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Biomedical subjects

G Morgan

Publications and source records attributed to G Morgan.

At least 73 records · Page 4Linked to original sources
PubMed1999

Influence of severe combined immunodeficiency phenotype on the outcome of HLA non-identical, T-cell-depleted bone marrow transplantation: a retrospective European survey from the European group for bone marrow transplantation and the european society for immunodeficiency.

We analyzed the outcomes of 214 HLA non-identical T-cell-depleted bone marrow transplantations (BMTs), performed in 178 consecutive patients for treatment of severe combined immunodeficiencies (SCID). Patients were treated in 18 European centers between 1981 and March 1995. SCID variants, that is, absence of T and B lymphocytes (B-) or absence of T cells with presence of B lymphocytes (B+) were found to have a major influence on outcome. The disease-free survival was significantly better for patients with B+ SCID (60%) as compared with patients with B- SCID (35%) (P =.002), with a median follow-up of 57 months and 52 months, respectively. Other factors associated with a poor prognosis were the presence of a lung infection before BMT (odds ratio = 2.47 [1.99-2.94]) and the use of monoclonal antibodies for T-cell depletion of the graft (odds ratio = 1.67 [1. 18-2.15]). Additional factors influencing outcome were age at BMT (<6 months) and period during which BMT was performed. Better results were achieved after 1991. Reduced survival of patients with B- SCID was associated with a higher incidence of early deaths from infection, a diminished rate of marrow engraftment, a trend to a higher incidence of chronic graft-versus-host disease, and slower kinetics of T/B immune function development. In both groups of patients, the use of busulfan (8 mg/kg total dose) and cyclophosphamide (200 mg/kg total dose) as a conditioning regimen provided the best cure rate (74% for patients with B+ SCID and 43% for patients with B- SCID, respectively), although results were not statistically significantly different from other regimens. This retrospective analysis should lead to the design of adapted measures to the performance of HLA non-identical BMT in patients with distinct SCID conditions.

Age Factors↗
PubMed1999

Radiotherapy for bone metastases: a critical appraisal of outcome measures.

Pain from bone metastases is a common problem in patients with advanced cancer, and radiotherapy plays an important role in its palliation. Single fraction treatments are often prescribed, but there is no clear consensus on this issue and clinical practice shows significant variability. This situation is unsatisfactory for all patients--the patient, the clinician, and the health care administrator. Randomized trials may use poor outcome measures and this contributes to practice variability. The credibility of outcome studies is often reduced due to poor study design, small sample sizes, and the use of endpoints that are both unreliable and unsuitable. The endpoints used have been narrowly defined, the patient's perspective has generally been overlooked, and quality of life has only once been used as an endpoint. A review of the current literature suggests that instruments specific to bone metastases are required. These must be based on patient experience, and rely on self-report. In addition, there is a need to understand the relative priority that patients attribute to treatment outcomes. The use of better instruments and methodologies in future trials will enhance the credibility of results and reduce practice variations.

Bone Neoplasms↗
PubMed1999

The rise in incidence of lymphomas in Europe 1985-1992.

A collaborative study was carried out of the descriptive epidemiology of the lymphomas from seven countries across Europe in the period 1985-1992. Careful attention was paid to sources of information and the data quality in close collaboration with expert histopathologists. The data were classified as non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD). An attempt was made to put the data into a modified version of the Revised European American Lymphoma (REAL) classification. We observed an overall rise in total NHL throughout the time period in all European countries but no such trend in HD. The increase in NHL overall being 4.2% per annum, representing an increase of 4.8% in males and 3.4% in females per annum, was only marked in middle and old age. Such increases were observed in all participating areas except in Burgundy. Different countries, however, have different base rates, the rates being highest in Scandinavia and the Netherlands. The analysis by subcategory classification suggested that the increase in NHL was confined to the follicle centre cell type, extranodal B-cell, nodal T-cell and nodal lymphomas not otherwise specified, categories. These new observations present a picture of real increase in case incidence with no obvious explanation. The increases in NHL do not appear to be due solely to better diagnoses. Pending other explanations or refutation, these present a compelling picture of an inexorable rise in incidence of this disease.

Adolescent↗
PubMed1999

Spatial and temporal expression of insulin-like growth factor-I, insulin-like growth factor-II and the insulin-like growth factor-I receptor in the sheep fetal mammary gland.

The mammary gland is an example of a tissue of epidermal origin that depends for the development of its characteristic morphology on underlying mesenchymal cells. The interaction between mesenchyme and epithelium appears to be mediated by polypeptide growth factors. In situ hybridization has been used to study, in the mammary gland of female sheep fetuses, the distribution of mRNA for the mammary mitogens, insulin-like growth factor (IGF)-I and IGF-II, and the IGF-I receptor, from 10 to 20 weeks of intrauterine life (term is approximately 22 weeks). At 10 weeks, secondary ducts had formed from the primary duct. By week 20, the gland had increased in volume and complexity, showing primitive lobules embedded in intralobular connective tissue disposed around main ducts. IGF-I and IGF-II mRNA were expressed in cells of the intralobular connective tissue underlying the epithelium, while the IGF-I receptor was expressed in epithelium. Quantitation by absorbance measurements showed that mRNA expression increased with pregnancy stage for IGF-I and IGF-II, but not significantly for the IGF-I receptor, and that IGF-II was more highly expressed than IGF-I. A role for the IGF system in mediating mesenchymal epithelial interactions in mammary development is indicated.

Animals↗
PubMed1999

Medical record innovations that can improve physician productivity.

Medical records are the fulcrum of patient care activities. They represent the primary reference point with respect to the patient's medical status and long-term planning. A significant portion of the patient care dollar is invested in the medical record document and its handling. The most critical part of this process takes place in the physician's examination room during the patient encounter. The use of SmartCharts is a way to expedite the chart generation process and improve the quality and consistency of the source information from which all future care and plans are generated. The process removes a substantial portion of the human memory cycle that is needed for chart development and improves the encounter process by exploring the full range of diagnostic signs and symptoms that are associated with a preselected diagnosis or patient problem. The system is designed for stand-alone operation or insertion into an already-functioning electronic medical record system.

Decision Support Systems, Clinical↗
PubMed1999

Tobacco and the risk of acute leukaemia in adults.

Self-reported smoking histories were collected during face-to-face interviews with 807 patients with acute leukaemia and 1593 age- and sex-matched controls. Individuals who had smoked regularly at some time during their lives were more likely to develop acute leukaemia than those who had never smoked (odds ratio (OR) = 1.2, 95% confidence interval (CI) 1.0-1.4). The association was strongest for current smokers, defined here as smoking 2 years before diagnosis (OR = 1.4, 95% CI 1.1-1.7). With respect to the numbers of years smoked, risk estimates were raised in all groups except those who had smoked for fewer than 10 years. Similarly, the odds ratio decreased as the number of years 'stopped smoking' increased, falling to one amongst those who had given up smoking for more than 10 years. No significant linear trends were found, however, with either the numbers of years smoked or the numbers of years stopped smoking, and no significant differences were found between AML and ALL.

Acute Disease↗
PubMed1999

Characterization of a mutant T-cell hybridoma line with defects in the TCR-mediated apoptotic pathway.

A mutant T-cell hybridoma line named mutant 51 was developed that, unlike the parental line, did not die after T-cell receptor (TCR) engagement and demonstrated reduced death in response to dexamethasone. Intracellular calcium measurements showed that available calcium stores were markedly reduced in the mutant cell line. Unlike control cells, secretion of IL-2 from mutant cells was also greatly reduced, although addition of exogenous IL-2 did not facilitate increased apoptosis. Although levels of the cell death gene product Nur77 were equivalent, additional studies showed that mutant cells expressed Nur77 predominantly in the cytoplasm following TCR engagement, while parental cells displayed a nuclear translocalization of Nur77. In addition, Fas levels and Fas ligand dependant killing were both markedly reduced in the mutant clone. From these data we hypothesize a role for available calcium stores and Nur77 nuclear localization in TCR-mediated apoptosis in T-cell hybridomas.

Apoptosis↗
PubMed1999

Isolation and characterisation of recombination events involving immunoglobulin heavy chain switch regions in multiple myeloma using long distance vectorette PCR (LDV-PCR).

Immunoglobulin class switching occurs as a result of recombination between pairs of switch region sequences located 5' to each constant heavy chain gene except Cdelta. In the B cell neoplasm multiple myeloma, tumour cells have generally undergone class switching and often contain oncogenic sequences translocated into switch regions, presumably as a result of aberrant switch recombination. We have developed a method (LDV-PCR) which combines long distance PCR with one-sided vectorette PCR that is capable of detecting and isolating both normal and aberrant switch recombination breakpoints from multiple myeloma cell lines and primary multiple myeloma tumour material. Using LDV-PCR we have directly cloned the translocation breakpoints present in two multiple myeloma cell lines and isolated a normal productive switch recombination event from a primary tumour. Furthermore, we have isolated a novel translocation t(14;22)(q32;q12) from a primary tumour sample and have demonstrated that internal deletions within switch regions can occur in multiple myeloma cells. Compared to a Southern blotting approach, LDV-PCR is simpler and more rapid to perform, allows the simultaneous detection and isolation of recombination events, and can also be applied to amounts of DNA which are too low to permit the conventional cloning of recombination breakpoints.

Base Sequence↗
PubMed1999

Distribution of myeloma plasma cells in peripheral blood and bone marrow correlates with CD56 expression.

There is a wide variation in the degree of marrow and blood involvement between patients with multiple myeloma. Both of these parameters are known to be highly significant prognostic factors, and the differences between patients may be due to variable expression of adhesion molecules. To test this we used three-colour flow cytometry to study three adhesion molecules associated with myeloma, namely CD38, CD56 and CD138. The level of expression of these molecules was compared with the distribution of myeloma plasma cells in bone marrow (n=59) and peripheral blood (n=26) in patients at presentation or relapse. The extent of marrow infiltration on the trephine biopsy correlated inversely with CD56 expression (Mann-Whitney U Test, P=0.022); there was no difference in CD38 or in CD138 expression. CD56 expression also correlated inversely with the number of circulating plasma cells (linear regression, R2=0.4268, slope=-0.58, P=0.0003). Peripheral blood plasma cell numbers correlated weakly with bone marrow plasmacytosis, and inversely with CD38 expression. The level of CD56 expression by neoplastic plasma cells was assessed in 37 patients over a median of 11 months (range 6-25). There was no significant change in expression (Wilcoxon Signed Rank, P=0.6271). We conclude that plasma cell CD56 expression is constant over the course of the disease; unlike CD138 expression, it is significantly linked to the degree of both bone marrow and peripheral blood involvement.

Bone Marrow↗
PubMed1999

Expression of parathyroid hormone-related protein and the parathyroid hormone/parathyroid hormone-related protein receptor in rat thymic epithelial cells.

Thymic epithelial cells are an important source of cytokines and other regulatory peptides which guide thymocyte proliferation and maturation. Parathyroid hormone-related protein (PTHrP), a cytokine-like peptide, has been reported to affect the proliferation of lymphocytes in vitro. The studies presented here were undertaken to test the hypotheses that PTHrP is produced locally within the thymus where it could influence thymocyte maturation and, more specifically, that thymic epithelial cells (TEC) could be the intrathymic source of PTHrP expression. To this end, immunohistochemical studies were performed to localise PTHrP and the PTH/PTHrP receptor within the adult rat thymus. Antibodies directed against 2 different PTHrP epitopes, PTHrP(1-34) and PTHrP(34-53), demonstrated prominent specific PTHrP immunoreactivity in both subcapsular and medullary TEC. In addition, faint but specific staining for PTHrP was seen in the cortex, interdigitating between cortical lymphocytes while sparing epithelial-free subcapsular areas, thus suggesting that cortical TEC could also be a source of PTHrP immunoreactivity. In contrast, PTH/PTHrP receptor immunoreactivity was only seen in medullary and occasional septal TEC; no evidence of cortical or lymphocytic PTH/PTHrP receptor immunoreactivity was detected. Immunohistochemical studies of cultured cytokeratin-positive rat TEC confirmed the results of these in situ studies as cultured TEC were immunoreactive both for PTHrP and the PTH/PTHrP receptor. Thus these results demonstrate that PTHrP is produced by the epithelial cells of the mature rat thymus. This suggests that PTHrP, a peptide with known cytokine, growth factor and neuroendocrine actions, could exert important intrathymic effects mediated by direct interactions with TEC, or indirect effects on PTH/PTHrP receptor-negative thymocytes.

Animals↗
PubMed1999

A novel syndrome of episodic muscle weakness maps to xp22.3.

We describe a family with a novel disorder characterized by episodic muscle weakness and X-linked inheritance. Eight males in three generations demonstrate the characteristic features of the disorder. Episodes of severe muscle weakness are typically precipitated by febrile illness and affect the facial and extraocular musculature, as well as the trunk and limbs, and resolve spontaneously over a period of weeks to months. Younger members of the family are normal between episodes but during relapses show generalized weakness, ptosis, and fluctuations in strength. In some cases, fatigability can be demonstrated. The proband has late-onset chronic weakness and fatigability. The clinical phenotype has features suggestive both of the congenital myasthenic syndromes and of ion-channel disorders such as the periodic paralyses. We have localized the responsible gene to chromosome Xp22.3, with a maximum two-point LOD score of 4. 52 at a recombination fraction of.0, between OACA2 and DXS9985.

Adolescent↗
PubMed1999

Autoimmune enteropathy with distinct mucosal features in T-cell activation deficiency: the contribution of T cells to the mucosal lesion.

BACKGROUND: Autoimmune enteropathy is normally characterised by crypt hyperplastic villous atrophy with enterocyte autoantibodies, activation of mucosal lymphocytes and increased epithelial HLA-DR. This case involved a severely affected Portuguese infant who was found to have lymphocyte activation deficiency and demonstrated correspondingly distinct mucosal features. METHODS: A female infant of nonconsanguineous parents was treated for vomiting and diarrhoea, first with milk exclusion and then with parenteral nutrition. Lymphocyte subsets and immunoglobulin concentrations were normal, but in vitro testing showed no activation in response to phytohaemagglutinin, Candida, or purified protein derivative, although the response to interleukin (IL)-2 was intact. Interleukin-2 deficiency was excluded. Analysis of jejunal biopsy specimens revealed only mild villous blunting with absent goblet cells, normal epithelial proliferation, and no crypt hyperplasia. The dense infiltrate of CD8+ and CD4+ T lymphocytes showed normal CD2 and CD3 expression but no activation or proliferation markers. HLA-DR was not increased on epithelium or lymphocytes. Thus, in addition to in vitro evidence for lymphocyte activation deficiency, the mucosal specimens showed no evidence of in situ T-cell activation. RESULTS: After development of overwhelming septicaemia, the patient died at 18 months, just before a planned bone marrow transplant. CONCLUSIONS: These findings confirm significant heterogeneity within autoimmune enteropathy. Formal immune function testing should be performed in all affected infants to identify T-cell activation deficiencies. The distinct mucosal findings suggest that activated T cells usually induce the crypt hyperplastic villous atrophy characteristic of classic autoimmune enteropathy.

Autoimmune Diseases↗
PubMed1999

Beneficial effects of NSAIDs in the gastrointestinal tract.

Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin exert irritant and toxic effects upon the organs of the gastrointestinal tract. NSAID toxicity in the gastrointestinal tract is related, at least in part, to the inhibition of the cyclo-oxygenase (COX) enzyme, leading to a reduction of 'cytoprotective' prostaglandin synthesis. In this paper, examples in which NSAIDs exert beneficial effects in the gastrointestinal tract are discussed. NSAIDs, particularly aspirin, are showing promise in the chemoprevention of colorectal, and, to a lesser degree, oesophageal cancers. The clinical value of NSAIDs in the treatment of established gastrointestinal tract cancers is also worthy of further study. There is good clinical evidence showing the value of diclofenac for the treatment of biliary colic and aspirin or ibuprofen for the prevention of gallstones. NSAIDs also have therapeutic potential against other inflammatory gastrointestinal diseases in the oesophagus and possibly pancreas and liver. To a lesser degree, there is some evidence that NSAIDs may have a therapeutic potential in certain gastrointestinal motility disorders, such as aspirin in the post-irradiation syndrome. It therefore follows that in these cancerous, inflammatory and motility pathologies, prostaglandins exert deleterious effects. The paradox of prostaglandins being 'cytoprotective' and potentially damaging can be explained by considering the enzymic origin of prostaglandins. COX-1 is expressed physiologically while inducible COX-2 is expressed in pathological situations. The beneficial clinical effects of selective COX-2-inhibiting NSAIDs in the gastrointestinal tract deserve further study. This paper challenges the concept of 'cytoprotection'.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1999

Elevated B-lymphocyte levels in lesional tissue of non-arthritic psoriasis.

Psoriasis is a chronic inflammatory skin disorder characterized clinically by maculopapular skin lesions and on the cellular level by increased T-lymphocyte activation in the peripheral blood and migration of activated T-lymphocyte into the lesions. The lymphocyte subpopulations in peripheral blood from 21 Kuwaiti patients showed elevated levels of the T-lymphocyte activation marker CD25, as well as increased expression of HLA-DR compared with a group of age and sex-matched controls, confirming published findings on psoriasis. In addition, there was a tendency towards a significant increase in the CD4+/CD45RO+ (memory cell) population that was also consistent with peripheral T-lymphocyte activation. Immunohistological studies showed a heavy infiltrate of all cell types into the lesional tissue including, as expected, activated T-lymphocytes. An unexpected finding was significantly higher levels of B-lymphocytes infiltrating the psoriatic lesions; they numerically exceeded the T-lymphocyte infiltrate. This has previously been reported only in cases of psoriasis with concurrent arthritis. None of the subjects had arthritis, suggesting an immunopathological variant of psoriasis possibly specific to this population group.

Adult↗
PubMed1999

Differential expression of interferon gamma by mitogen-stimulated peripheral blood mononuclear cells among Kuwaiti psoriasis patients.

Most diseases exhibit characteristic profiles of cytokine expression, broadly subdivided into Th1, involving primarily cell-mediated responses, of which Interferon-gamma (INF-gamma), Interleukin-2 (IL-2) and Tumor Necrosis Factor-alpha (TNF-alpha) are hallmarks, and Th2 processes, which often involve activation of the humoral arm of the immune system, resulting in elevated levels of IL-4, IL-5 and IL-10. Psoriasis, a disorder characterized by disfiguring skin lesions and elevated levels of activated CD4+ T helper lymphocytes in both peripheral blood and lesional tissue, exhibits a profile of cytokine expression that includes high levels of TNF-alpha and IFN-gamma, with low IL-5 and IL-10, indicating that immunologically, the pathogenesis of the disease is Th1. In this study, we report the results of an investigation of peripheral blood mononuclear cell cytokine expression among Kuwaiti psoriasis patients; we demonstrated two patterns of IFN-gamma production which may suggest differing pathogeneses. Whole, haparinized blood was donated by 17 patients with active psoriasis and 11 healthy control subject. Mononuclear cells were isolated by density centrifugation and cultured for 3 days in the presence or absence of a mitogen (PHA). Supernatants were assayed for IFN-gamma (a Th1 marker) and IL-10 (a Th2 marker) by enzyme-linked immunoabsorption assay (ELISA). IFN-gamma expression by both PHA-stimulated and unstimulated cultures from psoriatics significantly exceeded that of controls (p < 0.001), whereas no significant differences in IL-10 expression were noted between psoriatic and control subjects. Stimulation indices (cytokine concentration in PHA-stimulated/unstimulated cultures, SI) for psoriatic subjects were significantly higher than those of controls for IFN-gamma (p = 0.000), but not for IL-10. Ratios of SI (SI IFN-gamma/SL IL-10) for the psoriatic subjects also were significantly greater for the psoriatic subjects than for the controls (p = 0.003). However, within the psoriatic group, eight patients failed to show the expected elevation of IFN-gamma/IL-10 ratio as a result of high unstimulated levels of IFN-gamma production. The divergence of IFN-gamma expression within the psoriatic group may indicate two different modes of T lymphocyte activation contributing to the pathogenesis of psoriasis in this study.

Adult↗
PubMed1999

Perthes' disease and the relevance of thrombophilia.

Recent work has suggested that thrombophilia may be an aetiological factor in up to 50% of children with Perthes' disease, and that up to 75% may have a coagulopathy. Our aim was to test these findings in the local population of children with Perthes' disease and attempt to correlate them with the severity of the condition. In 64 children there were only eight (12%) with low levels of clotting proteins, as defined by normal paediatric ranges. Of these eight, only five could be said to show any thrombophilic tendency.

Child↗
PubMed1998

Different patterns of obstetric complications in myotonic dystrophy in relation to the disease status of the fetus.

The obstetric histories of 26 women with myotonic dystrophy (DM), who had a total of 67 gestations, were reviewed retrospectively comparing gestations with affected (DM-fetuses) and unaffected fetuses (UA-fetuses). Second, the influence of gestation on the disease course and the personal attitude towards family planning in DM was assessed. Miscarriages and terminations occurred in 11 pregnancies. Of the 56 infants carried to term, 29 had or most likely had inherited the gene for DM from their affected mothers at the time of investigation; 18 (61%) in this series were affected by the congenital form of DM. Perinatal loss rate was 11% and associated with congenital DM. The rate of obstetric complications was significantly increased in all women. However, preterm labor was a major problem in gestations with DM-fetuses (55 vs. 20%), as was polyhydramnios (21% vs. none). While forceps deliveries or vacuum extractions were required in 21% of deliveries with DM-fetuses and only 5% of UA-fetuses, the frequency of Cesarean sections was similar in both groups (24 and 25%). Obstetric problems were inversely correlated with age at onset of maternal DM, while no effect of age at delivery or birth order on gestational outcome was seen. DNA analysis confirmed the diagnosis in 19 patients by the presence of enlarged CTG repeats (EcoRI-expansions) on chromosome 19. Of the 17 patients whose CTG repeat length was known, 59% were classified as E2 (corresponding to 500-1000 repeats), 24% as E1 (<500 repeats), while larger expansions (E3; 1000-1500 repeats, or E4; >1500 repeats) were seen in three patients (17%). Obstetric complications or congenitally affected children occurred in all maternal phenotypes and CTG repeat classes. Eight (31%) patients experienced a worsening of symptoms that was temporary, weight related in three cases, and persistent in five. With the exception of three patients, most new mothers were able to care for their families. To conclude, pregnant women with DM need constant obstetric monitoring and should be advised to deliver in centres with perinatal facilities.

Adult↗