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Biomedical subjects

M J Doherty

Publications and source records attributed to M J Doherty.

At least 19 recordsLinked to original sources
PubMed2000

Antigen triggering selectively increases TCRBV gene transcription.

When the TCR binds Ag it is phosphorylated, internalized, and degraded. We wished to examine whether this process was accompanied by a specific concomitant increase in TCR mRNA levels. To do this, PBMC and a T cell clone were cultured with a series of superantigens and an alloantigen. Only T cells specifically responding to an antigenic stimulus had increased levels of TCR beta-chain variable (TCRBV)-specific mRNA. This response was apparent after 48 h, peaked around 72 h, and was still elevated after 7 days. Increased gene transcription appeared to be driven solely by Ag as specific Ag depletion prevented culture supernatants transferring this effect. The level of TCRBV mRNA elevation was not influenced by the stimulating Ag, but appeared dependent on the gene encoding the stimulated TCR. Reporter gene assays, using cloned TCRBV gene promoters, confirmed both that TCR gene transcription rises after stimulation and that basal and stimulated levels of TCR transcription vary between different TCRBV genes. These data conclusively demonstrate that there is no direct relationship between TCRBV mRNA and T cell number, and that future repertoire studies must take both factors into account.

Adult↗
PubMed2000

Role of pericytes in vascular calcification: a review.

Pericytes are defined by their location in vivo; the pericyte partially surrounds the endothelial cell of the microvessel and shares a common basement membrane with it. As an integral part of the microvasculature, pericytes play a fundamental role in maintaining local and tissue homeostasis. Current evidence also suggests that pericytes function as progenitor cells capable of differentiating into a variety of different cell types including osteoblasts, chondrocytes and adipocytes. It is now apparent that cells resembling microvascular pericytes, and termed 'pericyte-like' cells, have a widespread distribution in vivo. Pericyte-like cells have been identified in the inner intima, the outer media, and in the vasa vasora of the adventitia of large, medium and small human arteries (1, 2). Moreover, recent studies have suggested that these cells may be responsible, at least in part, for mediating the calcification commonly associated with atherosclerosis (1, 3, 4). In this review, we a) examine the evidence that microvascular pericytes deposit a bone-like mineralised matrix in vitro, b) compare the morphological and biochemical properties of microvascular pericytes, calcifying vascular cells (CVCs) and 'classical' smooth muscle cells (SMCs) isolated from bovine aorta, c) demonstrate that microvascular pericytes deposit a well-organised matrix of bone, cartilage and fibrous tissue in vivo, and d) discuss recent studies designed to gain a better understanding of how pericyte differentiation is regulated.

Animals↗
PubMed2000

Capsaicin responsiveness and cough in asthma and chronic obstructive pulmonary disease.

BACKGROUND: Chronic cough is associated with an increased sensitivity to inhaled capsaicin in a number of conditions but there are no data for patients with more severe asthma or chronic obstructive pulmonary disease (COPD). Moreover, the relationships between the capsaicin response (expressed as the concentration of capsaicin provoking five coughs, C5), self-reported cough, and routine medication is not known. METHODS: The cough response to capsaicin in 53 subjects with asthma, 56 subjects with COPD, and 96 healthy individuals was recorded and compared with a number of subjective measures of self-reported cough, measures of airway obstruction, and prescribed medication. In asthmatic subjects the relationships between the cough response to capsaicin and mean daily peak flow variability and non-specific bronchial hyperresponsiveness to histamine were also examined. RESULTS: Subjects with asthma (median C5 = 62 mM) and COPD (median C5 = 31 mM) were similarly sensitive to capsaicin and both were more reactive than normal subjects (median C5 >500 mM). Capsaicin sensitivity was related to symptomatic cough as measured by the diary card score in both asthma and COPD (r = -0.38 and r = -0.44, respectively), but only in asthma and not COPD when measured using a visual analogue score (r = -0.32 and r = -0.05, respectively). Capsaicin sensitivity was independent of the degree of airway obstruction and in asthmatics was not related to PEF variability or PC(20) for histamine. The response to capsaicin was not related to treatment with inhaled corticosteroids but was increased in those using anticholinergic agents in both conditions. CONCLUSIONS: These data suggest that an increased cough reflex, as measured by capsaicin responsiveness, is an important contributor to the presence of cough in asthma and COPD, rather than cough being simply secondary to excessive airway secretions. The lack of any relationship between capsaicin responsiveness and airflow limitation as measured by the FEV(1) suggests that the mechanisms producing cough are likely to be different from those causing airways obstruction, at least in patients with COPD.

Administration, Inhalation↗
PubMed1999

Gene expression during vascular pericyte differentiation.

Pericytes, an integral part of the microvasculature, are involved in a number of different processes, including angiogenesis. Many of the early studies on these cells are descriptive and concentrate on the location of pericytes in vivo, surrounding the endothelial cells in the microvessels. These studies led to the proposals that pericytes have a function in maintaining blood flow and contribute to the mechanical strength of the microvessels. However, with the advancement of tissue culture techniques and molecular technology it has been shown that these cells also have the ability to differentiate into a variety of different cell types, including osteoblasts, chondrocytes, adipocytes, fibroblasts, and smooth muscle cells. This review concentrates on the differentiation of pericytes along the osteogenic pathway. Pericytes behave like osteoblasts in vitro, by forming a mineralized matrix and expressing a number of genes that are also expressed by osteoblasts. These cells also form a well-defined matrix of bone, cartilage, and fibrous tissue in vivo, although it is not clear under what circumstances pericytes express osteogenic potential in situ. This review highlights the potential functional importance of pericytes in the growth, maintenance, and repair of the skeleton and in diseases involving ectopic ossification and calcification.

Animals↗
PubMed1998

Identification of the separate domains in the hepatic glycogen-targeting subunit of protein phosphatase 1 that interact with phosphorylase a, glycogen and protein phosphatase 1.

Deletion and mutational analyses of the rat liver glycogen-targeting subunit (GL) of protein phosphatase 1 (PP1) have identified three separate domains that are responsible for binding of PP1, glycogen and phosphorylase a. The glycogen-binding domain spans the centre of GL between residues 144 and 231 and appears to be distinct from the glycogen-binding (storage) site of phosphorylase. The regulatory high-affinity binding site for phosphorylase a lies in the 16 amino acids at the C-terminus of GL. The PP1-binding domain is deduced to comprise the -RVXF- motif [Egloff, Johnson, Moorhead, Cohen and Barford (1997) EMBO J. 16, 1876-1887] located at residues 61-64 of GL and preceding lysine residues at positions 56, 57 and 59. A possible approach for increasing glycogen synthesis in certain disorders is discussed.

Amino Acid Sequence↗
PubMed1998

Loss of the hepatic glycogen-binding subunit (GL) of protein phosphatase 1 underlies deficient glycogen synthesis in insulin-dependent diabetic rats and in adrenalectomized starved rats.

Hepatic glycogen synthesis is impaired in insulin-dependent diabetic rats and in adrenalectomized starved rats, and although this is known to be due to defective activation of glycogen synthase by glycogen synthase phosphatase, the underlying molecular mechanism has not been delineated. Glycogen synthase phosphatase comprises the catalytic subunit of protein phosphatase 1 (PP1) complexed with the hepatic glycogen-binding subunit, termed GL. In liver extracts of insulin-dependent diabetic and adrenalectomized starved rats, the level of GL was shown by immunoblotting to be substantially reduced compared with that in control extracts, whereas the level of PP1 catalytic subunit was not affected by these treatments. Insulin administration to diabetic rats restored the level of GL and prolonged administration raised it above the control levels, whereas re-feeding partially restored the GL level in adrenalectomized starved rats. The regulation of GL protein levels by insulin and starvation/feeding was shown to correlate with changes in the level of the GL mRNA, indicating that the long-term regulation of the hepatic glycogen-associated form of PP1 by insulin, and hence the activity of hepatic glycogen synthase, is predominantly mediated through changes in the level of the GL mRNA.

Adrenalectomy↗
PubMed1998

Survey of non-invasive ventilation (NIPPV) in patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) in the UK.

BACKGROUND: Non-invasive positive pressure ventilation (NIPPV) has been shown to be beneficial in the treatment of acute exacerbations of chronic obstructive pulmonary disease (COPD) complicated by respiratory failure. A survey was undertaken to assess the availability of NIPPV for the treatment of acute exacerbations of COPD and to determine how NIPPV is delivered in hospitals in the UK. METHODS: A questionnaire was sent to consultants with an interest in respiratory medicine from 268 of the hospitals found in the BTS directory. The questionnaire enquired about the hospital as well as the availability of NIPPV in the hospital. If NIPPV was available in the hospital, details of implementation, staffing and funding were determined. RESULTS: Replies to the questionnaire were received from 98.5% of consultants. NIPPV was available in 48% of hospitals, these hospitals tending to serve larger populations and to have more respiratory physicians than the hospitals where NIPPV was not available. There was considerable regional variation in the availability of NIPPV. In hospitals where NIPPV was not available the reason(s) were lack of consultant training in 53%, lack of other staff training in 63%, financial in 63%, and doubt about the benefit of NIPPV in 15% of cases. In those hospitals where NIPPV was available, clinical practice varied greatly: 68% of centres treated fewer than 20 patients a year with this form of treatment and 9% treated more than 60 patients a year. Although NIPPV was paid for completely from the trust equipment budget in 46 hospitals (41%), other money such as research or charitable funds were used at least partially in the other hospitals and NIPPV was financed solely from research or charitable funds in 41 hospitals (37%). CONCLUSIONS: Equipment for NIPPV is available in less than half of the acute hospitals in the UK. In those in which it is available it is generally underused. Lack of training and problems with funding are generally given for the failure to introduce NIPPV.

Acute Disease↗
PubMed1998

A vibrating trachea.

A case of relapsing polychondritis presenting as tracheomalacia is reported in which an unusual low pitched sound was heard at the mouth and over the chest wall during expiration. The sound was associated with expiratory airflow limitation and oscillation on the flow trace of approximately 50 Hz. Spectral analysis of the sound showed it to have the characteristics of sounds produced by flutter in flow limited flexible tubes. These observations suggest that the sound was produced by airflow induced flutter in the trachea and main airways and is further evidence in support of the dynamic flutter theory of wheeze production.

Airway Obstruction↗
PubMed1998

Vascular pericytes express osteogenic potential in vitro and in vivo.

At postconfluence, cultured bovine pericytes isolated from retinal capillaries form three-dimensional nodule-like structures that mineralize. Using a combination of Northern and Southern blotting, in situ hybridization, and immunofluorescence we have demonstrated that this process is associated with the stage-specific expression of markers of primitive clonogenic marrow stromal cells (STRO-1) and markers of cells of the osteoblast lineage (bone sialoprotein, osteocalcin, osteonectin, and osteopontin). To demonstrate that the formation of nodules and the expression of these proteins were indicative of true osteogenic potential, vascular pericytes were also inoculated into diffusion chambers and implanted into athymic mice. When recovered from the host, chambers containing pericytes were found reproducibly to contain a tissue comprised of cartilage and bone, as well as soft fibrous connective tissue and cells resembling adipocytes. This is the first study to provide direct evidence of the osteogenic potential of microvascular pericytes in vivo. Our results are also consistent with the possibility that the pericyte population in situ serves as a reservoir of primitive precursor cells capable of giving rise to cells of multiple lineages including osteoblasts, chondrocytes, adipocytes, and fibroblasts.

Animals↗
PubMed1998

Tuberculosis notifications in England: the relative effects of deprivation and immigration.

SETTING: Metropolitan areas of England, including London boroughs, in 1991. OBJECTIVE: To investigate the relative importance of deprivation, immigration and the elderly in explaining variations in tuberculosis rate. DESIGN: A retrospective study using multiple Poisson regression models to assess the interrelationship between various population parameters. RESULT: Significant differences ere observed between London and other metropolitan districts in the measures of tuberculosis, immigration and the elderly. In addition, all population parameters were significantly intercorrelated in London: areas with a high proportion of immigrants had high levels of deprivation and low proportions of elderly. In other metropolitan districts, only immigration and the Jarman index were significantly associated, and removing the immigration component from the index removed this statistical significance. Multiple Poisson regression models revealed that the immigrant index had the strongest explanatory power in explaining tuberculosis rates, but there were significant interactions between this and measures of urban deprivation indices. That is, there was a greater effect of increasing deprivation at lower levels of immigration than at higher levels. This phenomenon was more pronounced in London boroughs than other metropolitan districts. The elderly index had no significant influence on tuberculosis rates. CONCLUSION: Although the association between tuberculosis and deprivation previously reported for the city of Liverpool is confirmed across all urban areas of England, the immigrant proportion of the population has a greater statistical power in explaining variations in rates of urban tuberculosis. However, tuberculosis notifications can be most accurately predicted by combining both measures than by either one alone.

Aged↗
PubMed1997

Preschoolers' perception of other people's looking: photographs and drawings.

Children aged 3-4 years were tested for their ability to decide which of two photographs or drawings of a face depicted the act of fixating on a target object; in each control photograph or drawing the same face and object were present without fixation. Performance was above chance on both stimulus types, but low enough to call into question conclusions from previous research. The same children were also tested on their ability to discriminate between photographs/drawings depicting two faces fixating the same object (joint visual attention) and the same two faces fixating different objects. While discrimination of joint visual attention depicted in drawings was as good as discrimination of fixation in the single-face tasks, the ability to reliably choose between a photograph of two people attending to a common object and a control photograph was significantly poorer. The results suggest that, while young infants and children may be highly sensitive to face-on gaze, even well into the fourth year of life children are unable consistently to interpret (1) direction of non-self-directed gaze in static faces and (2) joint visual attention by others.

Art↗
PubMed1997

Cryptogenic fibrosing alveolitis with preserved lung volumes.

BACKGROUND: Cryptogenic fibrosing alveolitis (CFA) is an uncommon disorder of unknown aetiology characterised by interstitial fibrosis which typically shows a restrictive pattern on pulmonary function testing. Some patients with CFA and relative preservation of lung volumes have been described and it has been suggested that their volume preservation may be due to concomitant emphysema. In a retrospective study the relative frequency of preserved lung volumes in CFA, its relationship to emphysema determined by CT scanning, its clinical features, and its subsequent natural history were investigated. METHODS: Using predefined characteristics 48 patients with CFA were identified from pulmonary function records over a three year period. Volume preservation was defined as a forced vital capacity (FVC) of > 80% predicted at presentation. Patients with relative volume preservation were compared with those with more typical pulmonary restriction and clinical data at presentation, and details of their subsequent prognosis, treatment and loss of lung function with time were obtained. Where available, computed tomographic (CT) scans for the two groups were compared in a blinded fashion to score the extent of fibrosis and the presence of concomitant emphysema. RESULTS: Twenty one (44%) of the patients with CFA had a FVC of > 80% predicted. They were more likely to be male (76% versus 48%) and to be current smokers (57% versus 22%) with a heavier life time cigarette consumption than the restricted patients (mean (SE) 38 (4.6) versus 25 (4.5) pack years). There were no significant differences in prognosis and subsequent treatment between the groups. Comparable HRCT scans were available in 23 subjects (seven preserved, 16 restricted). They showed no difference in extent of the pulmonary fibrosis but patients with volume preservation were more likely to show concomitant emphysema (86% versus 19%). Patients with emphysema on HRCT scans were heavier smokers (41(10) versus 21(17) pack years) than those without emphysema but there was no difference in the extent of CFA score between the two groups. CONCLUSIONS: In this area of high smoking prevalence a significant number of patients with CFA presented with relative preservation of lung volumes and FEV1/FVC ratio. In many of these subjects this appears to reflect coincidental emphysema. This may make interpretation of gas transfer factor used to monitor progression in CFA difficult. However, there was no evidence that lung volumes at presentation were of prognostic significance.

Age of Onset↗
PubMed1997

The acoustic properties of capsaicin-induced cough in healthy subjects.

Acoustic analysis of cough both in the time and frequency domain has been reported using voluntary and spontaneous cough. The main aim of this study was to discover whether such analysis of capsaicin-induced cough enables differences between normal subjects to be recognized. We present data from 13 healthy subjects (with normal lung function and no history of respiratory disease) using a new method of acoustic analysis, which presents the data in three graphical forms: 1) spectrogram; 2) overall spectral energy, 3) root mean square (RMS) pressure plots. Using the RMS sound pressure traces, different subjects had either two peaks, a single peak or multiple peaks. The occurrence of single and multiple peaks has previously been associated with disease states but we found them in normal subjects. The number of peaks and the visual pattern of the spectrogram was reproducible within and specific to each individual over time. During a peal of coughs in a single expiration, the peak amplitude of successive coughs decreased as lung volume reduced. Despite similarities in the overall spectral energy between individuals, there were marked differences in the small visual details of the spectrograms. However, in an individual, these small details were remarkably constant both within and between days, and can be regarded as a "cough signature". This type of spectrographic analysis provides a new approach to the analysis both of normal and abnormal cough sounds, and has identified similarities and differences in capsaicin-induced cough in normal individuals. It has potential as a tool with which to study the pathophysiology of cough.

Acoustics↗
PubMed1996

Amino acid sequence of a novel protein phosphatase 1 binding protein (R5) which is related to the liver- and muscle-specific glycogen binding subunits of protein phosphatase 1.

A full-length cDNA encoding a novel human protein phosphatase 1 (PP1) binding subunit of molecular mass 36 kDa, termed PPP1R5, was sequenced. PPP1R5 shows 42% identity to the glycogen binding subunit (G(L)) of PP1 from rat liver and 28% identity to the N-terminal region of the glycogen binding subunit (G(M)) of PP1 from human skeletal muscle. Like G(L), PPP1R5 modulates the specificity of PP1, but it differs from G(L) in being present in a wide variety of tissues, besides liver. The amino acid sequence and properties of PPP1R5 indicate that it is not subject to the same modes of covalent and allosteric regulation by hormones as are G(M) and G(L).

Amino Acid Sequence↗
PubMed1995

Amino acid sequence and expression of the hepatic glycogen-binding (GL)-subunit of protein phosphatase-1.

A full-length cDNA encoding the putative hepatic glycogen-binding (GL) subunit of protein phosphatase-1 (PP1) was isolated from a rat liver library. The deduced amino acid sequence (284 residues, 32.6 kDa) was 23% identical (39% similar) to the N-terminal region of the glycogen-binding (GM) subunit of PP1 from striated muscle. The similarities between GM and GL were most striking between residues 63-86, 144-166 and 186-227 of human GM (approximately 40% identity), nearly all the identities with the putative yeast homologue GAC1 being located between 144-166 and 186-227. The cDNA was expressed in E. coli, and the expressed protein transformed the properties of PP1 to those characteristic of the hepatic glycogen-associated enzyme. These experiments establish that the cloned protein is GL.

Amino Acid Sequence↗