The acute toxicity of drugs acting at cholinoceptive sites and twenty-four hour rhythms in brain acetylcholine.
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Biomedical subjects
Publications and source records attributed to C A Walker.
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1. The circadian patterns for onset and duration of sleep after the administration of a constant dose of pentobarbitone sodium have been measured in rats adapted to and maintained under a fixed illumination cycle. The relationship of these patterns to others for rectal temperature and motor activity as well as for noradrenaline (NA), 5-hydroxytryptamine (5-HT) and histamine in mid-brain and caudate nucleus, and histamine and glucose in blood serum, has been examined.2. The onset of sleep is longest and duration shortest during the phase of the illumination cycle when motor activity and rectal temperature are maximal. An inverse relationship for these parameters is found during the light phase of the illumination cycle.3. In untreated rats, mid-brain NA and histamine and caudate nucleus histamine levels are maximal and 5-HT minimal during the dark phase of the illumination cycle. An inverse relationship for these parameters is found during the light phase of the illumination cycle.4. Pentobarbitone sodium treatment significantly elevates mid-brain NA and histamine and caudate nucleus histamine levels during the dark phase of the illumination cycle. Although 5-HT levels are reduced over the entire circadian cycle this change is significant only during the light phase of the illumination cycle.5. Pentobarbitone sodium treatment reverses the circadian pattern for body temperature, producing a mirror image of the control pattern.6. The circadian pattern for blood serum histamine levels differs from the C.N.S. pattern for histamine. Peak levels occur at the end of the light phase of the illumination cycle. After pentobarbitone sodium these levels are reduced, although the circadian pattern is similar to the control.7. Circadian blood glucose patterns have bimodal peaks; a primary peak at the end of the dark phase, a secondary peak at the end of the light phase of the illumination cycle. Pentobarbitone sodium did not significantly alter the pattern. The relationship between this pattern and C.N.S. and peripheral histamine and catechol amines is discussed.
1. The circadian rhythms of rectal temperature and biogenic amine levels in mid-brain and caudate nucleus have been measured in normal and adrenalectomized rats adapted to and maintained under fixed illumination cycle.2. Rectal temperature reaches a peak value between 24.00 hr and 06.00 hr during the dark phase of the illumination cycle at a time when motor activity is maximal. In adrenalectomized rats, the pattern is similar but the peak is significantly lower.3. Highest histamine levels in the caudate nucleus and mid-brain of normal and adrenalectomized rats are found at the time when body temperature and motor activity is maximal.4. Similarly, caudate nucleus and mid-brain noradrenaline levels reach their peak during the dark phase of the illumination cycle. These levels are significantly different from those found during the light phase of the illumination cycle. The rise in noradrenaline in the mid-brain of adrenalectomized rats, however, was not significant.5. Peak 5-hydroxytryptamine (5-HT) levels in the caudate nucleus of normal rats and the mid-brain of adrenalectomized rats were found to be 12 hr out of phase with peak values obtained for other parameters that were measured.6. The significance of these circadian rhythms in relation to states of sleep and wakefulness, general metabolism, and motor activity is discussed.
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Previous studies of peripherally injected mouse scrapie suggested that invasion of the CNS occurs initially in mid-thoracic cord by neural spread of infection from spleen and other visceral sites of extraneural replication. We now show that infection of the left sciatic nerve leads to direct spread of infection to brain (at a rate of approximately 1.0-2.0 mm/day), bypassing the need for extraneural replication and thus producing shorter incubation periods. However, the efficiency of intraneural infection is low. It can be increased by crush injury or by the injection of lysophosphatidyl choline, both of which temporarily increase the surface area of axolemma exposed to inoculum. Once infection is established, agent seems to spread throughout the nervous system but, at the clinical stage of disease, the titres in the PNS are much lower than in the CNS.
A case of Haemophilus parainfluenzae bacterial endocarditis is described. This is the first reported case of endocarditis caused by ampicillin resistant H parainfluenzae. Resistance was not mediated by a beta lactamase. Ampicillin therapy had not controlled the infection, but a four-week course of chloramphenicol was curative. Several general therapeutic points are discussed.
TME from a single source was transmitted by intracerebral injection to Chinese hamsters, producing clinical disease in all seven animals after incubation periods of over 600 days. The brain from each of the primary cases was used to establish separate intracerebral passage-lines of TME and this led to the isolation of two different strains of agent, designated 333K and 333W. These strains were easily distinguished by the incubation periods they produced (about 130 and 230 days, respectively) under standard conditions of infection, and by the characteristic profiles of vacuolation seen in different regions of the brain. Comparisons were made with a strain of scrapie passaged in Chinese hamsters, designated 34W, which could be distinguished from both strains of TME. Nevertheless the properties of the scrapie and TME strains overlapped, with one of the TME strains (333K) resembling the 34W strain of scrapie in Chinese hamsters more closely than the other TME strain (333W). These similarities strengthen the view that TME and scrapie are caused by a similar type of infectious agent. The very large 'species barrier effect' on transmitting TME to Chinese hamsters was in marked contrast to the minimal effect seen with scrapie and an explanation for this is suggested. Two interesting pathological features of the study were (a) the severe loss of pyramidal cells produced in the hippocampus by the 34W strain of scrapie, and (b) the focal, symmetrical vacuolation of the thalamus caused by 333K TME.
A pool of five oligonucleotides has been used to detect the pathogenic organism Mycobacterium avium subspecies paratuberculosis in PCR-amplified DNA from ruminants. The oligonucleotides were labelled at the 5'-end with three dinitrophenyl reporter groups and hybridised to the target DNA, which was fixed to a nylon membrane by ultraviolet irradiation. Colourimetric detection of the PCR product was carried out using an anti-DNP antibody conjugated to horseradish peroxidase or to alkaline phosphatase. Detection with alkaline phosphatase was more sensitive than with horseradish peroxidase but, in both cases, the PCR product could be easily detected. The DNP labelling system offers an economic and effective alternative to biotin, digoxigenin or fluorescein for the detection of PCR-amplified DNA.