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Biomedical subjects

C Clarke

Publications and source records attributed to C Clarke.

At least 127 records · Page 7Linked to original sources
PubMed1985

A stimulator for moving textured surfaces sinusoidally across the skin.

The stimulator allows textured surfaces to be moved sinusoidally across the skin of the fingerpad. Sinusoidal motion is produced by a "scotch yolk" driven by a DC motor. The amplitude of movement is adjustable up to a maximum of 80 mm peak to peak and the frequency is continuously adjustable from 0.1 Hz to 2.0 Hz. Movement of the surface is monitored by an optical transducer and contact force between the finger and the surface is monitored by a strain gauge bridge. The stimulator is simple and robust and is suitable for both neurophysiological and psychophysical experiments in animals and humans.

Animals↗
PubMed1985

Correlation between the stimulation of human neutrophil function by monoclonal antibody and by colony-stimulating factor.

Purified human neutrophils from 48 individuals were tested for their capacity to kill antibody-coated target cells in vitro in the absence or presence of stimulating agents. The agents used to stimulate cytotoxic capacity were the monoclonal antibody (MAb) WEM-G1, colony-stimulating factor (CSF-alpha), or mononuclear cell supernatant (MNC-SN). There existed an heterogeneity among the neutrophils of different individuals in the capacity to kill target cells both in the unstimulated ("resting") or the stimulated state. A positive correlation was found between the ability of neutrophils to kill in the "resting" state and their capacity to be stimulated by MAb WEM-G1, CSF-alpha, or MNC-SN. Furthermore, a strong positive correlation in the ability of neutrophils to be stimulated by the MAb WEM-G1 and either CSF-alpha (r = .76) or MNC-SN (r = .68), as well as between CSF-alpha and MNC-SN (r = .79) was demonstrated. No correlation was seen, however, between stimulation of neutrophil function in vitro and total blood leukocyte counts, neutrophil counts, monocyte counts, or intensity of binding of MAb WEM-G1. The observation that neutrophils respond to a similar extent to different types of stimulators, -such as cytokines (CSF-alpha and MNC-SN) and MAb, suggests that these two factors may be operating through a common mechanism and the degree of stimulation may reflect an intrinsic responsiveness of neutrophils that differs among individuals. Our results also suggest a potential clinical use of WEM-G1 in measuring neutrophil functional capacity in vitro and predicting the capacity to respond to CSF-like cytokines.

Animals↗
PubMed1984

Intestinal microflora as potential modifiers of sensitizer activity in vivo.

Treatment of mice (some bearing Lewis Lung tumors), with penicillin (PEN) at 500 mg/l drinking water for one week prior to treatment with misonidazole (MIS), resulted in: the elimination of their anaerobic cecal flora; a decrease in MIS-induced neurotoxicity; an increase in pharmacological exposure to MIS; a decrease in MIS chemopotentiation; a probable increase in MIS radiosensitization; an increase in MIS induced hypothermia. Assuming no chemical interaction between PEN and MIS, these observations indicate that the intestinal microflora can influence the activity of MIS in vivo. Therefore their influence should be considered in all sensitizer-related studies in vivo. The observed reduction in the neurotoxic but not the radiosensitizing potential of MIS following PEN treatment indicates a therapeutic benefit.

Animals↗
PubMed1984

The effect of phenytoin, phenobarbitone, dexamethasone and flurbiprofen on misonidazole neurotoxicity in mice.

Using a quantitative cytochemical technique for measuring beta-glucuronidase activity in the peripheral nerves of mice, we have investigated the effectiveness of four potential adjuncts for reducing the dose limiting neurotoxicity of misonidazole (MISO) in the clinic. Under the conditions used, the most effective adjunct was the steroid anti-inflammatory agent dexamethasone. When given over the week previous to MISO treatment, this agent almost completely eliminated the MISO neurotoxicity as determined at week 4 after commencement of MISO dosing. The second most effective adjunct was phenytoin, the third flurbiprofen and the last adjunct, phenobarbitone, was ineffective. Dexamethasone, phenytoin and phenobarbitone all reduced the clearance half-life of MISO and hence the drug exposure dose calculated as the area under the curve of MISO tissue concentration against time. However, no correlation was evident with these parameters and MISO neurotoxicity in the mouse. Dexamethasone, whilst affording protection against MISO toxicity, did not alter the radiosensitivity of the anaplastic MT tumour.

Animals↗
PubMed1984

The bowel, the genitourinary tract, and infective endocarditis.

Of 582 episodes of infective endocarditis 75 were attributable to organisms normally resident in the bowel and 12 others were associated with alimentary tract operations, investigations, or disease. The mean age of the 87 patients in this particular group was higher (59.7 years) than that of all the patients with infective endocarditis (51.4 years). As far as could be ascertained 41% had no pre-existing cardiac abnormality, and in a little under a half no predisposing event to initiate the illness was apparent. Where the portal of entry of the organism to the blood stream was evident it was slightly more often in the genitourinary than the alimentary tract. Bowel organisms are no less important than those associated with the teeth in causing infective endocarditis. It is suggested that in all those patients with known cardiac abnormalities and possibly in those over the age of 60 with normal hearts antibiotic cover should be considered when they undergo genitourinary or alimentary tract surgery or instrumentation.

Adolescent↗
PubMed1983

Animal model of aluminum-induced osteomalacia: role of chronic renal failure.

Both aluminum toxicity and a relative deficiency of parathyroid hormone have been implicated in the development of osteomalacia in dialysis patients. To study the effect of intraperitoneal (IP) aluminum injections on bone histology and parathyroid hormone and to determine if chronic renal failure accentuates aluminum toxicity, rats were divided into five groups: normals (N); low dose aluminum (LDA), 0.1 mg IP aluminum daily; high dose aluminum (HDA), 1.0 mg IP aluminum daily; chronic renal failure (CRF); and chronic renal failure plus high dose aluminum (CRF-HDA). At the conclusion of the study, there were no differences between N and LDA rats. Between the other groups, marked differences were observed. Compared to N rats, the relative osteoid volume (P less than 0.02) and the osteoid seam width (P less than 0.001) were increased in HDA, CRF, and CRF-HDA rats. Percent resorption and osteoclasts/mm2 were increased in CRF rats (P less than 0.02) and decreased in HDA rats (P less than 0.05). Compared to N rats, the amino terminal parathyroid hormone was decreased in HDA rats (P less than 0.02) despite the presence of hypocalcemia. These data suggest that (1) aluminum toxicity produces osteomalacia; (2) a relative parathyroid hormone deficiency may be a contributory factor; (3) chronic renal failure increases the severity of aluminum-induced osteomalacia; and (4) chronic renal failure alone does not result in osteomalacia.

Aluminum↗
PubMed1983

The teeth and infective endocarditis.

During 1981 and 1982 544 cases of infective endocarditis were investigated retrospectively by means of a questionnaire. Only 13.7% had undergone any dental procedure within three months of the onset of the illness, and in 42.5% there was no known cardiac abnormality before the onset of the disease. Furthermore, the number of cases occurring annually was about the same as or more than it was before the introduction of penicillin. The mouth and nasopharynx were the most likely sources of the commonest organism, Streptococcus viridans, and it is suggested that it is not dental extractions themselves which are of importance but good dental hygiene. In most patients with infective endocarditis the portal of entry of the organism whatever its nature cannot be identified. If this is so antibiotics are being given to only a small proportion of those at risk, and this would explain why the number of cases is much the same as it was before the introduction of penicillin. Furthermore, the large proportion of patients with no known previous cardiac abnormality adds to the difficulty of providing effective prophylaxis. The evidence suggests that antibiotic prophylaxis should still be given before dental procedures, and a schedule is appended. Much more importance should be given, however, to encouraging people to seek better routine dental care. We also believe that doctors and dentists should appreciate that the pattern of the disease has changed considerably in the past 50 years and that the information given here warrants a revised approach to the problem.

Adolescent↗
PubMed1983

The microbiology and pathogenesis of infective endocarditis.

Some details of 544 episodes of infective endocarditis occurring in 541 patients during 1981 and 1982 are reported. The mean age of patients was 51.6 years and there was a greater proportion of males (2:1). Of the 544 episodes 347 (63%) were due to streptococci, 19% to staphylococci, and 14% to bowel organisms. A wide variety of other organisms were responsible for a few cases, and 10% were culture negative. In 60% the portal of entry of the infection could not be ascertained: 19% were probably of dental origin: 16% arose from the alimentary, genitourinary, or respiratory tracts or from the skin or in association with drug addiction, fractures, or pregnancy; the remaining 5% were related to cardiac or other vascular surgery, cardiac catheterisation, haemodialysis, or other procedures involving the blood stream. Seventy-four (14%) of the 541 patients (mean age 59.0 years) died; the mortality was 30% in staphylococcal cases, 14% in infections due to bowel organisms, and 6% in other streptococcal infections. One hundred and seventy-one (32%) of the patients appeared to have had normal hearts before the onset of illness and another 59 (11%) had cardiac lesions not previously recognised. The aortic valve was the most common site of infection. Ninety (17%) of the patients had prosthetic valves or had undergone other cardiac surgery while 34 (6%) had had a previous episode of infective endocarditis. Nine (1.6%) episodes were not diagnosed until necropsy or operation and 34 (6.3%) required urgent valve replacement.

Adolescent↗
PubMed1982

An immunoglobulin promoter region is unaltered by DNA rearrangement and somatic mutation during B-cell development.

The V1 gene encodes the heavy chain variable region of antibodies that bind to phosphorylcholine in the Balb/c mouse. V1 genes have been cloned from mouse sperm DNA, an IgM-producing tumor HPCM2 and an IgA-producing tumor M167. The transcription start site of the V1 gene has been mapped 63 +/- 1 base pairs from the coding sequence for both alpha and mu transcripts. Comparison of flanking DNA sequence 574 base pairs 5' to the V1 transcription start site in sperm, HPCM2 and M167 DNA reveals that sperm and HPCM2 sequences are completely identical in this region and the M167 sequence differs from them by a single base change. Although the coding region of the V1 gene has undergone a high (4%) rate of somatic mutation in M167 we demonstrate that the somatic mutation mechanism stops near the transcription start site. These results demonstrate that initiation of V1 gene transcription remains unchanged with respect to location and 5' sequences throughout B-cell development.

Animals↗
PubMed1982

Enzymic synthesis of steroid sulphates. XV. Structural domains of oestrogen sulphotransferase.

Pure preparations of oestrogen sulphotransferase (3'-phosphoadenylylsulphate:oestrone sulphotransferase, EC 2.8.2.4), exhibiting the normal four-isoenzyme pattern on gel electrophoresis, revealed limited proteolytic splits in the protein chain when examined by SDS-polyacrylamide gel electrophoresis. In addition to the normal 74000 molecular weight (74 kDa) protein band, an additional major band was seen at 36 kDa, often accompanied by band at 24kDa and 12kDa. Such preparations, either alone, or after reduction and S-carboxymethylation, showed an extremely strong resistance to dissociation, a concentration of 2% SDS being required for dissociation on Sephadex G-100 column chromatography. These lower molecular weight fragments, isolated by several techniques employing dissociative conditions, all showed a remarkable ability to reassociate to a species of approx. Mr 70000 when examined by SDS-polyacrylamide gel electrophoresis. In addition, the 12kDa fragment yielded dimeric, trimeric, tetrameric, pentameric and hexameric forms. Results of amino acid analyses and tryptic digestion fingerprints of the 36kDa, 24kDa and 12kDa fragments, in conjunction with N-terminal amino acid determinations, suggested in initial protease cleavage at a susceptible region midway in the chain. One, or both, of the resultant 36kDa lobes was then further attacked to yield the 12kDa and 24kDa species - the latter again being capable of cleavage to two 12kDa species. Tryptic maps indicated that the 12kDa, 36kDa and 72kDa species were discrete polypeptide chains and not composed of subunits of the 12kDa species. These data suggest that the enzyme contains a number of domains and that strong interaction occurs between them. If these domains possess oestrogen-binding properties this would explain the most unusual wave-like kinetics exhibited by the enzyme consistent with a rate equation of degree greater than 4. Such properties also provide evidence further to that previously reported which suggests that the enzyme may be genetically related to serum albumin.

Amino Acids↗
PubMed1982

Enhancement of the cytotoxicity of radiosensitizers by modest hyperthermia: the electron-affinity relationship.

The cytotoxicity of 3 electron-affinic radiosensitizers has been studied in Chinese hamster V-79 cells as a function of pH and modest hyperthermia. When equitoxic concentrations were used and temperature was increased from 34 to 41 degrees C metronidazole, the compound with the lowest electron affinity showed the greatest enhancement of hypoxic-cell toxicity, and nitrofurantoin, the compound with the highest electron affinity, the least. The results can be explained if the mechanisms of toxicity involves a redox reaction, since it would be expected that the least toxic compound (lowest electron affinity) would have the largest activation energy and hence the greatest temperature effect. This appears to hold for these 3 compounds. Experiments also showed that nitrofurantoin which exhibits no increase in toxicity when the temperature was increased from 37 to 41 degrees C at pH 7.4, showed an increase in toxicity for the same temperature change at the pH of 7.0 and 6.6. Under aerobic conditions only metronidazole showed significant toxicity at 41 degrees C, where the differential between aerobic and hypoxic cell toxicity was minimal, both at pH 7.4, and at the low pH values of 7.0 and 6.6. In the clinical setting there is evidence that tumour cells are at a lower pH than their surrounding normal tissues. Hypoxic-cell cytotoxicity is enhanced at low pH, and even further enhanced at low pH in combination with a temperature of 41 degrees C. However, this finding correlates conversely with electron affinity. Thus, the radiosensitizer (and trichomonicide) metronidazole is most influenced by low pH and high temperature with the nitroimidazole, misonidazole, demonstrating a smaller enhancement due to higher temperatures.

Animals↗
PubMed1982

Quantitative cytochemical assessment of the neurotoxicity of misonidazole in the mouse.

A quantitative, cytochemical assay for measuring lysosomal enzymes in the peripheral nerves of mice has been developed. That the time course of lysosomal enzyme changes after misonidazole (MISO) treatment reflects the degree of neurotoxicity of this agent in the mouse, has been confirmed by the use of two known neurotoxic compounds: methyl mercury and acrylamide. This effect is specific to the peripheral nerves and was not found in liver, kidney, heart or cerebral cortex. Enzyme activities varied with mouse strain and sex, as did the response to MISO treatment. Of the mice studied, female C57 gave the greatest increase in beta-glucuronidase activity. With the MISO dose of 0.6 mg/g/dose the increased enzyme activity was independent of the route of administration and appeared to approach a plateau after 5 daily doses.

Acrylamide↗