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Biomedical subjects

A Holmes

Publications and source records attributed to A Holmes.

At least 163 records · Page 9Linked to original sources
PubMed1986

Synthesis of novel angiotensin converting enzyme inhibitor quinapril and related compounds. A divergence of structure-activity relationships for non-sulfhydryl and sulfhydryl types.

The synthesis and angiotensin converting enzyme (ACE) inhibiting activities of quinapril (CI-906, 22), its active diacid (CI-928, 33), and its dimethoxy analogue (CI-925, 25) are reported. These tetrahydro-3-isoquinolinecarboxylic acid derivatives possess equivalent in vitro potency and in vivo efficacy to enalapril. Sulfhydryl analogues with the same structural variation are also highly potent. In contrast, tetrahydro-1-isoquinolinecarboxylic acid and homologous isoindoline-1-carboxylic acid analogues show a striking divergence in potency between the two types, sulfhydryl analogues being essentially inactive, while non-sulfhydryl analogues are equipotent with the proline prototype. This is the first evidence suggesting that alternate binding modes may exist for the two major structural classes of small molecule ACE inhibitors.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1986

Sensitivity to X-irradiation of peripheral blood lymphocytes from ageing donors.

The proliferation of human blood lymphocytes from ageing donors, responding to concanavalin A, showed greater sensitivity to inhibition by X-rays than similar cells from younger donors. This increased sensitivity was associated with deficiency in repair of X-ray-induced damage to nuclear material, as measured by density in sucrose gradients, and with increased incidence of chromosomal damage following exposure of freshly isolated lymphocytes. There was also an increased frequency of spontaneous chromosomal aberrations in ageing subjects whose lymphocytes were deficient in repair of DNA damage.

Aged↗
PubMed1986

Food additives.

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Adult↗
PubMed1985

The distribution of dust in the rat lung following administration by inhalation and by single intratracheal instillation.

A comparison was made of the distribution of dust in the rat lung following its administration by inhalation and by a single intratracheal instillation. Due to the wide variety of instillation techniques, an "average" method was adopted based on the results from a survey of 15 laboratories in Europe and the USA. Novel techniques were developed to quantify the distribution of dust within the lung both microscopically and macroscopically. The distribution of dust obtained by instillation was shown to be much less homogeneous that that obtained by inhalation and penetration to the periphery was minimal. The effects of (a) changing the volume of suspension, (b) changing the concentration of the suspension, and (c) introducing air into the syringe were investigated. Although the use of air in the syringe was beneficial, none of the other modifications effected any improvement in the distribution. The difference in distribution following inhalation and instillation leads to the conclusion that the latter may be of use in establishing the nature and comparative response of the lung to different dusts, but not for establishing an absolute dose-response relationship. It is recommended that no more than 1 mg of fibrous or 5 mg of nonfibrous dust be given in a single instillation to adult rats.

Animals↗
PubMed1985

The enigmatic asbestos body: its formation and significance in asbestos-related disease.

It is well established that many different types of fibre, both organic and inorganic, can become coated with ferritin in lung to give ferruginous bodies. The presence of such bodies is one factor which is taken into account in assessing cases with asbestos-related disease for the purpose of compensation, although their presence is only an indication of past exposure and not proof of the causative role of asbestos. In this paper, evidence relating to the formation of ferruginous bodies in human lung is reviewed, to identify factors which predispose certain types and dimensions of fibre to become coated. Work with experimental animals is also summarised to give some indication of the time course of body formation.

Animals↗
PubMed1984

Alexander's law: its behavior and origin in the human vestibulo-ocular reflex.

Alexander's law refers to the phenomenon in which the spontaneous nystagmus of a patient with a vestibular lesion is more intense when the patient looks in the quick-phase than in the slow-phase direction. Alexander's law was investigated in normal subjects as well as patients with vestibular lesions. During sinusoidal rotations of normal subjects, there was no trace of this phenomenon when subjects looked 25 degrees left and right in the dark. The phenomenon of Alexander's law is therefore created centrally and is not due to any mechanical properties of the orbit. During rotation at constant velocity in the dark, normal subjects did weakly demonstrate Alexander's law because of a mild gaze-evoked nystagmus present in normal subjects in the dark. Gaze-evoked nystagmus from a cerebellar lesion involved a pronounced demonstration of Alexander's law during rotatory nystagmus. In patients with a vestibular lesion and a mild spontaneous nystagmus in the dark that obeyed Alexander's law, the nystagmus reversed upon far gaze in the slow-phase direction. We propose that in patients with a vestibular lesion, the phenomenon of Alexander's law is created by the sum of vestibular nystagmus and an abnormally large gaze-evoked nystagmus that is consequent to the vestibular lesion. This conclusion has a number of neurological implications concerning the ways in which the nervous system attempts to compensate for vestibular lesions.

Adult↗
PubMed1984

The distribution and characteristics of asbestos fibers in the lungs of Finnish anthophyllite mine-workers.

Measurements of the concentrations and dimensions of uncoated and coated fibers in blocks of tissue taken at the periphery and elsewhere from slices of lungs obtained from two anthophyllite-mine workers are reported. A single block from the lung of a third worker was also analyzed. For the subject examined in most detail, the mean peripheral fiber concentration was greatest in the lower lobe. In the other subject there did not appear to be much variation in fiber concentration with distance from the periphery. The count median lengths of uncoated fibers ranged from about 8 to 12 micron and for coated fibers from 40 to 50 micron. It was apparent that dicing tissue samples, before hypochlorite digestion, led to fracture of the longer uncoated and coated fibers. The results are compared with similar measurements made on the lung of an insulation worker and reported previously.

Aged↗
PubMed1983

Surface antigens of gonococci: correlation with virulence and serum resistance.

Encapsulated and non-encapsulated variants of one strain of gonococcus were compared for their capacity to produce infection in chambers implanted subcutaneously in mice, for their reactions with specific antibody and for their precipitation with wheat germ agglutinin. Only the encapsulated variant could infect implanted chambers. Specific rabbit antiserum raised against the non-encapsulated variant killed both variants. Saline extracts and lipopolysaccharide preparations of the encapsulated variant differed from those of the non-encapsulated one in their reactions with wheat germ agglutinin and antibody in diffusion and electrophoresis tests. Preparations from infective encapsulated gonococci reacted with wheat germ agglutinin while those from the non-encapsulated variant did not. Immunodiffusion tests showed that lipopolysaccharides from both variants share a common antigenic determinant, but saline extracts and lipopolysaccharides from encapsulated gonococci possess an additional determinant. The significance of these findings is discussed.

Animals↗
PubMed1983

Distribution and characteristics of amphibole asbestos fibres, measured with the light microscope, in the left lung of an insulation worker.

Concentrations of uncoated and coated amphibole fibres were measured postmortem in samples taken from the periphery of both upper and lower lobes of the left lung of an insulation worker. Similar measurements were made on a more limited range of samples from elsewhere in the lung and on a hilar lymph node. The mean concentration of uncoated fibres in the upper lobe was twice that in the lower. Significant differences were observed in the mean concentration of uncoated fibres in different regions of the periphery, the diaphragmatic region having the lowest value. Variations in the concentrations of both uncoated and coated fibres in the costal region of the lower lobe may have been related to the effect of rib structures on ventilation. Concentrations of fibrous and non-fibrous dust were well correlated in the peripheral samples. The length distributions of uncoated and coated fibres were also measured and differences detected in fibres from the various regions of the lung. This work emphasises the care required in sampling lung tissue in order to obtain representative material for the determination of fibre concentration.

Asbestos↗
PubMed1983

Evidence for a dose-dependent inflammatory response to quartz in the rat lung and its significance in early changes in collagen metabolism.

The response of the rat lung to a range of doses of quartz at 50 and 100 days after its administration by intratracheal instillation has been assessed by bronchopulmonary lavage. The effects on the number of polymorphonuclear leukocytes (PMN), lymphocytes and macrophages are described. In addition the concentrations of soluble protein and hydroxyproline and the activities of lactate dehydrogenase, PZ peptidase and collagenase in lavage fluid supernatants were measured and an assessment of the hydroxyproline content of recovered cells was made. Finally PZ peptidase and collagenase were assayed in PMN-enriched cell fractions and in samples obtained from short-term culture of recovered macrophages. There was a dose-dependent increase in the recovery of all three cell types, and in the amounts of lactate dehydrogenase, protein and hydroxyproline in lavage fluids, which showed no signs of resolution over the 100-day period studied. Measurements of PZ peptidase and collagenase suggested that the PMN, not the macrophages, are the major source of these degradative enzymes. The relevance of these findings with regard to the importance of PMN in quartz-induced fibrosis is discussed.

Animals↗
PubMed1983

The advantages and limitations of an in vivo test system for investigating the cytotoxicity and fibrogenicity of fibrous dusts.

The acute response of the rat lung to a range of fibrous materials has been investigated by bronchopulmonary lavage, at dose levels of 0.5 and 1.0 mg, 1 and 7 days after their administration by intratracheal instillation. The materials chosen for study included UICC chrysotile A, amosite, crocidolite and anthophyllite, and samples of S. African "long" amosite and glass fiber. In addition, the subacute response to 1, 2 and 3 mg of chrysotile and amosite has been studied at 50 and 100 days after instillation. In the acute phase at 1 day after instillation, the response to chrysotile was greater than that to any of the other materials, but by 7 days there was no gradation in the response to different dusts. In the subacute phase, cell recoveries were low, and it was not possible to assess the long-term cytotoxic or fibrogenic effects of amosite and chrysotile by analyses of lung washes, even though biochemical and histological methods indicated gross changes in lung pathology.

Animals↗
PubMed1983

Dose-dependent effects in the subacute response of the rat lung to quartz. I. The cellular response and the activity of lactate dehydrogenase in the airways.

The response of the rat lung to a range of doses of quartz at 50 and 100 days after its administration by intratracheal instillation was investigated by bronchopulmonary lavage. The effects on the numbers of polymorphonuclear leucocytes, lymphocytes and macrophages recovered are described. In addition, the size distribution of the recovered macrophages was followed and measurements of total numbers of macrophages in the lung were made using a radioactive tracer technique. Finally, the activity of the cytoplasmic enzyme, lactate dehydrogenase, in lavage fluid supernatants was recorded. There was a dose-dependent increase in the recovery of all three cell types and an increase in the total numbers of macrophages in the lungs which showed no signs of resolution over the 100 day period studied. Increasing levels of lactate dehydrogenase were also dose-dependent and well correlated with the numbers of polymorphs and lymphocytes recovered. The importance of this prolonged inflammatory reaction in relation to the fibrogenic action of quartz is discussed.

Animals↗