Individual differences in right and left reaction time.

Experiments designed to check the absence of effects for hands and handedness in simple and two-choice reaction time found unexpected individual differences related to stimulus laterality. The majority of subjects responded faster to the stimulus on the left and a substantial minority responded faster to the stimulus on the right in any choice pair. The right index finger was slower than the left index or the middle fingers. Choices tended to be faster between fingers on different hands than on the same hand and same-hand choices were faster with the left hand than the right hand. There were no effects attributable to hand preference or sex.


Emotionality in male and female rodents: a reply to Archer.

Archer (1979) has complained that his criticisms (Archer, 1971, 1973, 1975) of Gray's (1971 a, b) views on emotionality and on sex differences in fearfulness in rodents have not been answered. These criticisms are shown to lack substance and to depend on confused arguments and misleading reviews of the literature.


Negative recency and measurement of primary memory.

The technique of Waugh & Norman (1965) is widely used in measuring the capacity of primary memory. Watkins (1974) has proposed a modification of the technique which takes into account registration failure. A further modification is proposed which takes into account findings of negative recency in delayed recall.


Fitness assessment of English league soccer players through the competitive season.

A battery of 26 tests was administered to professional soccer players (n = 31) at 3 points during the competitive season. Significant changes from start to mid-season were limited to improved muscular power, increased resting heart rate (fH), decreased force expiratory flow (FEF) and ankle mobility. No further changes with the duration of the competitive season were observed. Differences between squads were predominantly cardiac function measures at mid-season, and strength, muscular power and limb girths at the end of the season. The First Team squad had consistently less fat and poorer ankle mobility. It seems that mean fitness levels remain relatively stable during the playing season, though the measures significantly discriminating between the top and reserve squads fluctuate.


The effect of regular exercise on cognitive functioning and personality.

The effect of regular exercise on cognitive functioning and personality was investigated in 32 subjects representing 4 discrete groups based on sex and age. Before and after a 10 week exercise programme of jogging, calisthenics, and recreational activities, a test battery was administered to assess functioning in a number of domains: intelligence (WAIS Digit Symbol and Block Design); brain function (Trail-Making); speed of performance (Crossing-Off); memory and learning (WMS Visual Reproduction and Associate Learning); morale and life satisfaction (Life Satisfaction and Control Ratings); anxiety (MAACL); and depression (MAACL). Improvement was observed on several physiological parameters. ANOVA revealed significant sex and age differences on Digit Symbol and Block Design and age differences on Trail-Making, Crossing-Off, Associate Learning, and anxiety. Regardless of sex and age, significant improvement in performance was observed from pre to post-test on Digit Symbol, Block Design, Trail-Making, Crossing-Off, and on Associate Learning. In addition, an increase on health status rating (p less than .01) and decrease in anxiety were observed from pre to post-test. These data illustrate beneficial effects of exercise on certain measures of cognitive functioning and personality.


A pilot study on left ventricular dimensions and wall stress before and after submaximal exercise.

Left ventricle dimensions and wall stress were measured echocardiographically before and immediately after exercise in 14 athletes and 7 control subjects. Our findings suggest that afterload is an important determinant of cardiac performance and wall hypertrophy in athletes. In spite of major changes in heart rate and blood pressure, left ventricular wall stress remains unchanged following submaximal exercise, in trained and untrained hearts. It would appear that the changes in heart size during exercise are to a large extent limited in untrained ventricles, as smaller left ventricular dimensions are required, to "normalise" wall stress. This results in a lower stroke volume for a given stroke dimensional change. Consequently cardiac output is a function of heart rate rather than stroke volume in untrained subjects. The effect of increased muscle mass in athletes, is to permit larger left ventricular dimensions for a given afterload, thus stroke volume can be augmented. The increase h/R ratio suggests that afterload is more important than preload in the development of left ventricular hypertrophy in rowers and swimmers.


Athletes' leg pains.

The frequency and nature of exertion pains of the leg in athletes were studied in 2,750 cases of overuse injuries treated at the Sports Clinic of the Deaconess Institute of Oulu, Finland, during the years 1972-1977. 465 cases of exertion pain (18%) were located in the shin. The medial tibial syndrome was the most common overuse injury among these athletes, comprising 9.5% of all exertion injuries and 60% of the leg exertion pains. Together with stress fracture of the tibia, the second most common exertion pain of the leg, it accounted for 75% of the total leg pains. There are certain difficulties in differentiating between the medial tibial syndrome and stress fracture of the tibia. They both occur at the same site with similar symptoms. Radiological examination and isotope scanning are needed. The medial tibial syndrome is an overuse injury at the medial tibial border caused by running exercises. The pain is elicited by exertional ischaemia. The pathogenesis is explained by increased pressure in the fascial compartment of the deep flexor muscles due to prolonged exercise. Similar chronic ischaemic pains from exercise are also found in other fascial compartments of the leg, especially in the anterior compartment. The only treatment needed for stress fractures is rest from training. Fascial compartment pains also usually subside. If chronic fascial syndromes prevent training, fasciotomy is recommended as a reliable method to restore the athlete to normal training without pains.


High definition imaging of carotid arteries using a standard commercial ultrasound "B" scanner. A preliminary report.

Sixteen carotid arteries in nine patients with transient ischaemic attacks and carotid bruits were examined by direct scanning grey scale ultrasound using a 10 HMz probe attached to a standard commercial apparatus. Findings using ultrasound were compared with a contrast arteriogram performed on the following day and, in two cases, with the surgical appearances during endarterectomy. Atheromatous plaques were demonstrated in five common carotid arteries by ultrasound. Arteriography failed to show proximal plaques in two common carotid arteries and extension of bifurcation disease into the adjacent common carotid in a third patient. Ultrasound detected four stenotic and one occluded internal carotid artery. One internal carotid artery with a 25% stenosis was shown by arteriography but not by ultrasound. Of the five external carotid stenoses, one with a minimal stenosis of less than 10% was not demonstrated. In all cases, stenoses in excess of 30% were shown by ultrasound. Surgical findings correlated more closely with details of the plaques as shown by ultrasound than by arteriography. It is suggested that ultrasound might be used to pre-select reliably those patients who would benefit from a contrast arteriogram and, thus, to protect those with normal carotid arteries from a potentially hazardous invasive investigation.


Contrast dose for enhancement of computed tomograms of the brain.

This study shows that contrast enhancement of cerebral lesions can be adequately achieved with a bolus injection of 60 ml of sodium iothalamate 70%. While the infusion of a larger dose of contrast agent increases quantitatively the level of enhancement of a variety of lesions, this method of examination does not appear to provide any more useful diagnostic information, and it introduces added and unnecessary inconvenience, cost and potential hazard.


A quantitative evaluation of film and film/screen combinations for mammographic examination.

A test phantom containing simulated micro-calcifications was constructed. This was imaged by seven systems suitable for use in mammography, firstly in scatter-free conditions and secondly with the addition of tissue-equivalent scattering material. The ability of the systems to resolve micro-particles of known size was assessed using the techniques of signal detection theory. The resultant receiver operating characteristic curves separated the systems into three major groups. Firstly, high resolution systems requiring high radiation dose techniques; secondly at the other extreme, a mediocre imaging system producing its results at low radiation levels; and thirdly a larger middle group producing intermediate resolution of fine particles at similar, acceptable dose levels. The ability to image small particles does not increase linearly with the radiation dose. Scatter did not affect all of the systems to the same extent.


The effect of recovery from potentially lethal damage on the determination of reoxygenation in a murine tumour.

The pattern of reoxygenation in the murine anaplastic MT tumour was investigated using the established method of determining the hypoxic fraction, at intervals after a priming X-ray dose, from test doses given either to unclamped or clamped-off tumours. Little reoxygenation was apparent whilst the tumour was increasing in size for 12--72 hours after a single dose of 20.3 Gy, but extensive reoxygenation was evident whilst the tumour was shrinking at nine days after a dose of 50 Gy. However, the degree of reoxygenation may have been underestimated, especially after the smaller priming dose. This is because only the chronically hypoxic cells in this tumour have the ability to recover from potentially lethal damage (PLD) and so are more radioresistant than cells rendered acutely hypoxic by clamping. Because of this, even when tumours are clamped off during irradiation, the resulting survival curve is biphasic and the apparent effect of the clamp becomes a function of the X-ray dose used. The larger the dose, the smaller the observed effect of the clamp, so the greater the apparent hypoxic fraction and hence the smaller the apparent degree of reoxygenation.


The effect of local hyperthermia on the small intestine of the mouse.

Small loops of mouse jejunum were exteriorized and heated by immersion in a bath of Krebs-Ringer salt solution. Crypts were lost in the heated regions with a half-time of approximately six hours and reached a steady level of damage by 10--16 hours. There was no recovery in crypt number for one week after hyperthermia. Using a 24 hour assay, crypt survival curves were obtained using various heating times in the temperature range 37.5 degrees C--44.5 degrees C. These curves were qualitatively similar to those resulting from radiation damage, showing a shoulder followed by exponential killing. As the temperature was increased, progressive changes in shape of the curves indicated a proportional inhibition of accumulation of sublethal heat damage combined with increased rate of expression of lethal damage. Over the temperature range 42.3 degrees C--44.5 degrees C, a linear relationship was found between the rate of crypt loss and the reciprocal of the absolute temperature. An activation energy of 600 +/- 70 kJ mole-1 was calculated using the Arrhenius equation. In this temperature range, doubling the heating time had the same effect as increasing the temperature by 1 degree C. At temperatures below about 42.3 degrees C, the tissue became relatively less sensitive to increasing the treatment time.


Recovery from sublethal damage by acutely hypoxic tumour cells in vivo and in vitro.

The ability of acutely hypoxic tumour cells to recover from sublethal damage following irradiation in vivo and in vitro has been measured using a single tumour system. The methods of assay were tumour growth delay, local tumour control and tumour cell survival in vitro following treatment in vivo or in vitro. Tumours in vivo or cells in vitro rendered acutely hypoxic during irradiation were irradiated with either single doses or two doses 24 hours apart. Cells left in situ had a greater capacity for recovery than those treated either in vivo or in vitro and then assayed in vitro. It is suggested that tumours may not show a systematically reduced capacity for recovery relative to normal tissues, unless chronically hypoxic tumour cells have a reduced capacity for recovery and determine the response. However, the results imply that deductions as to the ability of tumour cells to recover from sublethal damage (whether chronically hypoxic or not), which rely on in vitro assays, may underestimate the extent of recovery.


The management of gross refractory obesity by jejuno-ileal bypass.

Jejuno-ileal bypass has been performed in 226 massively obese patients, 190 of whom have been followed for a minimum of 1 year. End-to-side and end-to-end anastomoses were compared and no difference in the weight reduction achieved by either technique was seen throughout the 5-year follow-up. There was no significant difference in weight reduction achieved between groups of patients in which the jejunal length varied from 10 to 35 cm and the ileal length from 35 to 10 cm. The weight reduction achieved in the entire series averaged 36-7 +/- 9-4 per cent at 2 years, after which no further loss occurred. Good psychological benefits were recorded. Remission of diabetes occurred in 12 of 13 patients and marked long term lowering of serum lipids was seen. Side effects included fluid and electrolyte disturbances and fatty changes in the liver during the first year, improving thereafter. Early cirrhosis of the liver occurred in 8-6 per cent. Other side effects included abdominal bloating, arthralgia and renal colic. The operative mortality was 0-9 per cent and the late mortality directly attributable to the jejuno-ileal bypass, 3-1 per cent. In 19 patients the bypass was discontinued because of severe side effects.


Influence of thyroid surgery on voice function and laryngeal symptoms.

A comprehensive examination of voice function and laryngeal symptoms was applied systematically to 20 patients undergoing thyroid surgery. Patients were excluded from the series if there had been previous neck surgery or if postoperative indirect laryngoscopy showed abnormal cord mobility. Examination before operation showed that patients with sporadic non-toxic goitre or medically pre-treated toxic goitre had impaired voice function based on stroboscopy, electro-glottography, phono-oscillometry and determination of voice range, phonation time, pitch, and peak flow. Three months after thyroid surgery the voice function was significantly improved although not normal in non-toxic goitre patients, whereas the voice function in patients with thyrotoxicosis was unchanged. The number of laryngeal symptoms was significantly reduced in non-toxic goitres following surgery and unaltered in the group with thyrotoxicosis.


Lingual thyroid: a review of 12 cases.

Twelve patients with lingual thyroid are reviewed. Two of these patients had a follicular carcinoma in the ectopic gland and both are well 5 and 16 years after treatment. The diagnosis is essentially clinical but confirmation may be made with a thyroid scan. Six patients were treated conservatively with thyroxine with good results. Six patients were treated by surgical excision, 2 undergoing autotransplantation of the excised gland into the anterior abdominal wall.


Postprandial serum gastrin levels in patients with combined hypergastrinaemia and hyperchlorhydria.

We have determined the serum gastrin response to a standard test meal in 13 unoperated patients with combined fasting hypergastrinaemia (more than 150 ng/l) and basal hypersecretion of gastric acid (BAO more than 10 mmol/h). In 10 of 11 patients with proved of presumptive Zollinger-Ellison syndrome the peak postprandial rise in serum gastrin concentration was less than 50 per cent of basal value. The integrated gastrin response to feeding ranged from 71-9 to 211-8 mug/lX 150 min. In 2 patients with proved hypergastrinaemia of antral origin, however, serum gastrin rose to 223 per cent and 255 per cent respectively of basal value after ingestion of the meal. The integrated postprandial serum gastrin responses in these patients were 66-8 and 22-0 mug/lX 150 min. Two patiets with Zollinger-Ellison syndrome and total gastrectomy showed peak serum gastrin levels after feeding of 174 and 255 per cent of basal concentration. The integrated postprandial gastrin secretions were 365 and 366 mug/l X 150 min respectively. It is concluded that the serum gastrin response to feeding, when expressed as percentage change, may be helpful in the differential diagnosis of unoperated patients with fasting hypergastrinaemia and basal gastric acid hypersecretion.


Effect of epidural analgesia on metabolic profiles during and after surgery.

Blood concentrations of glucose, lactate, alanine, free fatty acids, glycerol and 3-hydroxybutyrate were measured during 24 h in 12 females undergoing elective hysterectomy under either general anaesthesia or epidural analgesia extending from T4 to S5. The results showed that the peroperative and immediate postoperative metabolic profiles in the group receiving general anaesthesia reflected substrate mobilization (increased glucose, lactate, 3-hydroxybutyrate), and that epidural analgesia blocked these changes, probably mediated through an inhibited adrenaline response to surgery. Peroperative values of free fatty acids and glycerol were significantly lowered by epidural analgesia, indicating inhibition of lipolysis. Alanine decreased similarly in both groups. In the later postoperative period metabolic profiles were similar in two groups, indicating that the influence of fasting may override the effect of the relatively minor trauma.


Prolonged post-vagotomy gastric atony treated by oxytocin.

Persistent and complete post-vagotomy gastric atony was treated in 3 patients by intravenous infusion of oxytocin. Despite failure of both conventional treatment with gastric aspiration and intravenous fluids or jejunal feeding, as well as the reported trials with bethanechol chloride and metaclopramide, these patients promptly responded to oxytocin. It appears that the latter may represent a solution to this uncommon but recalcitrant complication of peptic ulcer surgery.


Tracheal collapse after thyroidectomy.

Tracheal collapse after thyroidectomy is uncommon; when it occurs, complete airway obstruction is often sudden, unexpected and fatal. In this paper a patient treated for tracheal collapse by tracheostomy and followed up for 1 year is described and, from a review of the literature, a further 9 cases are presented. The aetiology of the condition, the patient at risk and the technique of management are discussed.


Autoparathyroidectomy: a case report.

This report describes a patient with primary hyperparathyroidism who became spontaneously normocalcaemic preoperatively. This was due to infarction in a parathyroid adenoma. Plasma parathormone (PTH) levels were monitored pre- and postoperatively.


Experiences with head injuries in a regional neurosurgical unit.

A review of all patients with major head injuries transferred to a regional neurosurgical unit for the years 1975 and 1976 has been carried out for comparison with the total number of patients with head injury admitted to district general hospitals of the region. Fifty-four per cent of patients admitted to the neurosurgical unit have resumed their old occupation and 20 per cent died. The significance of these figures is discussed, particularly in the light of the need for a more comprehensive policy for treating head injuries within the United Kingdom.


Carcinoma of the thyroid.

Total thyroidectomy with excision of any enlarged cervical lymph nodes was the usual operation practised for carcinoma of the thyroid in this series. Extended thyroidectomy afforded cures in some patients with locally advanced disease. Preoperative drill biopsy of the goitre was a useful procedure. Other noteworthy features were the increasing occurrence of papillary carcinoma and the comparatively high incidence of malignancy in solitary nodules.


Pyloric diaphragm, antral web, congenital antral membrane--a surgery rarity?

Three cases of pyloric diaphragm in elderly patients are reported. The finding of these patients within a 2-year period (1976-8) suggests that the condition is not as rare as previously thought. Diagnosis was achieved endoscopically and the condition managed surgically. While there has been controversy in the past over whether the disorder is acquired or congenital, the histological evidence of the cases presented here tends to suggest that it is a late presentation of a congenital abnormality.


Experience in the management of 50 consecutive penetrating wounds of the heart.

Fifty patients with penetrating wounds of the heart were grouped into three categories, based on the clinical severity of the injuries. Gunshot wounds consistently resulted in a higher mortality than knife wounds. Central venous pressure (CVP) was the single most important means of determining cardiac tamponade. The survival rates in the respective groups were 6, 79 and 100 per cent. The improved survival in our series was due to a rapid transportation system, increased awareness of the significance of cardiac injuries and an aggressive surgical approach.


Ingrowing toenails: the results of treatment.

Completed questionnaires were received from 208 patients on whom 245 operations for ingrowing toenails had been performed at King's College Hospital. Avulsion of a strip of nail had an 83 per cent recurrence rate, total nail avulsion 70 per cent, Zadik operations 28 per cent and wedge resections 29 per cent. It is recommended that immediate avulsion of ingrown toenails should not be a routine practice.


Solitary toxic adenoma of the thyroid gland.

The incidence of solitary toxic adenoma of the thyroid in a general surgical unit with an interest in thyroid disease has been reviewed over a 15-year period. Six hundred and thirty thyrotoxic cases were treated surgically, 35 (5.6 per cent) having a solitary toxic adenoma. Thyroid enlargement or toxicity had been present for more than 5 years in 7 patients (20.0 per cent). Cardiovascular complications were present in 6 cases (17.1 per cent). Thyroid lobectomy resulted in 30 (85.7 per cent) euthyroid and 5 (143.3 per cent) hypothyroid patients. One toxic adenoma contained a focus of carcinoma. The clinical features, diagnosis and management of solitary toxic adenoma, and the management of symptomatic nodules which are 'hot' but not biochemically toxic, are discussed.


A case of craniocleidal dysostosis presenting with vascular complications.

A case of craniocleidal dysostosis was presented. In spite of the skeletal abnormalities present, the disease was not diagnosed until the patient, a married woman of 63, developed ischaemia of her right upper limb, followed by cerebral symptoms. An arch aortogram demonstrated an occlusion of the first part of the right subclavian artery involving the origin of the vertebral artery and a post-stenotic dilatation of the left subclavian artery due to costoclavicular compression. Such vascular abnormalities have not been previously described in this condition.


Effects of stopping smoking for 48 hours on oxygen availability from the blood: a study on pregnant women.

The effects of stopping smoking for 48 hours on factors governing the availability of oxygen from the blood--that is, carboxyhaemoglobin (COHb), haemoglobin-oxygen (HbO2) affinity, and haemoglobin concentration--were measured in women in the last trimester of pregnancy. Three groups were studied: smokers, smokers who stopped smoking for 48 hours, and non-smokers. The 22 smokers had higher initial COHb values and greater HbO2 affinity than the 10 non-smokers, but their total haemoglobin concentrations were also higher, so that their oxygen availability was not significantly reduced. In the 11 smokers who stopped the reduction in COHb and decrease in HbO2 affinity led to a significant increase of 8% in "available oxygen" in 48 hours. Since even small improvements in oxygen delivery to the tissues may confer critical benefit to the fetus, particularly during labour or when exposed to general anaesthesia, smoking should be discouraged for 48 hours before elective deliveries. The same consideration might reasonably be applied to patients undergoing general anaesthesia for all elective operations.


Self-titration by cigarette smokers.

An 11-week crossover study was carried out in which 12 subjects smoked high-nicotine (1.84 mg standard yield) and low-nicotine (0.6 mg) cigarettes after an initial period of smoking their usual brands with a medium-nicotine yield (mean 1.4 mg). Plasma and urine nicotine concentrations, carboxyhaemoglobin (COHb) concentration, puffing behaviour, 24-hour cigarette consumption, and butt nicotine content were measured. The changes in plasma nicotine and blood COHb concentrations showed that the smokers compensated for about two-thirds of the difference in standard yields when switched to either high- or low-nicotine cigarettes. Thus, compared with the medium-nicotine brand, the intake of nicotine and carbon monoxide was only about 10% higher when subjects smoked the high-nicotine cigarettes, which had a standard yield 30-40% higher than the medium brands; and only about 15% lower when they smoked the low-nicotine cigarettes, which had a standard yield about 50% lower than the medium brands. But nicotine content and urine nicotine concentrations followed a similar pattern. Changes in puffing behaviour and in 24-hour cigarette consumption were only slight.The results show clear evidence of both upward and downward self-titration of nicotine and carbon monoxide (and tar) intakes when smokers change to cigarettes with standard yields that differ over the range studied.


Adverse reactions to frusemide in hospital inpatients.

Out of 2580 medical inpatients included in a drug-surveillance programme, 585 (22.7%) were treated with frusemide. Of these, 123 (21.0%) had a total of 177 adverse reactions. The most common were hypovolaemia (85 cases), hyperuricaemia (54), and hypokalaemia (21). Most reactions were mild, and only three patients had potentially life-threatening effects. The incidence of adverse reactions increased significantly with daily dose, occurring in 47 patients (13.5%) given up to 40 mg, 42 (26.3%) given up to 80 mg, and 34 (43.6%) given over 80 mg (P less than 0.001). There was no clear association between side effects and a raised blood urea concentration on admission, confirming that treatment with frusemide is not more hazardous in patients with renal failure. Frusemide is a safe and highly effective diuretic. Nevertheless, in view of the potential seriousness of volume depletion, dosage should probably begin at 20 rather than 40 mg daily.


Psychosocial stress in pregnancy and its relation to the onset of premature labour.

A modified life events inventory was presented over a four-month period to 132 consecutive women going into spontaneous labour in Hull and Manchester. Three study groups were identified according to the duration of pregnancy. The levels of psychosocial stress in pregnancy were found to be particularly high in the mothers whose babies were born preterm. Stressful events may precipitate preterm labour in some women. The concept of antenatal care may have to be broadened if the incidence of premature labour and resulting perinatal mortality are to be reduced.


Evaluation of the forced expiration technique as an adjunct to postural drainage in treatment of cystic fibrosis.

Sixteen patients with cystic fibrosis were treated with conventional physiotherapy aided by an assistant. The results were compared with those produced by physiotherapy using the forced expiration technique cleared more sputum in less time than conventional physiotherapy. A sputum in less time than conventional physiotherapy. A second study showed that an assistant did not further improve the results obtained by the patient performing the forced expiration technique himself. These findings mean that patients with cystic fibrosis who have had to rely on the help of others for their home treatment may now perform more effective treatment without help. The forced expiration technique might also be helpful for patients with chronic bronchitis, asthma, or bronchiectasis.


Referral of mothers and infants for intensive care.

During 1975-7, 96 mothers were referred to University College Hospital for delivery from 39 other hospitals because their pregnancies were considered to be at very high risk. One hundred of the 111 infants born to the 96 mothers weighed 2500 g or less and 60 weighed 1500 g or less. A high proportion of the infants developed serious illnesses necessitating intensive care. The birth-weight-specific neonatal mortality rates of the infants were much lower than those of infants born in England and Wales as a whole and were also lower than those of the 370 infants transported to this hospital for intensive care after delivery elsewhere. Whenever possible mothers with very high-risk pregnancies should be referred for delivery to centres with full facilities for the intensive care of the mother, fetus, and newborn infant.


Are increased individual susceptibility and environmental factors both necessary for the development of primary biliary cirrhosis?

A daughter, her mother, and an unrelated close friend developed primary biliary cirrhosis (PBC). The mother and the close friend nursed the daughter through her terminal illness and presented with PBC PBC within 21 months after her death. Half of the asymptomatic first-degree relatives in the two families had serum autoantibodies, including one with antimitochondrial antibody, suggesting some genetic susceptibility to abnormal immune reactions. It is concluded that some environmental factor may be present in PBC, perhaps in addition to a genetic susceptibility to that factor.


Meningococcal infections during infancy: confidential inquiries into 10 deaths.

The first 10 deaths from meningococcal infections in children aged under 2 years that were reported to a DHSS multicentre study were reviewed. Confidential inquiries were made of the parents, family doctors, health visitors, and hospital staff concerned with each case, and management was discussed with a paediatrician and pathologist. Diagnosis and treatment were often delayed because doctors did not realise the importance of the purpuric rash. One child died at home, and by the time they were admitted to hospital all the remaining nine were shocked and needed resuscitation. Prodromal symptoms, mainly changes in behaviour, preceded the rash in all cases. These prodromal symptoms should arouse the suspicion of septicaemia and prompt a search for petechiae so that early effective treatment may be started.


A unit for source and protective isolation in a general hospital.

An isolation unit consisting of 12 ventilated cubicles was investigated over 18 months. Out of 462 patients admitted, 262 (57%) required source and 200 (43%) protective isolation. Admissions of patients with staphylococcal sepsis fell from 16 in the first three months to six in the last three months. Staphylococcus aureus was recovered from 12% of nurses' fingers and often in small numbers from protective clothing and uniforms, but only two patients acquired a strain from a nurse or another patient. Gram-negative bacilli were rarely recovered from hands or protective clothing of nurses, and there was no evidence of spread of infectious diseases. This inexpensive unit, with simple but efficient isolation-nursing techniques, successfully prevented the spread of infection.


Alcoholism in the general hospital.

To assess the prevalence of alcoholism among people admitted to hospital 303 patients completed a drinking questionnaire. A total of 59 (19.5%) were found to have a drinking problem, which constituted a sixfold greater prevalence than recorded in a community survey using the same technique. The drinkers were mostly men and tended to be younger than the non-drinkers and to smoke more heavily, live in more crowded conditions, and be of lower social class. Significantly more of the drinkers had at least one parent who was an alcoholic. The results confirm that hospital inpatients comprise a larger proportion of alcoholics than found in the general population. Hence medical staff should be alert to such patients, so that treatment may be initiated at an early stage of social decompensation.


Optokinetic nystagmus and the accessory optic system of pigeon and turtle.

Optokinetic nystagmus (OKN) response functions were obtained in pigeon (Columba livia) and turtle (Chrysemys picta) before and after electrolytic lesions of the accessory optic nuclei (AON). Postlesion retinal input to the AON was evaluated using standard autoradiographic techniques. Bilateral destruction of AON in both pigeon and turtle did not abolish OKN, but was correlated instead with a reduction in OKN frequencies at high pattern velocities. A difference was observed between species with respect to the effects of partial lesions. Incomplete destruction of AON produced no observable change in OKN response functions in pigeon, but correlated with reduced OKN response functions in turtle. These results suggest that the AON mediate a portion of OKN in both pigeon and turtle, particularly at high pattern velocities, but are not essential for its occurrence.


Seaward orientation of hatchling turtles: turning systems in the optic tectum.

This paper reports studies on the mechanisms underlying seaward orientation in hatchling turtles. The particular aim was to investigate whether activity in different regions of the retina and associated tectal areas, as assessed by some comparator mechanism, results in turning in different directions. Hatchling green turtles (Chelonia mydas) were tested for sea-finding ability in a natural situation on the beach following lesions of the optic tectum. Asymmetrical bilateral lesions resulted in a number of turtles making circles in the direction of the tectum with the posterior lesion and in other turtles deviated in this direction. Bilaterally lesioned turtles were also slower and less consistent in their sea-finding behaviour. No major disruptions of sea finding were detected in animals with unilateral tectal lesions. By suspending lights in the nasal visual field of unilaterally blindfolded green and leatherback turtles (Dermochelys coriacea) it was possible to produce circling in the direction of the covered eye; in contrast, with the light suspended in the temporal field, turning was always in the direction of the uncovered eye. The results are consistent with the view that sea finding depends on a complex phototropotactic system with stimulation in different parts of a single retina being associated with turning in opposite directions.


Brain weight-body weight scaling in breeds of dogs and cats.

Autopsy data from 2,100 pet dogs are used to demonstrate that mean brain weight (y) in 26 breeds of dogs is related to mean body weight (x) by the function y = 0.39 x 0.27. Power functions with the exponent 0.27 appear to define intra-species brain-body weight scaling in several other species. These functions may serve as base lines for measuring increases or decreases in encephalization during species evolution. Curiously, averaged data from 1,250 domestic cats of 2 breeds can be plotted on a line with slope of 0.67, which is known to define inter- rather than intra-species brain-body weight scaling among mammals.


Indented synapses in Aplysia.

A new type of synaptic contact has been found in Aplysia californica, in which a post-synaptic spine extensively invaginates the pre-synaptic element. The post-synaptic spine, usually less than 0.25 micrometer in diameter, may protrude up to 2 micrometer into the pre-synaptic element. In some instances a larger post-synaptic element indents and forms multiple thin projections into the pre-synaptic varicosity. Along or at the end of these projections a zone occurs at which the surface membranes of the two apposed synaptic elements are rigidly parallel, and the extracellular gap is approximately 60% greater than normal and contains a small amount of electron-dense material. Synaptic vesicles are concentrated against the pre-synaptic membrane in these regions. There are twice as many vesicles per unit area positioned against the membrane at these zones than at similar active zones occurring in the alternative type of synapse, which has a flat, rather than indented, geometry. Single pre-synaptic varicosities have been found to form both flat and indented synapses. These findings raise the possibility that these two forms of synapse may be dynamic transformations of each other, having differing synaptic effectiveness.


Effect of polyamines on cell-free protein synthesizing systems from rat cerebral cortex, cerebellum and liver.

The naturally occurring polyamines spermine and spermidine stimulate in low concentrations the amino acid-incorporating activity of cell-free systems from cerebral cortex, cerebellum and liver from the rat to a significant degree, but in high concentrations they have strong inhibiting effects on these systems. Maximal polyamine stimulation is observed with suboptimal Mg2+ concentrations in the reaction mixtures; increasing Mg2+ to 15 mM results in an inhibition of cell-free protein synthesis by polyamines even at low concentrations. The stimulating effect of spermine and spermidine involves a facilitated binding of template RNA and aminoacylated tRNA to the ribosomes. In contrast, the aminoacylation of tRNA is not influenced. These data indicate that spermine as well as spermidine have regulatory functions during the translational process in cerebral cortex, cerebellum and liver. They seem to interact with ribosomal functions and to cause a shift in the optimal Mg2+ concentration required for the synthesis of brain and liver proteins.


Cholinergic neuronotrophic factors: I. Survival, neurite outgrowth and choline acetyltransferase activity in monolayer cultures from chick embryo ciliary ganglia.

Two key components of neural development and regeneration, survival of the involved neurons and elongation of neuritic elements, are likely to depend on the availability of an appropriate trophic drive to these neurons. At present, only one trophic factor, Nerve Growth Factor, is known to ensure both survival and neuritic growth for its target neurons. A search for a second such agent, a putative cholinergic neuronotrophic factor (CNTF), has been undertaken using as indicators neuronal survival, neurite outgrowth and choline acetyltransferase (CAT) activity in monolayer cell cultures. Eight-day chick embryo ciliary ganglia yielded two monolayer culture systems which appear to be well suited for a CNTF assay. Ciliary ganglionic dissociates, seeded on a highly adhesive collagen substratum, show no neuronal survival by 24 h if the medium is supplemented only with serum or chick embryo extract. However serum and embryo extract combined support survival of, and extensive neuritic outgrowth from, nearly the theoretical number of ganglionic neurons seeded. Alternatively, ciliary ganglionic neurons can be made to survive and produce a profuse neuritic outgrowth on polyornithine-coated dishes if supplied with medium conditioned over chick embryo heart muscle cultures, as already described by other laboratories. The two trophic sources differ markedly in their effects on the ganglionic neurons when tested on collagen or polyornithine substrata, and in some cases when different serum supplements are used. Neuronal survival, neurite production and, possibly, CAT activity appear to be subject to independent regulation. The culture systems used in this study can be developed into quantitative bioassays for the isolation of the different agents responsible for neuronal survival and neurite promotion, and for the investigation of their activities.


Evidence for a cholinergic influence on catecholaminergic pathways terminating in the anterior and medial basal hypothalamus.

Adult male Sprague-Dawley rats were given hourly injections of physostigmine for 1--4 h, and the effect of this treatment on dopamine (DA) and noradrenaline (NA) content or on DA and NA was estimated by measuring the decline in these amines produced following the inhibition of tyrosine hydroxylase with alpha-methyl-p-tyrosine (alpha MPT). In later experiments oxotremorine was administered instead of physostigmine at hourly intervals for 2 h. Physostigmine administration resulted in a highly significant increase in the depletion of NA produced by alpha MPT indicating that the turnover of NA was increased by this drug. This effect was observed in the medial basal hypothalamus and anterior hypothalamus but not in the telencephalon-thalamus. Oxotremorine also produced an increase in NA turnover, but this drug was effective in all three brain areas. Atropine pretreatment blocked the effect of both physostigmine and oxotremorine on NA turnover. However, in the case of physostigmine, atropine was only effective if it was given 30 min before each injection of physostigmine. Mecamylamine, a nicotine blocker, did not reverse the effect of physostigmine on NA turnover. These results suggest that there is a cholinergic input via muscarinic receptors which influences the activity of noradrenergic pathways terminating in the anterior or medial basal hypothalamus.


Immune lesions of central noradrenergic neurons produced by antibodies to dopamine-beta-hydroxylase.

(1) Intraventricular injection of antibodies to dopamine-beta-hydroxylase (DBH) caused degeneration of central noradrenergic nerve terminals in rats and guinea-pigs. In rats it was necessary to infuse exogenous complement in the form of guinea-pig serum together with the anti-DBH, whereas in guinea-pigs the anti-DBH was effective on its own. Control animals were infused with equivalent amounts of non-immune serum and complement and showed no signs of degeneration other than in the region of the needle tract. (2) There was a loss of varicosities in most terminal fields of the noradrenergic projections and swollen distorted axons were seen in both ascending and descending noradrenergic pathways. Noradrenergic cell bodies in the locus coeruleus and subcoeruleus appeared unaffected. No histochemical changes were observed in dopaminergic neurons. (3) The ultrastructural changes in degenerating axons that were first identifided by fluorescence histochemistry included swelling, vacuolation, accumulation of dense cored vesicles, lysosome-like bodies and smooth membranous sacs. The surrounding neuropil appeared normal. (4) There was a significant depletion of noradrenaline in all regions of the rat brain ranging from 20% in the hypothalamus to 80% in the neocortex. Dopamine concentrations were unaffected. (5) These observations provide a new approach to the production of selective lesions in specific neurotransmitter pathways that could be extended to non-adrenergic neurones. They may also be useful as a model for the study of autoimmune diseases of the nervous system.


The subcellular distribution of carnosine, carnosine synthetase, and carnosinase in mouse olfactory tissues.

The dipeptide, carnosine, its synthetic enzyme, carnosine synthetase, and its degradative enzyme, carnosinase, appear to be localized in the cytosol of mouse olfactory bulb and epithelium. Mouse olfactory bulbs and epithelium were prelabeled in vivo with [3H]carnosine following intranasal irrigation with [3H]beta-alanine. [3H]carnosine co-distributed in olfactory bulb with lactate dehydrogenase with only 10% in the crude mitochondrial fraction. Similar results were also seen with endogenous carnosine distribution. Over 70% of the carnosine present in the crude mitochondrial fraction was localized in synaptosomes following sucrose gradient centrifugation. However, further fractionation of vesicle containing fractions from osmotically lysed crude mitochondrial fractions indicated that [3H]carnosine was not associated with vesicles. Nearly 70% of all the [3H]carnosine present in olfactory epithelium was soluble with most of the remainder in the crude nuclear fraction. The enzymes carnosine synthetase and carnosinase were clearly soluble in olfactory epithelium with 98% and 85% of the activity in the cytosol. Less than 2% was found in the crude mitochondrial fraction. In olfactory bulb both enzymes also appeared soluble.


Deficits in luminous flux discimination by cats with lesions of the superior colliculus-pretectum.

(1) Intact cats and cats relearning or initially learning after bilateral ablation of the superior colliculus-pretectum were trained on a simple flux discrimination in a straight maze where the stimuli were either immediately side by side at the end of the runway or were separated by an opaque barrier. (2) After ablation of the superior colliculus-pretectum, each preoperatively trained cat had a significant deficit in retention of the luminous flux discrimination regardless of whether or not the stimuli were separated by a barrier or whether the correct stimulus was darker or lighter than the incorrect stimulus. (3) Under each of the different training conditions, every cat learning the flux discrimination initially after ablation of the superior colliculus-pretectum was retarded in comparison with intact cats. (4) The severity of the postoperative learning deficit correlated highly with the total extent of the lesion in the superior colliculus and pretectum.


The effects of L-dopa on dorsal horn cell responses to innocuous skin stimulation.

The effects of L-DOPA on responses of dorsal horn cells to innocuous mechanical skin stimulation were studied. Following intravenous administration of L-DOPA (10--40 mg/kg) to cats with intact spinal cords, dorsal horn cells, which could be activated by only innocuous or innocuous and noxious stimuli, demonstrated increased reponses manifested by an increase in the average number of spikes per stimulus, increased receptive field size and occasional changes in adequate stimuli. When cats with acute cord transections were studied, L-DOPA increased the responses of cells located in lamina 4 and those cells which responded only to innocuous stimuli; cells which responded to noxious stimuli and those located in other laminae had depressed responses following L-DOPA administration. The inhibitory effects of L-DOPA were in part abolished, in spinal cats, by pretreatment with parachlorophenylalanine, a serotonin depletor. Studies of dorsal cells in chronic spinal cats indicated that the effects of L-DOPA were largely dependent on functioning terminals of descending suprasegmental pathways. The conclusion was reached that descending noradrenergic pathways, indirectly, cause an increase in transmission from cutaneous afferents to dorsal horn cells and that some of the inhibitory effects of L-DOPA described by others are a manifestation of L-DOPA interactions with inhibitory serotonergic systems.


Conductance changes during bath application of beta-alanine and taurine in giant interneurons of the isolated lamprey spinal cord.

(1) Input conductances of giant interneurons in the isolated spinal cord of lampreys were measured with two separate intracellular electrodes. Bath applications of 0.4--3 mM beta-alanine and taurine produced large, reversible conductance increases which were Cl-dependent. (2) Strychnine at 1--2.5 microM might be a competitive antagonist of both amino acids, but had a stronger effect on taurine. Bicuculline and picrotoxin were weak antagonists of beta-alanine and taurine in some cells. (3) A few giant interneurons desensitized after repeated application of the amino acids, but most became more sensitive. Responses to the amino acids also increase at low temperatures in in Na-free fluid, suggesting effect of uptake mechanisms.


Tibialis anterior response to sudden ankle displacements in normal and Parkinsonian subjects.

It is well known that in Parkinsonian subjects with akinesia, reaction times are increased but reflex latencies remain normal. We have attempted to use this knowledge to distinguish between 'reflex' and 'voluntary' components of the electromyographic (EMG) response to ankle displacement. The EMG and torque responses of tibialis anterior (TA) to randomly applied servo-controlled plantar-flexing displacements of the ankle with and without the subject's intentional opposition were examined in 9 Parkinsonian and 9 age-matched normal humans. To obtain a measure of akinesia, the response latency to a visual stimulus was subsequently measured in the same subjects. Three principal findings emerged. (1) The intermediate latency EMG component (PSR) of the response evoked by ankle displacement with the subject instructed to relax was more regularly evoked and of lower threshold in Parkinsonians than in normals. This finding corresponds to the enlarged M2 component in upper limb muscles. However, the facilitation of PSR was not found to be associated with an increase in torque. In fact, the patients did not exhibit more stiffness than normals under our experimental conditions. (2) Mean latency estimate of the PSR was indistinguishable between Parkinsonians and normals. This finding puts the PSR in the nature of a reflex. Indeed, in accordance with reflex behaviour which is proportional to input characteristics, its area increased linearly with increase in the magnitude of displacement velocity. (3) In contrast, the 'late' EMG response (FSR) evoked by opposing sudden ankle displacement exhibited a significantly longer latency in 6 out of 8 Parkinsonians than normals. In the same patients, the EMG response latency to a visual signal was similarly increased. The delay of FSR in akinesia patients thus argued against its being a stereotyped reflex. The result is discussed with reference to the recent finding that preprogrammed responses are delayed in Parkinsonians.


Spinal projections from the lower brain stem in the cat as demonstrated by the horseradish peroxidase technique. I. Origins of the reticulospinal tracts and their funicular trajectories.

Using a retrograde tracer technique with horseradish peroxidase (HRP) attempts were made to determine the origins of reticulospinal tracts and their funicular trajectories. Reticulospinal tracts originating from the mesencephalic reticular formation (RF) were composed of: (1) descending projections arising from the cluster of cells located just lateral to the periaqueductal gray that course in the anterior funiculus (AF) and ventral part of the lateral funiculus (LF) with ipsilateral predominance; and (2) projections from the cluster of cells located dorsal to the brachium conjunctivum that course in the ipsilateral LF. Origins of the pontine reticulospinal tracts arising from the n. reticularis pontis oralis (Poo) have been divided qnto three parts: (1) medial one-third; (2) middle; and (3) ventrolateral. The axons from the medial part descend ipsilaterally via the medial part of the AF, while the axons from the ventrolateral part of the Poo give rise to diffuse descending projections in the AF and LF. The middle part of the Poo has been further subdivided into: (1) dorsal part that gives rise to spinal projections ipsilaterally in the ventrolateral funiculus (VLF); and (2) ventral, particularly its upper part, whose axons descend bilaterally via the DLF. Origins of reticulospinal tracts from the n. reticularis pontis caudalis (Poc) could be divided into three parts: (1) medial; (2) dorsolateral; and (3) ventrolateral. The medial part of the Poc is a source of axons via the medial part of the ipsilateral AF, while the ventrolateral part of the nucleus is a source of axons via the contralateral LF. The spinal projections from the dorsolateral part of the Poc appears to course diffusely in the AF and LF, but with DLF predominance. The n. reticularis gigantocellularis (Gc) was found to be a main medullary source of the spinal projections in the ipsilateral AF, while n. reticularis magnocellularis (Mc) is the major source of the fibers coursing ipsilaterally in the VLF. The most medial part of the Mc descends ipsilaterally via the medial part of the AF, while the ventrolateral part of the nucleus together with the n. reticularis lateralis of Meesen and Olszewski descends ipsilaterally via the DLF. It has also been found that the axons from the n. reticularis paramedianus pass via both the AF and LF with ipsilateral predominance, while the n. reticularis dorsalis and ventralis course via the LF with ipsilateral predominance.


The regression of synapses formed by a foreign nerve in a mature axolotl striated muscle.

A study has been made of the factors which determine that the terminals of a foreign flexor nerve at synaptic sites in a unrodele extensor muscle regress on return of the original extensor nerve. The quantal content (m) of the endplate potential (EPP) at flexor nerve terminal synapses, during innervation of a previously denervated extensor muscle, increased in about 8 weeks to reach the same size as at normal extensor nerve terminals; the same time was taken for m to reach normal size at extensor nerve terminals when these reinnervated their own muscle. At flexor nerve terminals, m decreased eventually to zero if the extensor nerve terminals returned within about 6 weeks of synapse formation by the flexor nerve terminals to the same or an immediately adjacent synaptic site to that occupied by these terminals. During this decrease in m at flexor nerve terminals, stimulation of the flexor nerves in the presence of horseradish peroxidase (HRP) showed HRP-labelled flexor nerve terminals present only in those regions of the extensor muscle in which the electrical signs of flexor nerve terminals were observed, indicating that the decrease in m at regressing flexor terminals was accompanied by their vacating synaptic sites. However, flexor nerve terminals failed to regress from the extensor muscle on return of the original nerve supply if the flexor nerve allowed to form synapses for more than about 10 weeks before the return of the extensor nerve.


Intracellular analysis of the development of responses of caudate neurons to stimulation of cortex, thalamus and substantia nigra in the kitten.

Intracellular recordings were made from caudate neurons in anesthetized kittens of 2-72 days of age. In adult cats, results of intracellular recordings indicate that caudate neurons respond most frequently to stimulation of their major afferents from cortex, thalamus and substantia nigra with a sequence of excitation followed by inhibition (EPSP-IPSP sequence). The results of the present study show that the prominent IPSP of this sequence is not well developed in young kittens and does not reach adult values in terms of frequency of occurrence until beyond 40 days of age. Amplitude and duration of the IPSP evoked by cortical stimulation also did not reach adult values until beyond 40 days of age. In contrast, EPSPs can be evoked in the youngest kittens by stimulation of afferents to the caudate. These findings suggest that the caudate nucleus may alter its role during development. In early postnatal periods it functions as a simple relay system transmitting incoming information to its outputs in a relatively unaltered fashion. Later in development it becomes a system capable of complex modulation and filtering of neural information.


The organization of the efferent projections of the substantia nigra in the rat. A retrograde fluorescent double labeling study.

The organization of three of the efferent projections of substantia nigra has been investigated in rat by means of combined injections of two fluorescent retrograde tracers: red fluorescent Evans Blue and blue fluorescent DAPI-primuline mixture. First the distributions of the retrogradely labeled neurons in substantia nigra after injections of each of the two tracers in the striatum, thalamus and superior colliculus were compared with the distributions of the retrogradely labeled nigral neurons after HRP injections in these same structures. The findings in these sets of experiments were the same. This indicates that the two fluorescent retrograde tracers are as effective as HRP in tracing the efferent fiber connections of the substantia nigra. Subsequently the retrograde labeling of the substantia nigra neurons was studied after combined injections of the two fluorescent retrograde tracers in two of the above structures, in different combinations. In these experiments both single labeled neurons fluorescing either red or blue, as well as double labeled neurons fluorescing both red and blue were found. Double labeled neurons were present only in pars reticulata and occurred only after injections of the two tracers in thalamus and superior colliculus respectively. From this it has been concluded that in rat the various efferent projections from the substantia nigra are mainly derived from different neurons, but that at least part of the neurons which distribute fibers to superior colliculus also distributes collaterals to the thalamus.


Permeability of the blood-brain barrier to mannitol in the rat following 2450 MHz microwave irradiation.

The radiotracer method of Oldendorf was used to determine if 2450 MHz continuous wave (CW) microwave energy increases blood-brain barrier permeability to [14C]mannitol, which is normally excluded from entering the brain. Anesthetized, adult rats were irradiated singly for 30 min in the quiet zone of an anechoic chamber, at average power densities from 0.1 to 30 mW/sq.cm. Afterwards each rat received an intracarotid bolus injection of [14C]mannitol/[3H]water mixture and was decapitated 15 sec later. Uptake of [14C]mannitol relative to the highly permeable reference substance, [3H]water, was calculated as the brain uptake index (BUI) for 4 brain regions. Mean BUI values for tissues from the microwave-irradiated rats did not differ significantly from sham-irradiated animals, and a microwave influence on barrier permeability was not evident. Irrespective of treatment, BUI values for cerebellum and medulla were much higher and more variable than values for cortex or diencephalon, and were associated with reduced absorbance or retention of [3H]water. Because of a compromising influence of the vertebral arterial supply on the distribution of intracarotid-injected radiotracers, BUI measurements in caudal brain regions are probably unreliable unless accompanied by data on regional radioisotope concentrations. The absence of such data in an earlier BUI study, suggests that increases in BUI for cerebellum and medulla attributed to microwaves were possibly misinterpreted as differences in barrier permeability to [14C]saccharides, when in fact changes in blood flow and [3H]water influx or egress were responsible.


Compartments of tubulin and tubulin-like proteins in differentiating neubroblastoma cells.

Cytoplasmic, tubular and particulate fractions of differentiating neuroblastoma cells were prepared and the tubulin together with tubulin-like proteins was measured in each cell fraction during different stages of cell differentiation. In undifferentiated cells, 73%, 5% and 22% of the tubulin and tubulin-like proteins were contained in the cytoplasmic, tubular and particulate fractions, respectively. After 5 days of differentiation, the overall content of tubulin and tubulin-like proteins had increased by 73%. This corresponded to increases of 45%, 145% and 100% in the cytoplasmic, microtubular and particulate fractions, respectively. The increase in membrane-bound (particulate) tubulin and tubulin-like proteins was significantly greater than the total increase of proteins in the particulate fraction. Polyacrylamide gel electrophoresis of the proteins in each subcellular fraction revealed the presence of protein bands corresponding to the alpha and beta subunits of tubulin. Whereas these bands indicated equal amounts of protein in the alpha and beta positions for the tubular and particulate cell fractions, an analysis of the cytoplasmic fraction revealed much more protein migrating to the alpha-tubulin position than to the beta-tubulin position, especially during cell differentiation. Furthermore, two overlapping but distinct protein bands were demonstrable in the position of the alpha-tubulin from the cytoplasmic fraction. These bands were designated alpha 1 and alpha 2. The particulate fraction contained only the alpha 1 and the tubular fraction only the alpha 2 protein band. The addition of 1 mM dibutyryl cyclic AMP to the neuroblastoma cells, at the time when the serum was withdrawn, enhanced the rate of differentiation and the redistribution of tubulin and tubulin-like proteins within the 3 cellular compartments. These results are discussed as they relate to the regulation, biosynthesis, turnover and compartmentation of tubulin and tubulin-like proteins in differentiating neuroblastoma cells.


Tactile neurons of the superior colliculus of the cat: input and physiological properties.

Neurons in the strata intermediale and profundum of the cat superior colliculus (SC) previously have been shown to be organized somatotopically and to respond to tactile stimuli. The stimulus properties required for neuronal activation suggest that these neurons are excited by inputs from selected classes of high-velocity, sensitive cutaneous mechanoreceptors, and that stimulus-response relationships indicate only a narrow range of information concerning stimulus magnitude. The properties of these neurons have been interpreted as serving a role in stimulus detection that recovers slowly and may be best suited for directed attention and orientation behavior. The input to the SC was studied by injection of horseradish peroxidase (HRP) for retrograde labeling of neurons projecting to this region. The main inputs subserving the tactile pathway are the principal trigeminal nucleus and the rostral portion of the spinal V subnucleus oralis and the main cuneate nucleus. Sparser labeling was found in other somatic relays, including the gracile and lateral cervical nuclei and posterior portion of the spinal trigeminal complex. Several other projections relating to visual mechanisms are also described.


Influence of midbrain stimulation on the excitability of neurons in the medial hypothalamus of the rat.

Extracellular action potentials were recorded from 1098 neurons in the medial hypothalamus of pentobarbital anesthetized male rats. Their excitability was analyzed after single 1 Hz stimulation of the midbrain periaqueductal gray (PAG) or adjacent reticular formation. Cells were also examined for their response to median eminence (ME), amygdala, lateral septum (LS) or anterior hypothalamic/preoptic area (AHA/POA) stimulation. Antidromic invasion from midbrain stimulation was recorded from 110 neurons. Eight of these neurons showed features of axon branching and displayed antidromic invasion from both midbrain and amygdala (2 cells) or AHA/POA (6 cells). Many neurons with midbrain projections displayed orthodromic responses to stimulation in the amygdala, but few responded to AHA/POA or LS stimulation. Midbrain stimulation evoked orthodromic responses from 99 medial hypothalamic neurons. Many of these cells also displayed orthodromic responses to amygdala or AHA/POA stimulation, whereas a small number were activated antidromically by stimulation in these sites. None of 42 neurons activated antidromically from median eminence stimulation were responsive to midbrain stimulation. These results provide electrophysiological evidence of reciprocal connections between medial hypothalamic and medial midbrain areas, and indicate that medial hypothalamic neurons with midbrain connections are subject to influences from other extrahypothalamic areas.


Release of [3H]serotonin and its binding protein from enteric neurons.

The release of [3H]5-HT and its binding protein, SBP, from the guinea pig enteric nervous system was analyzed. Release of both [3H]5-HT and [3H]NE from strips of longitudinal muscle with adherent myenteric plexus preloaded with the respective radioactive amine was evoked by high K+ and the ionophore X537A. However, Ca2+-dependence could not be shown for [3H]5-HT release by either agent or for [3H]NE release by X537A. However, Ca2+-dependence (as well as inhibition of release by high Mg2+ and tetrodotoxin) could be demonstrated for the release of radioactivity evoked by electrical field stimulation of everted segments of ileum preloaded by perfusion through the serosal lumen with [3H]5-HT. Light and electron microscopic radioautography revealed that the sources of released radioactivity were axons, especially axonal varicosities containing a mixture of small clear and large dense-cored vesicles. SPB, but not the cytosol marker protein, lactic dehydrogenase, was spontaneously released from the perfused everted ileum. A marked increase in SBP (but not LDH) release was provoked by electrical field stimulation at 10 Hz, and this increased release (but not the spontaneous release) was Ca2+-dependent. It is concluded that SBP and 5-HT are probably stored together, at least in part in vesicles, and that both can be released by exocytosis from depolarized axon terminals.


Effect of midbrain raphe lesion or 5,7-dihydroxytryptamine treatment on the prolactin-releasing action of quipazine and D-fenfluramine in rats.

The role of brain serotonin in regulating prolactin (PRL) secretion has been investigated by studying the effect of quipazine and D-fenfluramine, two serotonin-like drugs, on plasma PRL levels under various experimental conditions. Quipazine (5, 10 and 20 mg/kg i.p.) and D-fenfluramine (5, 7.5 and 10 mg/kg i.p.) induced dose-related increases in plasma PRL levels in male rats. Intraventricular injection of 5,7-dihydroxytryptamine (5,7-DHT) or electrolytic lesion of the nucleus raphe medianus (MR), which caused a marked and selective depletion of hypothalamic serotonin levels, significantly reduced the PRL-releasing effect of both quipazine and D-fenfluramine. These results suggest that the effect of these drugs on PRL release is mediated through a serotonergic mechanism in the brain.


L-[3H]Carnosine binding in the olfactory bulb. II. Biochemical and biological studies.

During the first 10 days after peripheral deafferentation of the mouse olfactory bulb stereoselective binding of L-[3H]carnosine declines markedly. The initial phase of this decline is due to a decrease in binding site stereoselectivity, which is then followed by a loss of assayable binding sites. The specificity of inhibition of L-[3H]carnosine binding by various peptides is also altered after denervation. Competitive inhibitors of carnosine binding become less potent after denervation, while analogues which are not competitive inhibitors remain equipotent before and after denervation. Several carnosine analogues that are normally poor inhibitors become more potent after denervation. Treatment of bulb membranes with trypsin, RNase and hyaluronidase, but not DNase or collagenase, resulted in significant alterations in carnosine binding. L-, but not D-carnosine, protected the binding site from trypsin digestion, and induced additional binding in bulb membranes in a dose-and temperature-dependent fashion. Preincubation of membranes with L-carnosine also led to the induction of additional carnosine binding in membranes from cerebral cortex, cerebellum and deafferentated bulbs but not from muscle. Bulbs from newborn mice contain about one-half of the adult levels of binding and no significant sex differences in carnosine binding were detected in bulbs from adult rats. L-[3H]carnosine binding was two-fold higher in the anterior compared to the posterior portion of the bulb, but there were no significant differences in binding of opiate, GABA, alpha-adrenergic, muscarinic cholinergic, benzodiazepine of glutamic acid receptor ligands.


Ribosomal RNA in Mauthner axon: implications for a protein synthesizing machinery in the myelinated axon.

RNA was extracted from myelin-free Mauthner axons of the goldfish on a microscale and fractionated by microelectrophoresis. Microextracts showed the presence of nominal 26 SE, 18 SE, 5 SE and 4 SE components, which co-migrated with rRNA from fish brain. In addition, a non-ribosomal 15 SE component was present in axon microextracts, but not in RNA extracts of fish brain or of myelin sheath from Mauthner axon, indicating an unusual enrichment of a putative mRNA class. Evidence was presented to support the contention that axonal rRNA was not due to contamination from the myelin sheath. Possible reasons for the lack of ultrastructural evidence for axoplasmic ribosomes are discussed.


Increase of large intramembranous particles in the presynaptic active zone after administration of 4-aminopyridine.

The effects of 4-aminopyridine (4-AP, 1 mg/kg i.v.) on the distribution of intramembranous particles in spinal motoneuronal synapses was examined in anesthetized (pentobarbital sodium, 50 mg/kg, i.p.) rats by freeze-etching electron microscopy. The particles were classified according to their size into small (4.2--10.5 nm in diameter) and large (10.5--18.9 nm in diameter). The active zone of the presynaptic membrane was identified on the basis of ultrastructural criteria. The large intramembranous particles in both protoplasmic (PF) and external fracture faces (EF) were aggregated more densely in the active zone as compared with its surroundings both in the control and 4-AP-treated group (P less than 0.001). The density of large particles in the PF rose from 300/sq.micron under the influence of 4-AP (P less than 0.001). The increased frequency of vesicle attachment sites at the presynaptic membrane (from 115/sq.micron in barbiturized controls to 150/sq.micron in 4-AP treated animals) seemed to be positively correlated with the increasing density of large particles. Based on these findings it is suggested that the large intramembranous particles of the presynaptic membrane may participate in the control of calcium fluxes which are essential to the transmitter release by exocytosis.


Involvement of catecholaminergic nerve fibers in angiotensin II-induced drinking in the Japanese quail, Coturnix coturnix japonica.

Monamine distribution in a septohypothalamic area was investigated in the Japanese quail using a histochemical fluorescence method. This area includes the subfornical organ (SFO) and the preoptic area (POA) which are inferred dipsogenic receptor sites for angiotensin II (AII) in the Japanese quail. Nerve fibers showing yellow-green fluorescence were found between the POA and the SFO. Thwy traversed from the POA to the SFO, and some fibers seemed to terminate on the neurons in the SFO. After a low dose of reserpine, a considerable number of fluorescent perikarya were found in the POA. These fibers and perikarya appeared to be of primary catecholamine judging from the fluorescence color. Following transection of these fibers, fluorescence disappeared from the fibers located on the SFO side of the transection plane, while it became a little more intense on the POA side. After transection, microinjection of AII into the POA was no longer effective in induction of drinking. On the other hand, sham operation or transection in areas other than between the POA and the SFO produced only minute changes in those fluorescent fibers and had little effect on the dipsogenic potency of AII injected into the POA. These results suggest that information of AII perceived at the POA is transferred to the SFO via those primary catecholamine-containing nerve fibers, which effect induced drinking.


Pineal N-acetyltransferase and hydroxyindole-O-methyltransferase: control by the retinohypothalamic tract and the suprachiasmatic nucleus.

The visual pathway and central neural structures involved in the photic and endogenous regulation of the activity of pineal N-acetyltransferase and hydroxyindole-O-methyltransferase were investigated. The results indicate that the visual pathway regulating both enzymes is the retinohypothalamic tract, and that the inferior accessory optic tract is clearly not involved in the regulation of hydroxyindole-O-methyltransferase activity, as has been previously thought. In addition, the suprachiasmatic nucleus was found to be necessary for the generation of a rhythm in N-acetyltransferase activity in blinded animals, and to be responsible for the tonic elevation of hydroxyindole-O-methyltransferase activity in blinded animals. Finally, it was concluded that the rapid and large daily changes in N-acetyltransferase activity seen in a normal lighting cycle and the much slower and smaller changes in hydroxyindole-O-methyltransferase activity seen only after weeks in constant lighting conditions are mediated by the same neural tract; the different time courses of the effects of environmental lighting may be explained on the basis of different intracellular regulatory mechanisms.


Radiometric assessment of experimental autoimmune encephalomyelitis in mice.

The cell-mediated inflammatory component of experimental autoimmune encephalomyelitis (EAE) in mice is measured by the radioisotopic technique. Mice are challenged with autologous spinal cord homogenate in Freund's complete adjuvant and at various time intervals after such immunization given [125I]5-iodo-2'-deoxyuridine which is incorporated into the mononuclear cell pool. The degree of cell-mediated inflammation is determined by radiometry of the brain and spinal cord tissues. Increased radiolabelling is detected in the brains 2 days prior to the onset of clinical signs of EAE; increased radioactivity of the spinal cord is concomitant with clinical signs. This technique is useful in staging the extent of EAE and may prove to be a powerful tool in studying cell-mediated reactions in other autoimmune diseases.


Reflex oral activity in decerebrate rats of different age.

Rats decerebrated at different ages (4 days to greater than 100 days) were tested for a rhythmic reflex 'suckling' response and for a simple digastric reflex. The ease with which the 'suckling' response could be elicited decreased with increasing age; the time course of this change approximated to that of changing characteristics of the digastric reflex. The mean latency of the simple reflex response decreased non-linearly from 70 msec in the 4 day postpartum animal to 5 msec in the adult animal; the duration of the response also decreased from 25 msec to 10 msec but this change took place mainly between 8 and 15 days postpartum. The latency of the digastric response also shortened in animals decerebrated on day 4 and kept for 2 days. It was concluded that the observed changes in the digastric reflex occurred independently of encephalic structures.


Partial purification and characterization of neutrophic substance affecting tetrodotoxin sensitivity of organ-cultured mouse muscle.

From mouse spinal cord homogenate, we isolated a trophic substance which reverses the post-denervation decrease in tetrodotoxin sensitivity of action potential in organ-cultured extensor digitorum longus muscle of mouse and characterized its physicochemical properties. The trophic substance was separated from macromolecules in homogenate by gel filtration on Biogel P2 column. The partially purified trophic substance was heat-stable, acid-stable and alkaline-labile. The trophic activity was destroyed by lyophilization at neutral pH but not at acidic pH. The trophic activity was abolished by incubation with pronase or leucine aminopeptidase, but not by trypsin, chymotrypsin, thermolysin or carboxypeptidase A. The trophic substance passed through an ultrafiltration membrane UM10 freely. A small part of the trophic activity passed through a UM2 or UM05, and the rest was retained on the membranes. The trophic substance adsorbed on CM-Sephadex at pH 7.2 but passed through DEAE-Sephadex at pH 8.4. These results suggest that the trophic substance regulating tetrodotoxin sensitivity of action potential in mouse skeletal muscle is a peptide with a rather low molecular weight of less than 10,000 and that while the N-terminus of the peptide is free, the C-terminus is probably blocked. This peptide differs from other trophic substances reported previously by other investigators.


Fate of presynaptic afferents to Purkinje cells in the adult nervous mutant mouse: a model to study presynaptic stabilization.

The hemispheric cerebellar cortex from 174- to 420-day-old nervous mice has been studied with Golgi, Cajal-reduced silver and electron microscopic techniques. In all mice, the existence of a continuous process of Purkinje cell death, indicated by the presence of few of these neurons in early stages of degeneration, has been established. The morphology of such degenerating cells, as well as the removal of the necrotic debris and the consecutive isolation of presynaptic fibers by glia are described. In the molecular layer, and in spite of the important Purkinje cell loss, numerous varicosities belonging to parallel fibers persist. They can be either synapsing on interneurons or concentrated in small clusters of 2-10 boutons covered by astrocytic processes. The synaptic investment of stellate and basket cells, as well as the length and the branching pattern of their dendritic fields are not significantly changed, besides the increase in afferent terminals deprived of their postsynaptic targets. Basket formations, as numerous as in control cerebellum, are forming a discontinuous row at the superficial third of the granular layer. Over 90% of these baskets are devoid of Purkinje cells, however, their ultrastructural features mimic those of the same terminals in control mice, with the exception that few of them can either establish heterologous synapses with granule cell dendrites, or develop gap junctions between them. The significance of the persistence of normal looking presynaptic elements long time after deprivation of their postsynaptic targets is discussed in relation to the role that function can play in the stabilization of synaptic contacts.


The effect of collateral sprouting on the density of innervation of normal target sites: implications for theories on the regulation of the size of developing synaptic domains.

The 'commissural' innervation of the dentate gyrus molecular layer has been analyzed in normal adult rats and in those in which the ipsilateral entorhinal cortex had been removed by aspiration at 14 days post-natal. This ablation severely deafferents the distal two-thirds of the molecular layer and induces 'sprouting' by the commissural afferents which are normally restricted to the more proximal dendritic zone. It was the objective of the present study to employ quantitative electron microscopy to determine (1) the extent of synaptic recovery in the deafferented field; (2) the magnitude of the contribution by the commissural fibers to the reinnervation of the deafferented field; and (3) if sprouting by the commissural projections causes a reduction in the density of the terminal field they generate in their normal target region. The synaptic density of the neonatally deafferented middle molecular layer was found to have returned to near control levels by adulthood. Degeneration studies performed in the adult revealed that commissural endings were located in equivalent numbers in the inner and middle molecular layers of rats in which the entorhinal cortex had been removed at 14 days post-natal; in normal rats (i.e. no neonatal surgery) the commissural terminals were found only in the inner molecular layer. Furthermore, and most importantly, the density of commissural terminals in the inner molecular layer was virtually identical in the 'sprouted' and control rats. Thus the tremendous areal expansion of the commissural terminal field which occurs after early deafferentation of the distal parts of the granule cell dendrites was not accompanied by any loss of input to the normal target of this afferent. Therefore, sprouting in this system represents an exaggeration of normal growth rather than a redistribution of a fixed population of endings. The relevance of these findings to theories concerned with the regulation of axonal growth and terminal proliferation during development is discussed.


Evidence for the existence of inhibitory postsynaptic potentials in dendrites and their functional significance in hippocampal pyramidal cells of adult rabbits.

(1) Hyperpolarizing potentials were studied in hippocampal pyramidal cells of normal, adult rabbits, anesthetized with Nembutal and, in addition, curarized. (2) Single shock stimulation of the fornix produced in these cells long-lasting hyperpolarizing potentials (400-2000 msec). As a rule, the early part of these potentials (about 200 msec from the onset) was influenced by the diffusion of Cl ions into the cell and current injections, whereas their late part was not. The early part exhibited impedance changes whereas the late part did not. From these results it was concluded that the former was the inhibitory postsynaptic potential (IPSP) occurring in the soma while the latter originated in the dendrites. Evidence was obtained suggesting that the latter was also a Cl-mediated IPSP. The hyperpolarization elicited in these cells by mesencephalic stimulation was similar in properties to the latter. (3) Disfacilitation in the dendrites and the functional significance of the dendritic IPSP were discussed.


Sodium outflux and influx within nerve terminals from chronic epileptogenic foci.

The Na+-pump (oMpNa) or maximal sodium outflux inhibited by ouabain was studied in nerve terminals isolated from the primary and mirror epileptogenic foci of freezing lesions. In addition, the Na+ for Na+ exchange diffusion that is sensitive to ethacrynic acid and furosemide was also analyzed. oMpNa in control and epileptogenic states had similar and indistinguishable activation curves for K0 (extracellular K) in a sodium medium except for a two-fold difference in magnitude. However, the apparent affinity of the Na+-pump for K0 as measured by K1/2 was shifted to the right or decreased in epileptogenic foci (2 mM K0 compared to 0.5 mM in controls) when measured in a magnesium medium. A decrease in the apparent affinity for internal sodium was also observed. Of the total sodium outflux (67.7 nmol/mg/min), Na+ movements which are insensitive to ouabain and external K+ but stimulated by external Na+ and inhibited by furosemide and ethacrynic acid (20 nmol/mg/min or 32% of sodium outflux) represented the Na+ for Na+ exchange diffusion in nerve terminals. Na+ influx rising with increasing internal sodium in the presence of ouabain and blocked by furosemide represent the corresponding inward Na+ movement. No differences were observed between controls and epileptogenic states.


The postnatal development of functional properties of central vestibular neurons in the rat.

The postnatal development of the responses of rat central vestibular neurons to horizontal angular acceleration was studied in the time and frequency domain. The resting discharge was very low and irregular during the first postnatal days, increased gradually and became more regular throughout the first month and reached adult values approximately by the end of the first month. The relative distribution of type I and type II units was the same in all age groups. Threshold for frequency increase to angular acceleration and sensitivity of unit responses became lower and higher, respectively, as time elapsed after birth. Adult values were reached approximately by the end of the first month. There was a slight tendency towards shorter time constants and smaller phase lags in one-month-old animals when compared with the younger animals. The results are discussed in conjunction with similar work performed in vestibular afferents and correlated with known morphological and behavioral studies.


Synapses as associative memory elements in the hippocampal formation.

This report analyzes long term potentiation (LTP) and associative interactions between synapses of the ipsilateral and crossed entorhinal cortical (EC) pathways to the dentate gyrus (DG). In the anesthetized rat, conditioning stimulation to one EC-DG pathway reliably elicits LTP at the ipsilateral synapses, while the synapses of the collateral, crossed pathway to the contralateral DG do not exhibit LTP. Furthermore, in the DG ipsilateral to the conditioning stimulation the convergent crossed pathway from the contralateral side, which had not been itself conditioned, failed to exhibit heterosynaptic LTP. These results are consistent with a specific 'synaptic' localization of the changes responsible for LTP, and suggest that some critical number of synapses must be activated in order to observe LTP. While the crossed EC-DG projection never exhibited LTP when conditioned alone, the crossed input could be potentiated under certain circumstances. Specifically, paired conditioning of ipsi- and contralateral inputs by nearly simultaneous conditioning stimulation of the EC bilaterally results in LTP in the crossed system. Furthermore, this associatively induced LTP of the crossed system can be reversed by subsequent conditioning of the ipsilateral system alone. Successive potentiating and depotentiating sequences are possible using paired and non-paired stimulation procedures even after lesions which prevent neural loops through the EC. The results are interpreted as evidence for a 'Hebb' type synapse which has the capability for erasure. This synaptic type is not appropriate for classical conditioning without appendant circuitry, but is suited for other forms of associative learning.


Release of immunoreactive alpha-MSH by synaptosome-enriched fractions of homogenates of hypothalami.

Immunoreactive alpha-melanocyte-stimulating hormone (alpha-MSH) was found to be concentrated in a synaptosome-enriched fraction prepared by differential centrifugation of rat hypothalamic homogenates. The release of the hormone from this preparation was investigated. After incubation, the synaptosomes were isolated by ultrafiltration and alpha-MSH in the ultrafiltrate was determined by radioimmunoassay. Particle-bound alpha-MSH, recovered by extraction with acid ethanol, and alpha-MSH released from the synaptosome preparation, were immunologically similar to synthetic alpha-MSH and had an accompanying melanotropic activity. Less than 10% of the particle-bound alpha-MSH was released during incubation in 0.32 M sucrose. However, in the presence of 2 mM Ca2+, alpha-MSH release increased with increasing concentrations (30-150 mM) of K+. The stimulatory effect of 60 mM K+ was complete within 2 min and was potentiated by increasing Ca2+ concentrations over the range of 0 to 2 mM. K+-induced release of alpha-MSH was independent of temperature from 1 to 30 degrees C, and neither glucose (10 mM) nor dopamine (10(-10)-10(-2) M) had any effect on the release of the peptide. It is concluded that a synaptosome-enriched fraction from the hypothalamus contains a releasable pool of immunoreactive alpha-MSH that is mobilized by depolarizing concentrations of K+ in a Ca2+-dependent manner.


Symmetric bilateral changes in dopamine release from the caudate nuclei of the cat induced by unilateral nigral application of glycine and GABA-related compounds.

The release of [3H]DA synthesized from [3H]tyrosine was estimated in the two caudate nuclei (CN) during the unilateral nigral application of glycine and GABA-related compounds in 'encéphale isolé' cats using push-pull cannulae. Glycine (10(-5) M) reduced the release of [3H]DA in both CN and these effects were antagonized by strychnine (10(-5) M). A decrease in [3H]DA release was also seen in both CN during the unilateral nigral application of diazepam (10(-5) M). In contrast, muscimol (10(-6) M) and GABA (10(-5) M) stimulated [3H]DA release on both sides. The effect of GABA was blocked by picrotoxin (10(-5) M). Picrotoxin alone stimulated the release of [3H]DA in the ipsilateral CN and was without effect in the contralateral side. Bicuculline (10(-5) M) stimulated [3H]DA release only in the contralateral CN. A symmetric increase in [3H]DA release in both CN was also observed during the unilateral nigral application of potassium (30 mM). A model involving a facilitatory polysynaptic pathway originating from the substantia nigra (SN) and acting presynaptically on ther terminals of the contralateral DA neurons is proposed to explain the changes in [3H]DA release induced in the contralateral CN in these various situations. The results are discussed taking into account previous data on the reciprocal control of the two dopaminergic pathways induced by the unilateral nigral application of dopaminergic drugs.


The effect of intracerebral ouabain administration on the composition of edema fluid isolated from cats with cold-induced brain edema.

Brain edema fluid was collected from cats with a freezing lesion in the left parietal cortex by the insertion into the brain of needles containing nylon wicks and connected to polyethylene tubes. The edema fluid samples which accumulated in the polyethylene tubes were regularly analyzed for Na+ and K+ content, colloid osmotic pressure, lactate dehydrogenase and creatine phosphokinase activity, and 99mTc-albumin radioactivity; the albumin tracer being introduced intravenously at the time of cold-injury. One series of cats received an intracerebral injection of ouabain solution, the control series an intracerebral injection of saline, at 100 min after the cold-injury. The ouabain injection was followed by an increase of K+ content, LDH and CPK activities but a decrease of Na+ concentration in the edema fluid, attributable to a concentration of solutes in the edema fluid as presumably water and Na+ were shifted into the cells and hence the extracellular space was reduced.


Changes in brain and spinal tryptophan and 5-hydroxyindoleacetic acid levels following acute morphine administration in normal and arthritic rats.

The effects of morphine (10 mg/kg/s.c.) on tryptophan (TRP), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels were studied in normal and arthritic rats. (1) In normal rats morphine induced a discrete but significant increase of 5-HIAA levels in the forebrain and the spinal cord. (2) By contrast, in rats suffering from experimentally induced arthritis large modifications were apparent. The basal levels of TRP, 5-HT and 5-HIAA were significantly higher than in normal rats. Morphine induced clear increases of 5-HIAA and TRP in the forebrain, the brain stem and the spinal cord, without any modification of 5-HT. The effects were dose-dependent and suppressed by naloxone (1 mg/kg/i.m.). Statistical analysis clearly revealed that arthritic rats were much more sensitive to morphine. The results support the hypothesis of an activation of a 5-HT descending pathway by morphine which parallels the activation of the ascending pathway previously demonstrated by several authors and confirmed here.


Effect of oxytocin and vasopressin on memory consolidation: sites of action and catecholaminergic correlates after local microinjection into limbic-midbrain structures.

The effects of local postlearning microinjections of arginine-vasopressin (AVP) and oxytocin (OXT) on one-trial learning passive avoidance behavior and the influence of AVP on alpha-MPT-induced disappearance of norepinephrine (NE) and dopamine (DA) in discrete brain regions have been studied in the rat. OXT injected bilaterally in the hippocampal dentate gyrus (25-25 pg) or in the midbrain dorsal raphe nucleus (50 pg) significantly attenuated passive avoidance behavior. Facilitation of passive avoidance behavior was observed when the peptide was injected into the dorsal septal nucleus. AVP facilitated passive avoidance behavior when administered into the hippocampal dentate gyrus, dorsal raphe nucleus or dorsal septal nucleus. Injection of either neuropeptides into the central amygdaloid nucleus appeared to be ineffective. One week after the behavioral experiments a repeated injection of AVP into the hippocampal dentate gyrus increased the disappearance of NE in the dentate gyrus and in the nucleus ruber. An injection into the dorsal septal nuclei decreased the NE disappearance in the dorsal septal nucleus itself and increased it in the nucleus ruber. Injection in the dorsal raphe nucleus led to an increase in the disappearance of DA in the locus coeruleus and in the nucleus ruber. It is concluded that memory consolidation can be oppositely influenced by local application of minute amounts of either OXT or AVP into certain limbic-midbrain structures, suggesting an involvement of these brain regions in the memory effects of these peptides. Modulation of catecholamine turnover in specific brain areas after AVP administration may be related to this behavioral effect.


The effects of acute and chronic morphine treatment on the process of facial nerve regeneration.

Prominent cellular responses to axonal interruption include enhanced synthesis of RNA and protein in the neuronal perikaryon, and proliferation of reactive Schwann cells. Since morphine has been shown to significantly depress cellular metabolism, we examined its effect on these and other reparative responses underlying nerve fiber regeneration. Rat facial nerve trunks from saline, acute morphine, and continuous morphine-treated animals were examined by light and electron microscopy at 3, 7 and 14 days after crush injury. The number of axonal sprouts/unit area and the diameters of regenerating axons were quantified at each survival interval. Both saline-treated and acute morphine-treated facial nerves demonstrated myelin degradation and Schwann cell hypertrophy (at 3 days post-axotomy), sprout outgrowth (at 7 days) and axon maturation and myelination (at 14 days). In the chronic morphine-treated animals, a retardation of the regenerative process was evident. Axon sprout outgrowth and axonal diameters were reduced at 3 and 7 days post-axotomy. In treated 14-day animals, axon diameters were normal; however, significantly fewer axon profiles/unit area were observed. After chronic morphine exposure, Schwann cell hypertrophy and proliferation, as well as myelin debris removal, were inhibited at all survival periods.


Effects of suckling on serum prolactin levels and catecholamine concentrations and turnover in discrete brain regions.

The effects of suckling on serum prolactin levels and catecholamine concentrations and turnover were examined in several discrete brain regions. Turnover rates were assessed by using the synthesis inhibitor alpha-methyltyrosine (alpha-MT) in combination with microdissection techniques for the removal of individual brain regions and sensitive radioenzymatic assays for norepinephrine (NE) and dopaime (DA). Prolactin secretion was induced by mothers experiencing 6 h of pup removal with subsequent pup replacement. Suckling or the administration of alpha-MT to mothers resulted in a marked increase in circulating titers of prolactin. A decrease in steady-state NE concentrations in the anterior hypothalamus and a decrease in steady-state DA concentrations in the ventromedial nucleus were noted in suckled mothers. The comparison of relative rates of NE depletion after alpha-MT treatment revealed a suckling-induced increase in turnover in the ventromedial nucleus and a suckling-induced decrease in turnover in the anterior hypothalamus. Neither suckling nor alpha-MT treatment produced any changes in NE or DA turnover rates in the arcuate nucleus or median eminence. These findings demonstrate that suckling-induced activation of prolactin results in changes in noradrenergic processes in the ventromedial and anterior hypothalamic nuclei. This suggests an involvement of noradrenergic systems in suckling-induced prolactin release.


Opioid peptides excite pyramidal neurons and evoke epileptiform activity in hippocampal transplants in oculo.

The effect of opiate peptide administration on the electrical activity of intraocular hippocampal transplants was studied. Similar to observations in situ, the administration of beta-endorphin or methionine enkephalin produces a concentration-dependent increase in the firing rate of identified pyramidal neurons within hippocampal formation transplants. In addition, these peptides elicit a profound increase in 'EEG' amplitude, which ultimately develops into epileptiform activity. The ability of naloxone to either reverse or prevent the peptide-induced changes in both single unit and EEG activity supports the hypothesis that the excitatory response of the hippocampus to opioid peptides is mediated via an opiate receptor. The results of this study also suggest that the excitatory response to the opiate peptides in hippocampus is the result of alterations in intrinsic neuronal circuitry and is not dependent upon extra-hippocampal afferents.