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Biomedical subjects

B D Harrison

Publications and source records attributed to B D Harrison.

At least 19 recordsLinked to original sources
PubMed2002

Expression of respiratory mucins in fatal status asthmaticus and mild asthma.

AIMS: The airways of patients with asthma are characterized by chronic inflammatory changes comprising mainly T-cells and eosinophils, and airway remodelling with goblet cell metaplasia and submucosal gland hyperplasia. Mucus hypersecretion is often a marked feature, particularly in status asthmaticus. The matrix of airway sputum consists of high molecular glycoproteins and mucins. In this study, the expression and distribution of the major gel-forming mucins MUC5AC and MUC5B were studied in fatal status asthmaticus tissues and bronchial biopsies of mild asthmatic patients. The effect of inhaled corticosteroids on the expression of these mucins was also investigated. METHODS AND RESULTS: Polyclonal antibodies specific for MUC5AC and MUC5B, and a monoclonal antibody for MUC5B were used to stain lung tissues and airway mucosal biopsies obtained from patients who died of status asthmaticus (n=5) and from mild asthmatics (n=4), respectively. Immunohistochemistry for MUC5AC revealed abundant staining of goblet cells situated in the epithelial surface lining and glandular ducts of tissues from patients with fatal asthma. MUC5B immunoreactivity was restricted to mucous cells of submucosal glands and to epithelial cells. In mild asthmatics, large amounts of MUC5B, but not MUC5AC, positive extracellular mucus was found in the airway lumen as plugs, adjacent to the epithelial lining and in the necks of glandular secretory ducts of mild asthmatics. The distribution of MUC5AC and MUC5B in bronchial biopsies of mild asthmatics was similar before and after inhaled steroid treatment. CONCLUSIONS: The expression of MUC5AC and MUC5B shares a similar distribution to normal airways in different states of asthma. The distribution is not affected by topical corticosteroid therapy.

Asthma↗
PubMed2001

Stimulation of autologous proliferative and cytotoxic T-cell responses by "leukemic dendritic cells" derived from blast cells in acute myeloid leukemia.

Effective presentation of tumor antigens is fundamental to strategies aimed at enrolling the immune system in eradication of residual disease after conventional treatments. Myeloid malignancies provide a unique opportunity to derive dendritic cells (DCs), functioning antigen-presenting cells, from the malignant cells themselves. These may then co-express leukemic antigens together with appropriate secondary signals and be used to generate a specific, antileukemic immune response. In this study, blasts from 40 patients with acute myeloid leukemia (AML) were cultured with combinations of granulocyte-macrophage colony-stimulating factor, interleukin 4, and tumor necrosis factor alpha, and development to DCs was assessed. After culture, cells from 24 samples exhibited morphological and immunophenotypic features of DCs, including expression of major histocompatibility complex class II, CD1a, CD83, and CD86, and were potent stimulators in an allogeneic mixed lymphocyte reaction (MLR). Stimulation of autologous T-cell responses was assessed by the proliferative response of autologous T cells to the leukemic DCs and by demonstration of the induction of specific, autologous, antileukemic cytotoxicity. Of 17 samples, 11 were effective stimulators in the autologous MLR, and low, but consistent, autologous, antileukemic cytotoxicity was induced in 8 of 11 cases (mean, 27%; range, 17%-37%). This study indicates that cells with enhanced antigen-presenting ability can be generated from AML blasts, that these cells can effectively prime autologous cytotoxic T cells in vitro, and that they may be used as potential vaccines in the immunotherapy of AML.

Acute Disease↗
PubMed2000

Megakaryopoiesis in vitro in myelodysplastic syndromes and acute myeloid leukaemia: effect of pegylated recombinant human megakaryocyte growth and development factor in combination with other growth factors.

Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) can stimulate megakaryopoiesis in vitro in some myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) patients. We assessed PEG-rHuMGDF combined with granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), interleukin 3 (IL-3), IL6, stem cell factor (SCF) or erythropoietin in 40 MDS, 33 AML and 16 normal bone marrow samples. CD61-positive cells in suspension cultures increased with PEG-rHuMGDF alone in 20/25 RA + RAS, 11/14 RAEB + RAEBt and 29/33 AML cases. Further increases when IL-3 and/or SCF were added to PEG-rHuMGDF occurred in 14/20 RA + RAS, 8/13 RAEB + RAEBt and 18/26 AML cases. CFU-Mk growth was poor overall, but could be enhanced by PEG-rHuMGDF combinations in some patients. Stimulation of megakaryopoiesis by PEG-rHuMGDF can be augmented by IL-3 and SCF in many MDS and AML patients.

Adolescent↗
PubMed2000

Multiple infection, recombination and genome relationships among begomovirus isolates found in cotton and other plants in Pakistan.

Begomoviruses occur in many plant species in Pakistan and are associated with an epidemic of cotton leaf curl disease that has developed since 1985. PCR analysis with primer pairs specific for each of four already sequenced types of DNA-A of cotton leaf curl virus (CLCuV-PK types a, 26, 72b and 804a), or for okra yellow vein mosaic virus (OYVMV), indicated that many individual naturally infected plants of cotton and other malvaceous species contained two or three begomovirus sequences. Similarly, sequence differences among overlapping fragments of begomovirus DNA-A, amplified from individual naturally infected plants, indicated much multiple infection in malvaceous and non-malvaceous species. Some cotton plants contained DNA-A sequences typical of begomoviruses from non-malvaceous species, and some non-malvaceous plants contained sequences typical of CLCuV-PK. Some DNA-A sequences were chimaeric; they each included elements typical of different types of CLCuV-PK, or of different malvaceous and/or non-malvaceous begomoviruses. Often an apparent recombination site occurred at the origin of replication. No complete CLCuV-PK DNA-A sequence was found in malvaceous or non-malvaceous species collected in Pakistan outside the area of the cotton leaf curl epidemic but chimaeric sequences, including a part that was typical of CLCuV-PK DNA-A, did occur there. We suggest that recombination among such pre-existing sequences was crucial for the emergence of CLCuV-PK. Recombination, following multiple infection, could also explain the network of relationships among many of the begomoviruses found in the Indian subcontinent, and their evolutionary divergence, as a group, from begomoviruses causing similar diseases in other geographical regions.

Base Sequence↗
PubMed1999

Milestones in the research on tobacco mosaic virus.

Beijerinck's (1898) recognition that the cause of tobacco mosaic disease was a novel kind of pathogen became the breakthrough which eventually led to the establishment of virology as a science. Research on this agent, tobacco mosaic virus (TMV), has continued to be at the forefront of virology for the past century. After an initial phase, in which numerous biological properties of TMV were discovered, its particles were the first shown to consist of RNA and protein, and X-ray diffraction analysis of their structure was the first of a helical nucleoprotein. In the molecular biological phase of research, TMV RNA was the first plant virus genome to be sequenced completely, its genes were found to be expressed by cotranslational particle disassembly and the use of subgenomic mRNA, and the mechanism of assembly of progeny particles from their separate parts was discovered. Molecular genetical and cell biological techniques were then used to clarify the roles and modes of action of the TMV non-structural proteins: the 126 kDa and 183 kDa replicase components and the 30 kDa cell-to-cell movement protein. Three different TMV genes were found to act as avirulence genes, eliciting hypersensitive responses controlled by specific, but different, plant genes. One of these (the N gene) was the first plant gene controlling virus resistance to be isolated and sequenced. In the biotechnological sphere, TMV has found several applications: as the first source of transgene sequences conferring virus resistance, in vaccines consisting of TMV particles genetically engineered to carry foreign epitopes, and in systems for expressing foreign genes. TMV owes much of its popularity as a research mode to the great stability and high yield of its particles. Although modern methods have much decreased the need for such properties, and TMV may have a less dominant role in the future, it continues to occupy a prominent position in both fundamental and applied research.

History, 19th Century↗
PubMed1998

Thin-section spiral volumetric CT for the assessment of lobar and segmental bronchial stenoses.

Thin-section volumetric computed tomography (CT) was used to examine the lobar and segmental bronchi of five patients who had stenoses of these airways diagnosed by previous bronchography and/or bronchoscopy. Four of 23 lobar bronchi and 42 of 72 segmental bronchi were judged to be stenotic by CT. Our findings in this small group suggest that thin-section volumetric CT is a promising non-invasive technique that is likely to prove useful in the assessment of such stenoses in the future.

Amyloidosis↗
PubMed1998

Accessibility and health service utilization for asthma in Norfolk, England.

BACKGROUND: Good access to health services may be important for effective asthma management amongst patients. Previously, we found elevated asthma mortality in parts of England with poor access to acute hospitals. A possible explanation is that barriers of access to care may lead to residents of more remote areas having a lower propensity to utilize health services, with the result that their asthma is poorly controlled. Here, we examine the relationship between utilization and the geographical accessibility of health services amongst self-reported asthmatics in a rural county of England. METHODS: The study involved analysis by logistic regression of questionnaire responses from a 10 per cent population sample of 9764 adults aged between 20 and 44 years, and resident within the catchment area of Norwich Health Authority. RESULTS: Utilization behaviour was associated with the smoking status of respondents, and levels of car ownership in their ward of residence. After controlling for these factors, respondents reporting asthma were less likely to have ever visited a general practitioner if they lived outside a settlement containing a surgery (odds ratio (OR) 3.07, 95 per cent confidence interval (CI) 1.11-8.48, p = 0.03), and the likelihood of consultation declined with distance from a surgery (OR for a 1 minute increase in travel time 0.79, 95 per cent CI 0.66-0.94, p < 0.01). Those living further from an acute hospital unit were also less likely to have consulted a hospital doctor in the previous 12 months (OR for a 1 minute increase in travel time 0.95, 95 per cent CI 0.9-0.99, p = 0.01). CONCLUSIONS: Our finding of lower levels of health service utilization amongst some self-reported asthmatics living further from health facilities suggests that the condition of some individuals might be poorly treated, which could increase the risk of fatality.

Adult↗
PubMed1998

Churg-Strauss syndrome in a district hospital.

Published series on Churg-Strauss syndrome (CSS) come from tertiary referral centres. We retrospectively studied 23 patients with CSS (18 male) seen over 14 years (1982-1995) in a District General Hospital serving a population of 500,000. Mean age of onset of vasculitis was 57, 10-19 years older than in previous series. The commonest clinical features were asthma (22) and eosinophilia > 1.5 x 10(9)/l (21). Systemic vasculitis involving two or more extrapulmonary organs occurred in 22 patients, with specific organ involvement of nervous system (18), joints (13), muscles (13), lungs (11), skin (11), kidneys (11), heart (10), and bowel (7). Various classification systems were applied including the Lanham criteria, which were met in 19 patients; the American College of Rheumatology criteria, met in 14; Churg and Strauss criteria, met in four; and the Chapel Hill Consensus definition, met only in two. ANCA was detected in 10/17 patients where measured. Treatment included corticosteroids (21), cyclophosphamide (8), azathioprine (9), immunoglobulin (2), and methotrexate (1). During follow-up six patients died, two due to myocardial vasculitis (mean age 52 years), three due to infection (mean age 80 years), and one cause unknown. Significant long-term disability was due to asthma in five and neuropathy in six.

Adult↗
PubMed1998

Types of variation in DNA-A among isolates of East African cassava mosaic virus from Kenya, Malawi and Tanzania.

Complete nucleotide sequences of the DNA-A-like molecules of three East African cassava mosaic virus (EACMV) isolates from Kenya (-K, 2801 nt) and Malawi (-MH and -MK, both 2804 nt) were determined. These sequences were compared with that published for a Tanzanian isolate (-T, 2801 nt) and the partial sequence of a third Malawian isolate. Intergenic region sequences of all isolates, and deduced amino acid sequences of their AC1 (Rep) proteins, each formed a tightly related cluster that was distinct from the comparable components of other begomoviruses. Other complementary-sense genes (AC2, AC3, AC4) differed between EACMV isolates in a way consistent with the accumulation of point mutations. In contrast, virus-sense genes (CP, AV2) of isolates -MH and -MK differed (substantially for AV2) from those of other EACMV isolates but somewhat resembled those of tomato yellow leaf curl virus-Israel, suggesting they had been acquired by recombination with an unidentified begomovirus.

Capsid↗
PubMed1998

Four DNA-A variants among Pakistani isolates of cotton leaf curl virus and their affinities to DNA-A of geminivirus isolates from okra.

Complete DNA-A sequences of nine Pakistani geminivirus isolates from leaf curl-affected cotton (CLCuV-PK) or from okra, and the partial sequences of several additional isolates were determined. Sequences of isolates from cotton were of four types. Isolates from leaf curl-affected okra had virtually the same sequences as those from cotton. Isolates from yellow vein mosaic-affected okra were of two types (OYVMV types 201 and 301), both distinct from but closely related to the virus isolates from cotton. Of these six types, two types of CLCuV-PK are the most closely related but another (CLCuV-PK type 72b) is the most distinct. Of the encoded proteins, coat protein (CP) is the most strongly conserved (92-100% amino acid sequence identity), and AC4 protein the most variable (41-87%). The 5' and 3' halves of the intergenic region of some isolates had different affinities and occurred in seven combinations, suggesting that recombination had occurred and that the origin of replication was a favoured recombination site. Similarly, the first 1520 nt of CLCuV-PK type 804a DNA resembled those of OYVMV type 301 DNA but the remaining 1224 nt were very different. The AC1 (Rep) gene and 5' part of the intergenic region of CLCuV-PK type 72b closely resembled those of OYVMV type 301, whereas the rest of the sequence did not. The cotton leaf curl epidemic in Pakistan is caused by several distinct variants, with recombination events involving OYVMV and other unspecified geminiviruses having probably been involved in their evolution.

Base Sequence↗
PubMed1998

Defective forms of cotton leaf curl virus DNA-A that have different combinations of sequence deletion, duplication, inversion and rearrangement.

Tobacco and tomato plants inoculated at least 9 months previously with a Pakistani isolate of cotton leaf curl virus (CLCuV-PK), a whitefly-transmitted geminivirus, contained substantial amounts of circular dsDNA molecules that were mostly about half the size of CLCuV-PK dsDNA-A. They appeared to be derived from CLCuV-PK DNA-A by various combinations of sequence deletion, duplication, inversion and rearrangement and, in a few instances, insertion of sequences of unknown origin. Each of ten tobacco plants contained a different predominant form of such a defective molecule; however, all the forms contained the intergenic region and part of the AC1 (Rep) gene. Some of the forms contained novel open reading frames and might have a role in the evolution of variant geminiviruses. The defective components were not detected at 3 months after the original culture of CLCuV-PK was transmitted by whiteflies (Bemisia tabaci) from cotton to tomato but were present after a further 6 months. They were transmitted, along with full-length DNA-A, between tobacco and tomato plants by grafting and by B. tabaci.

Animals↗
PubMed1997

Evidence that DNA-A of a geminivirus associated with severe cassava mosaic disease in Uganda has arisen by interspecific recombination.

Geminivirus isolates associated with the epidemic of severe cassava mosaic disease in Uganda were studied and compared with virus isolates from the part of Uganda outside the epidemic area, and with African cassava mosaic virus (ACMV) and East African cassava mosaic virus (EACMV). Isolates of a novel type [the Uganda variant (UgV)] were detected in severely affected plants from the epidemic area, whereas those from plants outside the epidemic area were typical of ACMV. The complete nucleotide sequences of DNA-A of UgV (2799 nt) and of a Tanzanian isolate of EACMV (2801 nt) were determined and are extremely similar, except for the coat protein (CP) gene. The CP gene of UgV has three distinct regions: the 5' 219 nt are 99% identical to EACMV (only 79% to ACMV); the following 459 nt are 99% identical to ACMV (75% to EACMV); and the 3' 93 nt are 98% identical to EACMV (76% to ACMV). UgV DNA-A therefore is considered to have arisen by interspecific recombination of EACMV and ACMV. Despite the hybrid nature of their CP, UgV isolates were indistinguishable from ACMV in tests with 20 monoclonal antibodies (MAbs), including seven which reacted with ACMV but not EACMV. The discontinuous epitopes detected by these seven MAbs must involve amino acids which lie in the central part of the CP (residues 74-226) and which differ in ACMV and EACMV. UgV isolates were detected in severely mosaic-affected plants from all 11 widely separated locations sampled. The probable role of recombination in geminivirus evolution in the short to medium term is discussed.

Base Sequence↗
PubMed1997

A simple radiographic scoring method for monitoring pulmonary sarcoidosis: relations between radiographic scores, dyspnoea grade and respiratory function in the British Thoracic Society Study of Long-Term Corticosteroid Treatment.

BACKGROUND: We used a simple semi-quantitative radiographic scoring system for a controlled prospective study of long term corticosteroids in pulmonary sarcoidosis, conducted by the British Thoracic Society. METHODS: Radiographic opacities were described in 4 categories: reticulo-nodular shadows [R], mass opacities [M], confluence [C], and shadows associated with possible pulmonary fibrosis [F]. The extent of each type was scored on a 0-4 scale by quartiles, and profusion by a 0-4 scale as absent, minimal (just perceptible), mild moderate or gross. Combined scores for each film were derived by multiplying the extent and profusion for each type of opacity. In the study 149 patients were examined at entry and periodically over a 5-year period. Using the whole study population we examined the relationship between the radiographic scores for extent and profusion, how predominant types change with time and how the scores correlated with other indices of disease severity. RESULTS: R was the predominant abnormality throughout the study with a strong correlation between extent and profusion. Significant correlations in the expected directions were demonstrated between the R and F scores and a dyspnoea score, spirometry and TLCO, both at study entry, after 6 months and after 5 years. Similarly, there were significant relations between changes in spirometry and TLCO over five years and changes in R and F Scores. CONCLUSION: This scoring system would seem to be suitable, perhaps after further validation work, for other prospective clinical studies.

Adolescent↗