The cardiovascular pharmacology of 7-propyl-theo-phylline-dopamine (D4975); comparison with dopamine and dobutamine. 1 The effects of a newly developed dopamine-xanthine derivative, 7-propyl-theophylline-dopamine (D4975), have been examined in cats anaesthetized with sodium pentobarbitone. When administered intravenously (in doses as low as 0.5 to 1.0 micrograms/kg) it increased systemic arterial pressure, left ventricular (LV) dP/dtmax, dP/dt at fixed ventricular isovolumic pressures and cardiac output. Heart rate effects were minimal. 2 D4975 was about 5 times more active than dopamine or dobutamine in elevating LV dP/dtmax or dP/dt at common peak isovolumic pressures (CPIP) and about 10 times more active than dopamine at increasing systemic arterial blood pressure. The effects of D4975 were also more prolonged than those of the other two agents. 3 The effects of D4975 on LV dP/dtmax were greatly reduced by the prior administration of propranolol. D4975 has no effect on peripheral beta 2-adrenoceptors. 4 It is suggested that the effects of D4975 on the myocardium involve both beta 1-adrenoceptor stimulation and inhibition of phosphodiesterase and that the marked and prolonged pressor response is due to resistance to enzymatic breakdown by monoamine oxidase. 5 The results suggest that D4975 might prove valuable in the treatment of the hypotension and reduced myocardial contractility of shock, especially as it is possible to select a dose that increases LV dP/dtmax without increasing either heart rate of systemic arterial pressure.


Presynaptic inhibitory action of 5-hydroxytryptamine in dog isolated saphenous vein. 1 The effect of 5-hydroxytryptamine on contractile responses to sympathetic nerve stimulation has been studied in the dog isolated saphenous vein.2 Electrical stimulation (0.1 to 10 Hz) of dog saphenous vein strips produced frequency-dependent contractions. Contractions produced by stimulation at 2 Hz were almost completely blocked by tetrodotoxin (3.1 x 10(-8) mol/l) or phentolamine (5.0 x 10(-6) mol/l) but mecamylamine (5.0 x 10(-6) mol/l) had little effect. This suggests that the contractions were mediated predominantly through noradrenaline release from postganglionic noradrenergic nerves.3 Contractions produced by intermittent electrical stimulation at 2 Hz were inhibited by 5-hydroxy-tryptamine (1.0 x 10(-9) to 1.0 x 10(-7) mol/l) in a concentration-dependent manner whilst contractions induced by exogenous noradrenaline were not affected.4 The inhibitory action of 5-hydroxytryptamine was most marked at low frequencies of stimulation and with low pulse numbers.5 High external calcium concentrations (3.9 and 5.2 x 10(-3) mol/l) reduced the inhibitory action of 5-hydroxytryptamine.6 Cyproheptadine (1.0 x 10(-8) mol/l to 1.0 x 10(-6) mol/l) or morphine (1.0 x 10(-7) mol/l to 1.0 x 10(-5) mol/l) did not antagonize the inhibitory action of 5-hydroxytryptamine. Methysergide (1.0 x 10(-7) mol/l) slightly reduced the contractions produced by electrical stimulation and only weakly antagonized the action of 5-hydroxytryptamine.7 It is suggested that a 5-hydroxytryptamine receptor exists presynaptically in the dog isolated saphenous vein strip and that stimulation of this receptor by low concentrations of 5-hydroxytryptamine inhibits the release of noradrenaline from noradrenergic nerves. This receptor type is resistant to blockade by ;classical' 5-hydroxytryptamine antagonists.


Urethane and contraction of vascular smooth muscle. 1 In vitro studies were undertaken on rat aortic strips and portal vein segments in order to determine whether or not the anaesthetic, urethane, can exert direct actions on vascular smooth muscle. 2 Urethane was found to inhibit development of spontaneous mechanical activity. This action took place with a urethane concentration as little as one tenth of that found in anaesthetic plasma concentratios, i.e., 10(-3) M. 3 Urethane (10(-3 to 10(-1) M) dose-dependently attenuated contractions induced by adrenaline, angiotensin and KCl. These inhibitory actions were observed with urethane added either before or after the induced contractions. 4 Ca2+-induced contractions of K+-depolarized aortae and portal veins were also attenuated, dose-dependently, by urethane. 5 All of these inhibitory effects were completely, and almost immediately, reversed upon washing out the anaesthetic from the organ baths. 6 A variety of pharmacological antagonists failed to mimic or affect the inhibitory effects induced by urethane. 7 These data suggest that plasma concentrations of urethane commonly associated with induction of surgical anaesthesia can induce, directly, relaxation of vascular muscle.


Attenuation by bradykinin of adrenergically-induced vasoconstriction in the isolated perfused kidney of the rabbit: relationship to prostaglandin synthesis. 1 In the isolated kidney of the rabbit perfused with oxygenated Tyrode solution, we studied the effect of bradykinin on the vasoconstriction evoked by sympathetic nerve stimulation (3Hz, 1 ms) and by injections of noradrenaline (50 to 75 ng) in the presence and in the absence of indomethacin (1 microgram/ml), an inhibitor of prostaglandin biosynthesis. Prostaglandin E(PGE)-like material in the renal effluent was measured by bioassay after extraction with organic solvents and separation by thin layer chromatography. 2 Bradykinin in concentrations of 10 to 100 ng/ml reduced the vasoconstrictor response to sympathetic nerve stimulation and to injected noradrenaline. Also, the peptide (1 to 10 ng/ml) increased the basal release of PGE-like material and the release induced by sympathetic nerve stimulation. 3 Indomethacin, 1 microgram/ml, diminished the inhibitory effect of bradykinin on the vasoconstrictor response to nerve stimulation, minimized the reduction of the noradrenaline-induced vasoconstriction caused by bradykinin (100 ng/ml), and abolished the release of PGE-like material. 4 This study indicates that bradykinin reduces the renal vascular reactivity to adrenergic stimuli and suggests that part of the action of the kinin at the vascular adrenergic neuroeffector junction in the rabbit kidney depends upon the biosynthesis of renal prostaglandins.


Effects of clonidine, prazosin and phentolamine on heart rate and coronary sinus catecholamine concentration during cardioaccelerator nerve stimulation in spinal dogs. 1 In spinal dogs, continuous electrical stimulation of the cardioaccelerator nerve produced a transient rise in aortic blood pressure and a sustained increase in both heart rate and coronary sinus blood flow. The latter effects were accompanied by a significant elevation in the coronary sinus plasma noradrenaline concentration without significant changes in the levels of dopamine and adrenaline. The concentrations of the three catecholamines in thoracic aorta plasma were not significantly changed by cardioaccelerator nerve stimulation.2 Clonidine (20 mug/kg, i.v.), given during cardioaccelerator nerve stimulation, increased both mean aortic blood pressure and coronary sinus blood flow and decreased heart rate and coronary sinus venous plasma noradrenaline overflow.3 Phentolamine (0.3 mg/kg, i.v.) completely antagonized these effects of clonidine. Prazosin (0.3 mg/kg, i.v.) inhibited by only 43 and 38% the respective reductions in heart rate and noradrenaline overflow elicited by clonidine.4 On termination of cardioaccelerator stimulation (about 10 min after either prazosin or phentolamine), heart rate and coronary sinus noradrenaline overflow returned to control prestimulation levels.5 Phentolamine or prazosin, administered alone during stimulation of the cardioaccelerator nerve, increased heart rate and noradrenaline overflow into the coronary sinus plasma. However, intravenous phentolamine and prazosin, in contrast to desipramine (0.3 mg/kg, i.v.) or tyramine (1.0 mg, i.a.), failed to change the tachycardia resulting from the local administration of noradrenaline into the sinus node artery (i.a.).6 These results show that in spinal dogs the clonidine-induced reduction in heart rate (elevated by electrical stimulation of the cardioaccelerator nerve) is accompanied by a fall in the quantity of noradrenaline overflowing into the coronary sinus plasma. The latter effect is presumably the result of an action of clonidine on cardiac presynaptic alpha-adrenoceptors, the activation of which is followed by a reduction in the release of noradrenaline per nerve impulse. Phentolamine and prazosin are both antagonists of cardiac presynaptic alpha-adrenoceptors in spinal dogs, as suggested by their action against clonidine and by their positive chronotropic effect when administered during stimulation of the cardioaccelerator nerve.


Relaxation of guinea-pig fundic strip by adenosine, adenosine triphosphate and electrical stimulation: lack of antagonism by theophylline or ATP treatment. 1 Theophylline relaxed isolated strips of guinea-pig stomach fundus in a dose-dependent manner; above 50 to 100 microM responses showed no fade for up to 90 min. 2 Relaxant responses to adenosine, adenosine triphosphate (ATP), noradrenaline, and to electric field stimulation of non-adrenergic inhibitory nerves were not affected in a significant manner in the presence of 50 microM theophylline. 3 In tissues which showed complete fade of initial responses in the continued presence of 50 microM ATP, the effects of stimulation of non-adrenergic inhibitory nerves remained unaltered, suggesting that the ATP receptor has no function in non-adrenergic inhibitory transmission in this tissue. 4 These findings are opposite to those of Okwuasaba, Hamilton & Cook (1977), who claimed that 50 microM theophylline almost fully inhibited relaxation induced by adenosine ATP and nerve stimulation and that ATP-induced fade also abolished sensitivity to inhibitory nerve stimulation.


Theophylline antagonizes some effects of purines in the intestine but not those of intramural inhibitory nerve stimulation. 1 Hyoscine- and guanethidine-treated preparations of longitudinal muscle of rabbit duodenum, guinea-pig taenia caeci and fundic strip relaxed when exposed to noradrenaline, adenosine, adenosine triphosphate (ATP) or to field stimulation of their intramural nerves. 2 In guinea-pig taenia caeci and fundus, theophylline 100 mumol/l had no effect on responses to noradrenaline, adenosine, ATP and intramural nerve stimulation. 3 In rabbit duodenum, theophylline 100 mumol/l antagonized some responses to adenosine but had no effect on responses to noradrenaline, ATP and intramural nerve stimulation. 4 Theophylline 1 mmol/l itself relaxed the intestinal tissues and in the fundic strip and taenia caeci, these relaxant effects were associated with abolition of spike activity and cellular hyperpolarization. In the taenia caeci, the amplitude of inhibitory post-junctional potentials was reduced. 5 Theophylline 1 mmol/l antagonized the twitch suppression produced by adenosine and ATP in the transmurally-stimulated guinea-pig ileum but not that evoked by noradrenaline. 6 It is concluded that theophylline can selectively antagonize some actions of purines in the intestine but that it does not specifically antagonize the effect of intramural inhibitory nerve stimulation.


The inhibitory material in extracts from the bovine retractor penis muscle is not an adenine nucleotide. Methods are described for the removal of adenosine or purine nucleotides from extracts of bovine retractor penis muscle (BRP). These methods did not interfere with the biological test preparations. Removal of adenosine and purine nucleotides by these methods did not modify the inhibitory action of the extract on the BRP. The effect of the extract on the BRP resembles that of inhibitory nerve stimulation. If the inhibitory substance present in the extract is the inhibitory transmitter, then the results indicate that, in this tissue, the transmitter is neither adenosine nor a purine nucleotide.


Ouabain receptor binding of hydroxyprogesterone derivatives. 1 A specific and sensitive radioreceptor assay ahs been devised which is based on high affinity, saturable binding of 9 nM [3H]-ouabain to the total particulate fraction isolated from dog heart. Ouabain and other cardiac glycosides, including the aglycones, were about equipotent in their ability to displace [3H]-ouabain from its receptor, the IC50s ranging from 10 to 30 nM. 2 The only other substances found to compete significantly in the assay were derivatives of hydroxyprogesterone having a 17 alpha-acetate substituent: chlormadinone acetate, megestrol acetate, cyproterone acetate and medroxyprogesterone acetate, with IC50s of 2, 7.4, 9 and 21 microM, respectively. Prednisolone-3,20-bisguanyl-hydrazone, reported to have inotropic activity, gave an IC50 of 6.4 microM. Cyproterone-17 alpha-OH was less active (IC50 90 microM) than cyproterone-17 alpha-acetate. 3 A large number of peptide and protein hormones, steroid hormones and their metabolites, amines, and drugs were inactive.


Dopamine agonists and cobalt-induced epilepsy in the rat. 1 Electrocorticogram (ECoG) recordings were made from conscious rats which had cortical implants of cobalt. The epileptiform spike activity was then assessed by means of an automated technique, based on peak angle measurements. 2 Apomorphine (0.5, 1.0 and 2.0 mg/kg i.p.) and lisuride (0.1, 0.25, 0.5 and 1.0 mg/kg i.p.) inhibited spike activity in established primary and secondary foci in a dose-dependent manner. Bromocryptine (10 and 20 mg/kg i.p.) and CF 25-397 (40 mg/kg i.p.) had a similar effect but only after a latent period of several hours. Chronic administration of bromocryptine (20 mg/kg i.p. daily) attenuated the normal development of the foci following implantation. 3 Pimozide (1 mg/kg i.p.) potentiated cortical epileptic activity in cobalt-implanted rats and blocked the antiepileptic effects induced by the dopamine agonists. 4 Intrastriatal administration of dopamine (25 micrograms) or apomorphine (60 micrograms) suppressed epileptiform spikes in the cortex. Destruction of striatal catecholamine terminals by 6-hydroxydopamine increased the spike activity. 5 It is concluded that the striatum may play an essential part in mediating the anti-epileptic effects of dopamine and its agonists in this model of epilepsy.


The effects of isoprenaline and bradykinin on capillary filtration in the cat small intestine. 1 Lymph flow, and both lymph and plasma protein concentrations were measured in isolated, blood-perfused loops of cat ileum. 2 Permeability-surface ares (PS) products and the osmotic reflection coefficient (sigma) of the intestinal capillaries were calculated. 3 Isoprenaline (one dose) or bradykinin (two different doses) was infused into the superior mesenteric artery. 4 Isoprenaline (blood concentration about 50 ng/ml) did not affect PS or sigma. 5 Bradykinin (about 36 ng/ml) increased PS but as a sigma was unaltered, this was primarily due to an increased capillary surface area. 6 Bradykinin (about 680 ng/ml) increased PS and as sigma was reduced, there was an increased capillary permeability. 7 Reasons for the lack of effect of isoprenaline at concentrations which increase capillary filtration coefficient are discussed. 8 These data show that this technique separates drug effects on capillary surface area from effects on capillary permeability.


The effects of ions on the binding of agonists and antagonists to muscarinic receptors. 1 There are no selective effects of Na+, K+, Ca2+, Mg2+ or Cl- on the binding of antagonists or agonists to muscarinic receptors in rat brain. A decrease in affinity related to ionic strength is found for all these ions. 2 Larger effects were produced by T1+, La3+, and some transition metal ions.


Concomitant development of [3H]-dopamine and [3H]-5-hydroxytryptamine uptake systems in rat brain regions. 1 Synaptosomal uptake mechanisms of 5-hydroxytryptamine and dopamine were examined in cerebral cortex, corpus striatum and midbrain plus brainstem of developing rats. 2 In all regions, there was generally a parallel biphasic development of both uptake systems; the most rapid increases occurred in the first two weeks postpartum, followed by a slower rate of increase. 3 Kinetic studies with dopamine indicated that the maturation involved increases in maximal uptake without a change in the substrate Km, suggesting that there is a change in the number or terminals but not in the uptake system per se.


The effects of glucocorticoids on the distribution and mobilisation of arachidonic acid in fat cell ghosts. 1 The prostaglandin synthesizing enzymes were found to be present in fat cell ghosts isolated from rabbit adipose tissue. 2 Prostaglandin E2 (PGE2) and PGF2, were synthesized by ghosts after stimulation with adrenocorticotrophic hormone (ACTH). 3 Indomethacin was found to inhibit this synthesis but not the synthesis of lipoxygenase products. 4 When fat cell ghosts were stimulated by ACTH, fatty acid release was observed from both neutral lipids and phospholipids. 5 The arachidonic acid (AA) pool within the ghosts and identified: approximately 90% was present in the phospholipid fraction, 8.5% in the neutral lipids and 1.5% unbound. 6 The glucocorticoids were found to stimulate incorporation of [14C]-AA into neutral lipids and inhibit its incorporation into phospholipids. 7 When fatty acid release was stimulated with ACTH, the glucocorticoids were found to inhibit the mobilisation of [14C]-AA from the phospholipids and enhance its release from the neutral lipids. 8 The glucocorticoids inhibit prostaglandin formation in fat cell ghosts.


An examination of the negative feedback function of presynaptic adrenoceptors in a vascular tissue. 1 The hypothesis was examined that presynaptic alpha-adrenoceptors exert a negative feedback function regulating noradrenergic transmission.2 Renal artery strips from cattle, pre-incubated with [(3)H]-noradrenaline, were stimulated with 300 pulses at 5 different frequencies, spanning the physiological range, and the efflux of tritium assessed both in the absence and presence of functional presynaptic receptors.3 Considerable variation in the synaptic level of free and active noradrenaline with increasing frequency was apparent from the rates of development and the magnitudes of the mechanical responses but the overflow of tritium was constant at 1, 2, 10 and 15 Hz and slightly elevated at 5 Hz, providing no evidence for presynaptic modulation of release.4 Phenoxybenzamine (3.3 x 10(-5) M) enhanced the overflow of tritium most at the lowest frequency tested and to a similar extent at the other test frequencies, except 10 Hz where its effect was slightly reduced.5 The conditions of the present experiments appeared optimal for the operation of the negative feedback system and the failure to observe an increased effectiveness of the antagonist with increasing frequency indicates that the physiological relevance of such a system is highly questionable and suggests that it may not function at all.


The psychiatrist in the terminal care unit. The types of problems of 49 patients referred to a psychiatrist in a terminal care unit are reported and their management reviewed. The findings suggest that a psychiatrist can play a useful role in such a unit, particularly in supervising medical and nursing staff in the psychological care of patients and in helping more directly in the management of psychiatrically complicated cases.


Compulsory admission to hospital: an operational review of the Mental Health (Scotland) Act 1960. The working of the Mental Health (Scotland) Act 1960 is examined by analysis of compulsory admissions both nationally and to one Glasgow hospital. Comparisons are drwn with England and Wales. Despite a six-fold increase in admissions since 1945 the use of compulsory powers has remained almost constant. It is suggested that an annual number of 45 compulsory admissions per 100,000 population may represent an inevitable basic level as foreseen by the Royal Commission in 1957. Section 31 ('Emergency Recommendation') secures 80 per cent of Part IV admissions, and Section 24 ('Full Recommendation') is employed in only 25 per cent. Part V accounts for only 300 admissions per annum, mostly remands for psychiatric report. Two suggestions are made for possible future amendments to the Act.


The psychiatric patient: a voice to be heard. Patients' view of psychiatric care and its implications is a neglected area of inquiry, partly due to ideological factors as well as structural aspects of the National Health Service. It is acknowledged that patient satisfaction per se cannot be the major goal of the Health Services, but the path to improved welfare and treatment may be facilitated by patient satisfaction or at least by an awareness of patient opinion. Further exploration of this area is recommended.


Psychiatrists' assessments of mental illness. A comparison of some aspects of Thomas Scheff's approach to labelling theory. The labelling theory of mental illness and particularly that version formulated by Thomas Scheff has been applied to psychiatry. Studies completed by Scheff have produced considerable evidence to support labelling theory. An attempt is made here to determine to what extent labelling theory applies to a group of British psychiatrists. The results give little support to Scheff's position.


Psychiatric disorders in children in long-term residential care: a follow-up study. Ninety-two children who had been examined in a psychiatric study of five to twelve year-olds in long-term residential care were followed up four years later. Three-quarters were still in children's homes, but over half had been moved to different establishments. At both the original study and follow-up, the majority showed evidence of psychiatric disorder. Considerable continuity of behavioural pattern was found, particularly amongst those who originally had antisocial disorders, who were also most likely to have had changes of care-taker during the four years. It is suggested that the persistence of their disorder may be due to a vicious circle of unacceptable behaviour and adult rejection.


Psychologically stressful events in the precipitation of manic episodes. The case notes of all 67 manic patients admitted to the psychiatric wing of a District General Hospital over a period of two years were screened for evidence of independent life events during a four week period prior to admission. The nature of such events and of the underlying stresses was examined and the data obtained were compared with data from a control group of acute surgical admissions. Four times as many manic patients had an independent life event closely preceding their admission. It is concluded that stress in the form of loss or threat is a common precipitant of mania. Some surprising findings are focused upon and discussed.


The EEG and differential diagnosis in psychogeriatrics. A model for differentiating cerebral dysfunction in senile, arteriosclerotic dementia, and depressive states is proposed on the basis of electrocortical topographic measures of EEG coherence. Bipolar EEGs were recorded from central, parietal, occipital and temporal areas in 24 elderly patients with a firm clinical diagnosis of senile dementia, senile arteriosclerosis or depression. Power and coherence spectra were computed on 20 second epochs recorded during eyes open, eyes closed and photic stimulation. Significant group differences were reported in both power and coherence measures. Power results were uniform for all channels but coherence values differed significantly with derivation. The best discriminator between groups was EEG coherence estimates between right parietal and temporal derivation. Correlations between clinical symptomatology and EEG coherence supported the direction of the discrimination between groups. The EEG coherence function is discussed as a potential measure of neuro-functional pathology in psychiatry.


Classification of personality disorder.

Classification of personality disorder. An interview schedule was used to record the personality traits of 130 psychiatric patients, 65 with a primary clinical diagnosis of personality disorder and 65 with other diagnoses. The results were analysed by factor analysis and three types of cluster analysis. Factor analysis showed a similar structure of personality variables in both groups of patients, supporting the notion that personality disorders differ only in degree from the personalities of other psychiatric patients. Cluster analysis revealed five discrete categories; sociopathic, passive-dependent, anankastic, schizoid and a non-personality-disordered group. Of all the personality-disordered patients 63 per cent fell into the passive-dependent or sociopathic category. The results suggest that the current classification of personality disorder could be simplified.


Reliability of a schedule for rating personality disorders. The inter-situational, inter-rater and temporal reliability of a schedule for rating personality disorders is described. In an initial study with a simplified form of the schedule in patients from different wards of a psychiatric hospital inter-situational reliability between raters was higher for patients with personality disorders than with no personality disorder. Using the full schedule, inter-rater reliability, using audiotaped and separate interviews, and temporal reliability at interviews conducted a mean of 12.5 months apart all reached a satisfactory level, suggesting that the schedule may be a useful instrument for measuring deviant personality traits. The interview may be used with a subject or an informant but agreement between ratings made with informants and psychiatric patients during illness was low, and the schedule is not recommended for use with patients alone during acute episodes of illness.


Evaluation of a detoxification service of habitual drunken offenders. The progress of 52 chronic alcoholic habitual drunken offenders who were offered a detoxification, assessment and referral service as an alternative to penal management for their public drunkenness was compared over a year with 48 control subjects, and each group's progress in the experimental year was compared with that in the previous year. The 'detoxification' patients were found not to have benefited as regards their alcoholism or episodes of drunkenness, though their periods of abstinence were longer. There were significant improvements in their accommodation and self-reported quality of life, and it is likely that their physical and perhaps mental health improved.


Nottingham and the Hospital Plan: a follow-up study of long-stay in-patients. The post-war development of psychiatric services in Nottingham, with their reduction in the number of beds and marked increase in in-patient turnover and day patient and out-patient attendances, represents a close approximation to the proposals of the 1962 Hospital Plan. These changes were achieved by redeployment of existing resources. A fifteen-year attrition study of 1960 long-stay in-patients shows a high rate of discharge, especially for males. The reasons for these findings and some implications are discussed.


Hostility and guilt in obsessive-compulsive neurosis. The enquiry relates to the investigation of 30 cases of obsessive-compulsive neurosis with special reference to the phenomena of hostility and guilt as revealed through Foulds' Five Punitive Scales and the Thematic Apperception Test. Controls consisted of an equal number of subjects suffering from neurotic depression. Analysis reveals acting-out hostility and extrapunitive tendency in the experimental group. No significant difference was found in terms of guilt scores.


Increased serum calcium and phosphorus with the 'switch' into manic or excited psychotic state. Small but statistically significant increases in serum total calcium and serum inorganic phosphorus concided with repeated onsets of psychotic agitation or mania in nine psychotic in-patients experiencing rapid cycles of illness. These increases were not accompanied by changes in magnesium or other constituents, which might suggest non-specific haemoconcentration. Similar increases in calcium or phosphorus were not present in patients without the same cycles of psychotic illness. The observed increases could neither be simulated nor altered by stress or activity, and it remains unclear whether they might be accounted for by dietary changes, sleep disruption, circadian phase shifts or by endocrine alterations.


The relationship between wrist-monitored motor activity and serum CPK activity in psychiatric in-patients. Motor activity, monitored by a wrist motion transducer, was related to serum CPK activity the following morning in a group of psychiatric in-patients. In 4 of 10 patients, studied for periods exceeding one week, total 24-hour activity was significantly correlated with morning serum CPK activity. Motor activity during the night was unrelated to serum CPK activity. In a larger group of 30 patients, studied for one or two-day periods, inter-individual differences in activity level were not related to serum CPK activity, although both sex and race were significantly related to variance between subjects in that activity.


The use of screening investigations in psychiatry. This is a study of the results of screening tests on all new psychiatric in-patients over a period of one year. Although none of the results indicated definite physical causes for the psychiatric illness, 10 per cent of the tests revealed abnormalities resulting from or co-incidental with the psychiatric illness. Of these abnormal results 61 per cent led to no further investigation or treatment, and the significance of this is discussed.


Psychotherapy of the dying patient.

Psychotherapy of the dying patient. The psychotherapeutic aspects of the care of the 49 terminally ill patients described in the preceeding paper are discussed. Their differing ways of coping with the stress of dying and the range of psychotherapeutic strategies used in treatment are described. The work suggests that the therapist's use of psychological insights can improve his understanding of the emotional pain of terminal illness, and well-aimed psychotherapy can contribute to its relief.


Amitriptyline: comparison of three different dosage schedules in neurotic depression. Three groups of neurotic depressed patients were treated with amitriptyline, one group receiving the customary three daily doses, another a single dose in the morning, and the third a single dose at night. All three groups showed significant decrements of total scores on the Hamilton Scale for Depression and the Zung Self-Rating Depression Scale without significant differences. Patients taking the drug at night showed a lower incidence of side effects.


Post-ECT cognitive defect and elevation of blood pressure. There is evidence that ECT causes a breakdown of the blood-brain barrier through the rise of blood pressure it induced. Using the Benton test of cognitive function the day before and three hours after ECT treatment in 27 depressed patients, impairment of function was highly correlated with the maximum rise of systolic BP during the treatment.


An XYY man.

An XYY man. This case report describes a young man with a 47, XYY karyotype who was convicted of arson. He suffered from a cardiac disorder which may well have been part of the XYY syndrome rather than a chance association. His abnormal karyotype was disclosed in court and used by the defence in a plea in mitigation.


Artistic productivity and lithium prophylaxis in manic-depressive illness. Twenty-four manic-depressive artists, in whom prophylactic lithium treatment had attenuated or prevented recurrences to a significant degree, were questioned about their creative power during the treatment. Twelve artists reported increased artistic productivity, six unaltered productivity, and six lowered productivity. The effect of lithium treatment on artistic productivity may depend on the severity and type of the illness, on individual sensitivity, and on habits of utilizing manic episodes productively.


Rupture of the abdominal oesophagus: a review. 'Spontaneous' rupture of the oesophagus usually affects the lower third, less commonly the middle third and rarely the cervical oesophagus. Rupture limited to the intra-abdominal oesophagus is rare. Such a case is described here and previously reported cases are reviewed. Vomiting-induced gastro-oesophageal injuries and their aetiology are discussed and the management of spontaneous rupture is reviewed.


Dysphagia following selective vagotomy.

Dysphagia following selective vagotomy. Progression of dysphagia after vagotomy to the stage of complete obstruction due to a peri-oesophageal fibrotic collar needing operation is a rare event. Review of the 4 such cases previously described, all needing further operation and all after truncal vagotomy, indicates that the oesophageal mucosa was normal on oesophagoscopy and that bouginage appeared to make the condition worse. This paper describes the first patient in whom (a) the vagotomy was selective and (b) no bouginage was carried out before the condition was relieved by a further surgical operation.


Anastomotic recurrence in the oesophagus complicating gastrectomy for adenocarcinoma of the stomach. Gastric adenocarcinomas often spread to the distal oesophagus. Failure to control the disease in this area during total and proximal subtotal gastrectomy results in recurrence at the oesophageal anastomosis. The incidence of recurrence in a series of 351 such patients was 10 per cent and was influenced by the location of the main lesion, the stage of the disease, the presence of tumour at the margin of resection and the length of clearance of the oesophageal margin. Recurrence were prevented only with in vivo margins greater than 12 cm. Dysphagia combined with radiological signs of oesophageal obstruction was diagnostic of anastomotic recurrence regardless of the results obtained by oesophagoscopy and biopsy. Treatment was seldom effective in patients developing recurrence. Complete excision of the entire recurrent process offered the only hope for a long survival in these patients. Prevention by obtaining adequate oesophageal clearance at the time of gastrectomy is the only reasonable approach to this problem. The adequacy of resection cannot be judged accurately by intraoperative palpation of the oesophagus or by frozen section examination of the surgical margins.


Bilio-pancreatic bypass for obesity: 1. An experimental study in dogs. Bilio-pancreatic bypass is a new procedure that tries to obtain a maldigestion syndrome with selective malabsorption of the main high calorie foods. The operation consists of a gastric resection and division of the proximal jejunum just distal to the ligament of Treitz. A gastroentero-anastomosis is then constructed using the distal end of the transected jejunum, while the proximal jejunum is anastomosed to the side of the distal ileum. An experimental study carried out on 12 dogs confirmed that the operation causes a selective malabsorption with loss of weight and no complications. On the basis of this study it is suggested that this procedure has the following advantages over jejuno-ileal bypass: (a) normal absorption of bile salts, water and electrolytes; (b) slow recovery of absorption; (c) absence of a blind loop.


Bilio-pancreatic bypass for obesity: II. Initial experience in man. After a successful trial of bilio-pancreatic bypass in dogs, a clinical study has been completed in 18 patients followed for more than 1 year. The operation has been modified to achieve the best weight reduction, and forming the bilio-pancreatic tract of equal length to the alimentary tract with a short common ileal tract, the average weight loss as a percentage of the preoperative body weight was 24.1 +/- 5.4 per cent (mean +/- s.d.) at 6 months and 33.7 +/- 4.1 per cent at 12 months. The only immediate complication was a wound dehiscence, and there were no late complications. Liver function studies showed the absence of hepatic deterioration and liver biopsies showed improvement of liver morphology 1 year after the operation. It is suggested that this procedure may be an alternative to jejuno-ileal bypass in the management of obesity.


A 10-year survey of large bowel carcinoma at Groote Schuur Hospital with particular reference to patients under 30 years of age. In a 10-year survey of large bowel carcinoma at Groote Schuur Hospital 926 cases were studied retrospectively. A marked difference was seen in both the age of presentation and histological differentiation in two different racial groups. All patients who were 29 years of age or less at the time of presentation have been studied in detail. Predisposing factors, symptomatology, treatment, pathology and prognosis are discussed. It is apparent that large bowel carcinoma in the young has a very poor prognosis.


The results of vaginoplasty in excision of the rectum. Vaginoplasty was used in a consecutive series of 45 patients undergoing rectal excision for neoplastic and inflammatory bowel disease. Forty-three patients achieved primary perineal healing and none developed a persistent perineal fistula. One patient with Crohn's disease developed a perianal fistula a year after operation but healing occurred after minor surgery. Another developed a pre-sacral abscess 9 years after operation; spontaneous discharge into the vagina occurred.


Bleeding duodenal ulcer: reduction in mortality with a planned approach. In a 6-year prospective study from 1972 to 1978 266 patients were admitted to a haematemesis and melaena unit with bleeding duodenal ulcer. There were 13 deaths, a mortality of 5 per cent. A comparison between the three consecutive 2-year periods of study showed an initial mortality of 6 per cent for the first 4 years falling to 2 per cent for the 93 admissions during the final 2 years of experience. Of the 120 patients treated surgically, 10 died in hospital, giving an operative mortality of 8 per cent. The trend in operative mortality was from 13 per cent for the initial 2-year period to 8 per cent for the second period and to 3 per cent for the final 2 years. The operative rate was consecutively 45, 50 and 34 per cent. There was 1 death in conservatively treated patients during each 2-year period of study. Three types of operation were performed: vagotomy, pyloroplasty and oversewing of the ulcer; Polya gastrectomy; and vagotomy and antrectomy. There was no difference in morbidity and mortality between these operations. At a mean follow-up of 3.1 years, 90 per cent of the patients had a good result from their operation. It is concluded that a prospective system of management with an active policy of early endoscopy, surgery and regular audit reduces the mortality from bleeding duodenal ulcer.


Anti-Xa factor as a predictor of postoperative deep vein thrombosis in general surgery. This study was stimulated by a recent report linking a low preoperative level of an endogenous coagulation inhibitor (anti-Xa factor) with an increased incidence of postoperative deep venous thrombosis (DVT) (Stamatakis et al., 1977). Preoperative and postoperative levels of anti-Xa were measured and correlated with the postoperative incidence of deep venous thrombosis assessed by the 125I fibrinogen uptake test to determine whether a high risk group could be isolated and a suitable regimen of prophylaxis introduced. In this study of 22 surgical patients the postoperative DVT rate was 41 per cent. However, preoperative measurements of anti-Xa activity failed to show any statistically significant difference between those patients with DVT and the non-DVT groups. The findings do not support the use of anti-Xa levels as a preoperative predictor of postoperative DVT in the individual.


The fibrinolytic activity of the vein following venous stasis. This animal study investigated the fibrinolytic activity in the vein wall of the pig following venous stasis, which was induced artificially using an intermittently inflated pneumatic cuff. The method used to measure the fibrinolytic activity was modified from Todd's original technique. The area of lysis and the area of the vein wall were measured and expressed as a ratio, called the fibrinolytic index. After 3 h of intermittent venous stasis the fibrinolytic index was reduced by 68 per cent, significantly lower than the control group. The reduction of the fibrinolytic index by venous stasis could play an important part in the development of deep vein thrombosis.


The incidence of deep vein thrombosis in Hong Kong Chinese after hip surgery for fracture of the proximal femur. Fifty-three Hong Kong Chinese patients with fractures of the proximal femur have been studied after hip surgery using functional ascending phlebograms for evaluating deep vein thrombosis. There was an incidence of deep vein thrombosis of 53.1 per cent in the fractured limbs and 14.3 per cent in the uninjured limbs. The majority of thrombi (84.6 per cent) were located in the calf. No clinical or fatal pulmonary embolism was observed.


Hyperparathyroidism in pregnancy.

Hyperparathyroidism in pregnancy. Primary hyperparathyroidism in pregnancy is uncommon and easily overlooked. It is associated with a complication rate of up to 80 per cent--mainly stillbirths, abortions and neonatal tetany. Surgical treatment during pregnancy offers the best chance for fetal and neonatal survival.


A safe and effective disposable low pressure suction drain. The physical and microbiological properties of a new disposable suction drainage system have been investigated under clinical and laboratory conditions. The system appears to have overcome the disadvantages associated with previous disposable and reusable low pressure suction drainage systems for use after surgical operation in that this system effectively prevents reflex and retrograde contamination.


Small bowel strictures after blunt abdominal trauma. Two patients with strictures of the small intestine after blunt abdominal trauma are reported. In the first there were multiple severe injuries and the ileal stricture due to a mesenteric tear was not diagnosed until 6 weeks later. In the second an apparently minor injury was responsible for direct damage to the wall of the jejunum and a subsequent stricture.


Total small bowel strangulation: a case report. A case of strangulation of the entire small intestine caused by an internal incarcerated hernia is presented. At laparotomy the small intestine was severely discoloured, paralytic and the viability of the bowel was questionable. No resection was performed. At a second laparotomy 10 h later the intestine was hyperaemic and exhibited lively motor activity. Recovery was complete. The importance of prolonged conservative management in avoiding extensive resection is stressed.


Randomized prospective matched pair study comparing peritoneovenous shunt and conventional therapy in massive ascites. A prospective randomized matched pair study was designed to test the efficacy of the peritoneovenous (LeVeen) shunt as a treatment for massive cirrhotic ascites compared with traditional medical therapy. Patients who failed to lose weight while on a low salt diet and fluids restricted to 1000 ml daily were placed in the study group. Weight loss, decrease in abdominal girth and diuresis were significantly greater (P less than 0.01) for surgical patients than for their medically treated counterparts. The surgical technique is simple, quick and inexpensive. The surgical patients outlived their matched partners in 12 of 14 pairs where a definitive comparison was possible (P less than 0.02). The median stay in hospital after randomization was shortened from 32 days with medical therapy to 15 days for those undergoing the shunt operation. Those treated medically experienced a significant rise in mean blood urea nitrogen and K+ (P less than 0.02). Patients with alcoholic hepatitis, hyperbilirubinaemia (bilirubin greater than 154 mumol/l), peritoneal sepsis, severe coagulopathy and those who had recently bled from oesophageal varices are poor risks for the surgical procedure.


The use of the Hickman catheter in the management of patients with leukaemia and other malignancies. The use of the Hickman right atrial catheter in 25 patients with leukaemia and other malignancies is reported, and it is concluded that with careful selection of patients, the benefits of this semi-permanent catheter outweigh the risks of infection. The catheter may be useful in the intensive care of children or adults with non-malignant conditions.


Large-bowel obstruction caused by cancer: a prospective study. Patients with obstructing large-bowel cancer may be treated by primary tumour resection or the conventional staged tumour resection, and a prospective study comparing these two treatments was carried out. The post-operative outcome in 174 patients (of whom 90 underwent primary and 47 staged tumour resection) showed that the overall mortality was similar in both groups but that the duration of hospital stay in patients who underwent primary tumour resection was half that of those who underwent staged tumour resection. The mortality for primary tumour resection, however, was unexpectedly high for lesions proximal to the splenic flexure and unexpectedly low for lesions distal to this point. Of patients with distal tumours in whom a staged resection was planned, 35% died after a loop colostomy. The most striking result was that the ratio of postoperative death for trainee surgeons compared with fully trained surgeons was 3:1. It is concluded that patients with large-bowel cancer who present with intestinal obstruction should be treated by a fully trained surgeon and that immediate resection of the tumour should be considered for every patient.


Decreased serum 24,25-dihydroxy vitamin D concentrations in children receiving chronic anticonvulsant therapy. Serum 24,25-dihydroxy vitamin D (24,25(OH)2D) and 25-hydroxy vitamin D (25-OHD) concentrations and the ratio between the two were measured in 31 Israeli children and adolescents receiving long-term treatment with phenobarbitone or phenytoin and in controls. 24,25 (OH)2D concentrations were significantly depressed in the patients, although the 25-OHD concentrations were similar to those in the healthy controls. In four patients with radiological evidence of osteopenia very low serum 24,25(OH)2D concentrations and serum 24,25(OH)2D: 25-OHD ratios were recorded. The findings suggest that 24,25(OH)2D deficiency may play an important part in the pathogenesis of osteomalacia in patients treated with anticonvulsant drugs and provide further indirect evidence that 24,25(OH)2D is important for normal bone structure.


High-carbohydrate diets and insulin-dependent diabetics. A high-carbohydrate-(HC)-modified fat diet was compared with a standard low-carbohydrate (LC) diabetic diet in 11 insulin-dependent diabetics. Basal and preprandial plasma glucose concentrations were appreciably lower when the patients received the HC diet derived chiefly from readily available cereal and vegetable sources (mean (+/- SE of mean) basal concentrations 6.7 +/- 1.2 mmol/l (121 +/- 22 mg/100 ml) with the LC diet and 4.3 +/- 0.7 mmol/l (77 +/- 13 mg/100 ml) with the HC diet; mean preprandial concentrations 11.1 +/- 1.2 mmol/l (200 +/- 22 mg/100 ml) LC diet and 8.9 +/- 1.3 mmol/l (160 +/- 23 mg/100 ml) HC diet). total and low-density lipoprotein cholesterol concentrations were lower when patients took the HC diet (mean 4.4 +/- 0.2 and 2.4 +/- 0.2 mmol/l (189 +/- 8 and 124 +/- 8 mg/100 ml) respectively), and the ratio of high-density lipoprotein cholesterol to total cholesterol tended to rise. The average percentage of glycosylated haemoglobin did not differ between the two diets. Thus several measures of carbohydrate and lipid metabolism appear to be more satisfactory when patients receive a HC diet, which is an acceptable alternative to that still recommended to most insulin-requiring patients.


Strongyloides stercoralis infection in former Far East prisoners of war. Out of 602 consecutive people who had been prisoners of war in the Far East and were screened for tropical diseases, 88 (15%) were found to have Strongyloides stercoralis infection a mean period of 30 years after their return from the tropics. The classical strongyloid creeping eruption was the most common symptom (84%), while gastrointestinal disturbances were rare (5%). Thiabendazole was highly effective in eradicating the infection. Strongyloidiasis is an important condition, as when the host is immunosuppressed fatal hyperinfection may occur. Many undiagnosed cases of strongyloidiasis must exist among former prisoners of war, and it is thus important to identify and treat these patients.


Apparent disapperance of hypernatraemic dehydration from infant deaths in Sheffield. The death certificates and necropsy reports of the 1115 Sheffield infants who died under 2 years of age in 1969-78 were examined. This study showed the apparent disappearance of deaths with hypernatraemia and in particular deaths presenting as cot deaths. The fall in incidence may be as much the result of an intensive local campaign on child care and infant feeding as of the change in the composition of dried milk for baby feeding.


Diagnosis of multiple pregnancy.

Diagnosis of multiple pregnancy. A study was made of 94 sets of twins born during 1975-8. Nine of these sets had not been diagnosed before labour started. Of the others, 75 were diagnosed as a result of clinical suspicion and 10 were diagnosed unexpectedly during the antenatal period, nine by ultrasonic examination. Thus, while ultrasonic examination has substantially reduced the incidence of undiagnosed twins, a fifth of all patients who had ultrasonography performed in the presence of a twin pregnancy were reported on at least one occasion to have a singleton pregnancy. Ultrasonography must be performed at least twice, therefore, before a multiple pregnancy can be confidently excluded.


Seven-year follow-up of heroin addicts: abstinence and continued use compared. Data from a seven-year follow-up study of drug addicts were examined to see whether there were any differences between those who had stopped using opiates and those who had continued to use them. Information about the addicts when they first entered the study in 1969 was also reviewed to determine whether any of their characteristics would have predicted whether they would stop using opiates or continue. Those who had stopped using opiates by 1976-7 were more likely than the continuing addicts to have a job and legitimate source of income, to be in good health, and to have a stable address and less likely to have problems with the law or contact with addicts. In 1969, however, there were few differences between those who eventually stopped using drugs and those who continued, though the former group were younger, had a shorter period of heroin use, and had worked less since they became addicted. Over the seven years' follow-up the addicts who stopped taking drugs changed most, while those who stayed on opiates changed their life-style very little.


New mechanical aid to physiotherapy in cystic fibrosis. The force of impact and frequency of percussion by physiotherapists and parents of children with cystic fibrosis were analysed on a special test rig and incorporated in a prototype percussor. In adult volunteers and cadavers a maximum intrathoracic pressure could be achieved by a critical frequency of mechanical percussion which was higher than that reached by physiotherapists and parents. Consequently the percussor was redesigned to operate at this optimum frequency. It was then discovered that if the percussor was pressed firmly enough against the chest, this maximum intrathoracic pressure could be indicated by quivering of the voice. In a continuing study of intrathoracic pressures obtained mechanically and manually the Salford percussor's produced higher pressures than the physiotherapists' and maintained them constantly, while the physiotherapists' efforts and results varied from one to another. Hospital and domiciliary use of the percussor have shown it to help in the first stage of the physiotherapy routine for patients with cystic fibrosis. The percussor should enable adolescents and adults to treat themselves and encourage twice-daily and more effective chest treatments. It is easy to apply and its speed and efficiency should enable parents to improve the quality of their chest therapy for younger children at home. Its long-term benefits are difficult to assess because of the nature of the disease.


Reproductive mortality.

Reproductive mortality. The transfer from traditional to modern methods of contraception in recent decades has been accompanied by a transfer of deaths from complications of pregnancy to deaths from complications of the modern contraceptive methods. In 1975, for example, it is estimated that there were more deaths at ages 25-44 years in England and Wales from adverse effects of oral contraceptive use than from all complications of pregnancy, delivery, and the puerperium combined. Thus maternal mortality is no longer an adequate indicator of the deaths associated with reproduction in the community. An alternative measure, the reproductive mortality rate should be used, which includes deaths from complications of contraceptive use as well as those from complications of pregnancy or abortion. The reproductive mortality rate in England and Wales seems to have declined continuously since 1950 for women aged 25-34. But after 1960 it increased for women aged 35-44, because of the higher mortality associated with oral contraceptive use in this age group.


The Manchester regional screening programme: a 10-year exercise in patient and family care. Up to the end of 1978 the Willink Biochemical Genetics Unit had screened 506821 babies for metabolic abnormalities over 10 years--98-99% of the children born in the region. Sixty-nine cases of phenylketonuria (PKU), 42 cases of histidinaemia, and six cases of homocystinuria were detected. As well as treating affected children, the staff of the unit have concentrated on providing full support for their families and maintaining good communications with parents, general practitioners, health visitors, and midwives. A clinic liaison sister has provided valuable support for health visitors and an important link between the unit and community services. A study of the costs of screening and treating cases of PKU for the year 1978 showed that this was cheaper, by pound 569000, than the costs of looking after patients with untreated PKU.


Patients' reactions to their investigations: a study of 504 patients. Five hundred and four patients who had undergone hospital investigations were interviewed to find out how much information they had been given about the tests; their reactions before, during and after the test; and any after effects. In 74% of cases the tests had been satisfactorily explained. Patients were told more about complicated procedures such as cardiac catherisation than about routine ones such as venepuncture or barium meal examinations. The comments doctors made while performing the investigations were generally reassuring and were only rarely worrying or impatient. About half the patients suffered pain or discomfort during the test and rather more complained of after effects. Only 5% of patients said they would refuse the test again, though 36% said they would agree only reluctantly. Communication lies at the heart of the problem. Hospitals should consider issuing handouts on investigations to back up the doctor's information and to dispel myths. Staff should be more careful in concealing frightening-looking equipment, and if patients have to wait during investigations it may help reduce their anxiety if they are provided with something to occupy their time.


Unblocking beds: a geriatric unit's experience with transferred patients. A study was made of all patients admitted to a geriatric unit over several years. The admission policy included a high degree of priority to requests for transfer from acute beds, which resulted in transferred patients accounting for 25% of admissions. Unblocking acute beds did not lead to prolonged delay in admitting patients from the community to the geriatric unit. Almost 30% of beds allocated to transferred patients were recovered in 30 days.


Doctors accept a challenge: self-assessment exercises in continuing medical education. A new approach to continuing medical education by distance learning has been implemented. A series of six patient-management problems or challenges were posted to 20 000 doctors throughout Britain. Each doctor had to decide on the diagnosis, investigations, and treatment of the patients described. The challenges covered problems that were important in the doctor's day-to-day work and were designed so that he could obtain immediate feedback about his decisions and compare his own responses with those of a specialist and those of his colleagues. Additional information was available by telephone and by post on request. The series has been well received and is being widely used.


Altered chromatin conformation in Alzheimer's disease. Chromatin samples were prepared from forty human brains. Chromatin was separated into a heavy heterochromatin fraction and two euchromatin fractions: intermediate euchromatin and light euchromatin. Employing a bacterial RNA polymerase as probe, only the euchromatin fractions were capable of RNA synthesis. In Control human brains, in brains of patients with dialysis dementia and in brains of elderly individuals without or with dementia of a type other than Alzheimer's disease, the euchromatin fractions accounted for about 75 per cent of the total DNA. In contrast, in brains of patients with advanced senile dementia or presenile dementia of the Alzheimer type, a wide range of euchromatin content was encountered with an average value of 55 per cent. Heterochromatization occurred in both neuron and glia enriched fractions suggesting that a major alteration in protein metabolism occurs in Alzheimer's disease.


Opposed adducting saccades in convergence-retraction nystagmus: a patient with sylvian aqueduct syndrome. We report high resolution oculographic recordings on a patient with convergent-retraction nystagmus (Parinaud's Sign). Recordings show opposed adducting saccades which are slightly asynchronous (8 ms), in contrast to the conjugate horizontal saccades which are exactly synchronous (0.3 ms). Normal saccadic velocity of these opposed adductions necessarily implies reciprocal innervation of horizontal and vertical agonist-antagonist pairs. Lateral view cine films show absence of retraction, apparently as a consequence of normal orbital mechanics. We suggest that normal mechanisms for dynamic overshoot saccades are involved in the production of these abnormal opposed adducting saccades.


Participation of the stretch reflex in human physiological tremor. Microneurographic studies were made of normal human muscle spindle afferent activity to evaluate the role played by these endings, and by the segmental stretch reflex, in various types of physiological tremor. Primary endings are sufficiently sensitive to respond to the minute tremulous movements normally seen in contracting muscles. Human muscle spindle endings appear to possess the same non-linear sensitivity to small stretches as has been reported for cat muscle spindles. The findings also support the notion that the segmental stretch reflex plays an important role in enhanced physiological tremor, in so far as it tends to synchronize the motor outflow in such a way as to produce rhythmical contractions properly timed to reinforce the mechanical resonant properties of muscle spindle endings, the stretch reflex also serves to damp the larger oscillations of finger or hand which result from a brisk tap or muscle twitch. There is no evidence for alpha-gamma co-activation in these enhanced physiological tremors.


Leber's optic neuropathy: a clinical and visual evoked potential study of affected and asymptomatic members of a six generation family. Fourteen clinically affected and 40 asymptomatic members of a six generation family with Leber's optic neuropathy have been studied clinically and by recording pattern-reversal visual evoked potentials. While 12 of the affected members had suffered the typical sequential bilateral failure of vision, in 2 the condition was still monocular after periods of 12 and 14 years. Reduced vascularity of the optic nerve head was found in 11 of these cases, all of whom had some degree of optic atrophy, and showed a significant correlation with the visual acuity. Excessive tortuosity of peripheral retinal vessels was noted in 6 cases and was a prominent feature in the unaffected eye of one of the subjects with monocular visual impairment. In cases with advanced visual impairment the VEP was absent bilaterally, while in those with less severe involvement responses which were delayed, desynchronized and much small than normal could still be recorded. Two subjects with early bilateral clinical involvement had normal or minimally abnormal responses. Repeat studies in 6 subjects after intervals of up to fifteen months showed no change in 4 and a deterioration in 2. It is concluded that the VEP findings in clinically affected subjects are in keeping with a severe demyelinating lesion of the optic nerve with associated nerve fibre loss. Mild impairment of colour vision, pallor or reduced vascularity of the optic nerve head, excessive tortuosity of retinal vessels, a small central scotoma, and/or mild abnormalities or atypical features of the VEP were found in 16 of the 40 asymptomatic family members studied. Such abnormalities were present in 50 per cent of descendants from the female lineage who were at risk of developing the disease, and also in 30 per cent of descendants from male lineages who were not at risk. These findings suggest that there is a stage prior to the onset of visual impairment during which subtle abnormalities may be detected in individuals at risk of developing or transmitting the disease. The finding of asymptomatic abnormalities in descendants from male lineages could be accounted for by transmission of a partial form of the disease by affected or unaffected males, which would be in accord with a cytoplasmic mechanism of transmission for the disease.


Central core disease: clinical and pathological evidence of progression within a family. A family is described whose members showed different clinical presentations of central core disease. In 4 members the myopathy was congenital and nonprogressive, but in 2, muscle weakness first developed in adult life. Two further members had raised CPK levels without muscle weakness. Muscle weakness in one of the late-onset cases increased over eighteen months. This was associated with evidence of loss of type 2 fibres and the appearance of type 3 fibres on muscle biopsy. It is suggested that central core disease involves reinnervation of type 2 fibres by type 1 axons, and that the clinical manifestation of the disease depends on the age of onset and rate of progression of this process.


Effects of brain-stem and thalamic lesions on the corneal reflex: an electrophysiological and anatomical study. In 9 patients with Wallenberg's lateral medullary syndrome, one patient with a midbrain lesion involving the right side of the tegmentum, and 2 patients with a thalamic lesion, corneal reflexes were investigated by a new electromyographic technique. The electrophysical results were compared with the results obtained by clinical observation. In the lateral medullary lesions the electrophysiologically obtained reflex responses showed four types of abnormality. Type A consisted of a bilateral delay and type B a bilateral absence of the corneal reflex response to stimulation on the affected side in combination with a normal reflex response on both sides when the cornea on the normal side was stimulated. Type C, which was present in one case, and type D which was seen in 3 cases, consisted of a bilateral absence of the corneal reflex upon stimulation on the affected side; stimulation on the unaffected side produced a normal reflex response on the intact side in combination with, respectively, a delay or absence of the corneal reflex response on the affected side. Comparison of the clinical observations with the electrophysiological findings revealed minor discrepancies in type A and B abnormalities. However, the electrophysiological type C and D abnormalities were not detected by clinical observation. These findings demonstrate that electrophysiological recording of the corneal reflex may reveal clinically undetectable abnormalities. From the electrophysiological findings it is concluded that the corneal reflex is conducted along medullary pathways running both ipsilaterally and contralaterally from the stimulated side before connecting, respectively, with the ipsilateral and contralateral facial nucleus. From the anatomical findings it is suggested that the ascending pathways from the spinal fifth nerve complex to the facial nuclei are located in the lateral reticular formation of the lower brain-stem. The normal corneal reflex responses in the presence of thalamic and midbrain lesions involving nociceptive fibres in the trigeminothalamic tract do not support a previously postulated long-loop reflex arc passing through this tract. The suprabulbar influence upon the corneal reflex is discussed.


Unilateral neglect, representational schema and consciousness. Right brain-damaged patients with unilateral neglect were asked to detect differences within pairs of patterns moving left- or rightward behind a narrow vertical slit. It was seen that differences occurring on the left side of the mentally reconstructed images were less easily detected; therefore it is suggested that a representational disorder plays a primary role in unilateral neglect. In the light of these findings, it is possible to take into consideration some implications of unilateral neglect for theories of conscious brain activity.


The carpal tunnel syndrome: localization of conduction abnormalities within the distal segment of the median nerve. Palmar stimulation was used to assess median nerve conduction across the carpal tunnel in 61 control patients and 105 patients with the carpal tunnel syndrome. With serial stimulation from midpalm to distal forearm the sensory axons normally showed a predictable latency change of 0.16 to 0.21 ms/cm as the stimulus site was moved proximally in 1 cm increments. In 47 (52 per cent) of 91 affected nerves tested serially, there was a sharply localized latency increase across a 1 cm segment, most commonly 2 to 4 cm distally to the origin of the transverse carpal ligament. In these hands, the focal latency change across the affected 1 cm segment (mean +/- SD: 0.80 +/- 0.22 ms/cm) averaged more than four times that of the adjoining distal (0.19 +/- 0.09 ms/cm) or proximal 1 cm segments (0.19 +/- 0.08 ms/cm). In the remaining 44 (48 per cent) hands, the latency increase was distributed more evenly across the carpal tunnel. Unlike the sensory axons the motor axons were difficult to test serially because of the recurrent course of the thenar nerve, which may be contained in a separate tunnel. The wrist-to-palm latency was significantly greater in the patients with carpal tunnel syndromes than in the controls for sensory (2.18 +/- 0.48 ms v 1.41 +/- 0.18 ms) and motor axons (2.79 +/- 0.93 ms v 1.50 +/- 0.21 ms). Consequently, there was considerable difference between the carpal tunnel syndromes and controls in SNCV (38.5 +/- 7.5 m/s v 57.3 +/- 6.9 m/s), and MNCV (28.2 +/- 4.5 m/s v 49.0 +/- 5.7 m/s). In the remaining distal segment, however, there was only a small difference between the two groups in sensory (1.48 +/- 0.28 ms v 1.41 +/- 0.22 ms) and motor latency (2.15 +/- 0.34 ms v 2.10 +/- 0.31 ms). The exclusion of the relatively normal distal latency made it possible to demonstrate mild slowing across the carpal tunnel in 36 (21 per cent) sensory and 40 (23 per cent) motor axons of 172 affected nerves when the conventional terminal latencies were normal. Sensory or motor conduction abnormalities were found in all but 13 (8 per cent) hands. Without palmar stimulation, however, an additional 32 (19 per cent) hands would have been regarded as normal.


Spinal projections from the lower brain stem in the cat as demonstrated by the horseradish peroxidase technique. II. Projections from the dorsolateral pontine tegmentum and raphe nuclei. The descending projections to the spinal cord arising from the dorsolateral pontine tegmentum and brain stem raphe nuclei have been investigated by means of the horseradish peroxidase (HRP) technique. Particular attention was taken to clarify the cells of origin and the funicular trajectory of these spinal projections. After injections of HRP into the spinal cord, a significant of HRP labeled neurons were observed in the following dorsolateral pontine tegmental structures: (1) an area ventral to the nucleus cuneiformis; (2) principal locus coeruleus; (3) locus coeruleus a; (4) locuse subcoeruleus; (5) Kölliker-Fuse nucleus; and (6) nucleus parabrachialis lateralis. As a rule, the projections are ipsilateral and descendaphe-spinal projections, we have demonstrated that the nucleus raphe dorsalis also sends axons to the cervical segment of the spinal cord. Furthermore, in accord with previous reports, HRP labeled cells were also identified in the nucleus raphe magnus, pallidus and obscurus, but not in the nucleus raphe centralis superior and pontis. On the whole the present study further clarified the organization of spinal projections from the dorsolateral pons and raphe nuclei and provided some additional anatomical data for the physiology of the tegmentospinal and raphe-spinal projections.


The effects of different photoperiods on circadian 5-HT rhythms in regional brain areas and their modulation by pinealectomy, melatonin and oestradiol. Differential circadian rhythms in 5-HT levels were found in the hypothalamus and pineal (but not in the cortex, hippocampus or midbrain) in ferrets kept in either long (14 h light/10 h dark) or short (8 h light/16 h dark) photoperiods. 5-HT decreased during the first 6 h of illumination in all areas examined from animals kept in short photoperiods. In long photoperiods, 5-HT in the hypothalamus (particularly the anterior region) increased during the first 6 h after onset of light and levels in the pineal became arrhythmic. There were no differential effects of light on 5-HIAA/5-HT ratios. Removal of the pineal or the superior cervical ganglia abolished these differential rhythms, as did subcutaneous implants of oestradiol (releasing about 5 micrograms/day). Melatonin (1 mg/day) injected 8 h after the onset of light into animals kept in long photoperiods resulted in circadian 5-HT rhythms resembling those from animals exposed to short photoperiods, whereas melatonin given at 14 h after onset of light did not have this effect. It is suggested that 5-HT containing neural systems may play a role in the way the pineal transmits information about the duration of the photoperiod to the neural structures controlling the pituitary.


The effect of selective lesions of brain noradrenergic systems on the development of barbiturate tolerance in rats. A method for chronic infusion of barbiturates into the central nervous system of rats was developed and used to study the importance of noradrenergic systems in the development of barbiturate tolerance. Destruction of noradrenergic neurons by intraventricular administration of 6-hydroxydopamine or by specific lesions of the dorsal or ventral noradrenergic bundles prevented the development of barbiturate tolerance without altering the animal's response to the acute administration of barbiturate.


Antiserum induced myelination inhibition in vitro without complement. Exposure of neonatal rat cerebellum cultures to antiserum to whole spinal cord or galactocerebroside inhibited myelin formation regardless of whether guinea pig serum was added fresh or after heating to 56 degrees C for 1 h in order to achieve complete removal of hemolytic complement activity. Myelination followed removal of antisera from the culture media. This suggests that the inhibition of primary myelination by anti-CNS tissue antiserum occurs through some mechanism other than as the result of a cytotoxic reaction against oligodendrocytes mediated via the complement system.


Effects of reduced cerebral blood flow upon EEG pattern, cerebral extracellular potassium, and energy metabolism in the rat cortex during bicuculline-induced seizures. Progressive cerebral ischemia was induced by blood pressure (BP) reduction in rats during status epilepticus, and the sequence of cerebral functional (EEG, extracellular K+ activity) and metabolic (levels of high energy phosphates, glucose, glucose-6-phosphate, lactate, pyruvate, alpha-ketoglutarate) changes were determined. Very moderate reductions of BP were accompanied by tissue lactate accumulation and a decrease of the rate of re-uptake of K+ extruded during discharges. These changes were pronounced at BP about 50 mm Hg, when also the energy state showed some deterioration, and the EEG activity changed from one of bursts and suppressions into single spikes. At BP about 30 mm Hg EEG activity was abolished, but not until a slightly lower BP level was there a severe energy depletion and a massive K+ release, indicating generalized membrane depolarization. The results show an increased susceptibility to ischemia during seizures with changes of membrane pump function, and energy metabolism appearing at moderate reductions of BP. Concomitant decrease of seizure activity delayed to some extent the development of massive energy failure and membrane depolarization.


Early changes in muscle glucose-6-phosphate dehydrogenase activity after denervation: locus and dependence on nerve stump length. Glucose-6-phosphate dehydrogenase (G6PD) activity of rat diaphragm muscle increased significantly 12 h after intrathoracic ('distal') denervation. Since this change represented one of the earliest known events after loss of innervation, the mechanism of neuronal regulation and the nature of the muscle response were further investigated. When, instead of distal denervation, the motor nerve was cut about 3.5 cm from the diaphragm, G6PD activity slightly decreased 12 h later. Denervations in which part of the same hemidiaphragm had a short nerve stump and another part, a long nerve stump, also showed a differential increase of G6PD activity dependent on length of nerve stump. In biochemical studies of the locus of the early post-denervation elevation of G6PD, enzyme activity was increased both in endplate and non-endplate regions of the muscle. Finally, the histochemical reaction for G6PD was more intense in both muscle fibers and interstitial elements, although the former made the major contribution to the biochemical results. In sum, muscle G6PD enzyme activity is closely regulated by a neurotrophic mechanism partly independent of nerve or muscle electrical activity.


Retinal ganglion cell response to axotomy and nerve growth factor antiserum in the regenerating visual system of the newt (Notophthalmus viridescens): an ultrastructural morphometric analysis. One 3.0 mg dose of the nerve growth factor antiserum (anti-NGF) injected into the vitreous chamber of the eye at the time of optic nerve transection elicits significant changes in the normal newt (Notophthalmus viridescens) retinal ganglion cell body response to axotomy at 7 and 14 days postaxotomy (DPA). Light microscopic observations indicate that anti-NGF treatment significantly reduces the per cent of retinal ganglion cells demonstrating nuclear chromatin reactivity (ie., homogeneous to a more heterogeneous state) from 33.36 +/- 3.02 to 22.82 +/- 2.98%. In addition, the per cent of retinal ganglion cells demonstrating prominent nucleoli is dramatically decreased from 32.08 +/- 1.64 to 18.20 +/- 1.79% at 7 DPA. It is also important to note that the number of prominent nucleoli in the 7 DPA group is reduced to such an extent by anti-NGF treatment that the value is not significantly different from that of intact controls. Intact controls will routinely exhibit approximately half the number of prominent nucleoli that are normal for the untreated 7 DPA group. A definite dose-response relationship can be shown to exist between the per cent of nuclear reactive ganglion cells demonstrating prominent nucleoli and various anti-NGF concentrations at 14 DPA. There does not appear to be a dose-response relationship between various anti-NGF concentrations and the per cent of retinal ganglion cells demonstrating nuclear reactivity at 14 DPA. However, the degree of nuclear chromatin reactivity appears to be less at the higher anti-NGF concentrations (ie., greater than or equal to 3.0 mg/eye) at 14 DPA. Electron microscopic morphometric analysis reveals that anti-NGF treatment significantly reduces the cell perikaryal area at 7 and 14 DPA while the nuclear area remains unchanged. Therefore, there is a significant decrease in the cytoplasmic/nuclear ratios at both 7 and 14 DPA in response to anti-NGF treatment which appears more pronounced by 14 DPA. Anti-NGF treatment also significantly reduces the mitochondrial and nucleolar densities, as well as the nucleolar areas of cells at 7 and 14 DPA. There are no significant changes in Golgi field densities in response to anti-NGF treatment.


Conductivity in the somatosensory cortex of the cat -- evidence for cortical anisotropy. Orthogonal conductivity components were determined for 3 depths in the somatosensory cortex of cats and relative vertical conductivities were determined for all depths. (2) For cortical layers II--III, the conductivity was nearly twice as large (1.7 times) in the anteroposterior direction as it was in the mediolateral direction, whereas in layer IV the conductivity in the mediolateral direction was about 1.4 times greater than it was in the anteroposterior direction. (3) With the exception of the anteroposterior direction of layers II--III and the mediolateral direction of layer IV, the vertical conductivity of the cortex was always greater than either of the horizontal conductivities. (4) Vertical conductivities varied with cortical depth. The lowest vertical conductivity occurred in layer I. It increased in layers II--III, dropped in layer IV, and increased again in layer VI to a value comparable to layers II--III. (5) Adjacent determinations of conductivity indicated that over short distances (1--2 mm) the cortex was electrically homogeneous. (6) These data suggest that the cellular organization of the somatosensory cortex changes markedly and abruptly with cortical depth. Furthermore, they suggest that a significant portion of the coritcal neuropile in layers II--III and in layer IV is highly polarized. The possible anatomical basis for this polarization is discussed as are the effects of cortical anisotropy upon conductivity measurements.


The role of locus coeruleus in decapitation convulsions of rats. The role of the central norepinephrine (NE) system, especially the locus coeruleus (LC), in the occurrence of decapitation convulsions was investigated in rats. Intraspinal injection of 6-hydroxydopamine (6-OHDA) caused a significant inhibition of decapitation convulsions as shown by prolongation of the latency and shortening of the convulsion's duration, as well as decreasing the NE content of the spinal cord to 35% of the control value without affecting the NE content of the various regions in the brain. Chemical lesion of the descending bundle from the LC by treatment with 6-OHDA significantly inhibited decapitation convulsions in a similar manner. Moreover, there was a decrease in the NE content of the spinal cord and hypothalamus to 24% and 47% of the control value, respectively. Bilateral electrolytic lesion of the LC also significantly inhibited decapitation convulsions and decreased the NE content of the cortex and spinal cord to 15% and 74% of the control value, respectively. However, lesions of the dorsal and ventral NE bundle by treatment with 6-OHDA, which caused a marked decrease in the NE content of the cortex and hypothalamus, respectively, did not affect the decapitation convulsion. Intraspinal injection of 5,6-dihydroxytryptamine resulted in a decrease in the 5-hydroxytryptamine content of the spinal cord only; moreover, it did not change the decapitation convulsion. These results suggest that coeruleospinal NE neurons play an important role in the occurrence of decapitation convulsions.


Phasically firing neurons in long-term cultures of the rat hypothalamic supraoptic area: pacemaker and follower cells. The firing of a proportion of hypothalamic neurons in long-term cultures from the supraoptic nucleus was characterized by a phasic discharge pattern. Burst duration and cycle time varied considerably between different cultures, but were similar in neurons of the same culture. The instantaneous frequency of firing was highest at the onset of bursts. The phasic activity of the majority of cells was synaptic in origin. In these follower cells, current injection through the recording electrode had no effect on burst duration and cycle time, and their activity was abolished by synaptic isolation. In contrast, the activity of bursting pacemaker cells persisted during applications of Co2+ and was a function of membrane potential. In both pacemaker and follower cells, action potentials and slow oscillations of membrane potential were abolished by application of tetrodotoxin.


Studies of human and bovine spinal nerve roots and the outgrowth of CNS tissues into the nerve root entry zone. The outpouching of CNS tissues into the entering spinal nerve roots was documented by light and electron microscopy of human and bovine tissues. Astrocytic processes containing large bundles of glial filaments were very prominent in the nerve entry zone and extended for short distances into the adjacent endoneurium of the spinal nerve roots. Antiserum raised to glial acidic fibrillary (GFA) protein stained these glial elements, thereby characterizing the dome-shaped evaginations of CNS tissues into the nerve root entry zones. Antisera to CNS basic protein showed enhanced staining in the nerve entry zone. Analyses of nerve proteins by SDS gel electrophoresis disclosed a prominent 49,000 MW protein in the bovine and human nerve root entry zone. This protein was also prominent in spinal cord white matter, but was not seen in nerve roots which were not admixed with glial tissues. This finding supported the view that a 49,000 MW protein is a glial filaments but is not a component of bovine or human neurofilaments.


Horizontal canal input to cat extraocular motoneurons. Synaptic potentials were recorded in identified extraocular motoneurons in the anesthetized cat, following stimulation of the horizontal canal nerve (HCN). Weak stimulation of the HCN evoked disynaptic EPSPs in ipsilateral medial rectus (i-MR), contralateral lateral rectus (c-LR) and disynaptic IPSPs in i-LR motoneurons. Weak stimulation of the HCN produced longer latency IPSPs (probably trisynaptic) in c-MR motoneurons. It is suggested that the HCN projects to an excitatory interneuron in the vestibular nucleus whose axon in turn projects to a third order inhibitory interneuron in the IIIrd nucleus which finally projects to c-MR motoneurons. Essentially there is no influence of the HCN stimulation on bilateral superior rectus (SR), inferior rectus (IR), superior oblique (SO) and inferior oblique (IO) motoneurons.


Excitability changes in lumbosacral spinothalamic neurons produced by non-noxious mechanical stimuli and by graded electrical stimuli applied to the face. The changes in the excitability of lumbosacral spinothalamic neurons produced by activating afferents in the trigeminal nerve using electrical or mechanical stimuli was investigated in cats anesthetized with alpha-chloralose. In most spinothalamic neurons, weak electrical stimuli or step indentations of the skin of the face produced an increase followed by decrease in the excitability of these cells. In experiments in which the effect of activating specific groups of trigeminal afferent fibers on these excitability changes was evaluated, the suppression could be produced by activating only the fastest conducting cutaneous afferent fibers. Step indentations of the facial skin affected the excitability of spinothalamic neurons in a manner similar to electrical stimuli. The duration of the suppression phase appeared to be largely independent of the duration of the step indentation of the facial skin. It was concluded that the descending system mediating the suppression phase is activated largely by cutaneous afferents from rapidly adapting receptors. The effects of subtotal spinal cord lesions on the excitation and suppression phases produced by facial stimulation indicate that the pathways mediating the supppression descend bilaterally in the dorsal part of the lateral fasciculus. The excitation phase appears to be mediated largely by pathways in the dorsal part of the ipsilateral lateral fasciculus.


Autoimmune alterations in the neurohypophysis of rabbits immunized against vasopressin. Rabbits immunized against vasopressin developed clinical signs of diabetes insipidus persisting for up to two months after the last boost. Ultrastructural and immunocytochemical studies of the neurohypophysis demonstrated autoimmune alterations: infiltration by immune cells and extracellular deposits of immunoglobulins. No alterations were observed in the hypothalamic nuclei synthesizing vasopressin nor in hormone-target cells of the kidney. Immunization against vasopressin may provide the first example of an autoimmune disease in the hypothalamo-neurohypophysial system.


Repeated electroconvulsive shocks and the brain content of endorphins. Repeated electroconvulsive shocks (ECS) cause an increase of [met5]-enkephalin (ME) content in hypothalamus and some limbic areas such as n. accumbens, septum and amygdala. The temporal characteristics of this increase resemble the time course of the clinical effects of electroconvulsive therapy (ECT). Single shock failed to change the ME content in any part of the brain. After 6 daily shocks ME content increases by 60% in hypothalamus and maximal effect (100% increase) was obtained after 10 daily shocks. The increase of ME content persists 6 days after the termination of ECS. Subconvulsive shocks failed to alter the content of ME in all the brain gions determined. When the seizure induced by ECS was prevented by pretreatment with an anesthetic dose of phenobarbital, the ECS-induced increase in hypothalamic and septal ME content was also blocked. beta-Endorphin content of hypothalamus remained unchanged after repeated ECS despite a two-fold increase in the ME content in the same region. These observations indicate that the time constant for the increase in ME content induced by ECS resembles the time constant for the appearance of the clinical benefits by ECT and may give credence to the possibility that the ME increase may participate in the antidepressive action of ECS.


Dompamine receptors in the rat frontal cortex: an autoradiographic study. Literature findings indicated that injection of low doses of [3H]spiperone results in a labelling of dopamine receptors in rat brain, but also in a labelling of serotonin receptors. Administration of pipamperone, a drug with serotonergic properties, to animals treated with [3H]spiperone reduced the serotonergic component of the binding and permitted an easier identification of dopamine receptor binding. At the level of Forceps Minor, there were elevated levels of receptors in the deeper layers of the cingulate cortex, in the region above the rhinal sulcus and in an area dorsal to the accumbens. This distribution is in agreement with the results of other biochemical, histochemical and electrophysiological studies.


The distribution and origin of glutamate decarboxylase and choline acetyltransferase in ventral pallidum and other basal forebrain regions. The distribution of choline acetyltransferase (ChAT) and glutamate decarboxylase (GAD), and the histochemical reaction for acetylcholinesterase have been studied in the basal forebrain and globus pallidus of unoperated rats and in rats with an electrolytic lesion of the nucleus accumbens. ChAT was highly concentrated in the substriatal region, the neostriatum and the lateral part of the rostral substantia innominata. The strongest intensity of staining for acetylcholinesterase was found in the substriatal grey and the neostriatum. Very high GAD activity was found in the substantia innominata, being even slightly higher than that in the pars reticulata of the substantia nigra. The lateral preoptic area, the bed nucleus of the stria terminalis and the globus pallidus also showed high activity of GAD. After lesions of the nucleus accumbens the activity of GAD decreased significantly in the substantia innominata and in a restricted part of the rostroventral globus pallidus, but not in the other regions studied. ChAT activity and acetylcholinesterase staining were unaffected in all regions. The results indicate that a dense GABAergic projection originates in the nucleus accumbens and terminates in the rostral substantia innominata and rostroventral part of the globus pallidus. The study gives neurochemical support to the suggestion that nucleus accumbens may be regarded as a ventral part of the neostriatum and that the rostral substantia innominata may be regarded as a ventral part of the globus pallidus.


Impeded cerebellar development and reduced serum thyroxine levels associated with fetal alcohol intoxication. Pregnant albino rats were placed on a complete liquid diet (Ensure) containing either 9% ethanol or an isocaloric amount of sucrose between the third and twentieth day of gestation. The pups born to these rats were sacrificed either day 11 or day 14 postnatum and morphometrical, histological and biochemical analyses were done on their cerebellums and cerebrums. Pups that were exposed to ethanol in utero had significantly smaller body weights, cerebrums and cerebellums than pair-fed controls. The cerebellar mass was reduced by 10% and the cerebral weight by 3% in the pups exposed to alcohol when body weights were normalized to that of pair-fed controls. Cerebellar aspartyl aminotransferase (EC 2.6.1.1) activity was reduced at day 11 and 14 in ethanol treated pups compared with controls. Serum T4 levels were also reduced in the ethanol treated group. Histological analyses revealed that the external granule cell (EGC) layer of ethanol treated pups was significantly thicker at 11 and 14 days postnatum than that of pair-fed control pups. Cerebellar ornithine decarboxylase (ODC, EC 4.1.1.17) activity was higher at day 11 in the ethanol treated pups than in controls. The reduced mass, AAT activity, T4 serum levels and the increased thickness of the ECG layer indicate a delayed or impeded maturation of cerebellum in ethanol treated pups. These data are considered from the viewpoint that ethanol, other drugs such as methadone and prenatal stress (malnutrition) may cause delayed cerebellar maturation by reducing serum T4 levels in the early postnatal period (day 5-14).


Intracranial self-stimulation in relation to the ascending noradrenergic fiber systems of the pontine tegmentum and caudal midbrain: a moveable electrode mapping study. Chronically implanted moveable electrodes were used to map the pontine tegmentum and caudal midbrain for intracranial self-stimulation in relation to the ascending noradrenergic systems as revealed by fluorescence histochemistry. In no area tested was there a consistent correlation between the quality or the presence of self-stimulation and the degree of noradrenergic fiber density or cellular aggregation. Of particular importance was the failure to obtain self-stimulation from the locus coeruleus, despite repeated testing and extensive attempts at behavioral shaping. Those areas supporting self-stimulation included the dorsal raphe nucleus, the superior cerebellar peduncle and the mesencephalic and motor nuclei of the trigeminal nerve. These data appear to rule out activation of the ascending noradrenergic systems as an explanation of the rewarding effects of stimulation in these areas. A gustatory-visceral fiber system is suggested as an alternative possible substrate.


The influence of electrical stimulation of certain brain regions on the concentration of acetylcholinesterase in rabbit cerebrospinal fluid. Electrical stimulation of either the caudate nucleus, substantia nigra or lateral hypothalamus led to an increase in the concentration of acetylcholinesterase in cerebrospinal fluid collected from the cisterna magna of the rabbit. This effect was not due to gross cell damage, fluid loss or contamination with blood plasma. Cerebrospinal fluid collected from the lateral ventricle contained a lower concentration of acetylcholinesterase than that collected from the cisterna magna; furthermore, stimulation of the ipsilateral caudate nucleus caused no change in the concentration of this enzyme in ventricular cerebrospinal fluid. After placing a large lesion in the ipsilateral substantia nigra, the 'resting' concentration of acetylcholinesterase in cisternal cerebrospinal fluid was 43% of the value in unoperated rabbits and stimulation of the caudate nucleus no longer led to an increase in the concentration of acetylcholinesterase in cisternal cerebrospinal fluid. The possibility is discussed that when the caudate nucleus is stimulated, acetylcholinesterase is released from the substantia nigra.


Visual discrimination impairments after lesions in zona incerta or lateral terminal nucleus of accessory optic tract. Possible visual functions of zona incerta (ZI) and lateral terminal nucleus of the accessory optic tract (LTN) in rats were investigated by comparing the effects of localized lesions on a series of discrimination learning tasks. In Experiment 1 animals with ZI lesions were impaired on a simultaneous black versus white (BW) discrimination but not on a simultaneous horizontal versus vertical (HV) task. Animals with LTN lesions were impaired on HV but not on BW. Rats with ZI lesions were impaired on a successive bright versus dim but not a successive HV discrimination when subsequently tested in Experiment 2. Animals with LTN lesions were impaired on both tasks. The results are related to the possibility that visual intensity information gains access to the motor system through a pathway running from the ventral lateral geniculate nucleus to the basal ganglia via ZI. Since LTN lesions impaired acquisition of a HV discrimination, a task highly susceptible to the effects of geniculostriate ablation, it is suggested that such lesions impair the use of visual information without distroying the sensory channels mediating the discrimination.


The intracortical distribution of norepinephrine, dopamine and serotonin in the cerebral cortex of the cat. The intracortical distribution of the biogenic amines (BA), norepinephrine (NE), dopamine (DA) and serotonin (5-HT), was determined for the parietal and occipital cortical areas of the cat. Under microscopic control, slices of each region were dissected out into 4 fractions: (1) an upper gray fraction (G1); (2) a medium gray fraction (G2); (3) a lower gray fraction (G3) and (4) a white-matter fraction (W). The BA were assayed by means of specific and sensitive radioenzymatic techniques; using catechol-O-methyltransferase (COMT) for the catecholamines (CA), and N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT) for the 5-HT. In the two cortical regions studied, NE and DA were found to be distributed in an orderly laminar fashion. The highest levels of endogenous CA were measured in the superficial layers (fractions G1 and G2) while the white matter (fraction W) exhibited the lowest content of both NE and DA. DA represented 32--38% of the total CA content of the parietal cortex and 32--41% of the total CA content in the occipital cortex. In the parietal cortex, the distribution of 5-HT was similar in pattern to that of the CA, i.e., a decreasing concentration gradient with the highest endogenous levels in the G1 fraction and the lowest content in the W fraction. In the occipital cortex, the distribution was also found to be laminar for the gray matter but the W fraction showed a higher endogenous content than the lower gray fraction (G3). The release of NE, DA and 5-HT was studied by means of cortical superfusion in an in vivo preparation. The concentrations of BA measured in 30 min interval superfusates was fairly constant in a given experiment under basal conditions but varied widely from experiment to experiment. Variations in the basal overflow of NE were often independent of those found for DA and the basal overflow of 5-HT seemed independent of those of CA. The laminar intracortical distribution of endogenous NE, DA and 5-HT in cerebral cortex demonstrated by microdissection and biochemical assay techniques suggests a definite and structured pattern of aminergic innervation. Furthermore, the fact that these BA are released and a basal overflow can be detected and measured appears compatible with significant roles of NE, DA and 5-HT in synaptic transmission in the cerebral cortex.


Muscarinic cholinergic regulation of epileptic spiking in kindling. Electroencephalographic monitoring of spontaneous interictal spiking (SIS) following kindling demonstrated that SIS occurs in both amygdalas and that it declines sharply during the days following kindling. Systemically administered muscarinic antagonists which pass the blood-brain barrier (atropine and scopolamine) activated interictal spiking in kindled rats but not in controls. Interictal spiking activated by atropine was reversed by physostigmine. Both physostigmine and choline, agents which increase brain ACh concentration by different mechanisms, caused a reduction in spontaneous (not drug activated) interictal spiking. The results of these pharmacologic studies indicate that the interaction of endogenous ACh with central muscarinic receptors is capable of suppressing SIS in kindled rats. Whether cholinergic suppression of SIS represents a convulsant or an anticonvulsant action is presently unclear.