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Biomedical subjects

M T Keogan

Publications and source records attributed to M T Keogan.

At least 55 records · Page 3Linked to original sources
PubMed1995

The control of neutrophil chemotaxis by inhibitors of cathepsin G and chymotrypsin.

Neutrophil chemotaxis plays an important role in the inflammatory response and when excessive or persistent may augment tissue damage. The effects of inhibitors indicated the involvement of one or more serine proteinases in human neutrophil migration and shape change in response to a chemoattractant. Monospecific antibodies, chloromethylketone inhibitors, and reactive-site mutants of alpha 1-antitrypsin and alpha 1-antichymotrypsin were used to probe the specificity of the proteinases involved in chemotaxis. Antibodies specific for cathepsin G inhibited chemotaxis. Moreover, rapid inhibitors of cathepsin G and alpha-chymotrypsin suppressed neutrophil chemotaxis to the chemoattractants N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) and zymosan-activated serum in multiple blind well assays and to fMLP in migration assays under agarose. The concentrations of antichymotrypsin mutants that reduced chemotaxis by 50% would inactivate free cathepsin G with a half-life of 1.5-3 s, whereas the concentrations of chloromethylketones required to produce a similar inhibition of chemotaxis would inactivate cathepsin G with a half-life of 345 s. These data suggest different modes of action for these two classes of inhibitors. Indeed the chloromethylketone inhibitors of cathepsin G (Z-Gly-Leu-Phe-CMK) and to a lesser extent of chymotrypsin (Cbz-Gly-Gly-Phe-CMK) mediated their effect by preventing a shape change in the purified neutrophils exposed to fMLP. Antichymotrypsin did not affect shape change in response to fMLP even at concentrations that were able to reduce neutrophil chemotaxis by 50%. These results support the involvement of cell surface proteinases in the control of cell migration and show that antichymotrypsin and chloromethylketones have differing modes of action. This opens the possibility for the rational design of anti-inflammatory agents targeted at neutrophil membrane enzymes.

Amino Acid Chloromethyl Ketones↗
PubMed1994

Evaluation of the skull base by SPECT. A comparison with planar scintigraphy and computed tomography.

Computed tomography is currently the standard diagnostic tool for the evaluation of the skull base. The complex anatomy of this area is the primary reason why planar bone scintigraphy is often unsatisfactory; exact localization of abnormalities may be very difficult. These limitations may be overcome by SPECT. Seventeen patients with clinical features of basal skull involvement were assessed by CT, SPECT, and planar scintigraphy. Subsequent clinical diagnoses were malignancy in 15 patients, vasculitis in 1 patient, and osteomyelitis in 1 patient. Computed tomography with IV contrast was performed through the skull base at 5 mm intervals. Planar scintigraphy with Tc-99m MDP was followed by SPECT. Bony involvement compatible with the clinical findings was demonstrated by CT scans in 6 patients, by planar scintigraphy in 7 patients, and by SPECT in 9 patients. The abnormalities that were identified by CT were all identified by SPECT. This study suggests that, in imaging the skull base, SPECT is more sensitive and provides better anatomical localization than planar imaging and appears useful in patients with a negative CT study.

Contrast Media↗
PubMed1994

Bilateral lower extremity evaluation of deep venous thrombosis with color flow and compression sonography.

Recognition of the accuracy of CUS for diagnosis of DVT has led to increased requests for bilateral lower extremity CUS studies. Compared to unilateral lower limb CUS studies, these examinations are often requested when the clinical suspicion of DVT is less strong. We undertook a 15 month prospective study of bilateral lower extremity CUS examinations to determine the diagnostic yield of positive studies and any correlation with clinical parameters. Eighty-six patients were studied; six patients (7%) had studies positive for acute DVT, and 78 patients (91%) had negative studies. Positive studies did not correlate with clinical parameters except erythema. Concurrently, 23% of unilateral lower limb sonographic studies were positive. Bilateral lower limb CUS is a low yield investigation, which may be indicated in view of the morbidity and mortality associated with DVT and pulmonary embolism.

Constriction↗
PubMed1994

Cerebellar vermian defects: antenatal sonographic appearance and clinical significance.

A partial or complete defect of the cerebellar vermis may occur sporadically or as a component of the Dandy-Walker syndrome, the Dandy-Walker variant, Down's syndrome, or Joubert-syndrome. We identified a defect of the cerebellar vermis in nine fetuses on routine antenatal sonographic studies. In five of the nine fetuses other abnormalities, including central nervous system and non-central nervous system lesions were identified. Three of these five fetuses died and two infants have remained well on follow-up. Four of nine fetuses (or infants) had no other abnormalities and have remained well on follow-up at 8 weeks to 4 years of age. Although cases of fatal and serious nonfatal outcomes have been reported by other investigators, in this small series the finding of an isolated inferior vermian defect was associated with a good prognosis.

Abnormalities, Multiple↗
PubMed1993

Anti-neutrophil cytoplasm antibodies (ANCA) increase neutrophil adhesion to cultured human endothelium.

ANCA have been demonstrated to activate normal neutrophils in vitro. This study demonstrates that ANCA positive IgG and Fab2 fragments increase the adhesion of normal neutrophils to cultured human umbilical vein endothelium (HUVEC), and that preincubation of the endothelial monolayers with tumour necrosis factor (TNF) to activate the endothelium enhances this effect. Preincubation of neutrophils with anti-CD18 monoclonal antibodies inhibited adhesion, suggesting that the observed effect was integrin mediated.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1993

The significance of pulmonary nodules detected on CT staging for lung cancer.

Small pulmonary nodules of soft tissue density are often found during computed tomography for the staging of lung cancer, but CT cannot reliably distinguish benign from malignant uncalcified pulmonary nodules. The purpose of this study was to assess the significance of pulmonary nodules discovered on staging CT. 551 patients with lung cancer who had a staging CT and who were considered operable were studied. Eighty-eight patients (16%) were found to have small non-calcified pulmonary nodules. Adequate follow-up was possible in 25 patients who had a total of 36 nodules. Twenty-five nodules (70%) were subsequently confirmed to be benign, four (11%) were malignant and the nature of seven (19%) could not be determined. The high prevalence of benign nodules in this population should be taken into account when staging lung cancer.

Aged↗
PubMed1993

Spontaneous in vitro production of rheumatoid factor during infectious exacerbations of cystic fibrosis: correlation with circulating immune complex levels.

Rheumatoid factor (RF) production has been demonstrated during infections, including infectious exacerbations of cystic fibrosis (CF). The aim of this study was to evaluate the relationship of RF production to infection, and examine the mechanisms involved. Serial peripheral blood mononuclear cell (PBMC) cultures with measurement of spontaneous production of IgM RF, IgA RF, total IgM and IgA, and measurement of serum levels of immune complexes were carried out during exacerbations of CF. The percentage of B cells expressing CD5 was examined in a second cohort of acutely infected CF patients, and related to IgM RF production. IgM RF production was significantly elevated during acute infection compared with convalescence (P < 0.05), stable CF subjects (P < 0.005) and normal controls (P < 0.05). IgM RF production did not correlate with total IgM production in the majority of patients, but was closely related to circulating immune complex levels in 8/10 subjects. IgA RF production did not increase significantly during infection, and did not correlate with total IgA or IgM RF production, or with circulating immune complex levels. CD5+ B cells were not increased in the CF group, and the percentage of CD5+ B cells did not correlate with IgM RF synthesis. These observations suggest that RF production during infection is specifically induced, possibly by immune complex autoimmunization, and is not simply the result of polyclonal B cell activation. Different patterns of IgM RF and IgA RF synthesis suggest different mechanisms of induction.

Acute Disease↗
PubMed1993

Circulating T cell subtypes in polymyalgia rheumatica and giant cell arteritis: variation in the percentage of CD8+ cells with prednisolone treatment.

OBJECTIVES: Some reports have described a decreased percentage of circulating CD8+ cells in patients with polymyalgia rheumatica and giant cell arteritis (PMR/GCA) before treatment and persisting for some months during treatment with corticosteroids. Other studies have found no such changes. There are overt methodological variations between these studies and there may also hidden differences, such as the timing of blood samples. The purpose of this study was to investigate T cell subtypes in patients with PMR/GCA while controlling for variables known to affect T cells. METHODS: Circulating T cell subsets were measured in 36 patients with PMR/GCA before and during treatment with prednisolone. Blood samples during treatment were taken before the daily dose of prednisolone. The whole blood lysis method was used followed by flow cytometry. RESULTS: Compared with controls, CD8+ cells were not reduced before treatment in patients with PMR/GCA (0.44 x 10(9)/l; 28% of lymphocytes). CD4+ cells were also normal (0.78 x 10(9)/l; 48% of lymphocytes). During treatment with prednisolone total T cells increased from 1.18 to 1.59 x 10(9)/l and CD4+ cells increased from 0.78 to 1.05 x 10(9)/l. The percentage of CD8+ cells decreased on treatment from 28 to 25%. CONCLUSIONS: This study does not confirm the finding of some groups that the percentage of circulating CD8+ cells is reduced in patients with PMR/GCA before treatment. It does show that the percentage of CD8+ cells decreases during treatment with corticosteroids. This needs to be considered when designing studies of lymphocyte subsets in diseases treated with corticosteroids.

Aged↗
PubMed1993

Effects of single dose compared with three days' prednisolone treatment of healthy volunteers: contrasting effects on circulating lymphocyte subsets.

AIMS: To investigate the effects of longer term corticosteroid treatment on circulating lymphocyte subsets. METHODS: Prednisolone (20 mg daily) was given to 12 healthy volunteers in a single morning dose for three days. Circulating lymphocyte subsets were measured by flow cytometry after whole blood lysis. RESULTS: Seven hours after the first dose of prednisolone there was a significant fall in absolute numbers of lymphocytes, T cells, CD4+ and CD8+ cells, and B cells. The percentage of T cells fell significantly, due to a fall in percentage of CD4+ cells. In contrast to the seven hour findings, at 72 hours there was a significant rise in absolute numbers of lymphocytes, T cells, CD4+, CD8+, and B cells. This trend was already apparent by 24 hours. The percentage of CD4+ cells was significantly raised at 72 hours, while that of CD8+ cells had fallen significantly. The percentage of natural killer cells had fallen at 72 hours; that of B cells remained increased at 72 hours. CONCLUSIONS: These findings show that corticosteroid treatment causes significant changes in lymphocyte subsets, and that such changes must be considered when designing studies of lymphocyte subsets during illness.

Adult↗
PubMed1992

Humanised monoclonal antibody therapy for rheumatoid arthritis.

Monoclonal antibodies that target T cells have shown some benefit in rheumatoid arthritis although responses have not been long lasting. This is partly due to insufficient therapy consequent upon antibody immunogenicity. Use of humanised antibodies, which are expected to be less foreign to man than conventional rodent antibodies, might overcome this problem. We therefore assessed in a phase 1 open study the potential of a "lymphocyte depleting" regimen of the humanised monoclonal antibody CAMPATH-1H in 8 patients with refractory rheumatoid arthritis. Apart from symptoms associated with first infusions of antibody, adverse effects were negligible. Significant clinical benefit was seen in 7 patients, lasting for eight months in 1. After one course of therapy, there was no measurable antiglobulin response, although 3 out of 4 patients have become sensitised on retreatment. Humanisation reduces the immunogenicity of rodent antibodies but anti-idiotype responses may still be seen on repeated therapy, even in patients sharing immunoglobulin allotype with the humanised antibody.

Adult↗
PubMed1992

Chest radiography for general practitioners: scope for change?

In order to derive guidelines for general practitioners on the value of chest radiography we prospectively reviewed all chest radiographs over a 10 month period. Radiographic chest examinations (frontal with or without a lateral view) were performed on 2017 patients in the radiology department or at the chest clinic. Patient details were noted, referring practice and waiting times monitored. The adequacy of the referral letter was assessed, and specific predetermined clinical findings were correlated with the radiographic findings. Results were divided into three groups (normal, abnormal with a clinically unrelated or chronic abnormality, and abnormal with a clinically related abnormality). Of these patients, 1245 (62%) had normal examinations and 460 (23%) had clinically related abnormalities. Abnormalities were rare in the 10-29 year age group, and when reassurance was sought for patients with symptoms of non-specific chest pain or general ill health. Patients presenting with haemoptysis or with symptoms of lower respiratory infection, or of chronic airways disease often had an abnormal radiograph. A clinical diagnosis was indicated or implied in 1664 (82%) and confirmed in 876 (53%). The most frequent reason for referral was for reassurance (618 patients). Guidelines based on age and symptoms should rationalize the use of chest radiography by general practitioners.

Adolescent↗
PubMed1992

Association of IgM with IgG ANCA in patients presenting with pulmonary hemorrhage.

ANCA are markers for systemic vasculitis such as Wegener's granulomatosis (WG) and microscopic polyarteritis (MPA) and are usually of the IgG isotype. However, IgM ANCA may rarely occur in isolation, and in these circumstances, we have found that they are associated clinically with a syndrome of pulmonary hemorrhage and systemic vasculitis. How frequently IgM ANCA may occur in conjunction with IgG has not previously been investigated. We report here a study of 24 consecutive patients with IgG ANCA-positive systemic vasculitis (14 WG, 10 MPA) in whom we determined whether IgM ANCA occurred in association with IgG ANCA, and if so, whether this had clinical importance. Eight patients were found to have IgM ANCA as well as IgG ANCA, and of these, seven presented with severe pulmonary hemorrhage. None of the IgM ANCA-negative patients presented with pulmonary hemorrhage. Although the occurrence of pulmonary hemorrhage in ANCA positive vasculitis was closely correlated with the presence of IgM ANCA, the antigen specificity of these IgM autoantibodies was variable, since both myeloperoxidase (4 patients), PR3 (3 patients), and an unknown ANCA antigen (1 patient) were found to be targets. We conclude that knowledge of ANCA isotype may have important clinical and therapeutic implications for the management of patients with systemic vasculitis.

Adolescent↗
PubMed1992

Activation of normal neutrophils by anti-neutrophil cytoplasm antibodies.

Anti-neutrophil cytoplasm antibodies (ANCA) are markers of systemic vasculitis for which a pathogenetic role has been postulated. We have examined the effect of these autoantibodies on the function of normal human neutrophils in vitro. In the presence of ANCA positive sera luminol-amplified chemiluminescence was significantly increased compared to the values seen in the presence of normal or anti-double stranded DNA positive sera (P < 0.01). Five of six ANCA positive F(ab)2 preparations also produced significant neutrophil activation as demonstrated by the chemiluminescence response. This response was totally abrogated by the addition of neutrophil cytoplasm extract, containing the ANCA antigen. Addition of inhibitors to the chemiluminescence system demonstrated that the chemiluminescence response was inhibited by azide and salicylhydroxamic acid and reduced by histidine, suggesting that the chemiluminescence response was due to activation of myeloperoxidase, with generation of singlet oxygen. The chemotactic response to f-Met-Leu-Phe, a bacterial chemotactic peptide, was significantly augmented in the presence of ANCA. Chemotaxis to zymosan-activated serum and chemokinesis was not affected. Phagocytosis was also unaffected. We propose that neutrophil activation and modulation of neutrophil migration by ANCA may be of pathogenetic significance in systemic vasculitis.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1990

Skin reactivity to atypical mycobacteria in cystic fibrosis.

Atypical mycobacterial disease has been described in a small number of patients with cystic fibrosis. Apart from one uncontrolled study, there is little information regarding atypical mycobacterial skin reactivity in this group of patients. We evaluated delayed cutaneous hypersensitivity to purified extracts of Mycobacterium avium, Mycobacterium intracellular, Mycobacterium kansasii and Mycobacterium bovis in 23 healthy controls and 43 adult and adolescent patients with cystic fibrosis. Fifteen of the cystic fibrosis group were receiving regular corticosteroids. Additionally, direct smear examination and Lowenstein Jensen culture were performed on sputum from the cystic fibrosis group. The prevalence of positive skin reactions was similar in the group with cystic fibrosis (30%) and in the control group (57%). Subgroup analysis showed that those cystic fibrosis patients receiving corticosteroids had a markedly lower prevalence of positive reactions (7%) compared to controls (P less than 0.01). When this subgroup was excluded from analysis, the prevalence of positive skin reactions among patients with cystic fibrosis was 43%. In the prospective sputum bacteriology study, one of the 43 cases grew Mycobacterium avium-intracellulare and had clinical and radiological evidence of this disease. Of note, this patient showed positive skin tests to all four mycobacterial species tested. Our data show no difference in the prevalence rate of positive skin reactions to atypical mycobacterial antigens between a control population and an adult cystic fibrosis population. In addition, the predictive value of skin testing is low in cystic fibrosis due to the high prevalence of cross-reactivity between different mycobacterial species and the high prevalence of anergy among those patients with advanced disease receiving treatment with corticosteroids.

Adolescent↗