The actions of vasoactive drugs on fetal and maternal plasma renin activity. The association between fetal arterial pressure and fetal plasma renin activity (PRA) was studied in 30 fetal lambs prepared acutely, but studied in utero. There was a negative correlation between resting fetal arterial pressure and resting fetal PRA (p less than 0.05). Fetal hypotension caused by intravenous infusion of sodium nitroprusside was associated with increases in fetal PRA. Fetal hypertension caused by intravenous infusion of phenylephrine to the fetus was associated with a decrease in fetal PRA. Maternal hypotension caused by infusion of sodium nitroprusside to the mother, and maternal hypertension caused by maternal infusion of phenylephrine caused an increase in fetal blood pressure and a fall in fetal PRA. It is concluded that the hypertensive response of the fetus to these changes in maternal blood pressure was not initiated by the fetal renin-angiotensin system. Isoprenaline caused a rise in fetal PRA. In 11 of 28 infusions this increase in fetal PRA occurred even though diastolic pressure was increased. It is concluded that there is a beta-adrenergic receptor in the fetal kidney which can release renin. The increase in fetal PRA with intravenous isoprenaline was blocked by propanolol. Infusions of adrenaline were not associated with increases in fetal PRA.


Effects of neonatal bulbectomy on later discrimination learning in mice. The olfactory bulbs of mice were lesioned at 24 h of age and their performance in learning a black-white discrimination task was compared with undernourished mice that grew from birth at the same rate as the bulbectomised animals. The mice were tested at 90 days of age and their behaviour in a Y-maze was compared with that of control operated and unoperated samples. The performance of the bulbectomised mice spent more time at the choicepoint and frequently failed to run the maze. The error rate reduction shown by the bulbectomised mice was similar to that of the controls and is accounted for in terms of a reduced frequency of entry and reversals into the maze arms. The results are discussed in relation to the size of the lesions and factors affecting the neurogenesis of the olfactory brain early in life.


Renal response to Ringer expansion in developing rats. Male rats were studied between 20 and 60 days of age. Standard renal clearance techniques were used. The efficiency of the diuretic response, the sodium response, and the potassium response were calculated as defined previously. Results indicate that both diuretic and sodium efficiency is lower between the ages of 20 and 30 days as compared to 40 and 60 days of age, whereas potassium efficiency shows no age dependence. In morphological studies, it has been observed that the proximal tubule cells of 22-day-old rats show changes in lateral intercellular spaces with comparable features to those of mature animals. The spaces widened during volume expansion. The change is quantitatively the same as that found in mature rats. Both blood pressure and hematocrit show continuous increase with age. The response of Ringer infusion in both immature and mature animals may be a mixed response involving changes in physical factors and renal responses to volume expansion per se.


Relationship between maturity, electrolyte balance and the function of the renin-angiotensin-aldosterone system in newborn infants. Simultaneous measurement of plasma renin activity (PRA), plasma aldosterone concentration (PA) and urinary aldosterone excretion (UAE) was made using the RIA method along with determination of Na and K balance in 1-week-old neonates with gestational age of 30-41 weeks (mean 35.9 weeks) and birth weight of 1,160-4,670 g (mean 2,680 g). It was demonstrated that PRA decreased from the value of 36.3 +/- 6.3 ng/ml/h (mean +/- SE) to a level of 10.2 +/- 2.1 ng/ml/h (p less than 0.001), PA did not change and UAE increased from 3.3 +/- 0.8 to 7.8 +/- 1.4 microgram/day (p less than 0.01) as the gestational age advanced from 30-32 to 39-41 weeks. There was no correlation between either PRA and PA and UAE. PRA showed a significant positive correlation with urinary Na excretion (p less than 0.001) and plasma K concentration (p less than 0.05), but it was negatively related to Na balance (p less than 0.001). Significant negative correlations were found between UAE and urinary Na excretion (p less than 0.05), urinary Na/K ratio (p less than 0.01 (and plasma K concentration (p less than 0.05); however, UAE positively correlated with Na balance (p less than 0.01). It is concluded that, in response to renal salt wasting and to the subsequent negative salt balance, premature infants can augment their PRA above values found for full-term infants. Their adrenals, however, failed to respond adequately to this stimulation.


Baroreceptor and chemoreceptor responses to umbilical cord occlusion in fetal lambs. 11 fetal lambs with gestational age of 116-135 days were studied while connected to a membrane-oxygenator replacing the ventilatory function of the placenta. Progressive increase in arterial oxygen tension from 20 to 220 mm Hg resulted in progressive decrease in baseline heart rate and baseline arterial blood pressure indicating presence of chemoreceptor activity over this wide range of arterial oxygen tension. The effect of 60 sec complete umbilical cord occlusion was studied at progressively higher arterial oxygen tension and it was concluded that the chemoreceptor activity at fetal normoxic condition is very brisk and is markedly attenuated at hyperoxic levels. Although it was not possible to completely separate baroreceptor and chemoreceptor reflexes involved in cardiovascular response to umbilical cord occlusion, it is postulated that the chemoreceptor and baroreceptor reflexes are complimentary during cardiovascular responses to umbilical cord occlusion.


Thermic effects of glucose, amino acid and lipid in the term newborn. The thermic effect in term infants of intragastric isocaloric amounts of glucose, lipid and amino acid have been compared with control infants given water on the third to fifth days of life. In contrast with adults, the thermic effect of glucose was found to be non-existent and for lipids weak and ill-sustained. These results suggest that these nutrients are mainly oxidised and that processes involving an elevated metabolic cost, such as lipid synthesis, play a minor role. The ingestion of an isocaloric load of amino acids induced a small thermic effect (4.4% of the energy content of the load in 2 h). This effect is probably related to a low rate of protein synthesis or amino acid catabolism and an absence of tissue deposition. The small thermic effect observed suggests that a significant part of the load is not metabolised or channeled into protein synthesis. In term infants the weak thermic effect after amino acid and the failure of glucose and lipid to stimulate metabolism may possibly be analogous to the lack of post-prandial thermic effect reported in non-growing children suffering from malnutrition. It can be hypothesised that in both cases the energy storage related to lipid and protein synthesis is absent or minimal. Therefore, there is no stimulation of energy expenditure to produce a thermic effect.


Effects of upper respiratory tract stimuli on neonatal respiration: reflex and single neuron analyses in the kitten. Respiratory effects of electrical and chemical stimuli applied to nerves or sites associated with the respiratory tract were tested in kittens aged 6-70 days. Cessation of respiration occurred especially with superior laryngeal nerve stimulation and infusion of water and sodium bicarbonate into the larynx. The apneic reflex was more powerful and prolonged than that previously noted in adult cats and was sometimes irreversible. Brain stem respiratory neurons of the neonate also showed marked susceptibility to these stimuli: the respiratory-related rhythm of 80% could be powerfully suppressed, and only 25% received excitatory inputs. The susceptibility of the neonatal respiratory system to these stimuli may have physiopathological significance in conditions such as the sudden infant (crib) death syndrome.


Cold stress influence on lung lecithin in the newborn rabbit. Term, food-water deprived newborn rabbits exposed to a cold environment for 48 h demonstrated a significant decrease in total lung lipid (p less than 0.01), total triglyceride (p less than 0.001), total phospholipid (p less than 0.05), and total phosphatidylcholine (p less than 0.025). Disaturated phosphatidylcholine remained unchanged. Fatty acid methyl esters of total and disaturated phosphatidylcholine were not influenced by cold stress. Likewise, there was no alteration in pulmonary function as determined by deflation pressure-volume relationships.


Skeletal changes in the condylar cartilage of the neonate mouse mandible. Histological and histochemical qualitative and quantitative determinations are provided concerning the skeletal changes taking place in the growth center of the mandibular condyle in the neonatal ICR mouse. This study followed the changes in both the major matrical components (collagen, acidic glycosaminoglycans and glycolipids) as well as in the various cartilage cells throughout the maturational period of the neonatal condyle. It was found that the transformation of neonatal condylar cartilage to its mature form involved a significant decrease in its acid glycosaminoglycan content concomitant with a rapid increase in its collagen content. In addition, significant quantitative changes were found within the zone of hypertrophic chondrocytes. The period of highest growth activity along the mandibular posterior vertical dimension (ramus) was between birth and weanling 3rd postnatal week). At this time interval, the adaptive abilities of the growing condyle appeared maximal. A high degree of correlation was noted between the overall reduction in the height of the condylar cartilage and that of its hypertrophic zone. Further, the increase in the ramal height was highly correlated with the structural changes characteristic of the neonatal condyle.


Catatonia and mania: patterns of cerebral dysfunction. We performed a factor analysis on research data from 55 consecutive hospitalized psychiatric patients who showed one or more of eight catatonic motor features. Two factors were extracted, accounting for 32% of the variance. Factor 1 (mutism, negativism, stupor) corresponded to the clinical syndrome of negativistic stupor and was unrelated to diagnosis, sex, age at onset, family history, or treatment response. Factor 2 (mutism, stereotypy, catalepsy, automatic obedience) corresponded to the classical description of catatonia, was associated with a research diagnosis of mania, and tended (p less than 0.10) to predict a favorable treatment response. We suggest that the two factors may reflect different forms of cerebral dysfunction which, in the case of Factor 2, may provide clues as to the nature of the morbid process in mania. Republication is now in progress in a different sample.


Neuropsychological and power spectral EEG investigations of the obsessive-compulsive syndrome. Eleven consecutive patients with primary obsessive-compulsive syndrome were studied neuropsychologically and the power spectral EEG characteristic of ten of these patients unmedicated, at rest, and during cognitive tasks were analyzed. The finding of predominantly left frontal dysfunction in the obsessional syndrome is discussed in the light of neurophysiological and psychosurgical evidence which suggest that perturbation of the cingulate-orbital frontal connections modulates obsessive-compulsive symptomatology.


Eye movements in schizophrenia: a quantitative analysis. A quantitative comparison of smooth pursuit eye movements of acute and chronic schizophrenics was made. Horizontal, vertical, diagonal, and pendulum tracking targets with constant or variable velocity were presented. The frequency of saccades as well as the magnitude of the spatial and temporal error during tracking was significantly greater among schizophrenics than among normals. Yet the differences between acutes and chronics were not generally significant. Performance differences were generally unaffected by the type of stimulus. The frequency of nontracked half-cycles and eye blinks was greater for chronics than for acutes or normals, and greater for acutes than normals, suggesting that sustained voluntary attention was more difficult for schizophrenics in general and chronic schizophrenics in particular. A distinctive pattern of saccade bursts was observed in the fixation and tracking records of schizophrenic subjects. These bursts were suggestive of an oculomotor deficit.


Plasma neutral amino acids in mania and depression: variation during acute and prolonged treatment with L-tryptophan. The free tryptophan and plasma neutral amino acids including kynurenine have been determined before treatment, after a single load, and during prolonged treatment with L-tryptophan on a bipolar manic-depressive patient who has shown resistance to current treatments. The data of the patient were compared with the data of healthy control subjects in order to evaluate the availability of tryptophan to the brain. A relative deficiency of tryptophan in the plasma, as measured by the ratio of tryptophan to those amino acids which compete with tryptophan during transport processes, was found in the patient. Further, the patient showed an increased area under curve of plasma tryptophan after a load, and an increase in the competing amino acids during the load compared to a decrease in the control subjects. During the treatment with L-tryptophan the competing amino acids increased in the plasma. The results suggest that the patient suffered from a dysfunction of the processes which mediate active transport of tryptophan and other large neutral amino acids into tissues including the brain.


Visual evoked response modified recovery cycle and personality dimensions in healthy and schizophrenic subjects. The aim of this study was to compare the results of the VER recovery cycle as modified by Shagass, in correlation with Eysenck's PEN personality questionnaire scores, in 41 schizophrenic inpatients and 41 healthy subjects. All the subjects were male. In the patient group, a lack of R2 response amplitude facilitation was found. In normals with a high score on the neuroticism scale, less facilitation was found in comparison with the group with low scores in the scale. In the schizophrenic group, the R2 latency did not change with increased S1 stimulus intensity, but in the group of normals the R2 latency increased. The schizophrenic group got higher scores on the scales of psychoticism and neuroticism and lower scores on the extroversion scale. Differences between groups on the psychoticism scale were not significant. A small but significant negative correlation was found between the psychoticism score and facilitation of R2 amplitude in the group of normals. This correlation was greater in the group with low neuroticism.


Genetic markers for schizotaxia.

Genetic markers for schizotaxia. Evidence is presented for the occurrence of a locus for schizotaxia on the short arm of chromosome 6. This derives from study of 63 informative members of seven pedigrees in which the proband and a parent (or a sib of parent) suffered with schizophrenia and other kin were either normal or fell within a spectrum of conditions related to schizophrenia. For linkage of HLA and schizotaxia a Lod score, 2.57, at recombination frequency 0.15 is reported, which gives p = 0.008. This is in contrast to data on 54 informative members of six pedigrees with atypical (schizo-affective or mixed) psychoses in two generations. Glyoxalase isoenzymes were of value in linkage analysis in two pedigrees. No evidence for linkage was found for any erythrocyte surface antigen nor for 15 other genetic markers. Details for each pedigree are provided.


The relationship of the lithium erythrocyte: plasma ratio to plasma lithium level. The relationship of the lithium erythrocyte:plasma ratio to plasma lithium concentration was reviewed in inpatients and outpatients with affective disorders. For some patients, there was a linear correlation between the erythrocyte lithium:plasma lithium ratio and the plasma lithium concentration. For these patients a graph of the slopes and intercepts of the lithium erythrocyte:plasma ratio vs. plasma lithium data formed a line that was not significantly different from the data of Lee et al. (1975). Significant correlations were found between the slopes and intercepts of the lithium erythrocyte:plasma ratio vs. plasma lithium data and the magnitude of active lithium efflux (Ko) from the erythrocyte. Our data confirm the finding of Lee et al. (1975) that the lithium erythrocyte:plasma ratio is dependent on the plasma lithium concentration. We relate this finding to lithium efflux from the erythrocyte.


Implications of basal ganglionic dysfunction for schizophrenia. This paper is addressed to presenting evidence that the basal ganglia are involved in mediating schizophrenia. Data from the experimental and clinical literature suggest a basal ganglionic role in higher cognitive processes, affect, and attention. Deficits of these same factors serve to characterize the major symptoms of schizophrenia. Moreover, psychiatric patients tend to have frank motor problems characteristic of basal ganglia lesions and pathological conditions of the basal ganglia manifest psychiatric difficulties as a major symptom. Taken together, these data are in accord with the hypothesis that some dysfunction involving the basal ganglia is a major factor in schizophrenia.


CSF calcium: clinical correlates in affective illness and schizophrenia. In a study of electrolytes in lumbar cerebrospinal fluid (csf) from psychiatric patients, the authors found a positive correlation between calcium concentration and symptom severity in hospitalized depressed patients. CSF calcium levels tended to decrease as patients improved. In four rapidly cycling patients, CSF calcium was higher during depression than during mania. Mean CSF calcium for the depressed patients as a group was not significantly different from neurological controls or other psychiatric patients. Symptom remission from acute psychosis in schizophrenic patients was accompanied by a significant increase in CSF calcium concentration. These findings are discussed in relationship to calcium-induced alterations in neuronal and physiological excitability.


Energy and metastable characteristics in peptides. 1-Metastable/daughter ion ratios as an aid in peptide sequencing. The metastable/daughter ion ratios, [m*]/[D+] values were measured in the first field free region. The [m*]/[D+] values were found to be influenced by the amino acid sequence in peptide molecules.


Screening of organic acids in urine by chemical ionization mass spectrometry. A method has been developed for qualitative screening of carboxylic acids in human urine. The method uses direct chemical inoization mass spectrometry with isobutane as reagent gas. The carboxylic acids are separated from the urine samples by ion exchange. Normal carboxylic acid profiles have been determined and are compared with the profiles of patients suffering from certain metabolic disorders.


Studies on drug metabolism by use of isotopes. XXIV-Determination of 3-phenylpropyl carbamate metabolites using stable isotope labelling with deuterium or carbon-13. Metabolism of 3-phenylproply carbamate was investigated by using a stable isotope tracer technique. 3-Phenylpropanol, 3-hydroxy-3-phenylpropanol, 3-hydroxy-3-phenylpropyl carbamate, 2,3-dihydroxy-3-phenylproply carbamate, benzoic acid and hippuric acid were identified as the rat urinary metabolites. Using the dilution analysis, the amounts of metabolites in urine and faeces in rat and man were determined. In rats, 2,3-dihydroxy-3-phenylproply carbamate and 3-phenylpropanol glucuronide were excreted into the urine as the major metabolites of this drug. On the other hand, in man, the major metabolite was hippuric acid and about 30% of the administered dose was excreted as hippuric acid in the 24 h urine. The tracer technique using a singly labelled drug with carbon-13 employed in the present study provided a reliable methods for the analysis of drug metabolites and was comparable with the tracer technique using a multilabelled drug with deuterium.


Mass spectrometric analysis of deuterium dual labeled blood lipids. A gas chromatography selected ion monitoring mass spectrometer technique was developed to analyze deuterium dual labeled blood lipid samples from a human feeding experiment. In the metabolism experiment, described elsewhere. [2H2] labeled cis and [2H4] labeled trans fatty acids were fed to a human sujbect as a single pulse in order to determine whether the human body differentiates between cis and trans fatty acids in the diet. The analytical method described here was developed to accurately measure the ratio of [2H2]methyl oleate to [2H4]methyl elaidate in the presence of large amounts of [2H0] methyl oleate in samples derived from separated fractions of blood lipids. The technique is different from most selected ion monitoring methods in that the internal standard was fed to the subject along with the experimental material; the samples contained large amounts of unlabeled material chemically identical to the labeled material and the ratio of [2H2] to [2H4] fatty esters was of principal interest rather than the absolute value. Nine standards were analyzed eight or more times to form a basis for statistical evaluation of the method. Analysis of the plasma phosphatidyl ethanolamine fraction from the metabolic experiment is given as an example.


Quantitation of plasma warfarin levels by gas chromatography chemical ionization mass spectrometry. A quantitative assay for plasma concentrations of warfarin has been developed using a deuterated warfarin analogue as internal standard. The method employs methylation (diazomethane) of warfarin to its 4'-methoxy derivative and gas chromatography chemical ionization mass spectrometry. Selected ion monitoring was used to relate the response of warfarin methyl ether and the internal standard. This technique can measure warfarin plasma concentrations five days after a single oral (25 mg) dose. Warfarin half-lives were determined in 12 healthy male volunteers. Each plasma analysis required six minutes of instrument time.


A selected ion monitoring assay for primaquine in plasma and urine. The antimalarial drug primaquine was analysed in plasma and urine by gas chromatography mass spectrometry, using a deuterated internal standard. After freeze-drying and extraction with trichloroethylene the sample plus internal standard was reacted with Tri Sil TBT (a 3:3:2 by volume mixture of trimethylsilylimidazole, N,O,-bis-(trimethylsilylacetamide and trimethylchlorosilane) and an aliquot injected into the gas chromatograph mass spectrometer. The gas chromatographic effluent was monitored at m/z 403 and m/z 406, the molecular ions of the bis-TMS ethers of primaquine and 6-trideuteromethoxy primaquine. Calibration curves were prepared from standards made up in plasma and urine. Data from the analysis of plasma and urine samples from a volunteer who ingested the equivalent of 45 mg primaquine are presented.


The determination of testosterone in hamster prostate by gas chromatography mass spectrometry with selected metastable peak monitoring. Quantitative analyses of testosterone, as the methyl oxime t-butyldimethylsilyl ether, are performed by gas chromatography mass spectrometry with selected monitoring of the metastable peak corresponding to the fragmentation [M]+. leads to [M-C4H9]+ in the field free region preceding the electric sector of a double focusing mass spectrometer. A detection limit of c. 30 pg is observed during analyses of the standard compound. The method is applied to the quantitative determination of testosterone in extracts of prostatic tissue from the golden hamster, using epitestosterone as the internal standard. The analytical specificity is similar to that achieved during gas chromatography high resolution mass spectrometry with selected ion detection of [M]+. ions; gas chromatography low resolution mass spectrometry is of inadequate specificity.


Mass spectrometry of some ultraviolet absorbing derivatives of sugars and related alditols: identification in biologic fluids after separation by high performance liquid chromatography. The 70 eV electron impact mass spectra of the acyclic perbenzoyl 0-benzyloximes of several mono- and disaccharides of clinical interest and the perbenzoates of certain related alditols have been obtained and compared with those of other similar derivatives studied previously. In general, the spectra of the benzyloximes contain molecular ions and characteristic fragments due to [C6H5]+,[C7H7]+,[C6H5CO]+ and [C6H5CooH]+., losses of HCHO, C6H5COO. and C6H5COOH, and cleavages along the carbon chain. The most unique ions in these spectra arise from the combined loss of C7H7. and C6H5COO.from the molecular ion: m/z 191 (C3), m/z 339 (deoxy-C5), m/z 459 (C5), m/z 473 (deoxy-C6), and m/z 593 (C6). The alditol benzoates fragment similarly, but they do not yield molecular ions. These data are being used to help confirm the identities of carbohydrates in biologic fluids fractionation by high performance liquid chromatography, prior to the establishment of routine quantitative assays for several of these compounds.


Mass spectrometry of valepotriates.

Mass spectrometry of valepotriates. The mass spectrometry of eight valepotriates and their derivatives has been investigated. Mass spectral fragmentation schemes have been proposed as well as the use of this fragmentation for structural elucidation. Structures of two valepotriates, acevaltrate and homoacevaltrate, have been clarified.


Mass spectrometric peptide sequencing: cyclochlorotine. A potent toxin isolated from Penicillium islandicum Sopp was found to have the composition C24H31N5O7Cl2. Mass spectrometric investigation of a partial acid hydrolyzate showed that it has the structure of cyclochlorotine. The mass spectral characteristics of polyamino alcohol-related derivatives of peptides containing beta-phenylalanine, alpha-amino butyric acid and dichloroproline were determined in the course of this work.


Electron impact induced fragmentation of some 1-substituted trans-2-phenylcyclopropane compounds. The electron impact induced fragmentation of seven derivatives of trans-2-phenylcyclopropane substituted at position one with functional groups like amino (tranylcypromine), trifluoroacetamido, cyano, carboxylic acid, carboxylic acid chloride, carboxamide and carboxylate methyl ester was investigated. Mechanisms are proposed for the formation of the major ions of each compound. The nature of the substituent determined the relative abundances of [M]+., [M-1]+, [M-R]+, UM-RH]+. [M-C6H5]+ and m/z 115 ions. A molecular ion was present in all spectra except that of carboxylic acid chloride substituted compound. In most cases, metastable peaks are involved in the decomposition of the most abundant ions. An interesting elimination mechanism involving the opening of the cyclopropane ring to yield a 4-membered cyclic ion at m/z 56 was obtained in the spectrum of trans-1-amino-2-phenylcyclopropane. All the above compounds gave mass spectra containing diagnostic fragment ions which are of great value for identification purposes.


Immobilization of Streptomyces phaerochromogenes by radiation-induced polymerization of glass-forming monomers. Immobilization of Streptomyces phaerochromogenes was studied by radiation-induced polymerization of 2-hydroxyethyl methacrylate at low temperatures. Radiation damage of the enzyme could be avoided by choosing irradiation at low temperatures. The enzymatic activity of immobilized cells increased remarkably with a decrease in the irradiation temperature of about -24 degrees C. In constrast to the case of cell-free enzyme immobilization, the most characteristic case was than in these immobilized cells, the enzymatic activity did not decrease with repeated use even in the composite obtained at much lower monomer concentrations. Another characteristic of immobilized cells was the increase in enzymatic activity in the initial stage of repeated use, which could be attributed to the swelling effect of the polymer matrix, thereby increasing the enzymatic activity of whole cells.


[Analysis of the functional heterogeneity of the small intestine by glucose transport parameters]. Functional heterogeneity of the small intestine is discussed with consideration to the heterogeneity of the enterocyte populations by the accumulating and autoregulating properties and the systems of the initial and final absorption stages (particularly by their time organization parameters).


[Use of a laser photometer to determine blood platelet shape and aggregation in a flowing system]. The paper treats of an original device for studies with the photometric method of the platelets shape and of their aggregation and disaggregation processes in the flow. Experiments on the stenosed vessel model showed that in the presence of ADP stenosis potentiated the platelets aggregation in the rabbit platelet-rich plasma.


[Thyroid gland activity and motor activity during dog ontogenesis]. The locomotor activity (LA) and the level of the protein-bound iodine (PBI) in the blood serum were investigated in 62 puppies at the age of 1--12 months. A parallel elevation of PBI and the LA was observed the first 4 months after birth. The second peak of the LA at the age of 7--9 months was not accompanied by any PBI rise. Inhibition of the thyroid function with mercasolyl increased the LA at the age of 1--3 months and decreased it at the age of 7 months. An increase of the LA one month after thyroidectomy was found at the age of 1 and 3.5 months. The activity of puppies operated on at the age of one month showed a sharp fall after 2--4 months. The data on various effect of thyroid hormones on puppies of different age pointed to the complex relation between the LA and the thyroid gland function.


[Spread of excitation through the heart upon electrical stimulation of the atrioventricular valves]. Experiments were conducted on the isolated hearts of rabbits and dogs. Synchronous recording of the electrical activity of the right auricle, the right ventricle, and tricuspid valve demonstrated the existence of definite functional associations between the auricular, ventricular and valvular depolarization. The spread of excitation in the heart in electrical stimulation of the atrio-ventricular valves was investigated. The impulses from the heterotopic excitation focus localized in these valves could be conducted to the other parts of the heart and thus lead to cardiac arrhythmias.


[Characteristics of the late A-response of vasoconstrictor neurons in cats decerebrated at different brain stem levels]. In cats decerebrated at the level of the rostral border of the midbrain (the mesencephalic animals) and in those decerebrated at different pontine levels, including the ponto-bulbar junction level, and the most rostral parts of the medulla oblongata (the "pontine" animals), or more caudal parts (the bulbar animals), single stimulus of the tibial nerve A-fibres elicited a late response in the renal nerve consisting of excitatory and inhibitory components. The excitatory component was relatively small or absent in 53% of the "pontine" animals, in 42% of the mesencephalic animals, and in 18% of the bulbar animals. The "pontine" animals had the most active and most excitable system of the inhibitory component generation. However, the signs of a comparatively more powerful inhibitory component of the A-afferent action of the vasoconstrictor neurones in the "pontine" animals were not as constant as to explain completely the transition of somatic A-afferent hypertensive reflexes into the hypotensive ones, occurring in separating the ponto-bulbar structure and the rostral parts of the medulla oblongata from the mesencephalon.


[Formation of epileptic activity complexes in the cerebral cortex as a result of a determinant focus induced by acetylcholine]. Foci of increased excitability were created by means of weak strychnine and penicillin dilutions in experiments on cats. These foci worked at individual regimens. Creation with acetylcholine and proserine of a hyperactive focus led to increase of the amplitude and frequency of convulsive discharges at first in the nearest activity foci, and then in the ones remote from the hyperactive focus. The next stage was attended by qualitative changes in the activity pattern of strychnine and penicillin foci (the appearance of acetylcholine activity in them) and by the formation of a single functional focal complex working in the regimen of acetylcholine focus. Thus, the latter played the role of a determinant structure. Suppression of the determinant focus activity led to disappearance of the acetylcholine activity in all the other foci, restoration of the initial (penicillin and strychnine) activity, and to the epileptic complex decay.


[Plasma erythropoiesis inhibitors in humans during hyperbaric hyperoxia]. Before exposure of man to hyperbaric hyperoxia the blood plasma possessed marked erythropoietic activity. Erythropoietins disappeared completely and erythropoiesis inhibitors appeared in the plasma of persons untrained to hyperbaric hyperoxia after a 24-hour exposure to hyperoxic conditions (25% of oxygen in the inhaled air) in the high pressure chamber corresponding to the depth of 63 metres. A reduction of the peripheral red blood indices was observed by that time.


[Neuropathologic effects developing after administration of tetanus toxin to several rat brain structures]. Neuropathological syndromes following local tetanus toxin (TT) injection into different rat brain structures were studied. As demonstrated, there arose specific neuropathological signs dissimilar to those developing with different TT localization, i.e. as a rule the action of TT in the given brain parts was local. Experiments carried out confirmed the theory of the generator mechanisms of the neuropathological syndromes according to which specific manifestations of the corresponding syndrome were due to the localization of a generator of pathologically-enhanced excitation in definite brain structures.


[Dynamics of renin production by the juxtaglomerular and mesangial cells of individual rat kidney glomeruli following adrenalectomy]. Adrenal incompetence developed in rats 6 weeks after adrenalectomy without any salt and hormonal compensation. In individual fragments of the isolated glomeruli containing juxtaglomerular cells (JGC) renin activity increased 1.2 times on the average, and there was revealed renin-like activity (RLA) in the fragments containing mesangial cells (MC). Signs of intensified renin secretion (expressed in reduction of granule count, marked development of granular endoplasmic reticulum, Golgi complex and microtubules) were noted in the JGC. In MC such organoids were well developed, but no granules were revealed. The following occurred in 8 to 12 weeks with the restoration of the 11-OCS and sodium level in the plasma: renin JGC activity became normal, RLA activity in MC disappeared, and the initial ultrastructure of both of these cells was restored. The reserve role of MC as the source of renin-like substances was confirmed.


[Changes in active 14C-noradrenaline uptake by cerebral synaptosomes during elaboration of a conditioned reflex]. It was shown that active noradrenaline-14C (NA) uptake by the rat brain synaptosomes is inhibited by ouabain (0.1 M) and K-depolarization. Acquisition of the defensive conditioned reflex leads to inhibition of active NA uptake by the synaptosomes. This effect may be connected both with changes in the presynaptic membrane state and possible enhancement of the postsynaptic adrenoreceptor function.


[Restoration of blood supply and the intensity of phospholipid metabolism in different rat brain regions during the postischemic period]. Fifteen min after resumption of the blood flow in the common carotid arteries the arrest of which was caused by ligation, a considerable intensification of the blood supply in the hemispheres, diencephalon and the midbrain and its simultaneous reduction in the cerebellum and the medulla oblongata occurred. Sixty min later the cerebral blood supply in all the parts of the brain under study recovered completely, except the hemispheres. The complete postischemic recovery of the phospholipid metabolism intensity occurred in the brain regions showing a considerable diminution of the phospholipid metabolism during the ischemic period.


[Tissue-specific uncouplers of oxidative phosphorylation in mitochondria from rat heart, kidney, thymus and lung]. The influence of nonmicrosomal cytoplasm fraction from the rat kidney, heart, thymus and lungs on the oxidative phosphorylation of mitochondria (M) of the same tissues and from the ones of the liver and brain was studied. The existence of the tissue-specific uncouplers of the M oxidative phosphorylation was shown in the cross experiments; they were similar to that in the rat liver revealed earlier. A possibility of these regulators participation in the initiation of the M enzymatic degradation process through the activation of phospholipase A when calcium ions leave the M is discussed. The activation under these conditions of the DNA-ase 1, associated with the M membrane, is suggested.


[Effect of sigetin on the concentration of triglycerides and cholesterol in rat blood and liver]. It was shown in experiments on male rats that sygethin an analogue of synesterol devoid of estrogenic effect decreased cholesterol level in the intact animals and diminished hypercholesterolemia induced by dexamethasone. Sygethin inhibited the hypertriglyceridemia induced by diethylstilbestrol, as well as by ethanol and dexamethasone.


[Effect of silicoorganic compounds on protein biosynthesis in granulation-fibrous tissue]. The authors studied the effect of propoxysilatran (POS) on the biosynthesis of the main connective tissue biopolymeres. The use of POS in the form of 0.5 and 2.0% ointments on lanolin-vaseline base caused stimulation of cellular proliferation in the granulation fibrous tissue developing in the open skin defects of albino rats. Stimulation of cellular proliferation in these animals was accompanied by increase of collagen biosynthesis and of noncollagen proteins. In concentrations of 10(-3)--10(-4) M POS caused intensification of collagen biosynthesis (formation of peptide-bound nondialyzed 14C-oxyproline) in vitro in the cartilage tissue of chick embryos. Thus, silatrans are biologically-active substances producing a regulating effect on the course of the reparative-proliferative processes in the connective tissue.


[Effect of diazepam on the epileptic activity of rats with experimental photogenic epilepsy]. Chronic experiments were conducted on rats. A study was made of the effect of diazepam (in a dose of 4 mg/kg of body weight) on the specific and nonspecific mechanisms of experimentally-induced photogenic epilepsy developing as a result of tetanus toxin injection into the lateral geniculate body (LGB) and formation in this nucleus of a pathologically enhanced excitation generator (PEEG). Diazepam in the mentioned dose had a relatively weak effect on the extent of pathological enhancement of the sensory visual signal in the LGB under conditions of PEEG formation aided detection of focal interictal discharges in this nucleus, and completely inhibited generalized epileptic activity in experimental animals in the course of one hour.


[Quantitative histochemical study of the effect of benzodiazepine tranquilizers on cerebral GABA-transaminase activity]. The effect of diazepam and nitrazepam (0.5, 1, 2.5, and 5 mg/kg) on GABA-transaminase activity in the rat cerebellar cortex and hippocampus was investigated by quantitative histochemistry. Both the drugs suppressed the enzyme activity in the hippocampus; the maximal effect was produced by diazepam. It is suggested that the observed alterations are caused by the enzyme inhibition and also by a decrease of GABA turnover rate.


[Reduction of the hyperthermic effect of prostaglandin E2 by cholinomimetics, monoamines and calcium ions]. It was shown in experiments on unanesthetized rats with prostaglandin E2 (PGE2) hyperthermia, not preventable by aspirin that intraventricular (into the lateral ventricle) injections of arecoline, noradrenaline, 5-hydroxytryptamine (5-HT), histamine, and calcium ions and intraperitoneal eserine injection were capable of decreasing body temperature. PGE2 hyperthermia was not prevented by aspirin, but it was reduced by eserine. After the administration of arecoline and nicotine into the third ventricle of unanesthetized rabbits with PGE2 hyperthermia body temperature decreased as well. The effect of arecoline and 5-HT was reproducible in the same animals. The data are suggestive of the existence in the heat loss centre of mechanisms including cholinergic neurons whose activity was not completely suppressed by PGE2.


[Termination of the presynaptic effect of carbacholine by tubocurarine]. The presynaptic action of carbacholine (Cch) was studied in experiments on the frog sartorius muscle neuromuscular preparation. Cch proved to decrease the quantum content of the end plate potential (EPP); this effect was induced by a direct Cch action on the motor nerve endings. d-tubocurarine decreased the sensitivity of the nerve endings to Cch significantly. Both d-tubocurarine and Cch had concurrent antagonistic interrelations in respect to their action on the quantum content of EPP. Atropine in low concentrations had no influence on the presynaptic effect of Cch. It was concluded that Cch decreased the quantum content of EPP through the N-cholinergic structures of the motor nerve endings.


[Rat thrombocyte factor XIII and its role in platelet aggregation]. Factor XIII was isolated from rat platelets; it activity was 1430 units per 1 mg of protein. It was shown in experiments in vitro that addition of this factor (160--200 units/ml) to the suspension of washed platelets or those purified by passage through the column with sepharose 4B increased their aggregation capacity. Addition of inactive platelet factor XIII failed to influence the platelet aggregation induced by ADP.


[Extraneural metastasis of central nervous system tumours (author's transl)]. Extraneural metastases of central nervous system tumours are very rare (248 of histologically proven examples in the literature). They are mainly in adult males and in the following descending order of frequency: gliomas (39.5%), meningeal tumours and sarcomas (28.2%), neuronal tumours (14.1%), lymphomas-microgliomas (12.5%), pineal tumours (4%) and melanomas (1.6%); 10 cases out of 248 developed through a shunt. 19 were observed without any surgical operation. There are still many uncertainties about their pathogenesis. It seems however that in some tumours the increased survival time and the repetition of the craniotomy favorises the metastasis.


[Cellular differentiation and malignant transformation (author's transl)]. The mechanisms and determination of differentiation of normal and cancer cells were compared by distinguishing them from the phenomena of regulation, retrodifferentiation and maturation. Reference is made to the laws of order in time and space which are superimposed on the common genetic code during the various types of differentiation. In conclusion, the particular mechanisms of malignant differentiation are discussed by taking melanoma and tumor formation by papova-viruses as examples.


Studies on mechanisms of 5-fluorouracil resistance in murine and human tumors. An in vitro cell free assay system to measure phosphorylated products of 5-Fluorouracil is described. Total phosphorylated products and mono-, di and triphosphates of 5-Fluorouracil are measured along with the rate of fluorodeoxyuridylate generation. This assay has been applied to ten murine tumors and eight biopsy specimens from human breast adenocarcinomas. Phosphorylation patterns have been examined in murine tumors demonstrating in vivo sensitivity or resistance to 5-Fluorouracil. There are distinct differences in the patterns of phosphorylation between sensitive and resistant tumors. In a 5-Fluorouracil sensitive murine tumor, mono-, di and triphosphates are produced. In a resistant tumor only monosphophates are produced. Cell free supernatants from human breast tumors produce less total phosphorylation than murine tumors and some specimens produce only monophosphates whereas others produce mono-, di and triphosphates. Human tumors are in general more efficient producers of fluorodeoxyuridylate than murine tumors. These data suggest that resistance to 5-Fluorouracil may correlate with decreased concentration of di and triphosphates of 5-Fluorouracil in some murine tumors. Further experiences is required to demonstrate the value of this easily performed assay system in predicting clinical response to 5-Fluorouracil in man.


Nude mouse models as predictors of chemotherapy in man: thymidine and pyrimidines. The National Cancer Institute cancer treatment screening program has been reorganized incorporating, as an important feature, a panel of human tumors growing as xenografts in congenitally athymic mice. The new screening program is a prospective experiment in the search for new and more effective agents for the treatment of clinical neoplasia. The new program is described and questions that are being asked prospectively are presented. Data are summarized on the activity against human tumor xenografts for a number of clinically established antitumor drugs and examples are presented in which there is interest in compounds for the clinic on the basis of activity in the new screen. Studies are outlined in which high dose thymidine inhibited the growth of human melanoma and teratocarcinoma transplanted in athymic mice. Studies are discussed employing murine tumors in which marked augmentation of the in vivo antitumor activity of 5-fluorouracil was obtained by combination therapy with the pyrimidine nucleosides thymidine, uridine and cytidine. The desirability of investigating combination chemotherapy with pyrimidine nucleosides and 5-fluorouracil and other pyrimidine antagonists in the treatment of human tumor xenografts is stressed. There is a broad range of investigations that can be conducted in nude mouse models and it is important to conduct such programs in relation to the clinic.


Determination of 5-fluorouracil in plasma by GC/MS using an internal standard. Applications to pharmacokinetics. An analytic method, sensitive to 5 ng/ml and specific, has been set up for the determination of unchanged 5-fluorouracil in human plasma, using gas chromatography--mass spectrometry. Its applications to the pharmacokinetic study of unchanged 5-Fluorouracil in man following an intravenous bolus, 8 hours infusion and oral administration confirmed the non-linearity of the kinetic model. (The clearances obtained with an infusion--from 5 to 60 1/min--are 10 to 60 times higher than the ones observed with a bolus--from 0.5 to 1.4 1/min.) The bioavailability of the oral form seems to be about 60 per cent and the absorption appears to be very fast. A attempt to search a mathematical non-linear model of the 5-Fluorouracil kinetics, using computer simulation, is presented.


Determinants of 5-fluorouracil sensitivity in human tumors. It is not apparent that advanced human carcinomas of the breast or the large bowel are conprised of at least two populations: those responding to treatment with 5-fluorouracil (approximately 20 per cent) and those unresponsive to this drug. This classification cannot be made before chemotherapy on the basis of any clinical parameter. Biochemical parameters to distinguish between responding and nonresponding tumors are being sought in this laboratory. Techniques have been developed to measure thymidylate synthetase, the target enzyme for 5-fluorouracil, 5-fluoro-2'-deoxyuridylate, the active form of the antimetabolite, and 2'-deoxyuridylate, the naturally occuring competing metabolite. These methods are sufficiently sensitive to permit analysis of these parameters in needle biopsy specimens, and do not require exposure of patients to radioisotopes.


Pharmacokinetic parameters: potential for and problems with their use as predictors of response to cancer chemotherapeutic agents. The value of pharmacokinetic parameters of antitumor agents to predict for response to chemotherapy of patients with cancer is unknown. Factors which would lead to an expectuation that they would be of value in this regard are the requirement that cells be exposed to a minimum concentration of drug for a minimum period of time to produce cell kill and with certain agents the further requirement that this exposure be during a specific critical phase of the cell cycle. The potential limitations of these parameters for response prediction include the fact that they are whole body parameters which do not distinguish between targets for drug response and targets for dose limiting drug toxicity and that the way drugs are usually given clinically is such as to minimize the effect of patient variation in these parameters. Some practical limitations of their use are the need for very sensitive assays for their accurate definition, the need for computer analysis and the dependence of parameter estimates on the use of the correct model. It is concluded that by themselves pharmacokinetic parameters are unlikely to be of predictive value when drugs are used optimally in a clinical setting, but when considered with biochemical and other parameters may contribute to overall response prediction.


Ara-C metabolism: implications for drug resistance and drug interactions. Clinical studies of resistance to cytosine arabinoside have not produced agreement as to the specific biochemical lesions responsible for altered sensitivity, although experimental and clinical work supports the concept that a decreased ability to generate ara-CTP must be the ultimate effect of this lesion. 3-deazauridine, an inhibitor of CTP synthetase, was found to enhance ara-CTP production in murine tumor cells, and in the present study, was shown to inhibit deamination of ara-C at both the nucleoside and nucleotide level. Enhanced ara-CTP formation was observed in cells lacking cytidine deaminase (L1 210 and HL60), indicating that 3-deazauridine inhibition of deoxycytidylate deaminase may be important in this drug interaction.


[Induction chemotherapy in high risk breast cancer. Results of a prospective therapeutic study (author's transl)]. The action of an induction chemotherapy was studied in 54 patients with extensive localized tumour. An association of doxorubicin (adriamycin), vincristine and methotrexate were used in five days courses every three weeks. Three to four courses were applied before radiotherapy (minimum of two months of treatment). This chemotherapy gave very good immediate objective responses (87% of the cases), especially for breast tumors which follow an acute course. No adverse effects on the later sequences of the treatment program were observed. The follow up period is too short to establish long term efficacy. Nevertheless, it now seems of value to apply the chemotherapy from the onset of the disease: on one hand it represents a preparatory factor which is probably useful in reinforcing the action of loco-regional treatment; on the other hand it represents the first treatment for these high risk breast cancers, whose prognosis is mainly determined by metastasis.


Clinical pharmacological studies on 5-FU treatment for advanced gastro-intestinal carcinomas. The authors summarize clinical studies on 5-FU treatment for advanced disseminated colonic, rectal and pancreas cancers. The advantage of pushing intravenous (I.V.) injections slowly to avoid pain and using peristalt pumps for I.V. infusion are pointed out. Since the renal toxicity of 5-FU is minimal, higher doses may be envisaged which could give better results. Studies are in progress to try to determine a model for 5-FU kinetics.


A curious occipital polyp.

A curious occipital polyp. Muscles which lose their attachments are uncommon. During development this normally occurs in certain muscles, e.g. the muscles of the face and epicranius; these muscles lose their skeletal connections before migration. In the case presented here a muscle in the occipital region had lost its attachment and formed a peculiar swelling.


Arteriovenous grafts for vascular access in haemodialysis. The outcome of 68 arteriovenous grafts placed in 46 patients requiring haemodialysis was studied over a period of 3.5 years. The biological grafts included autogenous saphenous vein, modified bovine carotid artery and human umbilical cord vein allograft, whereas the synthetic grafts comprised Sparks Dacron mandril, expanded reinforced polytetrafluoroethylene and knitted Dacron velour. These subcutaneous grafts were arranged as looped or straight configurations in the forearm or thigh. Of 59 grafts evaluated in patients with end-stage renal failure, only 48 per cent of the forearm grafts performed well, compared with 85 per cent of the thigh grafts. Although only 38 per cent of the looped grafts were successful, 78 per cent of the straight grafts functioned satisfactorily. Synthetic grafts suffered less serious complications than the commercial biological grafts.


Spinal epidural abscess presenting as acute abdomen in a child. Spinal epidural abscess is seldom encountered in children and rarely occurs in the absence of spinal pain. A case is described in which a child with a thoracic epidural abscess presented with abdominal rather than spinal pain. Thoracolumbar radicular inflammation and visceroparietal reflexes initiated by a s'spinal ileus' probably produced the symptoms and signs of acute intra-abdominal disease. Consideration of intraspinal disease is advisable in all cases of acute abdomen which exhibit atypical features.


Pyeloduodenal fistula: a case report and review of the literature. A case of the rare condition of pyeloduodenal fistula is presented--the thirty-second case so far recorded in the literature. The authors consider that this instance shows some of the features typical of the cases so far reported. The literature is reviewed and the aetiology, presentation, diagnostic methods and treatment are briefly discussed.


Results of proximal gastric vagotomy over 1-5 years in a district general hospital. One hundred and seventy-three underwent proximal gastric vagotomy for duodenal ulceration over a 6-year period. One hundred and fifteen of these have been followed up for 1-5 years. The operative mortality was nil and the result was satisfactory in 91 per cent. The incidence of side effects was small, notably that of dumping being 2.4 per cent and of diarrhoea, 3.6 per cent. Incidence of postoperative heartburn was reduced from 13 per cent to 4 per cent by the introduction of hepatic interposition. The incidence of recurrent ulceration was 5.1 per cent after an average interval of 2 years and that of new gastric ulceration 2.6 per cent after an average of 4 years. There were no recurrent ulcers in those who had peroperative Burge tests, although secretory studies showed no difference between those tested and those not tested. Most recurrences occurred in the earliest cases operated on before Burge testing was introduced and when only 2 cm of the lower oesophagus were exposed.


Long term follow-up of patients with gastric ulcers treated by vagotomy, pyloroplasty and ulcerectomy. Vagotomy and pyloroplasty with excision of the ulcer has been performed in a series of 90 patients with benign gastric ulcers. Long term follow-up has shown only 2 patients with recurrent, ulceration . Fifty-eight patients with more than 2 years' follow-up attended for personal interview, of whom 96 per cent had a satisfactory result.


Pylorectomy and prepyloric antrectomy for gastric ulcer. From July 1970 to May 1977 79 patients with chronic gastric ulcer were submitted to a pylorectomy and prepyloric antrectomy (only 4--5 cm of the distal stomach being removed). In most, the excision extended in the form of a narrow tongue along the lesser curvature to include the ulcer. Vagotomy was added when signs of a healed or active duodenal ulcer were seen (19 cases). Associated lesions in the distal stomach were detected in 38 more patients. Up to the present no recurrence has been observed and functional results have been satisfactory in 90 per cent of patients. Preliminary results show that this operation produces a satisfactory cure for gastric ulcer, thus making more extensive resections unnecessary.


Toxic dilatation of the colon in salmonella colitis and inflammatory bowel disease. Toxic dilatation of the colon may be due to inflammatory bowel disease, either ulcerative colitis or Crohn's disease of the colon, but recent experience has shown that infective colitis due to salmonella can produce this complication. We present 13 cases with toxic dilatation (9 inflammatory bowel disease and 4 salmonellosis) and outline the diagnostic features and treatment in these patients. It is important to distinguish salmonellosis at an early stage because, whilst toxic dilatation in inflammatory bowel disease is an absolute indication for surgical treatment, cases with this complication due to salmonellosis may be treated conservatively in the majority of instances.


Colour lymphography in clinical surgery. In 38 patients undergoing femoral artery profundaplasty and in 18 having simple mastectomy with pectoral node biopsy, a 6.2 per cent solution of sodium sulphan blue was injected peripherally to outline the lymph nodes in the groin or axilla. Nodes and vessels were easily seen and the technique is now in routine use.


Splenectomy for undiagnosed splenomegaly. During the 9-year period 1968-76 116 splenectomies were performed at the General Hospital, Nottingham. Of these, 13 (11 per cent) were undertaken for unexplained splenomegaly. In 6 patients a diagnosis was established by the operative procedure (2 with sarcoidosis, 2 splenic cysts, 1 Gaucher's disease and 1 haemangiosarcoma). Histological examination of the excised spleens in the remaining 7 patients showed no specific features. Two of these patients benefited considerably from removal of very large spleens. Another patient died from lymphosarcoma which was diagnosed 21 months after splenectomy. In the remaining 4 patients with mild to moderate splenomegaly, there were no real diagnostic or therapeutic advantages. It is concluded that splenectomy should always be considered in patients with unexplained moderate or gross splenomegaly but it may not be helpful in the patient whose spleen is only midly enlarged.


Chylothorax following resection of the oesophagus. Chylothorax complicating operations on the oesophagus has been reported infrequently; it carries a mortality rate of about 50 per cent. A search of the literature has yielded only 10 cases. This paper reports 4 further cases which occurred among 685 resections of the oesophagus, giving an incidence of 0.6 per cent. The diagnosis should be confirmed with lymphangiography. Treatment should be early exploration and ligation in patients in whom the thoracic duct has been divided at operation. If the duct has been injured during blind dissection a period of conservative treatment is advisable. Parenteral nutrition is a useful adjunctive treatment.


Complications associated with the use of the Celestin tube for benign oesophageal obstruction. Two cases are described in which disruption of a Celestin tube took place after being lodged in a benign oesophageal stricture for 14 months. One patient presented with apparent acute pancreatitis and the other with a minor gastrointestinal bleed.


Translocating the aberrant right subclavian artery in dysphagia lusoria. A case of dysphagia lusoria with unusual associated symptoms in an adult is presented. The condition was treated by division of the aberrant right subclavian artery at its origin through a median sternotomy and translocating the distal subclavian artery to the aortic arch with an interposition Dacron graft. All the reported techniques of dividing and transposing the aberrant right subclavian artery in dysphagia lusoria are reviewed and discussed.


Gastric carcinoma and previous peptic ulceration. The incidence of patients with gastric carcinoma having had a previously diagnosed or suspected peptic ulcer was noted in two studies. These studies were the West Midlands Gastric Chemotherapy Trial (1974--6) and a retrospective study of patients presenting to the United Birmingham Hospitals with gastric carcinoma during the years 1958--62 and 1968--72. The incidence of patients found to have had a previous operation for duodenal ulcer or to have post-mortem evidence of one was 6.5 per cent and 5.7 per cent respectively. A radiologically proved duodenal ulcer had been identified in 5.5 per cent and 2.1 per cent respectively and the incidence of previous symptoms suggestive of a duodenal ulcer was 4.0 per cent and 5.2 per cent. These figures indicate the total incidence could be 12.97--16.0 per cent, which is much higher than previously reported. The mean time interval between operation for duodenal ulcer and the development of gastric carcinoma was much longer in patients having had a partial gastrectomy than in patients having had a vagotomy and drainage procedure. The incidence of previous benign gastric ulcers was 2.5 per cent and 0.9 per cent. Fifty-three per cent of patients having had a previous operation for duodenal ulceration were found to have an unresectable carcinoma, compared with the overall unresectable rate of 35 per cent.


A reappraisal of the value of carcinoembryonic antigen in the management of patients with various neoplasms. Eight hundred and eight patients with histologically proved malignant disease had carcinoembryonic antigen (CEA) estimations performed at the time of tissue diagnosis. An elevated level was found in 384 of 518 patients with gastrointestinal neoplasms (74 per cent) and in 162 of 290 patients with other neoplasms (56 per cent). No correlation was found between CEA elevations and tumour differentiation. There was a good correlation between tumour staging and CEA levels for patients with colorectal cancer; the more advanced the tumour, the higher the CEA. Several illustrative cases are presented and the role of CEA assay in the diagnosis and management of neoplasia is discussed. CEA assay is a poor screening test for neoplastic disease, but serial CEA monitoring is valuable in the detection of residual or recurrent cancer.


Arterial obstruction of the upper limb in Buerger's disease: its incidence and primary lesion. In the present study, the incidence of upper extremity involvement and the primary lesion of the arm in Buerger's disease were investigated with special regard to arteriographic findings in the upper limb. Of 34 patients with Buerger's disease admitted to our hospital during the 12-month period from March 1977 to February 1978, in 31 cases (91 per cent) the existence of arterial obstruction of the upper limb was confirmed. From the results of arteriographic study in 78 arms, the primary lesion of Buerger's disease appears to develop most frequently in the digital arteries. However, it is possible for the disease to develop independently in the arteries of the hand, or in the radial or ulnar artery. Although the aetiology of Buerger's disease is not definitely known, it is suggested that repeated blunt injury to the hand or fingers is involved in the evolution of the disease as well as in the appearance of symptoms.


Late revascularization of the lower limb following acute arterial occlusion. Thirty-four patients presenting with signs of grave ischaemia of the lower limb following acute arterial occlusion had revascularization procedures performed. Fifteen of the incidents followed embolism or thrombosis and 19 were due to a traumatic cause. Limb salvage was achieved in 67 per cent of the nontraumatic group and in 56 per cent of the traumatic group. Severe complications such as crush syndrome and disseminated intravascular coagulation occurred but there were no deaths. No significant adverse factors with regard to limb prognosis could be defined. We feel that late revascularization in the absence of major gangrene is worth while provided that facilities for critical postoperative care exist.


Ascaris lumbricoides and perforation of the ileum: a critical review. Ileal perforation due to typhoid bacilli is the commonest cause of peritonitis in the Tropics. Perforation due to Ascaris lumbricoides is rare. Three cases of ileal perforation believed to be due to A. lumbricoides are presented and the evidence critically reviewed. It is suggested that signs of heavy infestation with A. lumbricoides make a diagnosis of intestinal perforation more likely in a patient with an acute abdomen.


Surgical aspects of radiation injury to the intestine. The clinical features are described of 37 patients requiring surgical management for radiation injury to the intestine sustained as a result of treatment of abdominal or pelvic malignancy. Twenty-nine of the patients underwent operation and only 4 remained symptom-free after the procedure. Thirteen patients died in the postoperative period, and of these, 5 were free of the original disease. Possible predisposing factors in the production of intestinal injury are discussed, as are various means of dealing with the established condition.


Thyroid cancer in Kuwait: review of 117 cases. One hundred and seventeen patients with thyroid cancer were seen at the Radiotherapy and Isotope Centre, Al-Sabah Hospital, Kuwait, between 1963 and 1974. Thyroid cancer constituted 4.7 per cent of all cancer cases among females and 2.4 per cent among males. Of these carcinomas, 58 per cent were papillary, 25 per cent follicular, 11 per cent anaplastic and 1.7 per cent medullary. Four cases (3.4 per cent) were of malignant lymphoma. The 10-year survival was 74, 96 and 21 per cent for papillary, follicular and anaplastic tumours respectively. The present series confirms the prognostic value of age, sex and histology and shows that node metastasis does not prejudice survival. The study does not show any correlation between the type of operation and survival.


Volume infusion in experimental refractory shock. The postulated contribution of primary myocardial failure to the pathogenesis of refractoriness of shock to conventional therapy is in direct contradiction to the widely advocated clinical practice of infusion of large volumes of fluid in shock resuscitation. A standard volumes of fluid in shock resuscitation. A standard canine haemorrhagic shock model, in which refractory shock is induced by maintaining an arterial blood pressure of 40 mmHg for 2 h, has been used to assess the effects of volume infusion to maintain a central venous pressure of 0--2 mmHg for a further 2 h and the tolerance of such an infusion by the heart in refractory shock. Fluid infusion ensured significantly better figures for oxygen balance than in those animals where additional fluid was not given, and the volumes required appeared to be well tolerated by the shocked myocardium. Primary myocardial failure does not appear to be a major aetiological factor in refractory shock, and provided that the usual monitoring parameters are recorded, volume infusion remains a major part of shock resuscitation.


Sequential patterns of haemodynamic and metabolic changes in experimental hypovolaemic shock. II. Responses to reinfusion of shed blood. The haemodynamic and metabolic effects which follow the infusion of blood in experimental hypovolaemia have not been studied in detail. The 10 dogs that survived 90 min of hypovolaemia in a study of bleeding (Pardy and Dudley, 1979) were investigated during and shortly after the reinfusion of shed blood using the same techniques. Data from 9 animals were suitable for analysis. As with bleeding, 6 sequential phases were identified; reinfusion of blood was completed in the fifth phase. Initial reinfusion was associated with a rapid improvement in haemodynamic and metabolic status, although mean arterial pH fell because carbon dioxide production increased. Maximum metabolically effective tissue perfusion was probably attained in phase II, but haemodynamic improvement continued until phase IV. Arterial pH did not rise above the pre-infusion value until phase V, and this rise was the result of a fall in PaCO2 secondary to a reduction in physiological dead space and an increase in buffering capacity. Pulmonary artery pressure was superior to systemic artery pressure as a predictor of cardiac output during blood volume restoration. A number of conclusions pertaining to clinical practice are drawn.


The reproducibility of the station pullthrough technique for measuring lower oesophageal sphincter pressure. The results are presented of two studies of the station pullthrough technique for lower oesophageal manometry. The first part of the work is an assessment of the reproducibility of this technique using both an infused tube system and a system of subminiature, intraluminal strain gauge transducers. The second part of this report describes a study into the effect that the position of the recording hole on the probe may have in relation to the measured pressure for the lower oesophageal sphincter.


The surgical management of malignant tumours of the oesophagus and cardia: a review of the results in 292 patients treated over a 15-year period (1961--75). Of 292 patients, excision of the tumour with replacement by stomach or jejunum was carried out in 216 in whom the lesion was considered operable on both technical and general grounds, intubation was performed in 45 and the remaining 31 were managed without operation. Of the 216 in whom resection was performed, only 20 per cent were free from local spread, lymph node involvement or secondary deposits at the time of operation. Hospital mortality was 18 per cent and did not significantly differ between one 5-year period and another. Survival at 1 year was 54 per cent, at 2 years 25 per cent and at 5 years 14 per cent. The average length of survival following intubation was 2.6 months and following non-operative management 2.8 months. The poor average survival of between 3.5 and 5 months obtained in those patients with secondary deposits at the time of resection suggests that resection is of questionable value in this group. There was a marked difference in survival following Roux loop procedures compared with upper partial gastrectomy for tumours of the lower third and cardia in patients without lymph node involvement or secondary deposits, strongly suggesting that upper partial gastrectomy, although a rather simpler and quicker operation, is not the operation of choice in these patients. On 31 December 1976, after a minimum follow-up of 1 year, there were only 22 patients still alive of the original 292 (7.5 per cent).


Influence of body fatness in childhood on fatness in adult life. Comparison of skinfold thicknesses measured in childhood and again 15 years later in 318 male and 303 female subjects disclosed only a moderate relation between the two measurements. Where adult fatness could be predicted from combinations of skinfold thicknesses in childhood the accuracy in 95% of cases lay at the mean between +/- 8% and +/- 18% according to age and sex.


Characteristics affecting fibrinolytic activity and plasma fibrinogen concentrations. As part of a study to determine the extent to which the haemostatic system is implicated in the onset of clinically manifest ischaemic heart disease, characteristics influencing fibrinolytic activity (FA) and plasma fibrinogen concentrations were examined in 1601 men aged 18-64 and 707 women aged 18-59 in several occupational groups in North-west London. In men FA noticeably decreased till the age of about 58, when there was a small rise. In women a small increase in FA between 18 and about 40 was followed by a slightly larger fall between 40 and 59. There was a pronounced negative association of FA with obesity. FA was significantly less in smokers than non-smokers, though the effect was not large. FA increased with alcohol consumption. FA in men appeared to be greatest in the lower social classes, and men on night shift had poorer FA than those on day work. FA was greater in women using oral contraceptives than in those not using these preparations. In both sexes FA increased with exercise, but there were no associations between any of the characteristics studied and the increase. Plasma fibrinogen concentrations increase with age and obesity, are higher in smokers than non-smokers, and fall with alcohol consumption. In women the concentrations are higher in those using oral contraceptives. The general epidemiology of FA and plasma fibrinogen concentrations suggests that they may well be implicated in the pathogenesis of ischaemic heart disease.


Prospective study of ultrasonography in chronic pancreatic disease. Grey-scale ultrasonography was used in 212 unselected patients in whom the presence or absence of pancreatic disease was subsequently confirmed by other means. Ultrasonographic criteria were established in the first 92 patients and by reference to previous experience. The remaining 120 patients were studied prospectively. The accuracy and clinical impact of the ultrasonographic diagnosis were judged alongside a standard clinical assessment. Clinical diagnoses were tentative and inaccurate. Ultrasound failed in three cases; otherwise it detected all the 33 patients with chronic pancreatic disease and correctly distinguished cancer from chronic pancreatitis. The ultrasonographic diagnosis of a normal pancreas was always correct, but four false-positive diagnoses were made in patients subsequently judged to have no pancreatic disease. Ultrasonography gave more accurate or more confident and accurate information than the clinical assessment in 57 of the 98 patients studied as problems in diagnosis. With this degree of accuracy ultrasonography should be the first imaging investigation in patients suspected of suffering from pancreatic disease. In our gastrointestinal unit the combination of grey-scale ultrasonography with techniques designed to outline the duct systems (such as endoscopic pancreatography) provides precise diagnosis and documentation of pancreatic disease.


Abortion and the NHS: the first decade.

Abortion and the NHS: the first decade. Analysis of statistics published since the Abortion Act showed that from 1972 about half the abortions carried out on residents of England and Wales had been performed within the National Health Service. Regional variations in the proportions of abortions performed within the NHS had persisted. In some health regions fewer abortions were being carried out than before. In 1975 about 40% of abortions on single women and women with no existing children were performed within the NHS. Trends in the concurrent sterilisation rate, gestational age at operation, duration of stay in hospital, and mortality and complication rates suggested a steady improvement in the effectiveness and efficiency of abortion services. Nevertheless, the NHS still compares poorly with the private sector and some other countries.


Comparison of intravenous and oral high-dose methotrexate in treatment of solid tumours. An outpatient regimen of oral high-dose methotrexate was studied in 14 patients with solid tumours over 12 months. Detailed pharmacokinetic analysis in five patients showed high oral bioavailability (mean +/- SE of mean 87.6 +/- 1.5%), indicating that with this regimen oral methotrexate was well absorbed and the first-pass effect low. Oral administration resulted in peak plasma methotrexate concentrations of 8.4 +/- 0.5 mumol/l (382 +/- 23 microgram/100 ml) and was almost as effective as intravenous administration, which achieved peak concentrations of 9.9 +/- 0.4 mumol/l (450 +/- 18 microgram/100 ml). In all 14 patients the clinical response to oral treatment was comparable to that reported to intravenous administration of high-dose methotrexate used in combination with other cytotoxic drugs. The disease-free interval in cases of adult sarcoma was 7.4 +/- 1.3 months and the relapse rate 29%. Out of four patients with small-cell carcinoma, two showed an objective response to oral treatment. We suggest that oral high-dose methotrexate given in divided doses is a rational alternative to expensive intravenous high-dose methotrexate regimens, but further clinical evaluation is necessary.


Assessment of renal concentrating ability. Maximum urine osmolality was measured during a 24-hour control period in normal ambulant and working subjects and hospital inpatients and compared with that achieved after intramuscular injection of 4 microgram desamino-cys-1-8-D-arginine vasopressin (DDAVP). Most of the normal subjects passed maximally concentrated urine at some time during the control period. The results suggest that in less active subjects or hospital inpatients the DDAVP test is a suitable method of assessing renal concentrating ability.


Effect of prolactin on dopamine synthesis in medial basal hypothalamus: evidence for a short loop feedback. Several procedures were utilized to study the effects of prolactin on dopamine synthesis in the medial basal hypothalamus of the rat. Elevation of serum prolactin was produced by the administration of trifluoperazine (5 mg/kg, i.p.) and resulted in a significant increase in the conversion of [3',5'-3H]tyrosine to dopamine when measured in slices of medial basal hypothalamus and striatum. Hypophysectomy abolished this effect of trifluoperazine in the medial basal hypothalamus but not in the striatum. In addition, the synthesis of dopamine was significantly elevated in slices of medial basal hypothalamus obtained from rats bearing pituitary tumor implants that secreted microgram quantities of prolactin. In contrast, the in vitro synthesis of dopamine in the striatum of such rats was increased by the secretory products in one tumor line but decreased in another compared to that observed in control animals. It is suggested that the ability of prolactin to accelerate the synthesis of dopamine in the medial basal hypothalamus might constitute a short loop feedback system that finely regulates prolactin secretion.


Corticotectal and other corticofugal projections in neonatal cat. Adult physiological properties of cat superior colliculus cells develop gradually during the first two months of life. Since many of the neuronal properties in the adult cat appear to depend upon the integrity of visual cortex, it was postulated that the maturation of superior colliculus cells is, in large part, a reflection of corticotectal maturation. An attempt was made to study the development of the corticotectal pathway with the autoradiographic tracing technique. Injections of [3H]leucine were made in the visual cortex of kittens 6 h to 12 days of age and animals were sacrificed 20-24 h later. A dense projection from visual cortex to the superior colliculus and to the lateral geniculate nucleus was noted in all animals. Both projections appeared to be topographically organized. In addition, cortical projections to the lateral posterior-pulvinar region and sparse projections to the contralateral visual cortex were noted. Two, non-mutually exclusive, explanations for the presence of a corticotectal pathway in the absence of mature cell properties in the superior colliculus are most apparent: (a) corticotectal synapses are incompletely formed at birth and require many weeks to develop, and (b) corticotectal cells are immature during early postnatal life and cannot impress adult-like characteristics upon the superior colliculus cells until they, themselves, 'mature'.


Interaction of neural systems which control nutritional balance. The functional relationships of 5 nuclear masses of the cat brain were analyzed under conditions of general anesthesia by a combination of neurophysiological methods. The nuclear masses are known as (1) the area lateralis hypothalami (ALH), (2) the nucleus entopeduncularis (nEp), (3) the nucleus semilunaris accessorius (nSA), (4) the nucleus ventromedialis hypothalami (nVmH), and (5) the posterolateral portion of the zona incerta (ZI). Neurons of the ALH, nEp, and nVmH were tested for their responsiveness to electrical stimulation of the thalamic taste nucleus (nSA) and to intracarotid infusions of glucose and insulin. Following this, lesions were placed in some of the nuclei, and the responsiveness of the same neurons to glucose and insulin was re-evaluated. Additional experiments were performed to determine the influence of certain peripheral receptors on the 5 nuclear masses. Results indicated the following. (1) ALH-Ep neurons which are influenced by the nSA stimulation receive information about changes in plasma glucose from two sources: taste receptors and receptors located in the splanchnic area. The former are excited during the application of glucose to the tongue or with an increase in the plasma glucose concentration (intravascular taste); the latter, with a lowering of the plasma glucose level. (2) Destruction of the nSA leaves the ALH-Ep neurons unresponsive to glucose and insulin. (3) A negative feedback loop interrelates certain neurons of the ALH-Ep with the nVmH. (4) Interactions of the neurons of the 5 nuclear masses can account for the major events of the feeding cycle and for the specific hungers for some substances. Moreoever, the interactions can resolve several seemingly discordant experimental findings which have presented obstacles in previous attempts to link the control of nutrition with the availability of glucose to tissues.


Innervation of hippocampal explants by central catecholaminergic neurons in co-cultured fetal mouse brain stem explants. The ability of central catecholaminergic neurons to grow into and establish functional connections with the hippocampus in vitro was studied using organotypic tissue culture. Brain stem explanted from the region of the locus coeruleus and hippocampal explants, from 18-day fetal mice, were maintained as co-cultures and were also grown separately. After 1-4 weeks these tissues were analyzed by glyoxylic acid-induced histofluorescence, by light and electron microscopic radioautography after incubation with [3H]norepinephrine, and by electrophysiology. Brain stem explants exhibited specifically fluorescent catecholaminergic cell bodies and varicose fibers after 2-4 weeks in culture. In contrast, no fluorescent cells or neurites could be seen in isolated hippocampal cultures grown for 2-3 weeks in vitro. When hippocampal explants were grown near brain stem explants, catecholaminergic fibers grew out of the brain stem and entered the hippocampus. In additional experiments, co-cultures of brain stem and hippocampus were incubated with [3H]norepinephrine (0.5 micron) and the monoamine oxidase inhibitor nialamide (100 micron). Radioautographic analyses revealed that brain stem neurites which entered the hippocampus took up norepinephrine, whereas neurites in the isolated hippocampal explants did not. Electron microscopic studies of the hippocampus showed varicose axon terminals within the hippocampus to be preferentially labeled. Although close relationships could be seen between labeled axons and dendrites, junctions exhibiting the membranous modifications associated with synapses were never seen. Electrophysiological studies suggested that the catecholaminergic neurites within the hippocampus were functional. Complex synaptically mediated slow wave discharges could be evoked by electrical stimuli in isolated hippocampal explants. Introduction of the beta adrenergic antagonist propranolol (0.4-4.3 micron) did not alter, or slightly depressed, these hippocampal discharges. On the other hand, in hippocampus-brain stem co-cultures, these concentrations of propranolol enhanced the complex hippocampal responses to brain stem or hippocampal stimuli. Similar enhancement of hippocampal responses by propranolol also occurred in these cocultures after acute surgical extirpation of the brain stem explant. The data suggest, therefore, that the action of propranol was probably to block adrenergic inhibitory connections with hippocampal synaptic networks. These experiments provide morphological and electrophysiological evidence that catecholaminergic neurons from fetal mouse brain stem maintained in organotypic tissue culture can grow into and functionally innervate the hippocampus.


The lipid and protein content of cholinergic synaptic vesicles from the electric organ of Torpedo marmorata purified to constant composition: implications for vesicle structure. The lipid, protein, acetylcholine and ATP content of cholinergic synaptic vesicles isolated from the richly innervated electric organ of Torpedo marmorata and purified to constant composition has been determined. The number of vesicles present in the preparations has been estimated by quantitative electron microscopy and the mean composition of the vesicle deduced. The acetylcholine content of the purest preparations was considerably greater than that previously attained and reached a mean of 6.10 mmole/g of protein and 2.6 X 10(5) molecules/vesicle; the mean values, for all determinations, were 4.1 +/- S.E.M. 0.6 and 2.6 X 10(5) +/- S.E.M. 0.6 X 10(5) respectively. The lipid and protein content of the vesicle (about 140 and 80 ag/vesicle respectively) is relatively low, indicating a thin, lipid-rich membrane and a highly hydrated core of which not more than 1-2% can be occupied by protein. These findings are consistent with conclusions drawn from recent density determinations made at different osmotic pressures using penetrating and non-penetrating gradients.


Changes in hormone activity of single neurosecretory cell bodies during a physiological secretion cycle. Single neurosecretory cell bodies were dissected from the ventral ganglionic mass of Rhodnius prolixus, lysed in distilled water, and bioassayed for diuretic hormone (DH) activity on isolated malpighian tubules. DH was found in a least 10 somata within the ganglion; electron micrographs of isolated cells show a large population of elementary neurosecretory granules. Quantitative measures of hormone activity were made by bioassaying somata from unfed 5th instar larvae, and at the following times after feeding; 1 h, 4 h (near the end of DH-mediated diuresis), 1 day, 5 days, 10 days, 17 days and 21 days (just after the moult to adult). DH activity in cell bodies drops significantly within 1 h after feeding, and remains low long after hormone secretion ceases. Restocking of the soma with active hormone occurs during the period 10-21 days after feeding.


Sequential effects of thyroxine on the developing cerebellum of rats made hypothyroid by propylthiouracil. Young rats made hypothyroid by propylthiouracil (PTU) received a daily physiological dose of thyroxine (T4) from day 0, 4, 6, 8, 10, 11, 12 or 13 and their cerebella were studied on day 14. With the very low doses of T4 used and when the treatment was started at birth, cerebellar development was nearly normal in terms of the parameters studied (cell formation, migration, maturation and death). The effect of T4 on cell formation appeared after two days. With the same latency, T4 induced migration of the newly-formed granule cells. The effects on those processes requiring cell movements over long distances, e.g. the number of cells in the internal granular layer or the thickness of the molecular layer, were longer to appear. The most rapidly affected parameter was the pyknotic index in the internal granular layer. This index was half. The increased cell death in the cerebellum of hypothyroid rats is probably related to the decreased synaptogenetic competence of Purkinje cells. The rapidity of the effect of T4 on the pyknotic index may be related to an important effect of this hormone on the formation of synapses and, more generally, on the mechanisms of neuronal maturation.


Protein synthesis in rat brain in hypoxia, anoxia and hypoglycemia. The effect of cerebral hypoxia on protein synthesis was investigated by exposing rats to 5% O2, and examining polypeptide synthesis and size distribution profiles of ribosomes. The findings were compared with the results from cerebral anoxia (decapitation) and hypoglycemia. In cerebral hypoxia there was suppression of polypeptide synthesis, though to a lesser extent than in cerebral anoxia, while no effect was detected in hypoglycemia. Among 4 different ribosomal fractions used for polypeptide synthesis, the microsome was the most sensitive for hypoxia and anoxia, and the polyribosome after short centrifugation was the least sensitive. The size distribution profiles of 3 different ribosomes revealed an increase in the size of the monomere-dimer complex and a decrease of the polysome peak both in cerebral hypoxia and anoxia. Comparison of the energy state and the extent of lactic acidosis in cerebral hypoxia, anoxia and hypoglycemia available in the literature and the functional and structural state of polyribosomes in the present investigation suggests that intracellular acidosis may be the main cause of the suppression of polypeptide synthesis and disaggregation of polyribosomes in hypoxia, and the depletion of energy reserve may be the main cause in anoxia-ischemia.


Preparation of viable astrocytes from the developing cerebellum. A cell fraction enriched in viable astrocytes has been prepared from the developing rat cerebellum. The isolated astrocytes were identified by indirect immunofluorescence using antiserum to glial fibrillary acidic protein (GFAP). In comparison with the low incidence (6%) of GFAP-positive cells in the unfractionated cell suspension from trypsinized cerebellar tissue, these accounted for half of the cells in the final preparation. This was achieved by treatment at 6 days of age with hydroxyurea (an inhibitor of DNA synthesis) which enriched the tissue in GFAP-positive astrocytes at day 8. At the same time, by selectively removing the heterogeneously sized replicating cells, hydroxyurea treatment allowed resolution of a fraction enriched in GFAP-positive cells using unit gravity sedimentation. The isolated astrocytes differentiated in culture producing, by 3 days in vitro, a dense network of fine GFAP-containing processes.


Projection from the vestibular nuclei to the inferior olive in the cat: an autoradiographic and horseradish peroxidase study. Injections of horseradish peroxidase (HRP) in the inferior olive of 13 cats resulted in the labeling of neurons in the medial (MVN) and descending vestibular nuclei (DVN) as well as in subgroups g, p.h., s.v., x and z. The contribution of groups p.h. and z. could not be definitively established. Injections of triated leucine in the vestibular nuclei and adjacent reticular formation in 4 cats indicated that the previously identified vestibular nuclei and subgroups project bilaterally to the dorsomedial cell column and ipsilaterally to subnucleus beta of the inferior olive. In view of the known topography of olivocerebellar projections, the present results suggest that climbing fiber-mediated vestibular information may influence the uvula and the fastigial nucleus.


Responses in sympathetic nerves of the dog evoked by stimulation of somatic nerves. Responses in thoracic and renal sympathetic nerves evoked by electrical stimulation of cutaneous and muscle nerves in anaesthetized mongrel dogs were observed. Supramaximal stimulation of cutaneous nerves evoked two responses in both thoracic and renal nerves with latencies in the ranges 58--184 msec and 349--733 msec which are referred to as the early and late responses. It was shown that the early and late responses were evoked by group III and group IV afferent fibres respectively. Stimulation of muscle nerves of the forelimb and the hypoglossal nerve evoked smaller early responses which were considered to be due to activation of group III fibres and which had latencies in the range 92--157 msec. Supramaximal stimulation of muscle nerves in the hind limb failed to evoke any responses in approximately two-thirds of preparations and in the remainder only low level inconsistent early responses were observed. No matter how intense the stimuli applied to muscle nerves there were never any responses which could be related to the activation of group IV fibres.


Altered neuroanatomical organization in the central nervous system of the genetically obese (ob/ob) mouse. Genetically obese (C57BL/6J ob/ob) mice have significantly reduced brain weights (-14.6%) and cortical brain volumes (-7.9%) compared to lean control mice (C57BL/6J +/+). Morphometric analyses of soma cross-sectional areas of individual neurons in select brain region also reveals significant alterations in the ob/ob mouse. Neurons from 8 out of 9 brain regions, including the ventromedial hypothalamic nucleus, show significantly decreased soma cross-sectional areas in ob/ob mice compared to controls. Only lateral hypothalamic area neurons have equivalent soma cross-sectional areas for these two mouse strains. The decreased brain weight and volume coupled with the observed morphometric changes in individual neuronal soma size suggest that the ob/ob mouse brain differs considerably from that of controls. These differences may underlie some of the endocrine abnormalities seen in this genetic obesity syndrome.


Bidirectional movement of gamma-aminobutyric acid in cerebral cortex slices incubated in small volumes of medium. Rat cerebral cortex slices were incubated in small volumes of medium in order to study the bidirectional movements of gamma-aminobutyric acid (GABA) between tissue and medium, and to measure the extent of release of endogenous amino acids of interest as potential neurotransmitters. The apparent uptake, real uptake, and net change of GABA were calculated from the changes in [14C]GABA and endogenous GABA in the medium. The extent of release of endogenous amino acids was dependent upon the amino acid the duration of incubation, and the volume of incubating medium. Substantial amounts of endogenous amino acids may accumulate in the medium under conditions commonly employed in amino acid uptake studies. The accumulation of endogenous GABA may affect the calculation of GABA uptake when this is based on the initial specific activity of exogenous [14C]GABA. The difference between apparent uptake and real uptake was particularly prominent in the presence of the depolarizing agents, potassium or veratridine, which caused a marked increase in GABA release. Exchange or net release of GABA was found when slices were incubated briefly in media containing 1.3 micrometer or 12.5 micrometer exogenous GABA; net uptake accounted for 50% of observed uptake when slices were incubated in media containing 25 micrometer GABA.


Pharmacological study of a cholinergic mechanism within the rat posterior hypothalamic nucleus which mediates a hypertensive response. In unanesthetized freely moving rats, microinjection of a variety of cholinergic agonists into the posterior hypothalamic nucleus (PHN) consistently produced an elevation in mean arterial pressure (MAP). Experiments were undertaken to pharmacologically characterize this cholinergic mechanism. Microinjection of carbachol (0.1--100 nmol) into the PHN elicited reproducible and dose-related increase in MAP (17--47 mm Hg) and variable changes in heart rate. Similar responses, although longer in onset and duration, were produced by microinjection of the cholinesterase inhibitors, neostigmine, physostigmine and echothiophate. The pressor responses produced by neostigmine and physostigmine, but not by carbachol, were shown to be dependent upon intact stores of acetylcholine in the PHN. Blockade of postsynaptic muscarinic receptors by prior microinjection of atropine abolished the rise in MAP to subsequent injection of cholinergic agonists; however, similar pretreatment with the antinicotinic agent, mecamylamine, was without effect. The peripheral mechanism through which a rise in MAP was produced by cholinergic stimulation of PHN was the sympathetic nervous system since i.v. injection of an alpha-adrenergic blocking agent, phentolamine, attenuated the pressor response to intrahypothalamic injection of carbachol or neostigmine. Adrenal catecholamine release or vasopressin release were not important mechanisms in this regard. From this study we conclude that within the rat PHN there exists a muscarinic, cholinergic mechanism which, upon activation, mediates a rise in MAP through an increase in sympathetic tone.


The efferent connections of the nucleus raphe centralis superior in the rat as revealed by radioautography. By chronically implanting a glass micropipette filled with tritiated leucine in the raphe centralis superior of the rat, the projection of this nucleus was traced by radioautography. The majority of the ascending projections were located within the ventral tegmental area and, further rostrally, the median forebrain bundle. Along the course of this bundle numerous fibers branched successively into the mammillary peduncle, the fasciculus retroflexus, the stria medullaris, the fornix and the cingulum. The most significant projections included the ones to the interpeduncular nucleus, the mammillary bodies, the habenular nuclei and the hippocampus. No projections were detected in the striatum, the cortex piriformis or the amygdala. Descending projections diffused to the pontine reticular formation and central gray through the medial and the dorsal longitudinal bundles. In addition widespread projections were also seen in nuclei located near the raphe centralis superior: raphe nuclei, dorsal and ventral tegmental nuclei.


Cerebellar nuclear lesions in rats: subsequent avoidance behavior and ascending anatomical connections. Bilateral lesions of the rat cerebellar dentate and lateral interposed nuclei produced transient deficits in movement and posture, and facilitated acquisition of two-way active avoidance. Bilateral lesions of the fastigial and medial interposed nuclei of the rat cerebellum also produced transient deficits in movement and posture, but impaired acquisition of the avoidance task. Analysis of degeneration patterns after unilateral lesions to either the lateral or medial nuclear region indicated that the lateral area has a denser rostral projection than the medial area, while the medial nuclear region has a heavier caudal projection. It is suggested that these differences in anatomic connections may be related to the observed differences in lesion effect on two-way active avoidance.