 1 Pregnant rabbits were deprived of essential fatty acids from day ten of pregnancy, and results compared with a control group on a normal diet. 2 At term, cannulation of jugular and carotid vessels was performed under anaesthesia, to study the vascular sensitivity to angiotensin II and basal blood pressure. 3 Plasma renin levels, urinary electrolytes and protein were measured. 4 Placental and renal tissue was examined histologically. 5 Though no changes were found in tissues, blood or urine, a markedly significant increase in response to angiotensin II was found in the group deprived of essential fatty acids. This parallels the findings in vascular response in human pre-eclampsia.


Effects of noradrenaline and carbachol on temperature regulation of rats. 1 Noradrenaline (0.2 to 20 micrograms) and carbachol (0.1 to 1 microgram) injected into the preoptic/anterior hypothalamic area, evoked dose-dependent falls in core temperature at all sites tested, followed in most experiments by delayed increases that were not dose-related. Muscarine (0.1 to 10 microgram) produced effects similar to those evoked by carbachol. 2 These falls in core temperature were associated with increases in tail temperature, locomotor activity and CO2 elimination (a measure of metabolic rate). 3 The temperature responses to noradrenaline (10 microgram) and to carbachol (1 microgram) were antagonized by intrahypothalamic injections of phentolamine (10 microgram) and atropine (1 microgram), respectively. 4 Analysis of the temperature responses and their respective latencies indicates that carbachol-induced hypothermia was mediated by cholinoceptors in the anterior hypothalamus, whereas hypothermia after noradrenaline was mediated by adrenoceptors throughout the preoptic/anterior hypothalamic area. 5 Vasodilatation of the tail blood vessels contributed significantly to the hypothermia evoked by carbachol, and to that evoked by injections of noradrenaline into the anterior hypothalamus. 6 Hypothermia induced by noradrenaline injection into the preoptic area, was mediated by effector mechanisms additional to non-evaporative heat loss.


Effects of 2,4-dinitrophenol amylobarbitone and certain other drugs on the rate of oxygen consumption and force of contraction of isolated curarized diaphragm muscle of the rat. 1 A technique has been developed for studying over periods of 10 min or longer the effects of drugs on both the force of electrically-induced contractions and the oxygen consumption of an isolated, curarized, mammalian, skeletal muscle preparation.2 The resting oxygen consumption of the muscle was increased substantially by 2,4-dinitrophenol in concentrations (0.02 mM and higher) that eventually produced contracture. Two other uncoupling agents, 4,6-dinitro-o-cresol and carbonylcyanide-p-trifluoromethoxyphenylhydrazone, behaved similarly.3 The oxygen consumption over 10 min of the stimulated muscle was also increased by 2,4-dinitrophenol (0.05 mM), although the strength of the ;maximal' contractions was lessened.4 Amylobarbitone increased the strength of contraction at a concentration (0.2 mM) that did not affect oxygen consumption significantly. Amylobarbitone and pentobarbitone also increased it at a concentration (1 mM) that depressed oxygen consumption. They decreased both strength of contraction and oxygen consumption at a concentration of 5 mM. Phenobarbitone had a weaker action.5 S-n-decyl-thiouronium increased oxygen consumption when given at a concentration (1 mM) that diminished strength of contraction and eventually produced contracture of the muscle.6 Both S-methyl-thiouronium (1 mM) and 4-aminopyridine (0.1 mM and 0.5 mM) increased strength of contraction without increasing oxygen consumption. Neither strength of contraction nor oxygen uptake was affected by ouabain (up to 0.01 mM) or by phenformin (0.1 mM).7 It is concluded that the response to 2,4-dinitrophenol is due mainly, if not wholly, to its known ability to uncouple oxidative phosphorylation; that the response to the barbiturates is due to a combination of a known metabolic action (viz., blocking of the respiratory chain) and a stimulant action on muscle; and the response to S-n-decyl-thiouronium to a disruptive action on cell membranes. The disproportionate actions of 4-aminopyridine and S-methyl-thiouronium on strength of contraction relative to oxygen consumption are also attributed to a non-metabolic action.


Morphine depression and tolerance of nerve-induced parotid secretion. 1 The nerve-induced secretion produced by the rat parotid gland is proportional to the frequency of stimulation. Morphine decreased the flow rate during stimulation at 2.5 and 5 Hz, but not at 20 Hz. This frequency-dependent action of morphine and was partially reversed by naloxone. 2 The secretion produced by the rat parotid gland during an intravenous infusion of acetylcholine was not diminished by morphine. Therefore, the action of morphine on nerve-induced secretion is most probably on the motor nerve terminals, which release acetylcholine. 3 Animals that had been implanted with morphine base pellets tolerated 4 times as much morphine as controls; after 6 days the minute ventilation was less depressed by graded doses of morphine than non-implanted controls. 4 Nerve-induced secretion in morphine-implanted animals was less depressed by morphine than control animals 6 and 24 h after the pellets were removed. The flow rates in the 6 h group treated with morphine were greater after naloxone than control (precipitated withdrawal) but at 24 h when withdrawal symptoms were no longer evident, naloxone produced only a slight reversal.


Myocardial synthesis of prostaglandin-like substances and coronary reactions to cardiostimulation and to hypoxia. 1 Continuous recording of cardiac contractions and coronary flow from isolated perfused hearts of rats permitted the study of coronary reactions to: (a) cardiostimulation induced by single doses or slow infusions of noradrenaline, CaCl2, glucagon or electrically induced tachycardia; (b) short interruptions of coronary inflow (hypoxia). 2 Except during tachycardia the heart rate was kept constant at 210 beats/min by electrical pacing. 3 Metabolic coronary vasodilatation (MCD) resulting from cardiac hyperactivity induced by noradrenaline, Ca2+, tachycardia or glucagon was inhibited by administration of prostaglandin E2. Reactive hyperaemia response to hypoxia was unaffected by prostaglandin administration. 4 Inhibition of MCD could also be obtained by prolonged infusion with arachidonic acid (1.6 X 10(-7) M), presumably by its conversion into prostaglandin-like substance since arachidonic acid failed to block MCD in hearts from rats pretreated with non-steroidal anti-inflammatory drugs (indomethacin, naproxen, phenylbutazone). 5 Reactive hyperaemia was unaffected either by arachidonic acid or by blockade of the synthesis of prostaglandin-like substances by anti-inflammatory drugs. 6 Since prostaglandin synthetase inhibition does not prevent but may enhance MCD, we do not advocate prostaglandin-like substances as agents directly responsible for the coronary vasodilatation that follows cardiac hyperactivity. 7 We postulate that cardiac overproduction of prostaglandins may lead to a failure in the adaptive coronary flow response to cardiac hyperactivity (coronary insufficiency?).


Effects of adenosine 5'-triphosphate (ATP) and beta-gamma-methylene ATP on the rat urinary bladder. 1 High concentrations of adenosine 5'-triphosphate (ATP, 100 to 1000 micrometer) were required to cause contraction of the rat urinary bladder, while adenosine and adenosine 5'monophosphate (AMP, 1 to 50 micrometer) produced relaxation. 2 One hundred fold lower concentrations of beta-gamma-methylene ATP, which is resistant to degradation to AMP and adenosine, caused dose-dependent, phasic contractions which mimicked atropine-resistant responses to nerve stimulation. 3 Adenosine and AMP caused dose-dependent inhibition of carbachol-induced contractions; theophylline competitively antagonized this inhibition but not the contractile responses to beta-gamma-methylene ATP, ATP or atropine-resistant nerve stimulation. 4 These results suggest that the insensitivity of the rat bladder to ATP is due to its rapid degradation to AMP and adenosine and support the hypothesis that the bladder receives a purinergic excitatory innervation.


The binding of [3H]-oestradiol-17 beta in the immature rat uterus during the sequential administration of non-steroidal anti-oestrogens. 1 The binding of [(3)H]-oestradiol-17beta (0.08 mug) in the uterus, vagina, liver and heart of immature female rats has been studied in vivo and the effect of daily administrations of the non-steroidal anti-oestrogens, tamoxifen and monohydroxytamoxifen, on the 2 h accumulation of [(3)H]-oestradiol-17beta in the uterus has been determined.2 Doses of tamoxifen (8 mug daily) or monohydroxytamoxifen (1.28 mug daily), which have previously been found to antagonize completely the uterotrophic activity of oestradiol-17beta (0.08 mug daily), did not significantly reduce the total uterine binding of 0.08 mug [(3)H]-oestradiol-17beta administered on day 4 of a 3-day uterine weight test.3 The simultaneous administration of tamoxifen (8 mug) or monohydroxytamoxifen (1.28 mug) with [(3)H]-oestradiol-17beta (0.08 mug) on day 3 of a uterine weight test did not significantly reduce the total uterine binding of oestradiol-17beta. The binding of [(3)H]-oestradiol-17beta was reduced if monohydroxytamoxifen or tamoxifen was administered 4 h before the oestradiol.4 Tamoxifen (8 mug daily) or monohydroxytamoxifen (1.28 mug daily) did not prevent the translocation of [(3)H]-oestradiol (0.08 mug) to the uterine cell nucleus on day 3 of a 3-day uterine weight test.5 The measurement of total nuclear oestrogen receptors by an exchange assay technique demonstrated a higher concentration of oestrogen receptors in anti-oestrogen-treated animals compared with controls.6 Since the administration of anti-oestrogenic doses of non-steroidal anti-oestrogens during a 3-day uterine weight test did not inhibit the total binding of oestradiol in the uterus, or affect the translocation of the steroid to the nucleus, the mechanism of action of non-steroidal anti-oestrogens over the range of the partial agonist dose-response curve must involve an interaction, or competition of oestradiol-17beta- and anti-oestrogen-oestrogen receptor complexes for sites within the nucleus.


Barbitone-induced tolerance to the effects of sedative-hypnotics and related compounds on operant behaviour in the rat. 1 Pretreatment doses of barbitone, pentobarbitone, ethanol, and phenytoin (diphenylhydantoin) in non-tolerant rats produced increases in operant responding at low doses and at higher doses resulted in decreases in responding.2 Daily barbitone injections (100 mg/kg, i.p.) resulted in the development of functional tolerance to both the stimulant and depressant effects of barbitone on responding.3 Barbitone tolerance development did not result in any change in the brain or plasma pharmacokinetics of barbitone.4 Barbitone-tolerant rats were cross-tolerant to the behavioural effects of pentobarbitone, ethanol, and phenytoin. The dose-effect curves for all of these drugs were shifted to the right in tolerant rats, compared to non-tolerant rats.5 Comparison of the brain and plasma levels of these drugs in non-tolerant and tolerant rats provided a means of separating functional cross-tolerance from dispositional cross-tolerance. Barbitone-tolerant rats appeared to be functionally cross-tolerant to ethanol in that there was no change in the brain and blood ethanol levels at times when the degree of behavioural impairment was substantially reduced. In contrast to ethanol, cross-tolerance to phenytoin appeared to be due to a decrease in the brain and plasma levels (dispositional tolerance). Cross-tolerance to pentobarbitone appeared to be comprised of both functional and dispositional cross-tolerance.6 The usefulness of a multidisciplinary approach in the analysis of sedative hypnotic tolerance and cross-tolerance is discussed. It is concluded that without the concurrent determination of both brain and plasma drug levels it would not be possible to distinguish between functional and dispositional tolerance.


A comparative study of the action of frusemide and methyclothiazide on renin release by rat kidney slices and the interaction with indomethacin. 1 The effects of frusemide (a diuretic acting on the loop of Henle) and methyclothiazide (a thiazide diuretic) on renin release were studied on rat kidney slices. 2 Frusemide at concentrations of 1.5 and 7.5 mmol/l produced significant increases in renin release but had no effect at 0.15 mmol/l. 3 Methyclothiazide in a similar concentration range did not increase renin release; instead, at the highest concentration used, methyclothiazide (3.5 mmol/l) inhibited renin release. 4 Indomethacin (25 mumol/l) did not inhibit the increase of renin induced by frusemide. 5 Our limited study in vitro is consistent with the findings of other workers who have shown in vivo, in the absence of systemic electrolyte depletion, that only "loop diuretics" increase renin secretion. Under our experimental conditions, it is suggested that frusemide exerts a direct action either upon the epithelioid cells or upon the macula densa since the renal prostaglandin system does not intervene.


Presynaptic gamma-aminobutyric acid responses in the olfactory cortex. 1. Potential changes were recorded from the lateral olfactory tract in slices of rat olfactory cortex in vitro at room temperature. 2. Superfused gamma-aminobutyric acid (GABA) usually produced dose-related depolarization of the lateral olfactory tract. Muscimol and 3-aminopropanesulphonic acid appeared more potent depolarizing agents than GABA, and glycine and taurine appeared less potent. Carbachol and glutamate were virtually ineffective. 3. The GABA responses were at least partially Cl- dependent. 4. (+)-Bicuculline and higher concentrations of strychnine antagonized the GABA but not the glycine-induced depolarizations. Paradoxically, responses to high doses of GABA were sometimes potentiated by both bicuculline and strychnine. 5. It is suggested that GABA receptors could occur as widely on nerve terminals as they do postsynaptically in the CNS, where GABA could be involved in the modulation of transmitter output.


The appearance of noradrenaline and adrenaline and the developmental changes in the their concentrations in the gut of the chick. 1. The times of appearance and the concentrations of noradrenaline and adrenaline were determined fluorimetrically in the gut of the embryonic and developing chick. 2. In the duodenum and jejunum, noradrenaline was detected in embryos on the 12th day of incubation. The concentration continued to increase throughout the embryonic stage and attained a maximum within 3 days of hatching. Afterwards, it decreased to about one-third of the peak level. No adrenaline was detectable in most stages of development. 3. In the rectum, noradrenaline was detected in embryos on the 12th day of incubation; both noradrenaline and adrenaline were invariably found on the 15th day of incubation. The concentrations of both amines fluctuated after hatching, but the amount of adrenaline was always approximately 40% of the amount of noradrenaline, except in the adult.


Evidence that adrenaline is released from adrenergic neurones in the rectum of the fowl. 1 The rectum isolated from the fowl was perfused with Tyrode solution via the caudal mesenteric artery. Noradrenaline and adrenaline were biologically or fluorimetrically assayed in perfusates collected before and during stimulation of Remak's nerve or of the periarterial nerves.2 Perfusates collected during nerve stimulation relaxed the chick rectum and rat stomach strips which served as assay tissues. This effect was attributed to the action of noradrenaline or adrenaline released from adrenergic nerve endings which appeared in the perfusates.3 Perfusates obtained during stimulation (30 Hz for 60 s) of Remak's nerve contained both noradrenaline and adrenaline when measured fluorimetrically. The mean output per stimulus train was 0.8 +/- 0.2 ng/g wet wt. tissue for noradrenaline and 1.7 +/- 0.2 ng/g wet wt. tissue for adrenaline (n = 7). Perfusates obtained during stimulation (30 Hz for 60 s) of the periarterial nerves contained noradrenaline in a concentration of 1.6 +/- 0.3 ng/g wet wt. tissue per stimulus train, but almost no adrenaline (n = 7).4 Neither stimulation of Remak's nerve nor the periarterial nerves liberated catecholamines when the rectum was perfused with Tyrode solution containing low Ca(2+) (0.1 mM) and high Mg(2+) (10 mM).5 Infusion of high potassium solution (50 mM) increased markedly the output of noradrenaline and adrenaline.6 Adrenaline as well as noradrenaline may function as the adrenergic neurotransmitter in the rectum of the fowl.


Release of [3H]-acetylcholine from the isolated retina of the rat by potassium depolarization: dependence on high affinity choline uptake. 1. The effect of potassium depolarization on the release of [3H]-acetylcholine ([3H]-ACh) from the isolated retina of the rat was studied. 2. Exposure of retinae to medium containing KCl (50 mM) evoked a large increase in the efflux of [3H]-ACh with only a small concurrent increase in the efflux of [3H]-choline. The KCl-evoked release of [3H]-ACh was almost abolished in calcium-free medium. 3. Incubation of retinae with [3H]-choline in sodium-free medium, or medium containing hemicholinum-3 (HC-3), procedures that are believed to inhibit selectively the high affinity choline transport system, reduced the retinal uptake of [3H]-choline by approximately 50% and the synthesis of [3H]-ACh by about 97%. 4. The potassium-evoked release of [3H]-ACh was almost abolished in retinae that had been loaded with [3H]-choline in sodium-free medium or medium containing HC-3, and subsequently superfused in normal medium. 5. It is suggested that as in other areas of the nervous system, a sodium-dependent, high affinity uptake system for choline is important in retinal cholinergic nerve terminals.


Augmentation by chlordiazepoxide of the inhibitory effects of taurine, beta-alanine and gamma-aminobutyric acid on spike discharges in guinea-pig cerebellar slices. 1. Chlordiazepoxide (Cdp, 1 to 100 micrometer) enhanced the inhibitory action of externally applied gamma-aminobutyric acid (GABA) upon spontaneous spike discharges in guinea-pig cerebellar slices; the actions of externally applied beta-alanine and taurine, but not externally applied glycine, were also enhanced by Cdp. 2. It was suggested the Cdp might exert its action by enhancing the increase of membrane permeability to K+ induced by the amino acid, but not to Cl-. 3. Cdp (5 to 100 micrometer) reversed the antagonism of picrotoxin to the inhibitory action of externally applied GABA and also the antagonism of strychnine to the actions of externally applied beta-alanine and taurine. 4. The inhibition of the spontaneous spike discharges of Purkinje cells, evoked by electrical stimulation of the slice, was also enhanced by Cdp (10 to 100 micrometer). 5. The blocking action of picrotoxin (10 to 20 micrometer) on the stimulus-evoked inhibition of spike discharges was reversed by Cdp (10 micrometer). 6. In a similar manner, strychnine (10 or 20 micrometer) was also found to block the stimulus-evoked inhibition of spike discharges. It is suggested that in the cerebellum strychnine-sensitive amino acid(s) may be involved in synaptic transmission. Strychnine blockade was also reversed by Cdp (10 micrometer).


Further observations on the interaction between glutamate and aspartate on lobster muscle. 1 The ability of bath-applied L-glutamate to enhance subsequent depolarizations produced by bath-applied L-aspartate on lobster muscle was further investigated by means of intracellular recording techniques. 2. Increasing the conditioning glutamate concentration or exposure time produced a greater enhancement of aspartate responses. Enhancement was also dependent on the time interval between glutamate and aspartate doses and was not prevented by overnight storage of preparations in vitro. 3. The dose-depolarization curve for enhanced aspartate responses (measured at a fixed time following a given dose of glutamate) was displaced to the left along the abscissa scale relative to control, with no detectable change in limiting log-log slope. 4. Conditioning doses of kainate or domoate (but not quisqualate, aspartate, or KCl) also enhanced aspartate responses; however, their conditioning effect was little affected by increasing the concentration, exposure time, or time interval before applying aspartate. The rate of onset and decline of the enhanced aspartate response always resembled that of the previous conditioning agonist. 5. D and L-Aspartate were approximately equieffective depolarizing agents whereas D-glutamate was approximately 1/40 as potent as L-glutamate. After a conditioning dose of D or L-glutamate, responses to D or L-aspartate were enhanced. 6. In a Na+-free (Li+) medium, both the glutamate depolarization and the conditioning effect towards aspartate were largely abolished. With kainate however, Na+ was not apparently important either for evoking the kainate response or for producing the conditioning effect. 7. Bath-applied glutamate greatly enhanced and prolonged the time course of the iontophoretic aspartate potential with only a small effect on the glutamate potential; however, these effects were not maintained after washout of glutamate. In contrast, bath-application of aspartate depressed the aspartate potential while enhancing the glutamate potential. Some sites that were insensitive to iontophoretically-applied aspartate became clearly responsive to this agent during a bath-application of glutamate. 8. It is proposed that during conditioning with bath-applied glutamate, kainate or domoate, some agonist is trapped by extrajunctional sites and is subsequently displaced by bath-applied aspartate to produce the long-term enhancement effect.


Reversal of DOPA-induced arousal in reserpine-treated rabbits and mice by histidine. 1 The behavioural effects induced by histidine were studied in two species. In rabbits, sedation was assessed by the presence of blepharospasm, loss of righting reflex, and loss of response to painful stimuli. In mice, sedation and arousal were assessed by changes in the locomotor activity, exploratory activity, and minimal electroshock seizure threshold.2 The administration of histidine to normal rabbits or mice, in doses of 800 mg/kg and 1000 mg/kg respectively, had no apparent effect on behaviour. Moreover, it did not affect the behavioural excitation induced by L-DOPA (100 mg/kg i.v. in rabbits and 750 mg/kg i.p. in mice) in these animals.3 The administration of histidine with or after L-DOPA in reserpine-treated rabbits (2.5 mg/kg i.v.) or mice (5 mg/kg, i.p.) produced sedation. This sedative effect was dose-dependent.4 The sedative effects induced by histidine after DOPA-induced arousal in reserpine-treated rabbits and mice were prevented by prior injection of the histamine H(1)-receptor blockers, chlorpheniramine (2.5 mg/kg) or diphenhydramine (5 mg/kg).5 Imipramine (7 to 10 mg/kg, i.v.)-induced arousal in reserpine-treated rabbits was also reversed by histidine infusion.6 The infusion of 5-hydroxytryptophan (100 mg/kg, i.v.) with L-DOPA, or of arginine (450 mg/kg, i.v.) with or after L-DOPA, or of histamine (100 mug/kg), i.v.) after L-DOPA, did not affect the DOPA-induced arousal in reserpine-treated rabbits.7 These findings indicate that histamine, formed centrally from exogenous histidine, and released in increased amounts at the synapses in reserpine-treated animals, possesses a central sedative effect. This effect may be sufficient to antagonize the behavioural excitation induced by high levels of catecholamines in the brain of these animals when aroused by L-DOPA administration.8 It is concluded that in addition to the other monoamines, histamine may also be implicated in the regulation of brain excitability.


The effect of veratridine on the release of catecholamines from the perfused adrenal gland. 1. Experiments on perfused adrenal glands of guinea-pigs were carried out to study the catecholamine output induced by veratridine in the presence of hexamethonium and atropine. 2. Veratridine (10 micrometer to 200 micrometer) caused a dose-dependent increase in catecholamine output. 3. The addition of veratridine to the perfusion medium for a period of 3 min caused an increase in catecholamine output which reached a maximum 5 min to 10 min after withdrawal of the drug. The catecholamine output then gradually declined and reached near resting values within 30 minutes. It was never sustained for a longer period, even when veratridine was infused for 1 hour. 4. Veratridine failed to increase the catecholamine output in the absence of extracellular Ca2+. However, the addition of Ca2+ after an infusion of veratridine (100 micrometer) in the absence of Ca2+ caused an increase in the catecholamine output which was proportional to the concentration of Ca2+ (0.55 mM to 8.8 mM) used. 5. Veratridine did not increase the catecholamine output in the absence of extracellular Na+ ions, NaCl being replaced by equimolar choline chloride or LiCl. Veratridine also failed to evoke catecholamine output in a Na+-free solution in which Na+ was replaced by sucrose; this was the case even in the presence of a high concentration of Ca2+ (8.8 mM). 6. Tetrodotoxin (0.1 micrometer) and excess Mg2+ (20 mM) reversibly inhibited the catecholamine output induced by veratridine. 7. Ouabain (10 micrometer) significantly potentiated the veratridine-induced catecholamine output. 8. It is suggested that Na+-dependent Ca2+ influx as well as voltage-dependent Ca2+ influx mechanisms may be involved in the catecholamine output induced by veratridine.


The relative toxicity of amitriptyline, imipramine, maprotiline and mianserin in rabbits in vivo. 1. Conscious or barbiturate-anaesthetized rabbits were slowly infused intravenously with solutions of amitriptyline, imipramine, maprotiline or mianserin, usually until death occurred. 2. Amitriptyline produced death at the lowest dose, imipramine and maprotiline were intermediate while much higher doses of mianserin were required. 3. Convulsions were induced by the antidepressants in all conscious rabbits and the order of potency of the drugs in producing this effect was amitriptyline greater than or equal to imipramine greater than maprotiline greater than mianserin. 4. All four drugs produced a reduction in heart rate and blood pressure in the anaesthetized rabbits and the order of potency in this respect was amitriptyline greater than imipramine greater than maprotiline greater than mianserin. 5. All four drugs produced significant changes in the ECG compared with control rabbits. The P-R interval was lengthened (potency order amitriptyline greater than imipramine greater than or equal to maprotiline greater than mianserin) and the QRS complex was widened (potency order amitriptyline greater than imipramine greater than or equal to maprotiline greater than mianserin). 7. It is concluded that all four drugs show the toxic effects classically associated with tricyclic antidepressants but the relative toxicity amongst these agents varies considerably and is in the order amitriptyline greater than imipramine greater than maprotiline greater than mianserin.


Responses of the guinea-pig isolated olfactory cortex slice to gamma-aminobutyric acid recorded with extracellular electrodes. 1. Potential changes between the pial and cut surfaces of slices of guinea-pig olfactory cortex in vitro produced by gamma-aminobutyric acid (GABA) were recorded with extracellular electrodes. 2. GABA, superfused over the pial surface (0.1 to 10 mM), produced a pial-negative potential deflection, accompanied by inhibition of the postsynaptic response to lateral olfactory tract (LOT) stimulation. 3. This effect was replicated by the following compounds (potency relative to GABA = 1, in brackets): 3-aminopropanesulphonic acid (5.3), epsilon-aminovaleric acid (0.07), beta-alanine (0.07), beta-amino-nibutyric acid 0.05), epsilon-aminocaproic acid, alpha-amino-isobutyric acid, L-leucine (less than 0.02). 4. L-Glutamate (1 to 10 mM) produced a very large surface negative shift, with relatively less synaptic inhibition. Glycine (1 to 10 mM) produced less surface negatively, accompanied by synaptic inhibition. 5. Responses to GABA were antagonized more effectively than those to glycine by bicuculline (3 to 30 micrometer) and picrotoxin (1 to 30 micrometer). Strychnine (1 to 10 micrometer) incompletely inhibited responses to glycine. 6. It is concluded that, while the locus within the slice of these effects is uncertain, the preparation may be useful for testing the interaction of drugs with cerebral GABA receptors.


Changes in self-rating of symptoms: a comparison of questionnaire graphic scales with test cards. Forty-five in-patients, with primary diagnoses of neurosis or personality disorder, completed the test cards and booklet versions of the Symptom Rating Test--Day (SRT). In order to facilitate retroactive interference the Manifest Anxiety Scale (MAS) and the Maudsley Personality Inventory (MPI) were administered between the two forms of the SRT. On the next day the patients were given the SRT (Week). The initial SRT, MAS and MPI testing was repeated one week later. On the assumption that positional set is an important consideration predictions were made as to the expected differences between the test cards and booklet modes of SRT administration. The results add support to the practical use of the SRT in its more recent standardized format.


Treatment of methadone withdrawal with cerebral electrotherapy (electrosleep). The use of cerebral electrotherapy (CET) in methadone detoxification was studied in 28 patients. Fourteen patients received active CET; the other 14 acted as controls and received either stimulated CET or only methadone detoxification therapy. One patient dropped out of the study. The Taylor Manifest Anxiety Scale and the Hamilton Anxiety Scale were administered before and after the study period. Nine of the patients receiving active CET were drug-free by the end of 8 to 10 days, and all experienced a marked reduction of their symptoms; the control group did not show significant changes. CET was clearly beneficial in the treatment of patients undergoing methadone withdrawal.


Delinquency by opiate addicts treated at two London clinics. 455 male and 120 female opiate addicts were treated at two London drug dependence clinics between 1968 and 1975. The delinquency pattern of 117 female addicts and of a systematic sample of 119 male addicts was analysed in relation to stages of their addiction career and outcome. Treatment had no effect on overall crime rate but there was a significant increase in the proportion of drug offences during the treatment stage. Comparisons between the sexes showed that the outcome of treatment was worse in women. In male addicts a history of delinquency had no prognostic significance, but in females convictions for non-drug offences before entering treatment might predict poor response to treatment of drug dependence.


Suicide in prison.

Suicide in prison. Records of 186 suicides among male prisoners in England between 1958 and 1971 emphasize the differences between the prison population and the population at large. The suicide rate may well be three times greater. The records show that sentence of more than 18 months' duration, whether anticipated or actually received, is associated with a greater risk of suicide than shorter sentence, and that suicide is most likely to be committed during the first few weeks in custody.


The outcome of severe acute schizophrenic illnesses after one year. Forty-five patients with acute schizophrenic illnesses (defined by PSE criteria) were assessed in clinical, cognitive and social terms before being entered in a four week study of the isomers of flupenthixol and placebo. At the end of one year they were re-assessed in the same terms. The clinical and psychological features of the acute illness and the drug treatment given did not predict outcome. Poor outcome in social terms was significantly related to severe social isolation in the initial assessment and to the presence of nuclear symptoms and negative schizophrenic features at follow-up.


Schizophrenia: diagnostic criteria and outcome. The files of a cohort of schizophrenic patients who were admitted to hospital for the first time in their lives in 1963, and who were representative of cases in a large unselected population, were examined , first by exclusion criteria, and then by the diagnostic criteria of Schneider's first-rank symptoms, Feighner et al's criteria, and the New Haven Schizophrenia Index (NHSI). Forty-three such cases were found who were schizophrenic on at least two sets of criteria, and who were followed up in 1977. Examination of the outcome showed no relationship with FRS presence or absence or number of first-rank symptoms, nor with the NHSI score, but did show a relationship to the Feighner et al criteria and an even stronger relationship to a simple score derived from these criteria.


The sensory filter in schizophrenia: a study of habituation, arousal, and the dopamine hypothesis. The possible failure of a notional sensory filter in schizophrenia was studied by means of habituation of the orienting response. Non-paranoid schizophrenics failed to habituate, but paranoids habituated normally. Paranoids, however, showed a different impairment: they responded to a dishabituating tone as if the novel stimulus were somewhat familiar. The failure of habituation in non-paranoids could not be explained in terms of arousal when the index was the rate of skin conductance fluctuation. Neurotic controls showed considerably higher levels than either group of schizophrenics. Non-paranoid schizophrenics had lost the normal inverse relationship between habituation and level of arousal as manifested in the rate of spontaneous skin conductance fluctuation.


The focus in brief interpretive psychotherapy: dilemmas, traps and snags as target problems. The need for a focus for brief interpretive psychotherapy is considered and a new approach is suggested. In this method, the ways in which the patient's construction of himself and his relationships are related to his problems are identified and expressed in the form of dilemmas, traps and snags. It is suggested that these formulations represent an appropriate level of abstraction, allowing patient and therapist to share provisional hypotheses about the goals of therapy and offering the basis for a method of measuring how far these goals are achieved.


Behaviour therapy in anorexia nervosa.

Behaviour therapy in anorexia nervosa. In three collaborating hospitals, 81 anorexia nervosa patients were randomly assigned to behaviour modification or its absence and followed over 35 days. There was no overall significant difference in weight gain in the two groups except in a subset of patients: those with no prior out-patient treatments.


Pretreatment predictors of outcome in anorexia nervosa. The relationship of selected pretreatment characteristics to weight gain during treatment was examined in 81 anorexia nervosa patients. Good prognostic indicators correlating positively with weight gain were: no previous hospitalizations for anorexia nervosa, a great amount of overactivity before treatment, less denial of illness, less psychosexual immaturity and the admission to feeling hunger. A perinatal history of delivery complications was associated with the poor outcome predictor of prior hospitalizations.


Comparisons of weight concepts in groups of neurotic, normal and anorexic females. A group of normal women and a group of women in hospital for treatment of a neurosis but without a disorder of eating were compared with a group of anorexic patients in terms of their attitudes to weight. All subjects completed a rank order form of repertory grid. Differences in construct patterning between the anorexic patients and the other female groups could not be accounted for by social class, age or neurotic disorder. The most psychologically significant finding was a positive correlation between the constructs  self at normal weight and ideal weight instead of a negative correlation which clinical experience would lead one to expect. Four explanations are proposed to account for this finding.


Psychotic and neurotic depression: I. Some points of method. Testing hypotheses on classification could be made more precise by using only clinical symptoms and signs as its basis. Analyses based on a mixture of clinical, aetiological and background variables give ambiguous results since they incorporate the assumption that aetiological and symptomatological patterns are related in a one-to-one manner. A set of simplified models of possible relationships between aetiology and symptomatology is used to discuss these problems of interpretation. The clinical variables to be used for discriminant analyses may be chosen by testing for the existence of lower-order and higher-order differences between groups.


Psychotic and neurotic depression: 2. Clinical characteristics. A series of discriminant function analyses based only on clinical symptomatology suggests that psychotic and neurotic depressives do not differ globally but at a fairly specific level and that the principal, if not only, clinical difference between the groups is one of severity. This interpretation is reinforced by the fact that there are few symptoms more common in the neurotic group. There is suggestive evidence that symptoms generally thought to characterize neurotic depression may conduce to referral to psychiatric services. The neurotic depressive syndrome as classically conceived may therefore be an artificial one, created by selective factors bringing patients with particular symptoms into hospital populations.


Kielland's forceps: role of antenatal factors in prediction of use. The association between certain antenatal factors and the use of Kielland's forceps was analysed retrospectively in liveborn singleton births that occurred at this hospital between January and December 1976. Factors significantly associated with the use of Kielland's forceps were primiparity, short maternal stature, induction of labour, late engagement of the fetal head, low ratio of maternal height to fetal occipitofrontal head circumference, slow dilatation of the cervix in labour, and the use of epidural analgesia in labour. The findings support a contribution of cephalopelvic disproportion in the genesis of malposition, and when associated with slow dilatation of the cervix delivery should be expedited. Long-term follow-up studies are needed, however, before the role of caesarean section in reducing morbidity associated with malposition can be properly assessed.


Role of catecholamines in hypotensive response to dieting. The effect of dieting on blood pressure and catecholamine metabolism was assessed in 11 normotensive obese women by providing first a weight-maintenance regimen high in carbohydrate and then a low-energy diet. All dietary constituents other than carbohydrate were maintained constant throughout the 18-day study. The low-carbohydrate diet led within 48 hours to a 41% fall in the urinary output of 4-hydroxy-3-methoxy mandelate and a significant fall in systolic and diastolic blood pressure. Plasma noradrenaline concentrations also fell and the hypotensive effect of the diet continued despite a maintained total body sodium. Thus the fall in blood pressure appeared to be mediated by changes in catecholamine metabolism independent of sodium intake. This may explain both the usefulness of weight reduction in hypertensive patients and the fainting that occurs in some normotensive obese subjects taking slimming regimens low in carbohydrate.


Isolation of mumps virus from the inner ear after sudden deafness. A 26-year-old woman with bilateral otosclerosis underwent right stapedectomy with an excellent result. One year later, however, she developed symptoms of mumps and within two days was completely deaf in the right ear. Prompt surgical exploration excluded a complication of the otosclerosis and a perilymph fistula, but culture of a sample of perilymph grew mumps virus. The case provides direct evidence of a relation between mumps virus infection and inner-ear damage.


Oligoclonal immunoglobulins and plasma cells in spinal fluid of patients with multiple sclerosis. A new modification of polyacrylamide gel electrophoresis (PAGE) was applied to cerebrospinal fluid proteins from patients with multiple sclerosis (MS). The same spinal fluids were also examined by a cytological technique. Over 90% of patients with clinically definite or early probable or latent MS showed abnormal PAGE patterns in the form of oligoclonal gammaglobulin bands. Reactive (atypical, large) lymphocytes or typical plasma cells were found in some patients. In all such cases an oligoclonal pattern was present. The findings of oligoclonal bands provides valuable supporting evidence for the diagnosis of MS in the less definite clinical categories.


Early growth retardation in diabetic pregnancy. Thirty-five insulin-dependent diabetic women with reliable menstrual histories were examined by ultrasonic scanning in the 7th-14th weeks of pregnancy. Judged from crown-to-rump length the fetuses were on average 5.4 days smaller than those in a local normal series. Ten of the fetuses were nine days or more smaller than normal and had a lower mean birth weight than the others, though the mean gestational age was similar. Maternal diabetes was not more severe in this group, but only two of the mothers had attended a special hospital for control of their disease as compared with 19 of the remainder. Although babies of diabetic mothers are often overweight, there appears to be a subgroup of cases in which fetal growth is retarded early in pregnancy, leading to low birth weight and possibly a higher incidence of congenital malformations.


Management and outcome of winter upper respiratory tract infections in children aged 0-9 years. Age-specific incidences for upper respiratory tract infections in children from a new-town population during 1975-7 were studied, and 965 consecutive upper respiratory tract infections in children aged under 10 during two winters were analysed in detail. Significantly different management plans made by seven doctors did not correlate with the clinical outcome as judged by complications, recall rates, and demand for treatment for similar episodes in the future. Two hundred and thirty-two children (24%) returned for another consultation for the same episode of upper respiratory tract infection. The main reason for these repeat consultations seemed to be that parental expectations about the natural history of the illness were not fulfilled. More realistic parental expectations might be set and safer clinical standards maintained if doctors warned parents about symptoms such as cough and occasional diarrhoea or vomiting that are commonly associated with upper respiratory tract infections in children.


10-year survey of 485 sterilisations. Part I--Sterilisation or hysterectomy? A survey was made of all sterilisations performed in an obstetric and gynaecological unit in Dunfermline in 1965-74 to determine the outcome and complications. Altogether 547 women were sterilised by the modified Pomeroy method, and 485 (88.7%) were interviewed and examined. No sterilisation was followed by serious complications, and the incidence of even minor complications was low (4.12%). There were no subsequent pregnancies. Altogether 57 women had to be referred for gynaecological operations in the years after sterilisation but only 18 of these had to have hysterectomies. At interview 59 women were found to have gynaecological symptoms (menstrual disorders in 46), and examination showed that 83 women had a gynaecological condition, which was in most cases unsuspected by the patient. Most of these conditions were minor but three women had carcinoma-in-situ of the cervix. Although 46 women suffered menstrual disorders after sterilisation 104 had done so at some time before the operation. These results therefore offer little support for the wider use of hysterectomy as a form of sterilisation.


10-year survey of 485 sterilizations. Part II: patients' views on their sterilization. As part of a study of the complications after sterilisation 485 of the 547 women who had been sterilised by a modified Pomeroy procedure in one unit over 10 years were interviewed. They were asked whether they regretted being sterilised and about the quality of their sex lives, mental health, social relationships, and marriages. Most women were pleased to have been sterilised, only 24 regretting it. Regret was more pronounced among women who had been sterilised in association with a third caesarean section, those sterilised for medical reasons, and those whose marriages had ended in divorce. In each case where a woman regretted a sterilisation that had been performed on the recommendation of a psychiatrist, the psychiatrists were still prepared to defent their opinions. On their sex lives, mental health, social relationships, and marriages, more women reported improvement than deterioration, and in most cases the deterioration could not be attributed to the sterilisation. The overall benefits from sterilisation to the women in this series therefore seemed to outweigh substantially the adverse consequences experienced by a few.


Kielland's forceps: association with neonatal morbidity and mortality. The incidence of certain neonatal complications associated with the use of Kielland's forceps was analyzed retrospectively in liveborn singleton babies delivered at this hospital between January and December 1976. The neonatal mortality rate attributable to use of the forceps was 34.9 per 1000. The incidences of delayed onset of respiration (17.4%), birth trauma (15.1%), and abnormal neurological behaviour--namely, apathy or irritability or both--(23.3%) significantly exceeded those in a matched group of babies born spontaneously. Fetal asphyxia played a major part in the aetiology of neonatal complications. Babies on whom Kielland's forceps were used, however, had a significantly greater incidence of abnormal neurological behaviour even in the absence of fetal asphyxia (14.3%), and in all of these babies the abnormal behaviour was transient and did not necessitate admission to the special-care baby unit. Neither maternal height nor the infant's birth weight or occipitofrontal head circumference influenced the occurrence of neonatal complications. The results also suggest that neither the speed of cervical dilatation nor the timing of engagement of the fetal head is of help in predicting the occurrence of neonatal complications after the use of Kielland's forceps.


Metabolic consequences of atenolol and propranolol in treatment of essential hypertension. A six-month study of triglyceride, cholesterol, free fatty acid (FFA), glucose, insulin, growth hormone, and glucagon concentrations was carried out in asymptomatic hypertensive normal-weight men randomly allocated to treatment with atenolol or propranolol. A highly significant increase in the basal plasma triglyceride concentration was observed in propranolol-treated patients after three and six months' treatment, with a smaller but significant increase in atenolol-treated subjects after six months' treatment. The changes in triglyceride concentration could not be ascribed to variations in plasma insulin, growth hormone, or glucagon concentrations. Basal FFA concentrations were reduced during the first three months of treatment in both groups but returned to pretreatment levels after six months. Plasma cholesterol concentrations were unchanged by either agent.


Detection of deep venous thrombosis by scanning of 99mtechnetium-labelled red-cell venous pool. A comparative study of 32 patients with suspected deep venous thrombosis was carried out using blood-pool radionuclide scanning and conventional x-ray phlebography. Results of the two methods showed close agreement, the sensitivity (positive correlation) of the scan being 100% and its specificity 89%. We conclude that a patient's red cells labelled with 99mtechnetium (99mTc) provide an excellent medium for this type of scanning. The technique has particular advantages in visualising the whole venous system, giving a persisting image, and obviating the need to inject into a vein of the affected limb. In view of the inherent disadvantages of contrast phlebography, 99mTc-red-cell scanning is clearly an acceptable alternative.


Value of positive myocardial infarction imaging in coronary care units. Positive myocardial imaging was undertaken on 120 unselected patients admitted to a coronary care unit with clinical suspicion of acute myocardial infarction. Multipurpose mobile gamma-cameras were used for serial imaging after administration of 99mtechnetium-labelled imidodiphosphonate, a low-cost radiopharmaceutical that is 97% specific for myocardial necrosis, with myocardial uptake and blood clearance most suitable for myocardial imaging. The sensitivty of detection was 94% for patients whose infarction was unequivocal on the ECG; when the presence of raised enzyme concentrations was also used as a criterion for myocardial necrosis, the overall sensitivity for all 120 patients remained 94%. In 73 patients (61%), whose ECGs were unhelpful or difficult to interpret, scintigraphy allowed infarction to be diagnosed in 11 (15%) and to be excluded in five (7%). In 32 (44%) of this group whose ECGs were totally uninterpretable due to previous myocardial damage or disorders of electrical activation, scintigraphy provided confirmation of a diagnosis that otherwise rested only on whether enzyme concentrations were raised. Myocardial imaging is thus a useful technique that permits more definite diagnosis in patients for whom ECG and enzyme data are uncertain.


Mianserin and agranulocytosis.

Mianserin and agranulocytosis. An alcoholic woman who was admitted to hospital for detoxification was prescribed thyroxine because of hypothyroidism and mianserin to alleviate severe depression. After several weeks' treatment she became unwell and was readmitted to hospital. Haematological examination indicated agranulocytosis. Further extensive investigations elicited no cause for this other than the mianserin, since no such disturbance has been reported for thyroxine after years of use. Thus mianserin is probably implicated in this case of agranulocytosis. Although the response may have been idiosyncratic, it highlights the need to monitor new drugs during the early phases of widespread use.


Modulatory role for biogenic amines in the cerebral cortex. Microiontophoretic studies. In order to investigate the mode of action of biogenic amines in rat cerebral cortex, the unitary activity of spontaneously firing neurons and their excitatory response to acetylcholine (ACh) were examined using microiontophoretic administration of dopamine (DA), noradrenaline (NA) and serotonin (5-HT). The predominant effect of these biogenic amines on the spontaneous activity was a profound and prolonged inhibition of firing (2-4 min), which attained its maximum within 15-120 sec. This response was generally more abrupt in onset and of greater magnitude with NA and 5-HT than with DA. Most units inhibited by DA, NA and 5-HT also showed marked depression of their excitatory response to ACh when pretreated with these biogenic amines. With repetitive administration of ACh, it could be shown that the total duration of inhibition of ACh responses by DA and NA was not as prolonged as the inhibition of the spontaneous firing of the same cells. With 5-HT, the initial ACh responses of many neurons could be completely blocked, and this inhibitory effect lasted as long as the inhibition of spontaneous firing. In view of the anatomical data demonstrating a relative sparsity of monoamine nerve terminals in cerebral cortex, the strong inhibition induced by DA, NA or 5-HT may have reflected slow inactivation of the biogenic amines. However, it could also be indicative of underlying mechanisms of action dependent on metabolic changes. Indeed, the interaction between biogenic amines and ACh might imply a balance between the intracellular pools of cAMP and cGMP is directly or indirectly influenced by the biogenic amines and ACh, respectively. This hypothesis would not exclude other modes of local interaction between DA, NA, 5-HT and ACh, and appears compatible with the modulatory role of biogenic amines in cerebral cortex.


Adrenaline, noradrenaline and dopamine levels in specific brain stem areas of acutely immobilized rats. Catecholamines (adrenaline, noradrenaline and dopamine) have been measured in specific areas of the rat brain stem after acute immobilization stress. Adrenaline levels were significantly decreased after 240 min of immobilization in all areas studied: A1 area, nucleus commissuralis (NCO), A2 area, anterior part of the nucleus tractus solitarii (NTS), and the locus coeruleus. Noradrenaline concentrations in stressed rats were significantly reduced only in the NTS area. In contrast, during stress there were no significant changes in dopamine concentrations with respect to control values in any of the areas studied. These results implicate the participation of central adrenaline neurons, localized in specific brain stem areas, and noradrenaline neurons innervating the rostral part of the nucleus tractus solitarii, in the mechanism of central response to acute stress.


5-HT concentration in cat's brain.

5-HT concentration in cat's brain. Endogenous concentrations of TRP, 5-HT and 5-HIAA were determined in the different cortical and subcortical areas of adult cat's brain, using ion-exchange  chromatography and spectrofluorimetric methods. Tryptophan is homogeneously distributed in all structures of the brain. 5-HT is mainly accumulated in the brain stem, hypothalamus and caudate nucleus, but also in cortical areas as olfactory and piriform gyrus. The ratio 5-HIAA/5-HT shows that 5-HT utilization is higher in the structures containing small amounts of 5-HT. Using the radioenzymatic assay described by Saavedra et al. (1973), the rostrocaudal distribution of 5-HT content was determined in olfactory and piriform cortex. Important concentrations of 5-HT were detected in the prepiriformis and anterior amygdaloidea areas. Using the same assay and microdissection on frozen frontal slices of the brain, the distribution of 5-HT concentration throughout the different layers of cortical areas was studied. Piriform, olfactory and sigmoid cortex present high concentrations in the superficial layers, including the molecular one. These results were confirmed by uptake studies, made on crude homogenates from frozen tissue, suggesting that 5-HT is mainly contained in the most external cortical terminals.


Further observations on transganglionic degeneration in trigeminal primary sensory neurons. Transganglionic degeneration has been studied with the Fink-Heimer method in the trigeminal sensory nuclei of adult cats and rats following peripheral nerve transections. Degeneration was observed ipsilaterally as well as contralaterally in all cats, surviving 11-30 days after transection of the infraorbital nerve. In the rats the infraorbital or the auriculotemporal nerve was transected. After transection of the former nerve the first signs of transganglionic degeneration were observed after 7 days postoperative survival and even after 130 days there were still a lot of degenerating structures present. Between 7 and 14 days survival there was a small amount of degeneration in substantia gelatinosa. After transection of the auriculotemporal nerve, degeneration was observed only in the most caudal parts of the trigeminal sensory nuclear complex. Opposite to the situation in the cat, there was no contralateral degeneration in the rat. All degeneration areas were somatotopically organized, both in the cat and in the rat. The results are discussed in relation to a previous study of transganglionic degeneration in the trigeminal sensory nuclear complex by the authors and to anatomical and physiological studies of somatotopic organization in the trigeminal sensory nuclei. They clearly show the value of transganglionic degeneration used as a tool for analysis of central projections of primary sensory neurons.


Relative synthesis of myelin in different brain regions of postnatally undernourished rats. We used a double isotope procedure and starved and normal littermate rats to compare relative protein synthesis in the cerebellar nuclear, myelin, synaptosomal, mitochondrial, and microsomal subfractions of postnatally starved animals. The remaining brain tissue was dissected into 6 additional regions (cerebral cortex, medulla oblongata, midbrain, hippocampus, striatum, and hypothalamus) and these were frozen for similar subcellular fractionation and analysis at a later date. The microsomal fraction derived from frozen tissues was discarded. The results show that early postnatal starvation specifically depresses myelin synthesis to about the same extent in all major brain regions at 18 and 21 days of age.


Oxidative metabolism, extracellular potassium and sustained potential shifts in cat spinal cord in situ. Changes in the ratio of reduced/oxidized cytochrome a,a3 were measured by reflection spectrophotometry in decerebrate cat spinal cord during microelectrode monitoring of extracellular K+ and extracellular potential. In 'resting' cord, cytochrome a,a3 was approximately 60% reduced, compared to 30% in cerebral cortex and 1% in isolated mitochondria. Stimulation of a dorsal root or afferent nerve caused linearly correlated responses, consisting of oxidation of cytochrome a,a3, elevation of K+0 and a negative shift of potential. In spinal cord, unlike cerebral cortex, the local volume of blood increased upon stimulation. The rate of recovery of the oxidation response of cytochrome a,a3 was consistently faster in cord than in cortex. Pentobarbital (i.v.) in anesthetic dosage reduced the amplitude and slowed the rate of recovery of all 4 parameters, indicating that the optical signals originate from gray matter. It is speculated that the spinal cord, even more than cortex, may depend for its viability on the maintenance of PO2 above a certain level, and that much of the metabolic activity following stimulation is associated with the restoration of ionic gradients.


Maintained contraction of the crayfish claw opener muscle in the absence of motor neuron activity. In the whole crayfish (Astacus sp.), contraction of the dactyl opener muscle may persist for many minutes in the complete absence of action potentials in the excitor nerve or muscle. Such maintained contraction has not been observed in isolated claw preparations. Generally, maintained contraction resembles catch in that the muscle holds its previous position and does not recontract if stretched. In one animal, however, the muscle continued to slowly open in the absence of nerve activity. Maintained contraction occurred in 5 of 6 whole animal preparations; in those 5 animals it occurred on 49% of trials. We could find no difference in nerve activity or muscle potentials on trials when such contraction occurred and on those when it did not. It is proposed that in the whole animal maintained contraction may be controlled by a factor which is released into the blood supply when the animal is aroused.


An intraspinal sympathetic preganglionic pathway: physiologic evidence in the cat. Electrical stimulation of the zona intermedia of the lower thoracic/upper lumbar cat spinal cord resulted in increases of heart rate (HR), blood pressure (BP) and cardiac contractility (dp/dt). Sites of maximal cardiovascular response (SMCR) were localized histologically to the intermediolateral nucleus (ILN). The inotropic and chronotropic responses were abolished by spinal cord transection or hemisection two to three segments rostral to the site of stimulation. Discrete electrolytic lesions in the white matter adjacent to the ILN were also shown to markedly decrease or abolish the chronotropic and inotropic responses elicited by stimulation of a more caudal SMCR. Longitudinal spinal section resulted in decreased cardiovascular responses from an SMCR; these changes were larger on the left side and greatest for BP as compared to HR and dp/dt. These findings indicate the existence of an ascending intraspinal cardiovascular pathway located in the deep white matter adjacent to the ILN. They further suggest that this is the intraspinal sympathetic preganglionic pathway recently described anatomically.


Differential serotonergic innervation of individual hypothalamic nuclei and other forebrain regions by the dorsal and median midbrain raphe nuclei. Lesions in the midbrain median but not in the dorsal raphe nucleus significantly decreased the serotonin (5-HT) content of the hippocampus (61%), medial preoptic area (49%), suprachiasmatic nucleus (70%) and anterior hypothalamic area (60%). Electrolytic lesions restricted to either the median or dorsal raphe nucleus produced significant reductions in the 5-HT concentration of the caudate-putamen, anterolateral hypothalamic area (45%) and arcuate nucleus (48--58%). The fall in caudate-putamen 5-HT level was significantly greater after the dorsal (66%) than after the median (24%) raphe lesion. Neither lesion significantly affected the 5-HT content of the posterolateral hypothalamic area, the ventromedial hypothalamic nucleus or the dorsomedial hypothalamic nucleus. Thus, like their differential projections to the caudate-putamen and hippocampus, the mesencephalic dorsal and median raphe nuclei appear to innervate different preoptico-hypothalamic nuclei and areas. Whereas the median raphe nucleus seems to be the primary source of 5-HT fibers to the suprachiasmatic nucleus, anterior hypothalamic area and medial preoptic area, the 5-HT inputs to the anterolateral hypothalamic area and arcuate nucleus appear to derive from both the dorsal and median raphe nuclei.


Development of muscarinic cholinergic receptors in inbred strains of mice: identification of receptor heterogeneity and relation to audiogenic seizure susceptibility. The concentrations and biochemical properties of muscarinic acetylcholine receptors in the brains of two highly inbred strains of mice, DBA/2J and C57BL/6J, have been studied using [3H]quinuclidinyl benzilate (QNB), a potent and specific receptor antagonist. As is the case with rat brain, murine muscarinic receptors exist in at least two forms, which differ in their affinities for receptor agonists but which have the same high affinity for receptor antagonists. Carbamylcholine binding to mouse neural membranes can be resolved into two components with KDs of 5.2 times 10(-7) and 7.9 times 10(-5) M. There is a regional heterogeneity of brain receptors with respect to their distribution between these high and low agonist affinity forms. Brain stem and hypothalamus receptors display binding properties that would be expected if over 60% of their receptors were in the high affinity state, while only 30-40% of cortex, striatum and thalamus receptors appear to be in the high affinity form. Hippocampal receptors display the least amount of high agonist affinity character. Saturation curves and Scatchard plots of QNB binding at 2, 14, 21 and 42 days postnatal age in both strains indicate no differences or changes in the affinity or nature of the binding with age. Significant increases in QNB binding per mg membrane protein were observed between 14 and 42 days in the cortex, hippocampus, striatum, thalamus and hypothalamus, but not in the midbrain-pons-medulla region. In the hippocampus the DBA mice had significantly more QNB binding. In the hypothalamus decreases with age in total binding were noted in DBA, while slight increases were noted in C57. Compared to C57, hippocampal receptors in DBA displayed lower agonist affinity at 14 and 21 days, a trait which was not apparent when DBA had outgrown their audiogenic seizure sensitivity at 42 days. The differences in receptor density and agonist state distribution between the two strains may be related to audiogenic seizure sensitivity.


Development of the noradrenergic innervation of neocortex. The development of the noradrenaline (NA)-neuron innervation of rat neocortex was studied by fluorescence histochemistry, high affinity uptake of [3H-]NA, and biochemical assay of regional NA content. Fluorescence histochemistry indicates that NA axons enter areas of developing neocortex prenatally and the innervation matures rapidly during early postnatal life. Frontal and lateral neocortical areas are the first to be innervated followed by occipital and parietal areas. All cortical layers receive innervation. The distribution and density of neocortical NA innervation achieves the adult pattern by the end of the first postnatal week. High affinity uptake studies confirm the observations from fluorescence histochemistry and show a very rapid maturation of the NA axon innervation with adult levels of uptake occurring by postnatal day 9. Following birth, there is a brief rise in NA content from PO to P2 in all neocortical areas. NA content then drops to low levels in all areas by P4. This is followed by a gradual increase in NA content in all areas occuring over several months. This pattern of development of NA axon innervation of neocortex demonstrates that the density and distribution of NA axons in developing neocortex matures much earlier than shown in previous studies whereas the NA content of the developing axonal plexus achieves adult levels later in postnatal life.


Studies on the control of myelinogenesis. 3. Signalling of oligodendrocyte myelination by regenerating peripheral axons. Continuing from earlier work which demonstrated the peripheral axonal regulation of Schwann cell myelination, this study has investigated the possibility that a peripheral axon can stimulate oligodendrocyte myelination. To test this hypothesis, regenerating PNS axons were allowed to interact with uncommitted oligodendrocytes by transecting a rat peroneal nerve and inserting a segment of the autologous optic nerve between the cut ends. Grafts were maintained for 4-28 weeks and then examined by light and electron microscopy. A few regenerating peripheral myelinated nerve fibers penetrated the optic nerve graft. Some axons penetrated the outer margin of the graft, were myelinated by Schwann cells, and surrounded by astrocyte processes bordered by basal lamina. More centrally in the optic nerve graft, regenerating peripheral axons displayed myelin of CNS type. The outer myelin lamella abutted directly on the plasmalemma surface of surrounding astrocytic processes and was expanded focally to form a glial tongue. These observations demonstrate the experimental induction of central myelination by regenerating peripheral axons and suggest the existence of a common neuronal mechanism to stimulate myelin formation by both the Schwann cell and the oligodendrocyte.


Severe hypothyroidism and the maturation of the rat cerebral cortex. In order to study the influence of hypothyroidism on the maturation of the visual cortex, rats were thyroidectomized (T) surgically at 10 days of age and injected with 131I within 2 days after the operation. These T rats, and age-paired controls (C), were killed at 20, 25, 30, 40 and 80 days of life. The groups of T rats were subdivided into 'severely' hypothyroid and hypothyroid animals, on the basis, respectively, of complete or incomplete stasis of body growth and depletion of pituitary growth hormone stores. The pyramidal cells of the visual coretx of 'severely' hypothyroid rats were studied separately from those of hypothyroid animals. It was found that the number of spines along the apical shaft of such cells was markedly and equally reduced in all of the T rats, as compared to C rats, irrespective of the degrees of hypothyroidism attained, and stopped increasing in number by 30 days of age. From this age onwards, the distribution of the spines could no longer be fitted by a mathematical model31 which, however, adequately described for normal rats the developmental changes which take place with increasing age in the distribution of spines along the shaft of pyramidal cells from the visual cortex. This lack of fit was only found for the 'severely' hypothyroid animals; data from the other hypothyroid animals could still be fitted by the model. Such data show that the above-mentioned model31 may be a useful tool for the study of the intensity of the effects of hypothyroidism on the maturation of cortical neurons.


Pulmonary atelectasis and other respiratory complications after cardiopulmonary bypass and investigation of aetiological factors. Radiological evidence of pulmonary complications and possible aetiological factors were investigated in 50 consecutive patients after heart operations with cardiopulmonary bypass. Atelectasis was the most frequent pulmonary complication except for small pleural effusions, with an incidence of 64 per cent. Several types of atelectasis frequently co-existed, with a predominance of the less extensive plate and subsegmental forms. The incidence of atelectasis was the same on each side and the site of atelectasis was basal in three quarters of the patients. Preoperative clinical and catheter data were unrelated to the incidence of atelectasis. There was a significant positive correlation between a short cardiopulmonary bypass time and plate atelectasis, between a large fluid load after bypass and segmental atelectasis, between re-operation for bleeding and subsegmental atelectasis and between post-operative gastric dilation and atelectasis. The type of operation, the use of the intra-aortic balloon and the length of postoperative respiratory ventilation were unrelated to the incidence of atelectasis. The mechanism of development of atelectasis is discussed.


Glycopyrrolate and cardiac dysrhythmias in geriatric patients after reversal of neuromuscular blockade. The increase in cardiac muscarinic activity following injection of anticholinesterases can be minimized by the long-acting anticholinergic drug glycopyrrolate. In a series of 50 patients 65 years of age or older who had received glycopyrrolate (0.88 +/- 0.15 mg) mixed with neostigmine (4.40 +/- 0.66 mg) or pyridostigmine (17.46 +/- 2.92 mg) to antagonize neuromuscular blockade, the incidence of new postoperative cardiac dysrhythmias was 16 per cent. All dysrhythmias occurred in patients with pre-existing cardiovascular disease. There was no statistically significant relationship between the incidence of cardiac dysrhythmias and the choice of anaesthetic technique or anticholinesterase drug.


Anaesthesia for tracheal resection: a new way to manage the airway. A case of lower tracheal resection is reported. A number 28 Foley catheter was modified and successfully used to ventilate the lungs through the short distal tracheal stump.


Noninvasive evaluation of cardiovascular effects of preoperative sedation in children. The cardiovascular effects of two premedication regimes used in paediatric anaesthesia were studied. Eleven patients received rectal methohexitone (22 mg - kg) and 11 patients received intramuscular Innovar (0.03 ml - kg). The effect of these drugs on ventricular function was evaluated by measuring the shortening of the left ventricular minor dimension by echocardiography. No significant changes in this dimension, blood pressure, heart rate or respiratory rate were demonstrated with either drug. Both rectal methohexitone and intramuscular Innovar were shown to have minimal cardiovascular effects when used as preoperative sedation in paediatric patients. Echocardiography proved to be a valuable technique for the noninvasive evaluation of drug effects on myocardial contractility in children.


Chronic pain syndromes and their treatment. I. Cluster headache. Cluster headache is a form of unilateral headache which, in the past, has been very resistant to treatment. Lithium carbonate has been shown to be the only reliably effective treatment in this condition and, although only a few cases have so far been reported in the literature they have, with very few exceptions, been successful. Therefore we selected five patients who at one time or another had presented with cluster headache and who had no relief from conventional treatment, and treated them with lithium carbonate. This has been highly successful. Some patients who had suffered from the disease for many years have been completely or almost completely relieved of their affliction, while others have been markedly improved to the point where they can now function normally, both socially and professionally. The possible modes of action of lithium in this condition are discussed.


Anaesthetic considerations in the prolonged Q-T interval (LQTS): a case report. A case of prolonged Q-T interval syndrome (LQTS) with ventricular dysrhythmias is presented. The patient was unresponsive to medical treatment. Left stellate ganglion block, followed by surgical excision of the ganglion, resulted in reversion to normal sinus rhythm. The causes of LQTS, its treatment and the effects of anaesthetic agents are discussed.


[A case of malignant hyperthermia occuring in a dental clinic]. Malignant hyperthermia, a life-threatening complication of anaesthesia, occurred in a 5 1/2-year-old girl undergoing dental surgery in a dental clinic. During induction, after 20 mg of succinylcholine, the anaesthetist noted a moderate rigidity of the mandible that did not interfere with the tracheal intubation. However, after 45 minutes, the temperature rose to 38.8 degrees C, pulse was rapid at 160 per minute and the child was slightly cyanosed. The diagnosis of malignant hyperthermia was made (the temperature eventually reached 40.8 degrees C). The child was immediately treated with refrigeration, procainamide and sodium bicarbonate. She was then moved to a hospital centre where the treatment was continued and she recovered completely. After extensive investigation, we found that the paternal grandfather of the child died at age 58, several hours after a bilateral lumbar sympathectomy under general anaesthesia. The cause of the death, as confirmed by hospital records, was malignant hyperthermia. No genetic counselling was given at that time; this omission has since been corrected. Early diagnosis and the availability on the premises of the necessary drugs and equipment to treat such a complication probably saved this child's life. In 1975, "La Corporation Professionnelle des Médecins du Québec" published standards for practice of anaesthesia outside a hospital setting. The compliance of the dental clinic with such standards has contributed to the avoidance of a catastrophe.


A simple method of percutaneous cannulation of the pulmonary artery in small mammals. A simple technique for catheterization of the pulmonary artery in small mammals is described. An angled polypropylene introducer is used to allow easy placement of Swan--Ganz and triple lumen thermistor tipped catheters for haemodynamic evaluation. Hitherto such information has been unavailable because of difficulties in placement of catheters as well as an unacceptably high mortality rate. In an extensive experience with this new technique no instances of cardiac arrhythmia or of death have so far been encountered.


A technique for reducing the beam width of the Doppler ultrasound probe with potential application for accurate location of small superficial arteries. A simple technique for reducing the beam width of the Doppler ultrasound probe is described. This is accomplished by attaching a plexiglas prism to the transducer surface of the conventional probe. It reduces the beam width by a ratio of 2.8:1. This improves the precision with which the probe is able to locate small superficial arteries.


Effect of halothane on the pulmonary vascular response to hypoxia in dogs. The pulmonary vascular response to alveolar hypoxia with and without halothane exposure was measured in dogs. Hypoxia increased pulmonary artery pressure (Ppa) and pulmonary vascular resistance (PVR) so that in each case inverse linear relationships were found with arterial oxygen saturation. These responses were highly significant and reproduceable but varied greatly between individuals. Halothane administration resulted in an increased slope of PVR against oxygen saturation due to the fact that reduction in cardiac output exceeded the reduction in Ppa. An analysis of variance showed that it was possible to predict accurately the hypoxic PVR and Ppa responses under halothane anaesthesia from the control hypoxic responses. Animals with low PVR responses showed the greatest arterial oxygen desaturation with hypoxia, whereas high responders showed least oxygen desaturation. Thus it was possible to predict those individuals at risk from severe arterial oxygen desaturation under halothane anaesthesia.


Management of obstetric complications at a small rural hospital. To determine if there is a way of identifying obstetric patients in whom complications will develop, the experience of one small hospital was reviewed. It was found that there is no satisfactory method presently available that allows a hospital to select such patients so that they can be referred to a large centre. While the scoring system designed by Goodwin, Dunne and Thomas for assessing antepartum fetal risk is fairly effective in selecting fetuses at risk, its results do not correlate well with the frequency of obstetric complications. Since in a significant proportion of obstetric patients complications develop that require emergency intervention, it is important that hospital staff maintain their ability to do safe cesarean sections and to obtain blood for transfusion quickly. Hospitals in which there are fewer than 100 deliveries per year probably do not have a sufficient caseload to maintain the ability to do safe cesarean sections; it is therefore suggested that they discontinue obstetric practice. At hospitals with a larger caseload elective cesarean sections should be done so that the ability to do emergency procedures can be maintained.


Grey-scale ultrasonography for assessment of gynecologic pelvic masses. In a retrospective study the grey-scale ultrasonographic appearance of pelvic masses was correlated with the surgical findings in 93 patients. Of the masses found at the time of laparotomy 95% had been detected preoperatively. In most instances useful information about size, consistency and location of the mass was provided by ultrasonography. Certain pathologic entities produce a characteristic sonographic appearance, but there is a wide overlap for others. Data obtained by history-taking and physical examination must be integrated with the sonographic findings for a correct diagnosis.


Microvascular closure in malignant histiocytosis. Two patients with malignant histiocytosis were found to have capillary occlusion by aggregates of neoplastic histiocytes, in skeletal muscle in one, and in renal glomeruli in the other. One patient had clinical evidence of similar occlusions in the arterioles and capillaries of the ocular fundi. Occlusion of small vessels by tumour cells may explain the confusion of both patients.


Patient-initiated transtelephone transmission of electrocardiographic signals in the diagnosis of arrhythmias. Thirty-one patients who had complained of recurrent palpitations were given transtelephone transmitters of electrocardiographic signals and instructed to use the transmitters while they were having symptoms. From the transcribed electrocardiograms sinus tachycardia was documented in 12 patients, paroxysmal atrial tachycardia in 7, atrial fibrillation in 4, atrial flutter in 3, frequent ventricular premature beats in 4 and ventricular tachycardia in 1. Patient-initiated transtelephone transmission of electrocardiographic signals was found to be an effective means of documenting the nature of symptomatic paroxysmal tachycardia.


Bone and joint tuberculosis: a continuing problem. Although tuberculous disease of bones and joints is becoming uncommon, it still occurs and may cause devastating sequelae. It is frequently not diagnosed prior to the onset of permanent damage to the joints or spine; the most important reason for this delay may be the fact that it is not considered in the differential diagnosis of monoarthritis or back pain. Most persons with the disease have other evidence of tuberculosis. Not infrequently an aggressive approach (including synovial biopsy or surgical exploration of the back) is needed to confirm the diagnosis when there are no other clues.


Meningococcal meningitis in children.

Meningococcal meningitis in children. Forty-four cases of meningococcal meningitis in children at one hospital between 1971 and 1975 inclusive were studied to document the course and complications of this disease in children in the current therapeutic era. The mortality was 5%. Of the 41 survivors 76% were healthy 1 to 5 years after the episode of meningitis. Permanent severe sequelae (facial palsy, optic atrophy and ptosis) were seen in three (7%) of the survivors, and mild hearing loss, hyperactivity and nervousness were noted in seven (17%). Electroencephalography was not useful in determining management or prognosis. Both the mortality and the frequency of early and late complications among the survivors were lower than those reported from earlier studies.


Clinical efficacy and toxicity of netilmicin in the treatment of gram-negative infections. Netilmicin, a new semisynthetic aminoglycoside antibiotic, was used to treat 41 infections in 38 patients. The outcome of four infections could not be evaluated: two patients received inadequate therapy and two did not have gram-negative infections. Clinical improvement occurred in 36 (97%) of the 37 gram-negative infections, and bacteriologic cure occurred in 30 (86%) of the 35 evaluable infections. Therapeutic serum concentrations of netilmicin were readily achieved by both intramuscular and intravenous routes. Reversible ototoxic effects occurred in 1 (3%) of 35 courses of therapy evaluated, reversible nephrotoxic effects occurred in 5 (14%) of 36 courses and mild reversible alterations in liver function occurred in 3 (19%) of 34 courses. Netilmicin appears to be effective and safe in the treatment of aerobic gram-negative infections.


Clinical approach to the diagnosis of acid-base disorders. An ability to rapidly and effectively diagnose and treat acid-base disorders is essential to the management of seriously ill patients. In this paper an approach to the diagnosis of pure and mixed acid-base disorders is presented that is based upon an understanding of the bicarbonate buffer system and a knowledge of the well defined and predictable compensatory responses that occur in association with each of the primary acid-base disorders. With this approach a number of acid-base problems are presented and solved.


A Malaysian experience with animal disease. The report summarizes a one year period of investigation of death losses in West Malaysian livestock. Lesions and etiological agents are mentioned for cattle, sheep, goats, swine, poultry and companion animals as well as some miscellaneous species. Special observations related to a common paramphistome induced hepatic biliary infestation in cattle, a serious malignant head catarrh outbreak in which possible cattle to cow aerosol transmission occurred. Trismus observed in some cattle with malignant head catarrh was associated with arteriolitis and ganglioneuritis of the V cranial nerve. Parasitic, bacterial, viral toxic and neoplastic diseases are recorded in the various species. The occurrence of fatal chronic fluorosis in laboratory guinea pigs and cerebral nematodiasis in a Thoroughbred racehorse are documented.


A survey of disease conditions in adult and feeder sheep in Saskatchewan. A survey was carried out to identify disease conditions occurring in adult and feeder sheep in Saskatchewan. Necropsies were performed on 50 adult sheep submitted to the Western College of Veterinary Medicine during the period July 1976 to June 1977 and data were assembled from necropsy records of sheep submitted between January 1975 to December 1976. The diseases encountered were briefly described. Conditions of the respiratory and digestive systems were the most significant as causes of mortality. Burdens of helminth endoparasites were generally low. In the flocks included in the necropsy survey, annual mortality among adult and feeder sheep was estimated to be three percent.


Case report: Abomasal involvement in bovine diaphragmatic hernia and surgical management. Two rare cases of internal herenia in bovines (Bubalus bubalis), in which reticulum and abomasum had herniated into the thoracic cavity, were successfully treated. Involvement of abomasum did not exhibit any additional symptoms other than those commonly observed in cases where only reticulum is herniated. The term diaphragmatic hernia has been considered appropriate for this condition by the present authors.


Protocols in medicolegal veterinary medicine. I. Identification of cases and preparation for court. Guidelines for the identification of potential legal cases and the correct procedures for recording and handling of information and exhibits are described. Preparation for court appearance as an expert witness is discussed.


The effects of radiotherapy on immunity in patients with localized carcinoma of the cervix uteri. To assess the effects of radiotherapy on immune status, a wide range of assessments have been performed on patients with localized carcinoma of the cervix uteri undergoing and initially responding clinically to radical pelvic radiotherapy. Neutrophil function was essentially unchanged by treatment. Absolute neutrophil and lymphocyte counts fell after treatment and remained depressed 3 and 12 months following treatment. The proportions of T and B cells dropped with treatment but recovered to near-presentation levels during the follow-up period even though absolute counts remained depressed. In vitro tests of cellular immunity were depressed by treatment and remained so 3 and 12 months following treatment whereas skin test responses remained normal throughout the assessments. Inhibitory plasma effects were observed in phytohaemagglutinin lymphocyte transformation studies on 4 untreated patients; at follow-up these effects were not evident. A variable response in immune indices has therefore been observed in patients in remission after treatment of localized carcinoma cervix stressing the importance of assessing several aspects of immune function and implying that persistent depression of certain indices does not adversely affect the host tumor response. In two patients relapsing after apparently good initial response all aspects of immunological assessment (except serum immunoglobulin levels and neutrophil function) deteriorated.


Secondary malignant neoplasms following radiotherapy of a mouse mammary carcinoma. Long-term observations were made for the development of secondary neoplasms following radiotherapy of animal tumors. Experimental tumors were 3rd generation isotransplants of a mammary carcinoma which arose spontaneously in a C3Hf/He mouse. A single dose of TCD20-TCD98 was followed by weekly observations. Most recurrences were observed in the first 150 days, while only a few were seen in the subsequent 150 days. Secondary neoplasms developed frequently following this period, i.e., 41 out of 67 animals surviving more than 300 days developed secondary neoplasms. They were osteogenic and soft tissue sarcomas, and half the new tumors were found within 490 days after radiotherapy. The results obtained were compared with literature reports of secondary neoplasms following postoperative radiotherapy for carcinoma of the breast and treatment of retinoblastomas. Most of these secondary human neoplasms were nonepithelial sarcomas as in the present study. Secondary carcinomas have been reported following radiotherapy of carcinoma in other locations, i.e., the cervix or head and neck; however, only a limited number of studies have been reported.


On the prognostic importance of white depressed areas in the primary lesion of superficial spreading melanoma. The lesions of 163 patients with superficial spreading melanoma (SSM) were examined for the presence of white, depressed areas; and lesions with and without these areas of "regression" were compared. There was no statistically significant correlation with the histological level of invasion (Clark-Mihm), sex or age of the patient, location of the melanoma, or presence of local, intransit or regional lymph node metastases. It is apparent from examining the recurrence rate and patient survival, that white depressed areas in an SSM are not of prognostic importance. There was a striking correlation of the presence of white depressed areas with the size of the area covered by the malignant melanoma (p less than or equal to 0.001).


A reliable method for evaluating drug compliance in children with cancer. Poor drug compliance may cause a decreased survival of children with malignancies. Children who fail to take their medications are not receiving optimum amounts of chemotherapy and suboptimal therapy causes a shortened survival in children with cancer. This is a study of prednisone compliance in 52 children with cancer during three distinct phases of therapy. The patients were either known to be taking prednisone (on-therapy group), off prednisone (off-therapy group), or their compliance was unknown (unknown group). Evaluation of prednisone compliance was attempted by measuring hemoglobin level changes, weight changes, and random urinary 17-ketogenic steroids. The results obtained show that while hemoglobin and weight changes are not helpful, a random urine 17-ketogenic steroid assay is able to differentiate clearly those patients who are taking their prednisone. By the use of this assay it was found that 33% of patients who by protocol and instruction were supposed to be receiving prednisone were not complying. Separate analysis of adolescents revealed an even more alarming 59% noncompliance rate. This striking level of noncompliance strongly suggests that the survival of patients may be threatened by noncompliance.


A cancer registry for the community radiation center. A common problem for cancer treatment centers is maintenance and utilization of the cancer registry. Computerization of the large amount of patient information involved is desirable. Organization and implementation of a patient registry using a PC-12 treatment planning computer is described. This application is reasonable and effective for community radiation centers, and retains the interactive features that make these dedicated mini-computers so useful. Details of organizing and running this type of registry are included. Examples of the patient data from a radiation therapy department are given and the possibilities for analysis of the information discussed. An important part of the registry is the one-line summary of individual cases, termed the "patient status graph," that condenses patient follow-up history for quick review. The importance of a pertinent and practical registry for all cancer centers is discussed.


Stromal sarcoma of breast: a light and electron microscopic study. A case of stromal sarcoma of the breast was studied by light and electron microscopy. The tumor comprised of uniform, plump spindle cells with neither epithelial nor "metaplastic" mesenchymal elements. Ultrastructurally most of the tumor cells appeared immature containing abundant free ribosomes, variable amounts of microfilaments and profiles of rough endoplasmic reticulum, with scant intercellular collagen and elastic fibers. The cells often showed prominent nesting as well as a variety of cell junctions, including desmosomes. We believe this tumor is a poorly differentiated, precursor mesenchymal sarcoma which belongs in the category of "stromal sarcoma of breast," a term coined by Berg et al. in 1962. To our knowledge, this represents the first published electron microscopic study on this tumor. Despite a high mitotic figure count in the tumor, the patient has survived a simple mastectomy with no evidence of metastasis 30 months later.


Growth characteristics of human skin fibroblasts in vitro: a simple experimental approach for the identification of hereditary adenomatosis of the colon and rectum. Kinetic parameters of cell growth have been studied in cultured skin fibroblasts derived from individuals with hereditary adenomatosis of the colon and rectum. The growth parameters consisted of saturation density, plating density, cloning efficiency and colony-forming ability. The results suggest deployment of these selective assays to distinguish skin fibroblasts of presumptive ACR positive individuals from those of normal subjects in vitro.