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Biomedical subjects

M M Morris

Publications and source records attributed to M M Morris.

At least 37 records · Page 2Linked to original sources
PubMed1997

Irradiation in the setting of collagen vascular disease: acute and late complications.

PURPOSE: Based on reports of greater toxicity from radiation therapy, collagen vascular diseases (CVDs) have been considered a contraindication to irradiation. We assessed the complications of radiation therapy in patients with CVD. PATIENTS AND METHODS: A total of 209 patients with documented CVD were irradiated between 1960 and 1995. One hundred thirty-one had rheumatoid arthritis (RA), 25 had systemic lupus erythematosus (SLE); 17 had polymyositis or dermatomyositis; 16 had scleroderma; eight had ankylosing spondylitis; five had juvenile RA; three had discoid lupus erythematosus; and four had 4 mixed connective tissue disorders (MCTD). The mean follow-up duration of curative cases was more than 6 years. Doses ranged from 10 to 87.6 Gy, with a median of 45 Gy. RESULTS: Overall, 263 sites were assessable in 209 patients. Significant (> or = grade 3) acute toxicity was seen in 10% of irradiated sites. Severe late effects were associated with significant acute reactions and with non-RA CVDs (6% v 21% at 5 years). No difference was seen in late effects according to timing of CVD onset, presence of concurrent vascular insults, radiation dose, or other technical factors, or by measures of disease activity. CONCLUSION: RA does not appear to have an elevated rate of late toxicity. While non-RA CVD is significantly associated with increased radiation late effects at standard doses, radiation-related mortality remains exceedingly rare. The choice of therapeutic modality in this radiosensitive group of patients should be made on a case-by-case basis.

Actuarial Analysis↗
PubMed1996

Encephalitogenic epitopes of myelin basic protein, proteolipid protein, myelin oligodendrocyte glycoprotein for experimental allergic encephalomyelitis induction in Biozzi ABH (H-2Ag7) mice share an amino acid motif.

Myelin basic protein (MBP) and synthetic MBP peptides were screened for their ability to induce experimental allergic encephalomyelitis in Biozzi ABH (H-2Ag7) mice. In contrast to the failure of native MBP to induce experimental allergic encephalomyelitis, the use of overlapping MBP peptides revealed epitopes within MBP 12-26 and MBP 21-35, which induced mild disease. In comparison with disease induced by spinal cord homogenate or peptides of myelin oligodendrocyte glycoprotein (MOG) or proteolipid protein (PLP), the low incidence indicates that, at least in ABH mice, MBP is a minor encephalitogen. However, the data suggest the presence of a peptide core between MBP 21-26 (HARHGF), which contains similar elements to the previously defined encephalitogenic MOG 1-22 and PLP 56-70 peptides. The fine specificity of these epitopes was further investigated using frame-shifted peptides, which indicated cores between MOG 9-15 (GYPIRAL) and PLP 62-68 (NVIHAFQ). Based on these pathogenic peptides, a putative H-2Ag7 binding motif is suggested that contains a series of hydrophobic, basic, small, and large hydrophobic residues within a 6 to 7 amino acid core. The core and particular importance of these four residues in PLP 56-70 was confirmed in vitro using amino acid substitution studies. These findings support many of the predictions made by computer modeling of peptide:H-2Ag7 interactions. This may have relevance in the design of strategies in the treatment of experimental autoimmune diseases in animals that express this haplotype.

Amino Acid Sequence↗
PubMed1996

Role of immune responses in protection and pathogenesis during Semliki Forest virus encephalitis.

The course of Semliki Forest virus (SFV) A7(74) infection in immunocompetent BALB/c, athymic nu/nu and severe combined immunodeficient (SCID) mice was compared. BALB/c mice remained healthy and exhibited transient viraemia and infectious virus in the brain from days 2 to 7. Antibodies were detectable by day 5. In comparison, SCID mice displayed a high incidence of paralysis and died: the average day of death was day 23. From infection until death, virus was present in blood and brain. No antibodies were detectable. Athymic mice were intermediate with a transient viraemia and a persistent (> 210 days) sub-clinical central nervous system (CNS) infection. These mice produced anti-viral IgM but not IgG. The pattern of infection in BALB/c or nu/nu mice could be recreated in infected SCID mice by transfer of immune serum from BALB/c or nu/nu mice with the important exception that although BALB/c immune serum could abolish infectivity titres in the CNS, scattered cells positive for viral RNA remained. Transfer of serum decreased mortality and delayed the onset of paralysis. Transfer to infected SCID mice of a non-neutralizing IgG anti-E2 monoclonal antibody did not affect the viraemia but could also reduce brain virus titres. Irrespective of specific immune responses, virus replication in CNS cells was restricted, was generally non-cytopathic and in the absence of specific immune responses could persist. From day 14 lesions of inflammatory, primary demyelination were observed throughout the CNS of BALB/c mice. In contrast, despite prolonged brain virus titres, no demyelinating lesions were observed in infected nu/nu or SCID mice. Lesions could be initiated in the latter by transfer of spleen cells but not antibody. In summary, the focal restricted infection in the CNS of adult mice infected with SFV A7(74) is independent of specific immune responses. IgM antibodies clear the viraemia. IgG antibodies including non-neutralizing antibodies reduce and clear infectious virus but cells positive for viral RNA remain. These may normally be cleared by T cell responses which are damaging and give rise to lesions of demyelination.

Alphavirus Infections↗
PubMed1996

Elevated B cells in sputum of asthmatics. Close correlation with eosinophils.

Sputum examination is a useful noninvasive method to study airway inflammation. We investigated the reproducibility and validity of the measurements of lymphocyte subsets in the sputum of 11 stable patients with asthma and 10 nonasthmatic smokers. Sputum was dispersed with 0.1% dithiothreitol. A differential cell count was made with Wright's stain. Aliquots were stained with antibodies to CD19 (B cells), CD3 (T cells), CD4 (helper), CD8 (suppressor), and the activation marker CD25 (IL2 receptor) on T-cell subsets and were assayed by flow cytometry. Sputum from patients with asthma compared with nonasthmatic subjects had more eosinophils (mean +/- SEM, 32.5 +/- 8.5 versus 1.3 +/- 0.5%, p < 0.01) and a higher proportion of lymphocytes that were B cells (16.2 +/- 3.2 versus 4.0 +/- 1.0%, p < 0.01), and these correlated closely with the eosinophils (r = 0.8, p < 0.01). Patients with asthma also had more activated T-helper cells (39.3 +/- 4.6 versus 9.0 +/- 9.0%, p = 0.05), but the comparison was limited to two smokers because of macrophage autofluorescence. The repeatability of measurements of helper T-cells (R = 0.94), suppressor T cells (R = 0.88), and activated helper T cells (R = 0.77) was good; repeatability of measurements of T and B cells could not be examined because these were reciprocals of each other. Asthmatic sputum has different lymphocyte profiles than sputum from nonasthmatic smoking control subjects. The results demonstrate a potential importance of antibody-producing lymphocytes in the airway and their relation to sputum eosinophilia in asthma.

Adult↗
PubMed1996

Indices of airway inflammation in induced sputum: reproducibility and validity of cell and fluid-phase measurements.

Methods to examine sputum for indices of airway inflammation are evolving. We have examined the repeatability and the validity of an improved method to measure sputum cells and fluid-phase eosinophil cationic protein (ECP), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), albumin, fibrinogen, tryptase, and interleukin-5 (IL-5). Sputum was induced with hypertonic saline twice within 6 d in 10 healthy subjects, 19 stable asthmatics, and 10 smokers with nonobstructive bronchitis. The method included the processing of freshly expectorated sputum separated from saliva, treatment with a fixed proportion of dithiothreitol 0.1% followed by Dulbecco's phosphate-buffered saline, making cytospins, and collecting the supernatant. The reproducibility of measurements, calculated by the intraclass correlation coefficient, was high for all indices measured with the exception of total cell counts and proportion of lymphocytes. Asthmatics, in comparison with healthy subjects and smokers with bronchitis, had a higher proportion of sputum eosinophils (median percent 5.2 versus 0.5 and 0.3), metachromatic cells (0.3 versus 0.07 and 0.08), ECP (1,040 micrograms/L versus 288 and 352), MBP (1,176 micrograms/L versus 304 and 160), and EDN (1,512 micrograms/L versus 448 and 272). Asthmatics differed from healthy subjects, but not from smokers with bronchitis, in the proportion of neutrophils (46.9% versus 24.1%), albumin (704 versus 288 micrograms/mL), and fibrinogen (2,080 versus 440 ng/mL). Smokers with bronchitis showed a trend for a higher neutrophil count and levels of albumin and fibrinogen than healthy subjects. The proportion of sputum eosinophils correlated positively with ECP, MBP, EDN, albumin and fibrinogen levels, and metachromatic cell counts correlated with tryptase. In asthmatics, IL-5 correlated with eosinophil counts. There was a significant negative correlation between sputum indices and expiratory flows and methacholine PC20. Thus, the methods of measuring cell and fluid phase markers in induced sputum used in this study are reproducible and valid. They can therefore be used to reliably measure these indices of airway inflammation.

Adult↗
PubMed1996

Effect of salmeterol compared with beclomethasone on allergen-induced asthmatic and inflammatory responses.

Salmeterol is a selective long-acting beta 2-agonist bronchodilator considered to have added anti-inflammatory effects, but this is controversial. We investigated the effects of a single dose of salmeterol, 100 micrograms, on the physiological and inflammatory responses to inhaled allergen and compared these with the effects of a single dose of beclomethasone, 500 micrograms, and of placebo. Eight atopic adults with mild stable asthma, treated only with inhaled short-acting beta 2-agonist when needed, attended the laboratory sequentially for screening tests, two single-blind control inhalation tests preceded 30 min by placebo or salmeterol and three allergen inhalation tests preceded by placebo, salmeterol or beclomethasone double-blind in random order. Airway responsiveness to methacholine (assessed as the provocative concentration of methacholine producing 20% fall in forced expiratory volume in one second (PC20)), induced sputum eosinophils, blood eosinophils and serum eosinophil cationic protein (ECP) were examined before and 7-48 h after treatment. The statistical power to detect twofold changes in blood and sputum parameters was > or = 90%. Salmeterol inhaled before allergen challenge completely prevented the early asthmatic response, late asthmatic response and fall in methacholine PC20 at 24 h, and produced additional bronchodilatation. These effects were similar to those obtained by the inhalation of a single dose of salmeterol before the control inhalation test, and significantly better than those observed after a single dose of beclomethasone inhaled before the allergen test. Beclomethasone had no effect on the early asthmatic response or on the fall in methacholine PC20 at 24 h but partially inhibited the late asthmatic response. Neither salmeterol nor beclomethasone had any significant effect on sputum or blood inflammatory changes 7-48 h after allergen inhalation. In conclusion, whilst salmeterol had no demonstrable anti-inflammatory action in sputum after allergen challenge in asthma, neither did a single dose of the positive anti-inflammatory control, beclomethasone. The latter result excludes a more positive judgement on the possible anti-inflammatory action of salmeterol. However, the results do indicate that potent functional effects of a single dose of salmeterol can mask the airway inflammatory cell influx caused by inhaled allergen.

Administration, Inhalation↗
PubMed1994

Identification of epitopes of myelin oligodendrocyte glycoprotein for the induction of experimental allergic encephalomyelitis in SJL and Biozzi AB/H mice.

A recombinant protein corresponding to the Ig-like domain of myelin oligodendrocyte glycoprotein (MOG) and synthetic 15-mer peptides of the whole MOG molecule with eight amino acid overlaps were screened for their ability to induce experimental allergic encephalomyelitis (EAE) in Biozzi AB/H (H-2dq1) and SJL (H-2S) mice. Clinical and histologic evidence of EAE developed after sensitization with the recombinant MOG protein in both AB/H and SJL mice. In AB/H mice at least three MOG epitopes within residues 1-22, 43-57, and 134-148 induced clinical and histologic EAE, whereas only the sequence 92-106 was encephalitogenic in SJL mice. Histologically, the inflammatory response in the central nervous system consisted of perivascular accumulations of CD5+ T cells and F4/80+ macrophage/microglia cells equally distributed in the brain and spinal cord. The subpial/meningeal infiltration, characteristic of mouse EAE induced with spinal cord homogenate, was only observed in cases of severe clinical disease in SJL mice in which the cellular infiltrates predominated in the spinal cord. In spite of the presence of histologic lesions in AB/H mice immunized with MOG, clinical disease either rapidly resolved or was clinically silent. In contrast to immunization of SJL mice with recombinant MOG, sensitization to MOG 92-106 induced severe clinical paralysis. After recovery these animals relapsed and exhibited demyelinated lesions. This study is the first to describe encephalitogenic epitopes of MOG that induce both clinical and histologic signs of EAE in mice. These and previous findings implicating MOG as a target Ag for Ab-mediated attack in EAE suggest that such autoreactivity to MOG may be significant in the development of human demyelinating diseases such as multiple sclerosis.

Amino Acid Sequence↗
PubMed1991

For those left behind. An educational inpatient rehabilitation program.

1. An interdisciplinary program model was developed for the treatment of mentally ill individuals remaining in long-term state mental institutions that focused on self-maintenance, social functioning, and community living skills. 2. Patients were categorized according to their levels of functioning and diagnoses, and were assigned to programs that were developed to meet the needs of a specific group of patients. 3. The goals of the program were to enhance the quality of life for the patients; promote self-direction and capacity for self-care by increasing the patient's opportunities to make life decisions; and prepare the patients to live in a less restrictive environment.

Activities of Daily Living↗
PubMed1990

The inflammatory response in asthma exacerbation: changes in circulating eosinophils, basophils and their progenitors.

Circulating eosinophils, basophils and eosinophil/basophil (Eo/B) progenitors were examined in 12 patients at the time of an exacerbation of asthma accompanied by sputum eosinophilia and after resolution of the exacerbation with inhaled corticosteroid treatment. Differential counts were performed and peripheral blood non-adherent mononuclear cells were cultured for 14 days in methyl-cellulose to determine the number of Eo/B and granulocyte-macrophage (GM) colonies without knowledge of the clinical conditions or findings. With resolution of the asthma exacerbation on beclomethasone therapy, there were significant falls in circulating eosinophils, basophils and Eo/B colonies whereas GM colonies were unchanged. To elucidate whether the observed changes could be due to systemic absorption or local action of inhaled corticosteroid, seven subjects with allergic rhinitis and no current evidence of lower airway inflammation (no symptoms of asthma and normal methacholine airway responsiveness) received 14 days' treatment with the same dose of inhaled beclomethasone or of placebo in a double-blind randomized cross-over study. No significant changes in airway function or in circulating cell counts were observed. The results suggest reduced production of eosinophils and basophils after the resolution of an exacerbation of asthma. This effect may be due to reduced levels of airway-derived eosinophil-basophil growth and differentiation factors.

Adrenal Cortex Hormones↗
PubMed1989

Cellular characteristics of sputum from patients with asthma and chronic bronchitis.

The reproducibility of sputum cell counts was examined and the cell counts in patients with asthma were compared with those in patients with chronic bronchitis. Three groups of subjects were studied. Sputum from eight patients with chronic asthma and with sputum production were studied to determine the reproducibility of sputum cell counts. The findings in 10 non-smokers with asthma uncomplicated by other airway disease examined at the time of an exacerbation with sputum (group 2) were compared with those from eight smokers with chronic cough and sputum but no features of asthma (group 3). Sputum plugs were selected by microscopy to ensure their origin from the lower respiratory tract. A total cell count was performed on a trypsinised suspension, and differential and metachromatic cell counts were performed on undiluted plugs. The within specimen and test-retest reproducibility of these measurements was high (reliability coefficient, R, = 0.99 and 0.89). The sputum of the asthmatic patients was characterised by eosinophilia (69%, range 46-92%) and the presence of formaldehyde blockable metachromatic cells (1.5%, range 0.6-2.8%). In comparison, the sputum of the patients with chronic bronchitis had few eosinophils (0.5%) or metachromatic cells (0.14%); the dominant cell type was the macrophage (83%). It is concluded that sputum cell counts are reproducible in the short term, the inflammation of asthma is characterised by eosinophilia and metachromatic cells in sputum, and sputum may provide a useful source of cells for investigating the cellular characteristics of airway inflammation.

Adult↗
PubMed1989

Effect of a leukotriene antagonist, LY171883, on cold air-induced bronchoconstriction in asthmatics.

Isocapnic hyperpnea (ISH) of cold air induces bronchoconstriction in many asthmatic subjects. Although this response is well described, it is unclear whether this bronchoconstriction is related to the release of bronchoactive mediators. We examined whether pretreatment with LY171883, a competitive antagonist of leukotriene D4 activity via LTD4 receptors, reduced the bronchospastic response to cold air ISH in asthmatics using a randomized, double-blind, two-phase crossover design. In 20 subjects, 2 wk of treatment with either LY171883 600 mg twice a day or placebo did not result in a change in FEV1 (3.45 +/- 0.21 L placebo versus 3.59 +/- 0.20 L LY171883; p greater than 0.05). Nineteen subjects underwent cold-air ISH; LY171883 increased the geometric mean respiratory heat loss required to reduce the FEV1 by 20% (PD20RHE) from 1.00 kcal/min with placebo to 1.24 kcal/min with LY171883 (p less than 0.05). A similar difference was noted when responses were expressed as a function of minute ventilation. LY171883 produced greater shifts in the PD20RHE in more reactive subjects (r = 0.69, p less than 0.002). Among 11 different symptom scores recorded by 18 subjects, there was a significant decrease in daytime chest tightness with LY171883 (p less than 0.03). The increase in PD20RHE while the subjects received LY171883 is consistent with the hypothesis that LTD4 becomes available during cold-air ISH and may mediate bronchoconstriction. The small magnitude of the effect on the PD20RHE may be due to the role of other mediators in cold-air-induced bronchoconstriction or, alternatively, to an inadequate blockade of LTD4 effects.

Acetophenones↗
PubMed1987

Airway constriction by isocapnic hyperventilation of cold, dry air: comparison of magnitude and duration of protection by nedocromil sodium and sodium cromoglycate.

The protective effect of 1, 2 and 4 mg of nedocromil sodium against airway constriction induced by hyperventilation of cold, dry air was compared with 10 mg sodium cromoglycate and placebo in a double-blind randomized trial. On 5 days, twelve asthmatic subjects received one of the trial medications from a metered dose inhaler. Twenty minutes, 2.5 and 5 hr later, airway responsiveness to hyperventilation of cold, dry air was measured. At 20 min, there was significant protection by all four active medications when compared to placebo, with a trend towards a nedocromil dose relationship but there was no statistical difference between the four active medications. All four showed a similar progressive decrease in protection over 5 hr. The results of this study suggest that nedocromil gives protection against hyperventilation-stimulated airway constriction and that the magnitude and duration of effect for all three doses is similar to 10 mg of cromoglycate.

Air↗
PubMed1986

Airway responsiveness to leukotrienes C4 and D4 and to methacholine in patients with asthma and normal controls.

Leukotrienes C4 and D4 may serve as chemical mediators in asthma. Although patients with asthma are known to be hyperresponsive to the bronchoconstrictive effects of histamine and methacholine, whether the same is true for the leukotrienes is controversial. We compared the airway responses to methacholine and to leukotrienes C4 and D4 in 12 asthmatic patients and 6 controls. We found that the patients were more responsive to the leukotrienes than the controls, and we observed a linear correlation between airway response to methacholine and that to leukotriene C4 (r = 0.68, P less than 0.01) and D4 (r = 0.79, P less than 0.001). However, relative to the airway response to methacholine, the response to the leukotrienes was much greater in the controls than in the patients. Furthermore, the asthmatic subjects who were most responsive to methacholine had the lowest relative airway response to both leukotrienes. Thus, the patients with the greatest airway responsiveness to methacholine paradoxically showed the lowest relative airway response to the leukotrienes. In contrast, this difference in relative airway responses has not been observed between methacholine and other bronchoconstrictor mediators, such as histamine. Although no adequate explanation for these observations has yet emerged, our data suggest that leukotrienes C4 and D4 are unique bronchoconstrictors with a possible role in the pathogenesis of asthma.

Adult↗
PubMed1986

Airway responses to hyperventilation of cold dry air: duration of protection by cromolyn sodium.

The magnitude and duration of the inhibitory effect of three doses of cromolyn sodium on the airway response to hyperventilation of cold dry air was examined in a double-blind, randomized controlled trial. Eight subjects with well controlled asthma were studied. On 4 separate days, doses of either 2 mg, 10 mg, 20 mg, or placebo were administered by metered-dose inhaler. Twenty minutes, 2 hours, and 4 hours after each medication, airway responsiveness to isocapnic hyperventilation of cold dry air was measured by use of a standardized dose-response method. At 20 minutes, all three doses inhibited bronchoconstriction, and there was no evidence of any difference in the magnitude of the inhibition between the doses. All three doses progressively provided less protection with time. By 2 hours, the inhibition induced by 2 mg was no longer different from placebo, and by 4 hours, only 20 mg still provided significant protection. The results demonstrate that, although the initial magnitude of inhibition may not be different between 2 mg and 20 mg, the rate at which the protective effect wears off is dose related.

Adolescent↗
PubMed1986

Interpretation of the variability of peak flow rates in chronic bronchitis.

Increased diurnal variation of expiratory flow rates has been documented in patients with chronic bronchitis, but this could be secondary to the disease process of bronchitis rather than an associated disease--namely, asthma. Peak expiratory flow was measured twice daily before and after inhalation of 200 micrograms salbutamol in 34 subjects with chronic bronchitis. The FEV1 ranged from 38% to 121% predicted. Diurnal variation (expressed as highest-lowest/highest (%)) was increased in 18 subjects, all but three of whom had airflow obstruction and an increase in methacholine airway responsiveness. There was only a weak correlation between diurnal variation and airway responsiveness (r = -0.54) or the severity of the airflow obstruction. This finding, together with the occurrence of an increase in diurnal variation without an increase in methacholine airway responsiveness in three subjects, suggests that the increased diurnal variation in chronic bronchitis may have a different underlying mechanism from that in asthma.

Airway Resistance↗