Diagnostic yield of the analysis of the pattern of electrical activity of muscle and of individual motor unit potentials in neurogenic involvement. The pattern of electrical activity and the properties of individual motor unit potentials were analysed in the flexor muscles of the forearm of 15 patients with motor neurone disease and 15 patients with a lesion of the brachial plexus. The best diagnostic yield from the pattern of electrical activity was obtained when the force was 30% of maximum: The number of spikes (turns/15 s) was diminished in 70% of the patients; none showed the increase in turns characteristic of myopathy. The decrease in the number of turns was often associated with an increased incidence of long time intervals between turns and with an increased amplitude between turns. The mean duration of individual motor unit potentials was prolonged in 78% of the patients; none showed the decrease in mean duration characteristic of myopathy. Prolongation of the mean duration of motor unit potentials produced by cooling of normal muscle, led to a decrease in the number of turns. This suggested that the diminished number of turns in neurogenic involvement was due mainly to the prolonged duration of motor unit potentials.


Axonal dysfunction in the neuropathy of diabetes mellitus: a quantitative electrophysiological study. The extent of axonal dysfunction in a group of patients with diabetes mellitus has been investigated using recently introduced quantitative techniques of electromyography. In 40 diabetic patients, estimates of motor unit numbers in the extensor digitorum brevis muscles and measurements of the parameters of electrically evoked motor unit potentials therein are presented, along with significant correlations between these parameters and motor nerve conduction velocities and distal motor latencies in the lateral popliteal nerves. The results indicate that axonal dysfunction and concomitant collateral reinnervation are prominent and integral features of the neuropathy of diabetes mellitus. Axonal dysfunction is present in proportion to and parallels the severity of the demyelinative lesion. It is also extensive in patients without clinical evidence of neuropathy in whom the accompanying collateral reinnervation is of sufficient magnitude to mask the clinical signs of motor involvement.


Effect of diphenylhydantoin on gamma aminobutyric acid (GABA) and succinate activity in rat Purkinje cells. A study has been made of the effect of diphenylhydantoin (DPH) upon the levels of gamma aminobutyric acid (GABA) and succinic dehydrogenase in rat Purkinje cells. DPH was administered over 26 days in chronic experiments using controls receiving the same injection vehicle without DPH. Animals in this group received daily 1.25 mg/kg body weight, 12.5 mg/kg body weight, and 50 mg/kg body weight DPH. Acute experiments were carried out over the course of not more than four days, three groups of animals receiving 75 mg/kg body weight, 87.5 mg/kg body weight, and 100 mg/kg body weight DPH. No effect upon succinic dehydrogenase could be demonstrated at any dose level. There was a significant progressive loss of GABA with increasing dosage of DPH.


Conditioning of H reflex by a preceding subthreshold tendon reflex stimulus. The soleus H reflex excitability cycle has been studied using, as conditioning stimulus, a mechanical tap, subthreshold for the tendon reflex, which was applied either on the Achilles tendon, the short biceps tendon, or the quadriceps tendon. In all cases there was an early facilitation followed by a longlasting inhibition of the test H reflex. The same results were obtained in patients with a complete spinal cord section. Wherever the site of the conditioning stimulation, these modifications disappeared after ischaemia of the leg. It is concluded that the effects observed are due to the activation by the tendon tap of the Ia nerve fibres from the soleus muscle, and that the longlasting inhibition is probably due to a transmitter depletion.


Critical cerebral blood flow for production of hemiparesis after unilateral carotid occlusion in the gerbil. Transient cerebral ischaemia, produced by temporary unilateral common carotid artery (CCA) occlusion, was studied in the gerbil by means of chronically implanted hydrogen electrodes. Unilateral CCA occlusion produced behavioural signs of neurological deficit only when regional cerebral blood flow values in the ipsilateral cerebral hemisphere fell below a critical range of 0.20-0.22 ml/gm brain/min. Postischaemic poor perfusion (no-reflow) was an infrequent observation after removal of CCA occlusion.


Oculopharyngeal myopathy with distal and cardiomyopathy. Two patients are described with distinctive clinical features including an insidious onset, slow progression, bilateral ptosis, weakness of facial muscles, dysphagia, muscle atrophy, and weakness with a distal distribution in the extremities, and cardiomopathy with conduction system disorders. Electromyographic studies and muscle biopsy showed features highly suggestive of a myopathic disorder. One case is considered to be sporadic. The other seems to be a familial disorder, because of the presence of a mild atrioventricular block and right incomplete bundle branch block in the patient's son and the presence of eyelid ptosis in his sister. This may be a variant of oculopharyngeal myopathy with distal and cardiomyopathy. It will be necessary to perform long-term follow-up studies in these families.


Cerebral dominance for language in cerebral palsy. A test of cerebral dominance for language was administered to 51 cerebral palsied adults. The test consisted of dichotically presented words and in normal speaking adults had previously demonstrated very marked right ear superiority, interpreted as left cerebral dominance. The group of cerebral palsied subjects did not show the predicted right ear superiority. This finding may represent a chance maldistribution of side of cerebral injury within the 51 subjects. If substantiated, however, it would suggest either that the cortical damage in cerebral palsy is commonly widespread or else that the inherent left cerebral dominance of neonates is less tenacious than is generally assumed.


Electrophysiological studies in familial spastic paraplegia. Motor and sensory conduction studies have been performed in 10 patients from three families with uncomplicated familial spastic paraplegia whose ages ranged from 4 to 41 years. In all cases the values fell within the control range. The findings may be contrasted with those in Friedreich's ataxia and some other spinocerebellar degenerations in which peripheral nerve abnormalities are present.


Effects of postural changes of the upper limb on reflex transmission in the lower limb. Cervicolumbar reflex interactions in man. The influence of passive changes in upper limb position on the excitability of three myotatic arc reflexes (soleus, quadriceps, and biceps femoris) of the lower limb has been explored on 42 volunteers. The results indicate that the excitability of the three myotatic arcs can be influenced at a distance by postural modifications of the upper limb. When the ipsilateral upper limb is forwards or the contralateral backwards, a facilitation of both soleus and quadriceps tendon reflexes is observed while the biceps femoris reflexes are reduced. This pattern of facilitation and inhibition is reversed when the ipsilateral upper limb is backwards or the contralateral forwards. The facilitations as well as inhibitions of proximal myotatic arc reflexes are quantitatively more marked than that of the soleus reflex. Facilitation and inhibition are not linearly related to the angle of the arm with the trunk. Effects begin at a considerable angle, become maximal at 45 degrees, and progressively disappear for greater values. It is suggested that the distinct pattern of facilitation and inhibition which is exerted in reciprocal fashion on extensor and flexor motor nuclei might depend on the long propriospinal neurones connecting cervical and lumbar enlargements.


Incorporation of [U-14C]glucose into neutral lipids and sn-glycerol-3-phosphate in muscle from Duchenne muscular dystrophy and control patients. Muscle biopsy tissue from patients suffering from a wide range of neuromuscular disorders, normal muscle removed during regular orthopaedic procedures, and muscle from aborted human fetuses of 12--20 weeks gestation was dissected into fibre-bundles and incubated at 37 degrees C with [U-14C]glucose at a final concentration of 4 mM. Extracts made: (i) after 30 min were used to determine content and radioactivity of sn-glycerol-3-phosphate, and (ii) after 160 min for separation of lipid species. Dystrophic muscle from 8 patients with typical Duchenne dystrophy converted significantly more glucose than normal muscle (11 samples) into neutral lipids, but less into polar lipids. Of total lipid radioactivity a mean value of 66% was found in neutral lipid in the Duchenne group, while in various control groups this proportion was about 40%. The disparity observed was the result of greater incorporation of glucose label into triglycerides, chiefly in the glycerol moiety of the Duchenne group lipids, and was some 3 times greater than normal. Other muscle disease groups also showed slightly raised levels of incorporation but these were not statistically significant in the present series of results. The content and radioactivity of glycerol phosphate in muscle from 15 patients with Duchenne dystrophy were also significantly higher than in normal muscle. These findings are discussed in relation to glucose metabolism in muscle and the energy cost of transforming glucose into triglyceride.


Blood flow and uptake of glucose and amino acids in ischemic muscle. In order to examine muscle ischemia, muscle blood flow in the rat hindlimb was decreased by vessel ligation. Amino acid uptake, studied with [14C]alpha-aminoisobutyric acid, was decreased in ischemic Type I (soleus) muscle. Glucose uptake, studied with [14C]deoxyglucose, was increased in Type I muscle. These changes were temporally associated with histologic changes of ischemia in soleus muscle. Denervation, atrophy, and hypertrophy also produced uptake changes with these techniques, and although more prominent in soleus, the changes were also seen in Type II muscle.


Acute tissue response to cerebral ischemia in the gerbil. An ultrastructural study. The Mongolian gerbil, because of the uniqueness of the anatomical features of its circle of Willis, has become an increasingly useful model in the study of cerebrovascular disease. The present work defines acute changes at the ultrastructural level following ischemic insult. The pathomorphological responses include initial astrocytic involvement and, when the degree of insult is increased, a progression of morphological changes is evident in neuronal and other parenchymal elements. Animals with vessels occluded for more than 3 hr without neurological signs suggestive of ischemia exhibited limited perivascular edema. Contralateral changes (perivascular astrocytic) were observed in the basal ganglia at 24 hr in animals with neurological deficit. Astrocytic and basal ganglia susceptibility to ischemia was consistent with previous findings in primate models. An additional association was found in that limited edematous involvement could exist in animals without neurological deficit but neuronal changes were only present in animals with signs of ischemic neurological deficit.


Canine globoid cell leukodystrophy. Part 1. Further ultrastructural study of the typical lesion. The ultrastructural changes of typical lesions in canine globoid cell leukodystrophy (GLD) have been studied. The globoid cells were located in the cerebral parenchyma as well as in the perivascular Virchow--Robin space. Features suggestive of a passage of the globoid cells from the cerebral parenchyma to the Virchow--Robin space were also observed through the interruptions in the basal lamina. The globoid cells had numerous thin pseudopods and contained various cytoplasmic inclusions which have been described previously. Detailed studies of these inclusions suggest that they represented aggregates of filamentous or linear sub-unit structures. Typical oligodendroglial cells were found on only a few occasions. Both globoid cells and oligodendroglia contained myelin debris, dense bodies and honey-comb like inclusions composed of numerous small myelin figures. In a few instances, crystalline polygonal inclusions identical to those found in the globoid cells, were found in the cytoplasm of the cells which were, with reasonable certainty, identifiable as oligodendroglia. In less affected areas where myelin was still present, degenerating oligodendroglia, with or without recognizable inclusions, were frequently encountered. Astrocytes and endothelial cells contained concentric lamellar inclusions and dense bodies but did not contain the tubular inclusions as seen in globoid cells. The possible significance of the ultrastructural features in regard to the pathogenesis of the GLD have been discussed.


Numbers of Hirano bodies in the hippocampus of normal and demented people with Alzheimer's disease. Hirano bodies were counted in the pyramidal layer of the hippocampus in the brains of 34 demented patients with Alzheimer's disease or senile dementia of the Alzheimer type and 24 non-demented subjects of 60 years and over who had been psychometrically assessed. Hirano bodies were also counted in an additional 27 people between the ages of 18 and 59 who had not been assessed but were thought to be intellectually normal. Hirano bodies were found at all ages, but in normal subjects they were significantly more numerous from the age of 60 onwards. Demented subjects of 60 years and over with Alzheimer's disease had significantly more Hirano bodies than normal subjects in the same age range.


Evidence for inorganic phosphate binding at nodes of Ranvier in peripheral nerves. Ferric ion is bound to different sites at nodes of Ranvier, depending on how the nerves are prepared. By immersing fresh, unfixed nerves in phosphate buffer, cacodylate buffer, or physiological saline prior to staining with ferric ion and ferrocyanide, it can be shown that binding of ferric ion to the extracellular nodal gap substance requires pretreatment with inorganic phosphate. This implies that phosphate anions are bound to the gap substance where they may then promote precipitation of ferric ion. These results call for a re-evaluation of data that depend on ferric ion binding to nodes of Ranvier. They also open the possibility that affinity for anions in general, or phosphate in particular, may be a significant feature of extracellular molecules present at nodes.


Motor neurone disease with neurofibrillary tangles in a Brazilian woman. The occurrence of neurofibrillary tangles in both the cerebral cortex and brain stem is typically seen in the Guam type of amyotrophic lateral sclerosis, but is exceedingly rare in the classical form of the disease. Only 3 cases of sporadic amyotrophic lateral sclerosis with such histopathologic features have so far been reported, all in the United States. A 49-year-old Brazilian woman had an 18-month history of amyotrophic lateral sclerosis involving predominantly the left-sided extremities with prominent bulbar signs. Autopysi disclosed moderate to severe loss of motor neurones in the hypoglossal nuclei and anterior spinal horns, absence of pyramidal tract demyelination, depigmentation of the substantia nigra and numerous neurofibrillary tangles in the hypothalamic region, parahippocampal gyrus, reticular substance of the mesencephalon and pons and in some brain stem nuclei. The topographical distribution of these changes was closely similar to that of Guamanian amyotrophic lateral sclerosis.


Statistical variation of nerve conduction velocity. An analysis in normal subjects and uraemic patients. The maximal nerve conduction velocity (NCV) of 6 sensory nerves (N. radialis, suralis and peronaeus superficialis, bilaterally) was determined in 88 normals and 59 uraemic patients. When the effect upon nerve conduction velocity of age and temperature was removed through partial correlations, it became possible to verify the negative correlation between the height of the patient and NCV. This explained as much as 35% of the remaining variance in males. There were also other significant differences in the nerve functions between the sexes. A set of "statistical corrections" (grouping of NCV's according to the subject's sex, computing of the average NCV's of an individual, and height-, age- and temperature normalization of single or mean NCV values) substantially decreased the variability of NCV. At the same time, the sensitivity of NCV measurement in the early diagnosis of nerve dysfunction caused by uraemia was increased. It is suggested that the results of NCV measurements should not only be reported as rough, absolute data, but also as normative values, taking into account the known physiological determinants.


Abnormally combined myelinated and unmyelinated nerves in dystrophic mice. Abnormally combined M- and U-nerves were observed in the peripheral nerves of C57BL dystrophic mice. They were counted in the sciatic nerves of the dystrophic mice 3 times more frequently than in control mice. The myelin disappeared beyond the nodes of Ranvier just as in the dysmyelination of dystrophic mice. Some of the U-axons inside the myelin were enveloped by Schwann cell cytoplasm while others were not. The myelinated U-axons contained cored vesicles, dilated endoplasmic reticulum and degenerate mitochondria. These abnormalities might cause disordered function and be related to the pathophysiology of murine muscular dystrophy.


The relationship between surface potentials and the number of active motor units. One of the assumptions inherent in a technique recently devised for enumerating motor units in human muscles is that the surface potentials from active motor units summate in a linear fashion. We present an electrical model of a muscle which predicts that a linear relationship between the number of active units and the electrical response recorded at the surface overlying the muscle would not be expected. The extent of the non-linearity, and hence the error in the calculation of the number of motor units in a given muscle, depends upon the ratio between the mean conductance of the motor units themselves and that of the external conduction pathway through which the electrical signal is fed (Gu/Ge). The extent of non-linearity is assessed experimentally in human hypothenar muscles using a "collision" technique. The average underestimate introduced into the calculation of the number of motor units in this particular case was concluded to be 26%. The value of Gu/Ge derived from these experiments, in 2 subjects, was checked by simulating an intramuscular action potential and determining the attenuation at the surface. The 2 independently obtained values were sufficiently close to suggest that the model may be a valid one. We conclude that caution should be employed in the interpretation of experiments which purport to determine the number of motor units in a muscle by means of surface recordings.


Remyelination in the spinal cord of the cat following intraspinal injections of lysolecithin. Intraspinal injections of small volumes of lysolecithin were made in the cat. These produced a local area of primary demyelination at the site of injection and all the demyelinated axons were subsequently remyelinated either by oligodendrocytes or Schwann cells. In general the type of remyelination depended on the position of the axon relative to the point of injection; those near the centre of the lesion were remyelinated by Schwann cells while those at the edges were remyelinated by oligodendrocytes. At the very centre of the lesion there was fairly extensive axonal degeneration. Oligodendrocyte-remyelinated axons were enclosed within astrocyte processes which were usually covered by basement membrane on the surface next to Schwann cells. The pattern of remyelination in the cat was compared with similar lesions in the rat and it was concluded that the more vigorous astrocytic response in the cat was responsible for the differences observed in the lesions in the 2 species.


Metabolic changes during glucose tolerance tests in migraine attacks. (1) Intravenous glucose tolerance tests have been carried out on 6 migraine sufferers on two occasions. The first study was carried out during a migraine attack and the second was performed in an attack-free period. The patients had fasted overnight and the investigations were carried out in the morning. Samples of venous blood were taken for measurement of concentrations of glucose, lactate, pyruvate, free fatty acids (FFA), glycerol, ketone-bodies, insulin and growth hormone. (2) an impaired tolerance to glucose was found during the migraine attacks compared with the control studies. Elevated ketone and FFA levels were found during the attacks and may have accounted for the glucose intolerance. The elevation of plasma FFA levels during the migraine attacks paralleled changes in blood glycerol concentrations suggesting increased lipolysis during the attacks. Growth hormone and cortisol were raised and insulin was depressed during attacks. (3) Our observations, in which the patients acted as their own controls, imply increased lipolysis during migraine attacks and are in contrast to previously reported studies. The patterns of metabolic and hormonal changes are consistent with a stress response during the attacks and the significance in relation to the causation of the attacks is discussed.


Early changes in the Schwann cells in experimental allergic neuritis. Experimental allergic neuritis (EAN) was induced in guinea-pigs by intradermal injection of rabbit peripheral nerve emulsified in Freund's adjuvant. Both sciatic nerves were obtained between 12--24 hr after clinical symptoms were evident. Several fascicles from each nerve were isolated for histochemical studies with NADH-diaphorase (NADH) and acid phosphatase (AP) applied to teased nerve fibres. Small pieces were processed for electron microscopy, and a fascicle was teased after staining with osmium tetroxide. In isolated nerve fibres stained with histochemical techniques myelin lesions of segmental character were found closely related to inflammatory cells; Schwann cell cytoplasm in contact with mononuclear cells showing a heavy enzymatic activity (NADH and AP). Under polarized light, the underliying myelin showed focal loss of birefringence. Some electron-microscopic pictures suggested active myelin breakdown by mononuclear cells. The possibility of primary Schwann cell damage by mononuclear cells with subsequent demyelination is discussed.


The Landry-Guillain-barré syndrome. Complications, prognosis and natural history in 123 cases. One hundred and twenty-three patients, 68 males and 55 females in whom acute polyradiculitis Guillain-Barré appeared at an age of between 1,6 and 76 years were re-examined after 0.9 to 12.3 years. The initial symptoms, the signs during the acute phase, in particular the cranial nerve signs and central nervous signs, as well as findings in the cerebrospinal fluid and complications are described. Three patients died during the acute phase. At follow-up only 57% of the patients were completely cured. In 22% motor signs, mainly distal in the lower extremities were found. Only 6 of these patients however were handicapped. Twenty-two patients had loss of one or more tendon reflexes, in general the ankle jerk. Only 6 showed very slight central nervous system signs. Eleven of 55 follow-up cases had pathological findings in needle electromyography. A disturbance of conduction velocity or distal latency was also found in several adults and children without residual clinical signs. The time span between the maximum of the initial signs and the beginning of recovery seemed to be particularly long in patients who showed residual signs on follow-up. These patients also seemed frequently to have had a severe tetraparesis in the initial phase. We could not confirm the therapeutic effect of cortisone or ACTH in our patients: amongst the 30 adults treated with cortisone 6 (20%) had residual signs at follow-up, whilst 5 (25%) of the 22 untreated ones had similar findings.


Concomitance of basophilia, ribonucleic acid and acid phosphatase activity in regenerating muscle fibres. Regenerating fibres from tibialis anterior muscles of mice and hamsters transplanted as minced fragments for 7 and 9 days respectively were compared for basophilia, ribonucleic acid (RNA) and acid phosphatase activity with fibres in muscles of patients with Duchenne muscular dystrophy, limb--girdle dystrophy and dermatomyositis. Normal muscles of mice, hamsters and humans were used as controls. In normal muscle fibres basophilia and RNA activity were restricted to the nuclei and acid phosphatase activity was occasionally observed in the nuclei, endomysial connective tissue and around muscle spindles. Diseased human muscle fibres were rich in acid phosphatase activity, the enzyme being most prominent in degenerating and basophilic fibres. When examined in serial sections, all basophilic fibres showed RNA and acid phosphatase activity. Similarly, all regenerating fibres in minced transplants which were basophilic to haematoxylin contained high RNA and acid phosphatase activity. It is suggested that basophilia in diseased human muscle fibres represents regeneration and that the lysosomes, as defined by acid phosphatase activity in these fibres, may be promoting their growth and differentiation by facilitating greater nucleocytoplasmic communication which ultimately could lead to protein synthesis.


Dendritic bottlenecks of crustacean motoneurons. Cobalt-labelled fast flexor motoneurons of the crayfish (Procambarus) were studied by electron microscopy after treatment with diaminobenzidine. The neurons were traced into the abdominal ganglion to locations at which they made contacts with the lateral giant fibres of the nerve cord. Fine secondary dendritic branches extended from the primary dendrites of the fast flexor motoneurons to the lateral giant fibre. These fine branches had bottlenecks at various places along their lenghts and also at their junctions with primary dendrites. Chemical synapses occurred at the bottlenecks and at other locations on the fine branches. It is postulated that chemical synapses at dendritic bottlenecks could act to modify the effectiveness of the excitatory drive provided by the lateral giant fibres to the fast flexor motoneurons, most likely by 'gating' electrical signals conveyed by the fine dendrites.


The ultrastructure of astrocytes, oligodendrocytes, and microglia in the optic nerve of urodele amphibians (A. punctatum, T. pyrrhogaster, T. viridescens). Recent ultrastructural studies which indicate a single types of glia cell in the amphibian optic nerve are contradicted by the results of the present investigation demonstrating three types of glial cells in the optic nerve of adult newts T. viridescens and T. pyrrbogaster, and the neotenous salamander A. punctatum. Well differentiated astrocytes, oligodendrocytes and microglia are the principal glial constituents with cytological characteristics corresponding to glial elements in the optic nerve of mammals. Immature astrocytes and oligodendrocytes are also present in the nerve indicating continuing production of cells from neuro-ectodermal precursors. Astrocytes constitute approximately 80% of the total. Processes of the large multipolar elements divide axons into bundles and extend to the pial surface to form the glia limitans. A distinct inter-species variability (6--17%) in oligodendrocytes is apparently related to differences in the incidence of myelinated axons. Microglia are the least numerous element constituting only 2--6%. They arise, in part, from monocytic cells near the pial surface.


The effects of postganglionic axotomy and nerve growth factor on the superior cervical ganglia of developing mice. Sectioning of the two major outflows from the superior cervical ganglia in two week mice results in a marked drop in the number of neurons within one week of operation and a smaller drop over the following two weeks. In animals receiving daily injections of nerve growth factor (NGF), the effect of axotomy is modified. One week after axotomy, the number of neurons in the axotomized ganglia is approximately the same in NGF treated animals as in the control, sham operated ganglia. Over the next two weeks, however, the cell death that results from axotomy is no longer prevented by treatment with NGF. The normal, hyperplastic response to NGF appears to occur independently of the cell reaction caused by axotomy.


Cell division in the developing sympathetic nervous system. Cell division in the rat superior cervical and stellate ganglia has been followed from 6 days before birth until 14 days after birth by [3H] thymidine autoradiography. Neuronal division ceased at the postnatal day 4 in superior cervical ganglia and postnatal day 3 in stellate ganglia, whereas division of non-neuronal cells continued throughout the entire period studied. Dividing cells in both ganglia were predominantly neuronal before birth and non-neuronal after the postnatal day 3. Nerve growth factor treatment resulted in an increase in the number of neurons in the ganglia when given either over the first four postnatal days while neuronal division was still occurring or from postnatal days 6--8 after neuronal division had ceased. The increase in neuron numbers was not due to increased neuronal division and was apparently due to an increased survival rate of differentiated neurons. An increase in the rate of division of non-neuronal cells accompained the administration of nerve growth factor.


Responses of single cells in cat visual cortex to prolonged stimulus movement: neural correlates of visual aftereffects. 1. The activity of single cortical cells in area 17 of anesthetized and unanesthetized cats was recorded in response to prolonged stimulation with moving stimuli. 2. Under the appropriate conditions, all cells observed showed a progressive response decrement during the stimulation period, regardless of cell classification, i.e., simple, complex, or hypercomplex. 3. The observed response decrement was shown to be largely cortical in origin and could be adequately described with an exponential function of the form R = Rf +(R1-Rf)e-t/T. Time constants derived from such calculations yielded values ranging from 1.92 to 12.45 s under conditions of optimal-stimulation. 4. Most cells showed poststimulation effects, usually a brief period of reduced responsiveness that recovered exponentially. Recovery was essentially complete in about 5-35 s. 5. The degree to which stimuli were effective at inducing response was shown to have significant effects on the magnitude of the response decrement. 6. Several cells showed neural patterns of response and recovery that suggested the operation of intracortical inhibitory mechanisms. 7. A simple two-process model that adequately describes the behavior of all the studied cells is presented. 8. Because the properties of the cells studied correlate well with human psychophysical measures of contour and movement adaptation and recovery, a causal relationship to similar neural mechanisms in humans is suggested.


Neuronal organization of crayfish escape behavior: inhibition of giant motoneuron via a disynaptic pathway from other motoneurons. 1. A circuit that produces a 70-100 ms IPSP in the crayfish giant motoneuron is described. The IPSP is produced by a disynaptic pathway from the nongiant fast flexor motoneurons to the motor giant. 2. An inhibitory interneuron in the pathway has been identified. Its axon runs at least the entire length of the abdominal nervous system. The inhibitory interneuron is excited bilaterally in all abdominal ganglia except the last and bilaterally inhibits the motor giants thoughout the abdominal CNS. 3. Evidence for a monosynaptic connection between the interneuron and the motor giant includes short latency, stability during repetitive stimulation, gradual decrement in high-Mg2+ solutions, and persistence in high-Ca2+ solutions. Similar but less complete evidence suggests a monosynaptic connection from the fast flexor motoneurons to the inhibitory interneuron. 4. A single impulse in the inhibitor can produce a prolonged IPSP in the motor giant. The inhibitor did not display trains of impulses and was not spontaneously active. 5. The inhibitory interneuron appears to be highly specific; no other outputs were observed. 6. Direct stimulation of axons in the connectives suggests that four pairs of inhibitory interneurons converge on the motor giants; at least two pairs are activated by the fast flexor motoneurons. 7. This circuit limits the burst duration of the motor giant and may function to protect the motor giant's depression-prone neuromuscular junction.


Somatotopic projections of mystacial vibrissae on cerebral cortex of cats. 1. Using classical evoked-potential techniques and 100-micron deflections of one vibrissa, at least three loci of potentials were identified in cats' cortices. 2. The relationships of these loci to cortical landmarks and to each other varied sufficiently to prevent specification of homologies between animals. 3. Attempts to differentiate the loci on functional criteria were unsuccessful. The areal extent of each locus appeared similar and there was evidence of a specific somatotopic pattern within each locus; in each locus different vibrissae were represented at different cortical points. 4. Latencies differed slightly between the loci, being shortest at the most rostral site and longest at the caudal site. In all loci, off-center latencies were longer, but this difference was detected only after complete maps of all three loci were produced. 5. The focus of potentials for an individual vibrissa was radically different, depending on the parameter measured (negative peak, positive peak, and latency). The focus of potentials could also be shifted by changing the velocity or direction of the stimulus. 6. The effects of these stimulus parameters on the cortical map suggest that a cortical focus represents more than simply a point on the skin surface.


The outcome from severe head injury with early diagnosis and intensive management. In the belief that secondary cerebral compression, hypoxia, and ischemia materially influence the outcome from severe head injury, a standardized protocol was followed in 160 patients, with emphasis on early diagnosis and evacuation of intracranial mass lesions by craniotomy, artificial ventilation, control of increased intracranial pressure, and aggressive medical therapy. Of these patients, 36% made a good recovery, 24% were moderately disabled, 8% were severely disabled, 2% were vegetative, and 30% died. The mortality rate compares favorably with outcomes in similar patients reported from other centers and there has been no increase in the numbers of severely disabled or vegetative patients. It is proposed that vigorous surgical and medical therapy, by preventing or reversing secondary cerebral insults, enables some patients who would have died to make a good recovery without increasing the proportion of severely disabled patients.


Significance of intracranial hypertension in severe head injury. Measurements of intracranial pressure (ICP) were begun within hours of injury in 160 patients with severe brain trauma, and continued in the intensive care unit. Some degree of increased ICP (greater than 10 mm Hg) was present on admission in most cases (82%), and in all but two of the 62 patients with intracranial mass lesions requiring surgical decompression; ICP was over 20 mm Hg on admission in 44% of cases, and over 40 mm Hg in 10%. In patients with mass lesions only very high ICP (greater than 40 mm Hg) on admission was significantly associated with a poor neurological picture and outcome from injury, while in patients with diffuse brain injury any increase in ICP above 10 mm Hg was associated with a poorer neurological status and a worse outcome. Despite intensive measures aimed at prevention of intracranial hypertension, ICP rose over 20 mm Hg during the monitoring period in 64 of the 160 patients (40%). Postoperative increases in ICP over 20 mm Hg (mean) were seen in 52% of the patients who had had intracranial masses evacuated, and could not be controlled by therapy in half of these cases. Even in patients without mass lesions, ICP rose above 20 mm Hg in a third of the cases, despite artificial ventilation and steroid therapy. Of the 48 patients who died, severe intracranial hypertension was the primary cause of death in nearly half and even moderately increased ICP (greater than 20 mm Hg) was associated with higher morbidity in patients with mass lesions and those with diffuse brain injury. Measurement of ICP should be included in management of patients with severe head injury.


Experimental cerebral concussion. Part 1: An electron microscopic study. Cerebral concussion was produced in rats by an iron pendulum hitting the external occipital protuberance. This resulted in loss of consciousness lasting from 3 to 10 minutes with prompt recovery and no focal neurological signs. The energy absorbed by the head at the impact was calculated to be about 1450 gm/cm. Light microscopic survey showed only minor pathological changes. However, electron microscopic observation revealed considerable alteration which began at 30 minutes, reached a peak at 1 hour, and disappeared at 24 hours after concussion. The salient changes included severe swelling of the neuronal mitochondria at the point of impact (occipital cortex), and extracellular edema at the site of contre coup (frontal lobe). Topographically, the most severe alteration was seen in structures at the craniospinal junction (medulla oblongata and upper cervical cord), consisting of both mitochondrial and edematous changes. Although there was no visible opening of the capillary interendothelial junctions, extravasated ferritin particles were accumulated in the edematous regions, indicating a transient increase in the permeability of the blood-brain barrier.


The physiological basis of intracranial pressure change with progressive epidural brain compression. An experimental evaluation in cats. Sequential cerebrospinal fluid (CSF) pressure-volume studies were carried out in seven cats during the expansion at a constant rate of an epidural balloon. The same studies were performed in three control cats. Beginning after 20 minutes of inflation and continuing to the point of pupillary dilatation there was a progressive increase in the pressure-volume index (volume required to change intracranial pressure (ICP) by tenfold). During the course of balloon inflation, there was also a progressive increase in CSF elastance (instantaneous ICP change per unit change in CSE volume). At the point of pupillary dilatation there was a marked, abrupt increase in the pressure-volume index and an equally dramatic decrease in CSF elastance. The CSF outflow resistance increased to a variable extent during balloon inflation. The plot of the CSF pressure versus balloon volume (the mass lesion pressure-volume curve) was of the classical configuration with an initial relatively flat segment and a final steep segment. A hypothesis is presented that interprets the shape of the mass lesion pressure-volume curve in terms of changes occurring in the elastic properties of the tissues surrounding the CSF space and the volume of the CSF space. It is proposed that this hypothesis will explain most of the commonly observed variations in CSF pressure. Confusion regarding the ICP-volume relationships has arisen because of lack of specificity regarding which anatomical spaces are being perturbed.


Anterior cervical discectomy without bone graft. Report of 71 cases. Anterior cervical discectomy without bone grafting may become the procedure of choice for acute cervical disc protrusions. This operation was performed on 71 patients, all of whom were followed from 1 to 6 years. Complications were minor in nature. The results were excellent and sustained.


Brown-Séquard syndrome and cervical spondylosis. Six patients with a rapidly progressive myelopathy of the Brown-Séquard type are presented (two in detail). Their clinical history, results of laboratory investigations, and surgical exploration revealed cervical spondylosis as the sole cause of this syndrome. We believe that a rapidly progressive myelopathy of Brown-Séquard type even in younger individuals, is often a presenting clinical feature of cervical spondylosis.


The effect of norepinephrine on the spinal cord circulation and its possible implications in the pathogenesis of acute spinal trauma. The effect of intra-arterially administered norepinephrine (NE) upon spinal cord blood flow (SCBF), before and after disruption of the blood-cord barrier was studied in dogs. Barrier disruption was accomplished with an intra-arterial bolus injection of 2.5 M urea. Multiple ligations of branches of the posterior aorta and cannula placements ensured that the urea was directed to the lumbar and sacral segments of the cord. The SCBF was measured by the hydrogen clearance method. Intra-arterial urea by itself had no significant effect on SCBF. The intra-arterial infusion of NE (12 microgram/min and 30 microgram/min) was without overall effect on SCBF. However, if the blood-cord barrier had been previously disrupted with hypertonic urea, both concentrations of NE resulted in large reductions in SCBF. No such reductions in SCBF were seen with blood-cord barrier disruption and NE if the animals had been pre-treated with the alpha-blocker, phenoxybenzamine (1.5 mg/kg). Some aspects of the possible involvement of NE in the pathophysiology of acute spinal injury are discussed.


Objective clinical assessment of motor function after experimental spinal cord injury in the rat. A new method was developed for the clinical assessment of motor function in rats after experimental spinal cord injury. The method consists of placing the animal on an inclined plane which can be adjusted to provide a slope of varying grade, and then assessing the maximum angle of the plane at which the animal can maintain its position without falling. The method was used to quantitate motor function in normal rats and in rats subjected to myelectomy, and consistently showed major differences between the two groups. The method has many positive features: the plane is easy to construct and of low cost; and the test is rapid, non-invasive, repeatable, and consistent.


Ocular bobbing with superior cerebellar artery aneurysm. Case report. A teen-age girl became comatose after the sudden onset of headache. Initial angiography did not reveal the site of bleeding. The subsequent onset of ocular bobbing directed attention to the region of the pons. Repeated angiography showed an aneurysm of the superior cerebellar artery. At surgery, the fundus of the aneurysm was adherent to the pons and there was a small hematoma within the pons. Ocular bobbing is rare, but is most commonly seen in association with destructive lesions of the pontine tegmentum, and is a useful localizing sign.


Pituitary apoplexy producing internal carotid artery occlusion. Case report. The authors report a case of pituitary apoplexy occurring several hours after carotid angiography. The event was associated with stupor, focal headache, and left hemiparesis. Repeat angiography demonstrated intracranial occlusion of the right internal carotid artery. At surgery, a hemorrhagic pituitary adenoma was found to be compressing the internal carotid artery, and the removal of the tumor resulted in restoration of flow. The mechanism, presenting symptoms and signs, and treatment of pituitary apoplexy causing compression of a major vessel are discussed.


Vermian agenesis and unsegmented midbrain tectum. Case report. A male infant had spells of tachypnea leading to apnea. He had vermian agenesis and and unsegmented midbrain tectum. This identifies the time of teratogenesis at about embryonic stage XVII to XVII (40 days gestation).


Dysplastic gangliocytoma (Lhermitte-Duclos disease) of the cerebellum. Case report. A case of dysplastic gangliocytoma, or Lhermitte-Duclos disease, of the cerebellum is reported. The patient was the seventh reported survivor of this rare disease. A review of the known biology of the disease allows some optimism. The treatment of choice appears to be surgical resection only.


Operative approach to persistent trigeminal artery producing facial pain and diplopia. Case report. A case is reported of persistent trigeminal artery producing intermittent facial pain, the last episode being associated with diplopia. The trigeminal and abducent nerves were attached to the trigeminal artery by a congenital membrane. Blood supply to the vertebrobasilar system was via the persistent vessel. A new operative approach along the petrous-temporal ridge is described.


Localization of velum interpositum AVM with metrizamide ventriculography and simultaneous stereoangiography. Case report. The combination of metrizamide (Amipaque) ventriculography and vertebral angiography with stereoradiography provided precise localization of an arteriovenous malformation of the velum interpositum and an associated hematoma in the lateral ventricles that had not been detected by computerized tomography. This dual technique is recommended for precise localization of suspected intra- or periventricular lesions before surgery.


Spinal cord vascular malformations with symptoms during menstruation. Report of two cases. Two patients had the initial complaint of fluctuating paraparesis, which was most evident at menstruation. One patient had a semimonthly fluctuating deficit. Spinal cord compression and ischemia, secondary to the vascular mass, were considered the most likely mechanisms. Blood levels of estrogen and progesterone during the menstrual cycle may have had a contributory effect. Fluctuating spinal cord deficits associated with a consistent portion of the menstrual cycle should alert the physician to the possibility of an arteriovenous malformation of the spinal cord.


Sarcoidosis of the pineal gland. Case report. The authors report a case of sarcoidosis of the pineal gland with no other organ manifestation of the disease. The tumor was successfully removed by a direct surgical approach.


Aneurysmal bone cyst of the skull. Case report. A case of giant aneurysmal bone cyst of the skull is reported. Treatment was by total excision in three-staged surgery. The patient made a good recovery.


Influence of diet composition on nitrogen balance and body composition in meal-eating and nibbling rats. A series of experiments was conducted to evaluate the influence of meal frequency on nitrogen balance and body composition of rats. Rats were either fed 2 hours per 24 or 48 hours (meal-eaters), or pair-fed to meal-eaters with an automated feeding machine (nibblers). Rats weighing approximately 250 g initially, were fed 10%, 20%, or 30% casein, high-carbohydrate diets or a 20% casein high-fat diet for 7 to 8 weeks. Meal-eaters gained essentially the same amount of body weight as the nibblers. Meal-feeding once per 24 or 48 hours did not adversely influence nitrogen balance or the body composition of the rats. In one experiment, smaller rats, weighing approximately 150 g initially, were utilized. Meal-eaters again, retained as much nitrogen as nibblers, and contained less body fat than the nibblers. In these studies, meal-eating did not cause a depression in nitrogen retention or an increase in body fat deposition in rats.


Anemia of lead intoxication: a role for copper. Lead-induced anemia in rats, which is of a microcytic, hypochromic type, has been shown to be a result of an interference with the metabolism of copper and iron. In this complex interaction, copper may be the target upon which ingested lead has its antagonistic effect on hematopoiesis. The depressions in hematocrit and hemoglobin levels resulting from exposure to lead may occur secondarily to the effects of a lead-induced copper deficiency on iron mobilization and utilization. The metabolic fault induced by lead is seen in a reduction of serum iron, elevation of serum iron binding capacity, and increase in liver iron, all manifestations of systemic effects related to an interference with copper metabolism. These results relate many of the characteristics of the lead-induced anemia to those found in the copper-deficiency anemia.


Oxidative deterioration of the muscle proteins during nutritional muscular dystrophy in chicks. Nutritional muscular dystrophy in the chick results from the simultaneous deficiency of vitamin E and cystine. Being a biological antioxidant, vitamin E might be functional in maintaining a proper redox state of the sulfur-containing amino acid in the proteins. The analyses of protein-bound sulfhydryls and disulfides at onset of muscular dystrophy in young chicks were carried out. The ratio of disulfide to sulfhydryls increased two- to three-fold in dystrophic muscle as compared to that in the control muscle proteins. Dystrophic and normal muscle proteins also were subjected to SDS-gel electrophoresis. Proteins of low molecular weight, supposedly derived from proteolysis, were present in the gels of the dystrophic muscle and absent in those of normal muscle extracts. As a result of these studies, a chemical model has been proposed to explain the oxidative deterioration of proteins in nutritional muscular dystrophy due to vitamin E deficiency.


Effect of dietary vitamin E and aging on tissue lipofuscin pigment concentration in mice. This study reports a re-investigation of the effect of dietary vitamin E upon tissue organic solvent soluble lipofuscin pigment concentrations. Female weanling mice were fed a vitamin E deficient, vitamin E or N,N'-diphenyl-phenylenediamine (DPPD) supplemented diet up to 18 months of age. Lipofuscin concentrations were measured by a quantitative method which is based on fluorescence spectroscopy. Of all tissues measured (uterus, lung, spleen, kidney, liver, heart and brain), only the liver responded and showed lower pigment concentrations due to vitamin E treatment. In addition, in the liver, up to 12 months of age, vitamin E supplementation resulted in gradually decreasing pigment concentrations, but by 18 months of age, pigment concentrations were increased by 5 to 10 times in all diet groups. The effect of DPPD was similar to vitamin E. Tissue lipofuscin pigment concentrations in 18-month-old mice were lowest in the uterus and highest in the heart. The data indicate the possibility of a turnover of the organic solvent soluble lipofuscin pigments in the liver.


Fetal and maternal vitamin A levels in tissues of hypervitaminotic A rats and rabbits. Pregnant rats and rabbits were given excess vitamin A, in the form of retinyl acetate or retinoic acid, for the 3-day period just prior to palatal closure in the fetuses. Twenty-four hours later, the various forms of vitamin A, and their levels, were determined in fetal liver and carcass and in maternal liver and serum by thin-layer chromatography. The predominant forms of vitamin A found in both fetal and maternal tissues were retinyl palmitate, retinol and retinoic acid. In both species, the tissues from the groups treated with retinoic acid contained levels of vitamin A similar to those found in control tissues. After retinyl acetate treatment in the rat, both of the maternal tissues studied had elevated vitamin A, whereas in the rabbit only maternal liver levels increased. In the groups treated with retinyl acetate, the ratio of the vitamin A levels in fetal liver: maternal serum reflected a species difference: the ratio was lower than the control value in the rabbit and higher than controls in the rat. Radiotracer studies in the rat, using either 3H-retinol or 14C-retinoic acid, demonstrated vitamin A transport across the placenta, with vitamin A concentrating in the fetal liver.


Effect of aspartame and aspartate loading upon plasma and erythrocyte free amino acid levels in normal adult volunteers. Aspartame is a dipeptide (L-aspartyl-L-phenylalanyl-methyl ester) with a sweeting potential 180 to 200 times that of sucrose. Questions have been raised about potential toxic effects of its constituent amino acids, aspartate and phenylalanine when the compound is ingested in large amounts. Plasma and erythrocyte amino acid levels were measured in 12 normal subjects after administration of either Aspartame (34 mg/kg) or equimolar quantities of aspartate (13 mg/kg) in a crossover design. No changes in either plasma or erythrocyte aspartate levels were noted at any time after either Aspartame or aspartate ingestion. Plasma phenylalanine levels decrease slightly after aspartate loading, and increased from fasting levels (4.9 +/- 1 mumoles/100 ml) to 10.7 +/- 1.9 mumoles/100 ml about 45 to 60 minutes after Aspartame loading. Phenylalanine levels returned to baseline by 4 hours. Erythrocyte phenylalanine levels showed similar changes.


Some carbohydrates found in pollen and pollen substitutes are toxic to honey bees. Carbohydrates in some pollen substitutes (galactose, lactose, raffinose, stachyose, glucuronic acid, galacturonic acid, polygalacturonic acid, and pectin) were toxic to caged adult Apis mellifera L. These toxins can be diluted to safe levels by sucrose. Collected nectar apparently dilutes the toxic sugars in pollen thus permitting assimilation of essential nutrients from pollen.


Ketogenic response to medium-chain triglyceride load in the rat. We studied ketonemia induced in rats by a single oral load of medium-chain triglycerides (MCT) (C8:0 50.5%, C10:0 48.0%, C12:0 1.0%). Medium-chain fatty acids, rather than being incorporated into the lipids synthesized by the liver, are oxidized there, with high production of ketone bodies. Severe and long-lasting hyperketonemia developed rapidly. With increased MCT loads, ketonemia also increased, although not linearly. The level of the hyperketonemia seemed equal in the two sexes. Ingestion of MCT by fasting rats caused an additional rise in ketonemia. Long-chain triglycerides were not ketogenic, since their constituent fatty acids are incorporated into lipids and are thus less subject to oxidation. Lipids induce less severe ketonemia in genetically obese rats than in normal-weight rats.


A strain specific increase in blood glycerol level of the carbohydrate-sensitive BHE rat. A strain-specific, elevated serum free glycerol has been found in stock diet fed, carbohydrate-sensitive, hyperlipemic BHE rats. This suggests that considerably more peripheral lipolysis is taking place in the nonfasting BHE rat than in its Wistar counterpart. This observation further suggests that the BHE rat may exhibit metabolic changes in the fed state that are similar to those found in normal fasting rats. Individual, serum free glycerol levels were not correlated with individual serum insulin values. In the nonfasted BHE rats, serum free glycerol concentrations were found to be sufficiently high to initiate gluconeogenesis or to contribute to a maximal rate of triglyceride synthesis.


Effects of thiamin deficiency on acetylcholine levels and utilization in vivo in rat brain. Cerebral regional acetylcholine (ACh) levels and utilization were studied in vivo in thiamin deficient (TD), pair-fed asymptomatic (PFC) and ad libitum fed control (ALC) rats. ACh levels in the cortex, corpus striatum, midbrain, diencephalon and brainstem of TD rats were comparable to those observed in the control groups. However, ACh utilization was slightly to moderately (10-41%) decreased in cortex, midbrain, diencephalon and brainstem. The decrease was significantly different in the midbrain of TD rats as compared to PFC and ALC rats.


Formation of methionine from alpha-amino-n-butyric acid and 5'-methylthioadenosine in the rat. Adult rats may utilize two metabolites of methionine for the biosynthesis of this essential amino acid. In separate experiments methionine, labeled with 14C or with 35S was observed in plasma and urine following the administration of [2-14C]-alpha-amino-n-butyric acid or [35S]-5'-methylthioadenosine by stomach tube. Although alpha-amino-n-butyric acid (ABA) or homoserine, alone or with dietary sodium sulfate, choline, and/or S-methylcysteine, was not utilized for growth, weight loss in weanling rats was decreased by dietary cysteine when fed as an additive to a basal methionine-free, cysteine-free, labile methyl-free, sulfur-free diet. Following the addition of 10 mg ABA and 28 mg 5'-methylthioadenosine/day to the basal diet, growth response was equivalent to that occurring in rats receiving 27 mg of methionine/day with the basal diet. The implications of these findings for adaptation to protein restriction and a discussion of equilibrium and steady state conditions related to the increase in methionine content in the blood are presented.


Effect of folacin deficiency on folacin-binding proteins in the rat. The effect of experimental folacin deficiency on the uptake and distribution of radioactive folic acid in the rat was investigated. Less radioactivity was taken up by livers of deficient rats than controls 24 hours after intraperitoneal injection of [3H]-folic acid, although more radioactivity was incorporated by the brain and kidneys of deficient rats. The distribution of radioactivity among the three folacin-binding proteins of rat liver cytosol and the binding protein of mitochondria was also studied. In deficiency, very little radioactivity was incorporated into cytosol binding proteins I and II, while more radioactivity was incorporated into cytosol binding protein II and the mitochondrial binding protein. A decrease in the endogenous folacin associated with all protein-bound and free forms was seen in deficiency with the major decrease coming at the expense of unbound folacin, and cytosol binding protein I. This latter protein may have a primary storage role in the liver.


Psychological problems in an industrial setting. A study was undertaken to identify psychological problems reported by workers in an industrial setting and the degree to which these problems (1) affected an individual's ability to carry out work and home responsibilities and (2) were related to physical and psychophysiological disorders. In addition, an analysis was made of various medical-psychiatric services that were needed to provide comprehensive understanding of individual health problems and good case management.


Mortality by cause among stationary engineers and stationary firemen. Causes of death among 1,113 stationary engineers and firemen identified from union death benefit listings were analyzed to determine if there were conditions occurring with unusual frequency suggestive of exposure to hazards in the work environment. The relative frequencies of specific disease conditions in the study group were compared to the experience of the general population by the method of proportionate mortality. Deaths from cancer of the buccal cavity and pharynx and cancer of the rectum occurred twice as often as expected, each result being statistically significant at the 5% level. Lung cancer deaths were 20% higher than expected overall, and consistently excessive in each of four geographic subdivisions of the United States. Mortality from coronary heart disease was elevated in each region, particularly at ages under 55. No increase in the relative frequency of deaths from nonmalignant respiratory disease was found nor were fatal accidents more frequent than expected. Some of the findings may be important in view of potential exposure to carbon monoxide and several carcinogenic materials for these occupational groups.


Ocular medical surveillance on microwave and laser workers. Results of over 800 medical surveillance ocular examinations on microwave and laser workers were evaluated using multiple regression analysis techniques. No lenticular or retinal defects were noted that could be attributed to work with either microwave or laser radiation. Increased incidences of minute lenticular defects were noted with increasing age. A high variability in the recording of such defects at different locations was attributed to differences in the subjective evaluation of individual examiners. It was concluded that periodic medical surveillance as conducted on the microwave and laser workers under study was nonproductive and suggestions were made to limit medical surveillance for these worker groups to preassignment, postaccident exposure, and termination eye examinations.


Pulmonary problems associated with the use of polytetrafluoroethylene. The experience of a group of nine men employed in a manufacturing plant, who developed attacks of illness during the course of working with polytetrafluoroethylene (PTFE), is reported. The cause was presumed to be the inhalation of fumes from PTFE-contaminated cigarettes. Eight of the nine employees reported chest pain, shortness of breath, and cough. One had documented pulmonary edema. In view of the potential seriousness of the respiratory complications reported by use and by others we raise the question whether "polymerfume fever" is an adequate or appropriate term to apply to the human inhalation reaction to pyrolysis products of PTFE. Under some conditions of PTFE use, special precautions need to be taken, in addition to those usually recommended, to prevent exposure of to this substance.


Interaction between rod and cone signals studied with temporal sine wave stimulation. If a temporal stimulus is presented through the cones, the threshold for a rod stimulus may be influenced even if the cone stimulus remains subthreshold. We have used sinusoidal stimulation to study the process underlying this rod-cone interaction. A first-order model is proposed consisting of a single threshold mechanism preceded by linear summation of rod and cone signals with a pure latency difference. Two deviations from this model are described. First, occasional additivity failures appear; second, if the phase difference characteristic is corrected for latency, the remaining part cannot be explained in terms of the de Lange curves of the rod and cone systems.


Effect of shear mixing on in vitro drug release of capsule formulations containing lubricants. The influence of shear mixing on the in vitro dissolution properties of several experimental capsule formulations containing lubricants was investigated. The studies were carried out in 2.8-liter laboratory V-blender equipped with a high-speed intensifier bar, using nitrofurantoin and procainamide hydrochloride as active drugs, powdered lactose and starch as excipients, and magnesium stearate and magnesium lauryl sulfate as lubricants. These studies revealed a pronounced inhibitory effect on drug dissolution due to shear in powder mixtures containing magnesium stearate; even at the maximum lubricant level of only 2%, high mixing markedly altered the in vitro dissolution rate. In systems with magnesium lauryl sulfate, the shear effect was less pronounced (nitrofurantoin blends) or absent (procainamide hydrochloride blends). The poor dissolution characteristics noted with magnesium stearate--shear combinations seem to result from the formation of a hydrophobic film around the powder mass, preventing wetting and deaggregation.


High-pressure liquid chromatographic analysis of methotrexate in presence of its degradation products. Two high-pressure liquid chromatographic methods are described for the quantitative determination of methotrexate in the presence of its contaminants and degradation products. Method 1 takes less than 15 min and is recommended for routine assays of methotrexate in commercial products. Method 2 takes about 35 min and is the method of choice to detect and quantitate large amounts of degradation products. Quantitation to a level of 1 microgram of methotrexate/ml is feasible by these methods and thus provides potential applicability for the analysis of methotrexate in biological fluids.


Flow rates and repose  angles of wet-processed granulations. The equation of McDougall and Evans was found not to apply to granulations. The functional relationships among volumetric powder flow rates, angles of repose, and particle size were demonstrated to exhibit maxima (rather than minima) in five common pharmaceutical granulations produced by wet processing. The angular behavior of granules (such as the experienced range of angles) is explained via supported stacking geometries, and the shallow maxima in the angle of repose versus granule diameter was derived from this model.


Smooth muscle relaxant properties and vasomotor actions of 2-amino-1-p-nitrophenylpropane-1,3-diol. Experiments with the guinea pig ileum, trachea, and vas deferens, the rat fundal strip, the rabbit jejunum and aortic strip, and the toad heart indicated that 2-amino-1-p-nitrophenylpropane-1,3-diol, the hydrolytic product of chloramphenicol, inhibited smooth muscles. Its action was direct and not through any mediators. After intravenous administration, the compound produced vasodepression followed by an overshooting rise of blood pressure. Vasodepression was not mediated by adrenergic, cholinergic, or histaminergic mechanisms. Hypertension was a sympathomimetic effect. Muscle relaxant and cardiovascular effects of the compound were similar to those of chloramphenicol, although it had no antibacterial effect.


Constituents of West African medicinal plants XIX: Funiferine N-oxide, a new alkaloid from Tiliacora funifera (Menispermaceae). A phytochemical investigation of the roots of Tiliacora funifera (Menispermaceae) resulted in the isolation and identification of funiferine N-oxide, a new bis(benzylisoquinoline) alkaloid.


Cardiovascular actions of three harmala alkaloids: harmine, harmaline, and harmalol. Each of three harmala alkaloids, harmine, harmaline, and harmalol, decreased heart rate and increased pulse pressure, peak aortic flow, and myocardial contractile force in intact normotensive anesthetized dogs. Harmine reduced systemic arterial blood pressure and total peripheral vascular resistance; harmaline-evoked decreases were frequently followed by a secondary increase; and the effects of harmalol on these two parameters were inconsistent. A direct negative chronotropic effect of harmala alkaloids was suggested by observations of bradycardia in the isolated perfused rat heart and in the intact dog; neither vagotomy nor atropinization affected harmala alkaloid-induced bradycardia in the dog. Reduction in femoral vascular resistance by the alkaloids was not apparently due to activation of cholinergic, beta-adrenergic, or histamine (H1) receptors.


Kinetics of indomethacin degradation II: Presence of alkali plus surfactant. The kinetics of indomethacin were studied in the presence of the surfactants ethoxylated lanolin, polysorbate 80, and cetrimonium bromide under alkaline conditions at 30.3 degrees. The degradation followed apparent first-order kinetics. Plots of kobs versus surfactants; concentrations were curved with negative slopes for nonionic surfactants; but with the ionic surfactant, the plots showed a marked positive change in kobs as the surfactant concentration passed through the critical micelle concentration. Literature model systems adequately explained the data for nonionic surfactants but not for the ionic surfactant. A new set of equations was derived for each case using electrochemical potentials. The experimental data for all three surfactants fit the derived equations quite well.


High-pressure liquid chromatographic--mass spectrometric determination of delta9-tetrahydrocannabinol in human plasma following marijuana smoking. A method was developed for analyzing delta9-tetrahydrocannabinol (I), a psychotomimetic constituent found in marijuana smoke. The developed method utilizes a high-pressure liquid chromatographic (HPLC) gradient elution program to separate I from the other major cannabinoids in marijuana smoke. To achieve the sensitivity required to detect I in human plasma following marijuana smoking, a mass spectrometric quantification method was developed to analyze the HPLC eluant. To 1 ml of human plasma was added a known amount of internal standard, trideuterated I. This stable isotope provided a check on extraction efficiency, a marker for UV monitoring of the HPLC effluent and subsequent collection, and a convenient mass for mass spectrometric quantification. An ion-counting technique was used in conjunction with the peak matching accessory of the mass spectrometer to provide for a rapid comparison between molecular ions of I and the internal standard. The method was linear, accurate, and reproducible over the concentration range expected for I in plasma following marijuana smoking; 2.5 ng/ml was the lower practical limit of detection. Plasma from 11 male subjects was analyzed by the method at appropriate intervals up to 24 hr after the smoking of a marijuana cigarette containing 10.8 mg of I. Results demonstrated that levels of I could be determined accurately in the plasma of marijuana smokers in the 1-hr period following smoking.


Evaluation and optimal combination of TLC systems for qualitative identification I: sulfonamides. A mathematical criterion for the evaluation of chromatographic analysis procedures is given by the information content as derived from Shannon's equation. This information content yields a numerical value representative of the merits of each chromatographic separation and thus allows selection of the optimal systems. In most cases, however, one analysis is not sufficient to allow the qualitative identification of the sample. Therefore, several chromatographic systems are combined. Two approaches allow the desired combination; one either calculates the information content of several procedures as one mathematical value or classifies the systems according to mutual resemblance by numerical taxonomy techniques. From the resulting groups of dissimilar systems, one optimal system can be chosen per group according to the information content. The results obtained by these mathematical procedures are illustrated with a practical example: the selection and evaluation of systems for the TLC analysis of sulfonamides.


Comparative pharmacokinetics of coumarin anticoagulants XXIX: Elimination kinetics and anticoagulant activity of (S)-(-)-warfarin in rats before and after chronic administration. The kinetics of elimination and the anticoagulant effect of (S)-(-)-warfarin were determined in adult male rats before and after daily drug administration for 13 days. There was a small but statistically significant (p less than 0.05) decrease in the body clearance of (S)-(-)-warfarin (from 4.84 to 4.37 ml/hr/kg) and an increase in the serum free fraction of racemic warfarin (added to serum in vitro) from 0.00850 to 0.0107 (p less than 0.05). The concentration of (S)-(-)-warfarin in serum at which the synthesis rate of prothrombin complex activity is one-half of the pre-warfarin rate increased from 0.532 to 0.655 microgram/ml on the average (p less than 0.05).


Photosensitization by drugs.

Photosensitization by drugs. UV irradiation (365 nm) of air-saturated methanol solutions of 20 drugs absorbing in the 300--400 nm region gave rise to oxygen uptake, as determined with a polarographic oxygen electrode. The drugs were tested for photosensitizing capability by either a Type I (free radical) or a Type II (single molecular oxygen) mechanism. This testing was done by the inclusion of either acrylamide or 2,5-dimethylfuran in the irradiated drug solution, with observation of the subsequent polymerization or oxidation, respectively. Phenothiazine and thiazide derivatives appear capable of photosensitization by both mechanisms; promethazine, trifluoperazine, and furosemide show relatively high reactivity. Diazepam (weak), hexachlorophene, aminacrine, pyrilamine, tetracycline, demeclocycline, quinine, and anthracene (strong) react only by a Type II mechanism, with a photosensitizing efficiency increasing in the order given. A correlation appears to exist with reports of in vivo photosensitivity.


Isolation and identification of morphine 3- and 6-glucuronides, morphine 3,6-diglucuronide, morphine 3-ethereal sulfate, normorphine, and normorphine 6-glucuronide as morphine metabolites in humans. Morphine metabolites were isolated with column chromatography on a resin and neutral aluminum oxide and TLC from the urine of morphine-dependent subjects maintained on morphine sulfate at a dose of 240 mg/day. These metabolites were characterized as morphine 3-glucuronide, morphine 6-glucuronide, morphine 3,6-diglucuronide, morphine 3-ethereal sulfate, normorphine, normorphine 6-glucuronide, and, possibly, normorphine 3-glucuronide by free phenol and glucuronide tests, enzymatic hydrolysis, GLC, TLC, UV spectroscopy, and GLC--mass spectrometry.


Disposition of sulfonamides in food-producing animals V: Disposition of sulfathiazole in tissue, urine, and plasma of sheep following intravenous administration. The plasma, urine, and tissue sulfathiazole concentrations were determined at various times following intravenous administration to 12 sheep. The plasma and urine data were consistent with a one-compartment pharmacokinetic model, with an elimination half-life of 1.1 hr and a volume of distribution of 0.39 liter/kg. Sulfathiazole was eliminated by excretion of unchanged drug in urine (67%) and by formation of two metabolites. The data obtained from eight tissue sites were consistent with the one-compartment pharmacokinetic model presented and confirmed that tissue residues of sulfathiazole can be calculated from serum and urine drug concentration.


Cascarosides A and B.

Cascarosides A and B. Electron-impact and field desorption mass spectrometry, together with NMR and circular dichroism spectroscopy, were used to confirm that cascarosides A and B are C-10 isomers of 8-O-(beta-D-glucopyranosyl)barbaloin. Several batches of cascarosides A and B were prepared and oxidatively hydrolyzed to aloe-emodin. The results are discussed in relation to the assay for cascara given in the European Pharmacopoeia, 1971.


Evaluation of immunosuppressive potential of cryogenine using developing and established adjuvant arthritis in rats. Both developing (Days --1-+12 relative to inoculation) and established (Days +18-+29) stages of Mycobacterium butyricum adjuvant-induced polyarthritis in rats were treated orally with cryogenine (100 mg/kg/day), a prototype anti-inflammatory (phenylbutazone, 100 mg/kg/day), or a prototype immunosuppressive (cyclophosphamide, 6 mg/kg/day). During developing adjuvant arthritis, cryogenine and phenylbutazone significantly reduced the nonimmune-mediated inflammation in the inoculated hindpaw. Neither cryogenine nor phenylbutazone provided protection against the development of the delayed-onset, immune-mediated inflammation and the reduction in growth rate seen after Day +12 in unmedicated rats. Cyclophosphamide failed to reduce the nonimmune-mediated inflammation, but it provided significant protection against both the delayed-onset, immune-mediated inflammation and the reduced growth rate. During established adjuvant arthritis, cryogenine and phenylbutazone were effective against the established inflammation, while cyclophosphamide was ineffective. These results confirm the known anti-inflammatory and immunosuppressive activities of phenylbutazone and cyclophosphamide, respectively, and indicate that cryogenine lacks immunosuppressive capability at the effective anti-inflammatory dosage level used.


Calcium-prostaglandin aggregation and its effect on prostaglandin uptake by isolated rabbit intestine. A quantitative estimate of the role of calcium ions on the lipid--water partition coefficients of prostaglandin E1 and dinoprost suggested the possibility of prostaglandin molecules and calcium ions aggregating in a 14:1 ratio to produce a lipid-soluble aggregate. The aggregation is postulated to be a characteristic of prostaglandin molecules as compared to simple fatty acids, e.g., 1-octanoic acid, which, in the presence of calcium, behave differently than the prostaglandins. The uptake of prostaglandins by the mucosal surface of the rabbit intestine increased in the presence of calcium. For example, at 25 mM calcium, prostaglandin E1 was transported at approximately twice the rate as in the system containing no calcium. The uptake rate of dinoprost was estimated to be three times faster with 10 mM calcium than in the absence of calcium. Therefore, it is proposed that a carrier-mediated diffusion process, for both the prostaglandin molecules and calciumi ions, takes place in the uptake mechanism. Diffusion coefficients ranging from 0.48 X 10(-5) to 7.19 X 10(-5) cm2/sec and permeability coefficients ranging from 1.04 X 10(-2) to 15.6 X 10(-2) cm/sec were estimated for all systems studied.


Thermal decomposition of amorphous beta-lactam antibacterials. Thermal decomposition rates for amorphous samples of penicillin G potassium, cephalothin sodium, cefamandole sodium, and cefamandole nafate were determined as a function of water content and temperature. Even when rigorously dry, amorphous cephalosporins were at least one order of magnitude less stable than the corresponding unsolvated crystalline form. Absorbed water generally increased both the number of decomposition products and the net decomposition rate. Reaction kinetics were usually apparent first order, but an anomalously high effective reaction order was observed in several systems. Nonlinear Arrhenius plots were observed, and a qualitative model based on molecular relaxation in glayses is proposed. Although decomposition rates at 25 degrees were small for dry samples, even slight decomposition produced visually detectable changes. Thus, the unsolvated crystalline form was noticeably more stable, even at 25 degrees.


Colorimetric assay of quinine and quinidine in raw materials, formulations, and biological fluids. The two characteristic erythroquinine and thalleioquin tests for quinine and quinidine were studied to optimize the experimental conditions for quantitative analysis. Both methods were quantitatively sensitive for either quinine or quinidine in a concentration range of 0.1--10 microgram/ml with the erythroquinine method and of 3--50 microgram/ml with the thalleioquin method. A TLC--colorimetric method also is described for the assay of quinine and quinidine in the presence of cinchonine, cinchonidine, and other cinchona alkaloids. The results were compared with those obtained with a spectrophotometric method.


High-pressure liquid chromatographic determination of tetracyclines in urine. The quantitation of oxytetracycline, tetracycline, and chlortetracycline was accomplished by high-pressure liquid chromatography using an anion-exchange column. The tetracyclines were extracted from urine as their calcium complexes. Concentrations as low as 12 microgram of oxytetracycline/ml and 4 microgram of tetracycline and chlortetracycline/ml were quantitated accurately. The relative standard deviation of the method varied from 0 to 5%.


Drug interactions with isoniazid metabolism in rats. 14C-Isoniazid (20 mg/kg po or iv) was administered alone or in combination with aspirin (100 mg/kg po), rifampin (30 mg/kg po), ethambutol (100 mg/kg po), or ethanol (3 g/kg po) to rats. In another experiment, phenobarbital sodium (40 mg/kg/day ip) was administered for 3 days prior to isoniazid. Aspirin and ethanol retarted the rate of isoniazid absorption from the GI tract. None of the drugs significantly altered the 14C-elimination rate from the blood over the first 4 hr. A tissue distribution study showed that changes in the blood levels produced by ethanol were reflected in the other tissues. When isoniazid was given intravenously, ethanol increased the amount of carbon-14 excreted in urine up to 24 hr after dosing; no other changes were observed in the total carbon-14 recovered in urine. Aspirin inhibited the conjugation of isonicotinic acid with glycine. Ethanol increased N-acetylisoniazid excretion and decreased isonicotinic acid excretion. None of the other treatments had more than a slight effect on isoniazid metabolism. Acute doses of isoniazid failed to produce any signs of hepatotoxicity, as judged by measurement of serum transaminase levels. The data do not suggest that any of the drugs studied are likely to potentiate the hepatotoxicity of isoniazid when administered acutely. Isoniazid metabolism in rats differed quantitatively from that reported for humans.


Selective estimation of aconitine in presence of aconine and benzoylaconine. A selective and simple colorimetric method is presented for the estimation of aconitine in drugs in the presence of aconine and benzoylaconine. The method is based on the formation of an iron hydroxamate complex through the acetate ester group to which the biological activity is due. The color is measured at 530 nm (5--250 microgram/ml). Under the experimental conditions, neither the benzoyl group of benzoylaconine nor aconine is involved in the process of hydroxylaminolysis.


Synthesis and antituberculosis activity of thiocarboxamide derivatives of Schiff bases. Synthesis of some N-(4-thiocarboxamidobenzylidene)arylamines and N-(substituted benzylidene)-p-thiocarboxamidoanilines from various arylaldehydes and arylamines is described. Fourteen representative compounds were tested in vitro on the ground H37RV.


Phytochemical investigation of Adenium obesum Forskal (Apocynaceae): isolation and identification of cytotoxic agents. An ethanol extract of Adenium obesum exhibited cytotoxic activity against the human epidermoid carcinoma of the nasopharynx test system. Constituents in the active extract were identified as the cardenolides somalin, hongheloside A, 16-acetylstrospeside, and honghelin and the flavonol 3,3'-bis(O-methyl)quercetin. Their identities were proven by IR, UV, proton magnetic resonance, and mass spectrometry; elemental analyses; preparation of derivatives; and melting-point determinations. An inactive triterpene, dihydroifflaionic acid, and an inactive flavonol, 3-O-methylkaempferol, also were isolated and identified.


Perfusion and molecular modification of idoxuridine to alter its cerebrospinal fluid metabolism. Two methods to deter the rapid intrathecal degradation of idoxuridine were investigated: (a) rapid drug perfusion through the ventricular system, and (b) modification of the molecule to its uronic acid derivative, 2'-deoxy-5-iodo-5'-uridinecarboxylic acid, to make it less susceptible to enzymatic digestion. Perfusion of idoxuridine through the ventricular system (ventriculocisternal) of dogs at 0.97 ml/min saturated the metabolic pathway so that the outflow solution yielded a single spot (Rf 0.76) on TLC indicative of the intact molecule. The 125I-labeled uronic acid was synthesized from the 125I-labeled parent compound, and the labeled compounds were compared after their individual intracisternal injection in dogs. Since there was no difference in the disappearance rates, the stability of the uronic acid was, in fact, no greater than that of the parent compound in vivo. Ventricular perfusion of idoxuridine, however, seems a suitable means for increasing the amount of active drug delivered to central nervous system tumors and viral infections.


Synthesis of 10alpha-methoxy-delta8,9-lysergaldehyde from elymoclavine. A new synthesis is described for 10alpha-methoxy-delta8,9-lysergaldehyde involving the oxidation of elymoclavine with manganese dioxide in methanol. Lysergol and agroclavine provide no reaction under the same conditions.


Direct complexometric titration of calcium phosphates. Calcium was determined in calcium phosphate samples by dissolving the sample in hydrochloric acid, adding hydroxynaphthol blue indicator and triethanolamine, adjusting the pH to 12.3--12.5 with potassium hydroxide solution, and titrating with standard disodium ethylenediaminetetraacetate solution. Time can be saved and the formation of a precipitate (which dissolves readily during the titration) can be avoided by adding at least 85% of the amount of complexing agent required for titration before adjusting the pH.


Mass fragmentographic determination of plasma etomidate concentrations. The intravenous anesthetic etomidate was measured in human plasma by mass fragmentography. The method is accurate, sensitive, and specific. Results of the analyses indicate that after a single 0.3-mg/kg iv dose of etomidate, there are at least three phases in its disappearance from human plasma. Detectable plasma concentrations exist for more than 6 hr after injection.


Antitumor agents from Jatropha macrorhiza (Euphorbiaceae) III: acetylaleuritolic acid. The triterpene acetylaleuritolic acid was isolated from Jatropha macrorhiza (Euphorbiaceae) and showed tumor-inhibitory properties toward the P-388 lymphocytic leukemia test system. The compound was identified by means of IR, PMR, and mass spectrometry and by its transformation into the known methyl acetyloleanolate.


Anthelmintic dihydroquinoxalino[2,3-b]quinoxalines. A series of dihydroquinoxalino[2,3-b]quinoxalines was synthesized and tested for anthelmintic activity in a model assay. The most promising compound, 5,12-diacetyl-5,12-dihydroquinoxalino[2,3-b]quinoxaline, was orally effective in sheep at a dose of 200 mg/kg against a broad range of helminths.


Molecular connectivity and steric parameters. The possible relationship between molecular connectivity indexes, mchi, and Es, a thermodynamically derived parameter used to estimate steric effects in organic reactions and sometimes used in biological structure-activity relationships, was investigated. The extended chi terms, 2chi, 3chi, and 4chi, were correlated significantly to Es (r = 0.961). Aralkyl esters deviated from the correlations, possibly due to intramolecular interactions.


Indolizine derivatives with biological activity II: N'-Substituted hydrazides of 2-methyl-3-indolizinecarboxylic acid. Synthesis and study of the antimonoamine oxidase activity of some N'-substituted hydrazides of 2-methyl-3-indolizinecarboxylic acid are reported. The activities were generally of about the same order as those of the corresponding hydrazides of 2-indolizinecarboxylic acid.


Ganglion cell discharge and proximal negativity in the pigeon retina. 1. Proximal negativity has been compared with the spike responses and membrane responses of pigeon ganglion cells. 2. Spike discharge peaks develop during the rising phase of proximal negativity. 3. Proximal negativity is never directional, even when recorded concurrently with directional ganglion cells. 4. To  moving stimuli, on-centre cells respond in association with the leading edge of the stimulus, off-centre cells with the trailing edge, and on-off cells with the leading and trailing edges. Proximal negativity is produced in association with the leading and trailing edges. 5. Quasi-intracellular records show that discharge peaks occur in association with depolarizing potentials. The synaptic responses of on-off cells bear a closer resemblance to the proximal negative response than do the responses of on-centre cells, off-centre cells, or directional cells.


Responses of directional ganglion cells in the pigeon retina. 1. Extracellular single-unit records were taken from ganglion cells in the pigeon retina, and average response histograms were recorded, with base line spike counts. 2. Movements in the preferred direction in directional cells produce discharge peaks. Movements in the null direction produce spike deletion suggesting there is an inhibitory patch offset from the field centre, towards the start of the null sweep. 3. Bi-directional responses can be obtained from the preferred side of the field centre; bi-directional inhibition can be obtained at the null side. Scans orthogonal to the null-preferred direction passing through the inhibitory patch can produce deletions. 4. The latency of deletions from the inhibitory patch is slightly greater than of excitation from the field centre, judged by flashed or moving stimuli.


Rapid desensitization of acetylcholine receptors of eel electroplaques following iontophoretic application of agonist compounds. 1. The electrical potential difference across the innervated membrane of the electroplaque of Electrophorus electricus was measured with an intracellular micro-electrode while an extracellular double-barrelled micropipette was used to apply acetylcholine and carbamylcholine iontophoretically very close to the point of insertion of the recording electrode. 2. The average depolarizing response to brief (several msec) pulses of carbamylcholine decayed 22 times more slowly than the response to acetylcholine. Treatment of the electroplaque with eserine or neostigmine prolonged the acetylcholine responses. 3. When a steady current of acetylcholine was applied for  several seconds, the membrane first depolarized, then partially repolarized. Usually no repolarization was seen during long pulses of carbamylcholine or long pulses of acetylcholine in the presence of eserine or neostigmine. 4. During long conditioning pulses of acetylcholine or carbamylcholine, the responses to brief test pulses of acetylcholine showed a progressive decline in amplitude, but recovered after termination of the conditioning pulse. Desensitization half-times as short as 0-6 sec were observed, making these results similar to those obtained in the frog motor end-plate.


Slow mechanism for sodium permeability inactivation in myelinated nerve fibre of Xenopus laevis. 1. Single myelinated nerve fibres were isolated and the nodal currents were recorded under potential clamp conditions. The effect of membrane potential on the Na permeability (PNa) mechanism was analysed. 2. The available PNa increased slowly during negative polarization of the membrane. The time course of this change was about 10(3) times slower than the time course of the mechanism for the usual PNa inactivation (h-system). The slow PNa changes could be distinguished from changes in h because of the difference in rate. 3. The slow PNa variation was independent of the state of the h-system and was largely due to a slow inactivation system, which empirically could be described as separate from the other permeability variables. 4. In the steady state the slow inactivation appeared almost absent at a holding potential of -120 mV, whereas it was 30% complete at the resting potential (-70 mV) and 80% complete at a holding potential of -20 mV. 5. Changes in the slow inactivation system showed an approximately exponential time course. At 10-12 degrees C the time constant was about 3 sec with U = -70 mV, 7 sec with U = -100 mV and 1-5 sec with U = -127 mV. 6. High Ca shifted the steady state slow inactivation curve in the positive direction along the potential axis.


Reduction of multiaxonal innervation at the neuromuscular junction of the rat during development. 1. A study was made of the functional and structural changes that occur during the decrease in multiaxonal innervation of neonate rat muscle fibres 2-14 days after birth. 2. In day 8 to day 14 animals there was a constant daily loss in the average number of functionally transmitting axons/muscle fibre measured electrophysiologically. An investigation of synaptic transmission during this period revealed that the loss of functional contact from the supernumerary axons was not preceded by any sign of failing terminal conduction or a gradual decrease in transmission efficacy but rather appeared to occur abruptly. 3. Neonate end-plates showing signs of abnormal ultrastructure were observed during the period of synapse elimination. Some axon terminals had a high cytoplasmic density and condensation of synaptic vesicles. Signs of Schwann cell encroachment into the synaptic cleft were readily found and large areas of post-junctional membrane apposed only by Schwann cell were evident. 4. It is suggested that the mechanics of the process of synapse elimination in neonates is similar to that occurring during degeneration in the denervated adult. Transmission failure occurs abruptly at the supernumerary endings and they are disposed of by the Schwann cell.


An X-ray diffraction study of the cross-circulated canine heart. 1. The equatorial X-ray diffraction pattern was recorded from a papillary muscle of a cross-circulated canine heart at different phases of the cardiac cycle. The intensity ratio of the 1, 0 and the 1, 1 reflexions (I1, o/I1,1) was 0-79 in the systolic phase and 1-19 in the diastolic phase. 2. Using the intensity ratio obtained, the approximate proportion of the myosin projections present in the vicinity of the thin filaments was calculated. This was 70-71% in the systolic phase and 51-52% in the diastolic phase of the total myosin projections. 3. The peak systolic tension was roughly proportional to the proportion of the projections present in the vicinity of the thin filaments during systole. 4. The projections which stayed in the vicinity of the thin filaments during diastole did not produce significant contractile force.


Nasal field loss in kittens reared with convergent squint: neurophysiological and morphological studies of the lateral geniculate nucleus. 1. Recordings of single cells were made in layers A and A1 of the lateral geniculate nucleus of kittens raised with convergent squint in one eye, and morphological studies of cells representing the different parts of the visual fields in these layers were also made from histological sections.2. For the normal eye, cells receiving inputs from the nasal and temporal visual fields were evenly represented up to the periphery, whereas for the squinting eye, no cells which permitted quantitative studies of receptive field properties could be found in the periphery of the nasal field.3. The loss of nasal field, represented by the loss of functional cells in the LGN layer A1 fed by the squinting eye, depended on the severity of the squint. The greater the angle of convergent squint, the greater the loss of nasal field represented by the loss of functional cells.4. The cells fed by the squinting eye's temporal visual field retained their brisk function, although minor modifications in the receptive field organisation were apparent.5. The mean perikaryal size was smaller and the cell-density higher for cells in layers fed by the squinting eye. As found for the functional loss of cells, the shrinkage of perikaryal size and the increase of cell-density was smallest in the zones fed by the temporal visual field, and greatest in the zones fed by the peripheral nasal visual field.6. The functional and morphological changes in the cells in the LGN, which receive inputs from the nasal field of the squinting eye, are attributed to part of the temporal retina being hidden behind the bridge of the nose. It is proposed that this is a consequence of disuse atrophy, due to lack of stimulation during the sensitive period of development.


Nasal field loss in cats reared with convergent squint: behavioural studies. 1. The extent of the monocular visual field in cats reared with convergent squint in one eye was determined by a behavioural perimetry technique. 2. Significant reduction in the extent of the visual field was found in the squinting eyes. 3. The visual field defect is a graded one, located mainly in the nasal field, but in some cats extending into the temporal visual field. The defect includes a zone of absolute loss of response to stimuli at the extreme nasal field, adjacent areas of partial response and areas of 100% response in the periphery of the temporal field. 4. A direct relationship was found between the angle of horizontal deviation of the squinting eye and the amount of visual field loss: i.e. the larger the angle of squint, the greater the loss of nasal field. 5. It is suggested that the process leading to a loss in nasal visual field is independent of the loss of visual acuity in squinting cats, since the latter is not related to the angle of squint. 6. The significant loss in nasal visual field found by behavioural experiments in cats reared with a convergent squint thus correlates with comparable deficits found in the physiology and morphology of the lateral geniculate nucleus (Ikeda, Plant & Tremain, 1977), although the behaviourally determined loss of nasal field is greater than would be expected from the study of the response of the LGN neurones.


Active Na-K transport and the rate of ouabain binding. The effect of insulin and other stimuli on skeletal muscle and adipocytes. 1. The effect of stimulation or inhibition of active Na-K transport on [(3)H]ouabain binding has been investigated in isolated soleus muscles and adipocytes.2. In rat soleus muscle, the ouabain-sensitive component of (42)K influx was stimulated by insulin (100 m-u/ml.), adrenaline (6 x 10(-6)M), and by pre-incubation with veratrine (10(-5)M) or in a K-free buffer. In all of these instances, the rate of ouabain binding was increased by 41-113%. Conversely, pre-treatment with tetracaine (0.2 mM) decreased the (42)K-influx and diminished the rate of [(3)H]ouabain binding by 36%.3. Neither insulin, adrenaline or tetracaine produced any detectable change in the total number of ouabain-binding sites (as measured under equilibrium conditions) in rat soleus muscle.4. In mouse and guinea-pig soleus muscle and in fat cells isolated from rats, insulin also increased the rate of [(3)H]ouabain binding without producing any significant change in the total number of ouabain-binding sites.5. Both in soleus muscle and the epididymal fat pad of the rat, there was a linear correlation between (42)K influx and the initial rate of [(3)H]ouabain binding.6. It is concluded that the rate of ouabain binding is determined significantly by the rate of active Na-K transport, but within the time intervals studied (4-6 hr) stimulation or inhibition of the Na pump does not lead to any appreciable change in the total number of Na pumps. It seems unlikely that the stimulation of active Na-K transport by insulin or adrenaline is due to unmasking or de novo synthesis of Na pumps.


The influence of food intake and ambient temperature on the rate of thyroxine utilization. Young growing pigs of both sexes were subjected to changes in (1) energy intake, (2) ambient temperature, and (3) bulk of food. The rate of disappearance of injected 125I-labelled thyroxine from the plasma (K) was measured. An analysis of variance revealed that the effect attributable to changes in the energy content of the food intake was statistically significant (P less 0-01). A change in ambient temperature had no statistically significant effect on K, nor did a change in the bulk of food when energy intake was constant (P less than 0-05).