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Biomedical subjects

C L Morgan

Publications and source records attributed to C L Morgan.

At least 19 recordsLinked to original sources
PubMed1999

Soluble CD8 stabilizes the HLA class I molecule by promoting beta2M exchange: analysis in real-time.

Human soluble CD8 (sCD8) is secreted by activated CD8+/- cytotoxic T lymphocytes (CTLs). The immunological role of sCD8 is poorly defined, however. We have studied the influence of sCD8 on HLA class I interactions by real-time analysis. Using an optical biosensor we demonstrated that the binding of sCD8 to HLA-A2 promotes exchange of beta2-microglobulin (beta2m) in order to stabilize the complex. Kinetic analysis showed that sCD8 significantly increased the affinity (K(A)) of HLA-A2 for immobilized human beta2m; from 1.14 +/- 0.04 x 10(9) M(-1) in its absence, to 2.18 +/- 0.21 x 10(9) M(-1) following preincubation with sCD8. This suggests that the sCD8:HLA class I complex is unlikely to be degraded at the cell surface. Even in the presence of exogenous peptide (HLA-A2 specific or nonspecific), sCD8 has a stabilizing influence on the HLA class I molecule. These findings point to an immunosuppressive role for sCD8, because the binding of sCD8 to HLA class I would block the binding site for CTL-bound CD8 and, therefore, interfere with T cell activation and proliferation. This may have particular significance in pathological situations where elevated levels of sCD8 are found in extracellular fluids, and sCD8 may provide an alternative approach for immunosuppressive therapy.

CD8 Antigens↗
PubMed1998

Real-time analysis of cell surface HLA class I interactions.

Characterisation of the kinetics of assembly and dissociation of the HLA class I heterotrimeric complex provides valuable insights into the relative contributions of each element to complex stability. However, to date there has been no real-time binding analysis on whole cells. Here we have developed an optical biosensor model to investigate the binding of class I HLA complexes on whole cells to human beta 2-microglobulin (beta 2m) and the effects of different HLA-specific peptides on this binding. We immobilised beta 2m on an IAsys biosensor surface and established conditions to analyse the binding of this to HLA-A2 expressing cells (T2 cells). Using 721.221 cells as an HLA negative control we showed that HLA-A2 binding was optimal using a) a carboxymethylated dextran surface and b) no growth factors or supplements in the culture medium at the binding event. Using these conditions we verified specificity of binding by inhibition of the reaction with free beta 2m and determined the dissociation rate constant for T2 cell binding to beta 2m (0.03 s-1). In addition, we demonstrated the ability of different HLA specific peptides to modulate cellular HLA-A2 binding to beta 2m. This is the first time that interactions of cell surface HLA class I molecules has been investigated using real-time analysis. Furthermore, our peptide analysis has shown that this model can be used to characterise peptide specific HLA-binding responses on the whole cell surface in real-time.

Cell Line↗
PubMed1998

The matrix effects on kinetic rate constants of antibody-antigen interactions reflect solvent viscosity.

This study describes the influence of different matrices on two model antibody-antigen interactions; that between beta2microglobulin and anti beta2microglobulin, and that of rabbit anti mouse Fc fragment (RAMFc) with mouse IgG. The matrices investigated were; phosphate-buffered saline pH 7.4 containing 0.05% Tween 20 detergent, horse serum, a 50:50 mixture of phosphate-buffered saline/Tween 20 and horse serum, and four glycerol solutions of differing concentrations. A recently developed optical biosensor, the IAsys, was used to monitor the interactions in real-time and provide precise determinations of k(ass), k(diss) and KA values. The results show that the rates of association and dissociation for the two different antibody:antigen models are significantly affected by the surrounding matrix. Glycerol of known viscosity was used as a matrix in both models to show that this effect is attributable to the viscosity as opposed to proteins present in the matrix. The viscosity of the matrix has also been shown to have an apparent influence upon the overall equilibrium/affinity constant for the interaction, with measurements of KA tending to increase with viscosity. The significant effects of matrix on kinetic rate constants for antibody-antigen interactions shown here have important implications in the use of immunoassays where non-equilibrium measurements are made in serum matrices.

Animals↗
PubMed1998

The influence of exogenous peptide on beta2-microglobulin exchange in the HLA complex: analysis in real-time.

We used an optical biosensor to determine the relative binding affinity of peptides to purified HLA class I molecules. In this assay we monitor beta2-microglobulin (beta2m) exchange within the HLA-A2 molecule, whereby native beta2m in the complex is replaced by beta2m immobilized at the surface of the biosensor. Quantitative kinetic measurements permit us to obtain association rate (kass), dissociation rate (kdiss) and affinity constants (KA) for the beta2m exchange reaction, alone, (control) and in the presence of exogenous peptide. We tested a panel of six peptides which had been designed and synthesized with an HLA-A2 binding motif, and had also been tested by the T2-cell binding assay, along with control peptides. The biosensor results demonstrate that exogenous peptide influences the dynamics of beta2m exchange in a sequence-specific manner. Five of six peptides increased the association rate, decreased the dissociation rate, and significantly increased the affinity (KA=1. 55-1.88x10(9) M-1) of HLA-A2 for immobilized beta2m compared with the control (KA =1.14+/-0.04x10(9)M-1), demonstrating stabilization of the complex. One peptide was unable to stabilize the complex, as also shown in the T2 binding assay. However, analysis of peptide sequences demonstrated that the HLA-A2 secondary motif as well as primary motif residues are required for HLA-A2 stabilization. Further experiments demonstrated that beta2m exchange alone cannot stabilize the HLA class I complex at the cell surface until a peptide of sufficient binding affinity is bound. Hence kinetics equal to or below the control values in our biosensor assay probably represent an unstable complex in vivo. Unlike other methods described for the analysis of peptide stabilization, this approach is significantly faster, provides full kinetic analysis, and is simpler, since it requires no labeling of peptides. Furthermore, this may have important implications in the assessment of peptide vaccines.

Biosensing Techniques↗
PubMed1998

Evaluating CPR performance in basic life support: the VIDRAP protocol.

This paper presents the second part of the validated Cardiff test for one rescuer basic life support skills, based on observation of video recording combined with the Recording Resusci Anne printout (VIDRAP). The authors believe that this is a robust evaluation tool which is capable of assessing the potential value to a casualty of a simulated resuscitation. The adoption of a widely accepted test methodology would facilitate comparison of research in different centres, which is not possible at present.

Adult↗
PubMed1998

The demand for hospital services for patients with epilepsy.

PURPOSE: To describe the patterns of inpatient and outpatient hospital care for patients with epilepsy in our health district. METHODS: Routine hospital data for the health district of South Glamorgan (population 408,000) underwent record linkage to identify those records relating to the same patients and to flag those records for patients with epilepsy. This data was analyzed to determine inpatient and outpatient activity by specialty and compared with the nonepileptic population. RESULTS: We identified 2.267 patients representing a prevalence of 0.56%. The average age was 46 years in both male and female patients. This group, which constituted 1.5% of the hospital population, was responsible for 2.8% of all admissions but, because of increased length of stay, utilized 7.3% of all bed days. The total cost of care for this group lies between these two extreme values and is dependent on case severity. The patterns of associated diagnoses differed considerably in three arbitrary age groups (0-18, 19-55, >55 years). CONCLUSIONS: This study quantifies for the first time the level of demand that this subpopulation places on the service as a whole, and begins to illustrate that there may be evidence for cost containment by, for example, a reduction in multiple admissions. The demand for inpatient services is greater than we would have predicted.

Adolescent↗
PubMed1998

The epidemiology and cost of inpatient care for peripheral vascular disease, infection, neuropathy, and ulceration in diabetes.

OBJECTIVE: To describe the epidemiology and costs of the acute care of peripheral vascular disease, infection, neuropathy, and ulceration in a U.K. population with special consideration of those patients with diabetes. RESEARCH DESIGN AND METHODS: Routine data describing inpatient care for a 4-year period were analyzed (financial years 1991/1992 to 1994/1995). These data had undergone record-linkage to draw together records from the same patients, and records of patients with diabetes were flagged. Cost estimates were determined by attributing a diagnosis-related group cost-weight to each record. RESULTS: A total of 4,245 admissions (1.2% of all admissions) had a primary diagnosis of peripheral vascular disease, infection, neuropathy, or ulceration, and 7,379 (2.1%) admissions had these categories recorded in any one of six diagnostic fields. These figures were generated by 3,159 and 4,751 patients, respectively. This represented a range of crude annual incidence of admission of between 1.9 and 2.9 per 1,000 people. Patients with diabetes accounted for 625 (15.4%) of primary admissions, a crude annual incidence of admission of 18.8 per 1,000. The age-standardized relative risk of admission for patients with diabetes to the nondiabetic population was 7.61 for men and 6.85 for women. The length of stay for patients with diabetes was almost twice that of the nondiabetic population (15.5 vs. 8.7 days). The relative risk of hospital mortality (diabetes vs. non-diabetes) was 2.83. Surgical procedures were carried out on 857 patients, 272 (31.2%) with diabetes. This represented an age-standardized relative risk of 31.19. The estimated cost of admissions for primary diagnoses in these categories over 4 years was 6,128,211 pounds ($9,743,855). Patients with diabetes accounted for 1,236,623 pounds ($1,966,230), an excess of 87% attributable to the diabetic state. CONCLUSIONS: Diabetes is confirmed as a significant risk factor for peripheral vascular disease, infection, neuropathy, and ulceration. The severity of these disorders in terms of increased risk of hospital mortality, length of stay, and risk of surgical procedure is also demonstrated for those patients with diabetes.

Communicable Diseases↗
PubMed1998

Reinforcement frequency, but not gender, determines sensitivity to discriminative stimulus effects of morphine.

We demonstrated previously that several parameters of a morphine discrimination were significantly different in female versus male rats, using a fixed ratio (FR)-10 schedule of food reinforcement; however, this schedule produced a significant bias in reinforcement frequency between saline and morphine sessions in males but not in females. To determine whether this schedule-drug-sex interaction caused the sex difference in discriminability of morphine, female and male rats were trained to discriminate 3.0 mg/kg morphine from saline using a variable interval (VI) 15-s/VI 15-s (Phase I), a VI 7.5-s/VI 15-s (Phase II), and a VI 15-s/VI 15-s (Phase III) schedule of food reinforcement on morphine/saline levers, respectively. After a minimum of 40 training sessions in each phase, mean reinforcement rates in morphine sessions were highest, and the ED50 values for morphine discrimination were lowest, in Phase II. Thus, as predicted, the morphine dose-effect curves shifted to the left from Phase I to Phase II, and back to the right from Phase II to III, presumably due to the bias in reinforcement rate between saline and morphine sessions that was induced by manipulating the VI schedule on the morphine lever. However, there were no sex differences in the morphine versus saline reinforcement rate or in discrimination ED50 in any phase, suggesting that the sex difference observed in our initial study was probably due to the bias in reinforcement frequency (towards the saline condition) that occurred only in males under the FR-10 schedule. This study demonstrates the importance of considering group differences in schedule-drug interactions when comparing discriminative stimulus properties of drugs between groups.

Analysis of Variance↗
PubMed1997

Hospital utilization as a function of social deprivation: diabetes vs non-diabetes.

We tested the hypothesis that a relationship between ill health and deprivation exists for patients with diabetes, distinct from that experienced by the non-diabetic population. Age standardized admission and appointment rates and proportion of total activity for patients with and without diabetes were determined by electoral ward and correlated with the Townsend index of social deprivation for the health district of South Glamorgan (population 408,000). Both diabetic (r = 0.78, p < 0.001) and non-diabetic (r = 0.74, p < 0.001) in-patient admissions were positively correlated with social deprivation. This relationship also existed for attended out-patient appointments (r = 0.67, p < 0.001 and r = 0.45, p < 0.01, respectively). The proportion of diabetic to non-diabetic admissions by ward also showed a positive correlation for in-patients (r = 0.47, p < 0.001). This remained true for IDDM (r = 0.23, not significant) and NIDDM (r = 0.62, p < 0.001) diabetes, for admissions for coronary heart disease (r = 0.50, p < 0.001) and cerebrovascular disease (r = 0.29, p < 0.05), elective admissions (r = 0.30, p > 0.05), and emergency admissions (0.46, p < 0.001). Our results suggest that secondary care utilization is positively correlated with social deprivation and that this relationship is stronger in the diabetic population. This may be due to different prevalence rates or increased complications requiring hospital treatment in different social circumstances. Further research is required to examine these factors more closely.

Age Factors↗
PubMed1997

NHS acute sector expenditure for diabetes: the present, future, and excess in-patient cost of care.

We set out to determine the present proportion of in-patient revenue used for the care of diabetes and its related complications and to use these data to determine (1) the trend in future hospital costs for the condition and (2) the excess cost of admissions for diabetic patients over and above that expected had these patients not had diabetes, using a cross-sectional descriptive study in conjunction with a population modelling exercise in a District Health Authority with a resident population of 408 000 people. The crude proportion of admissions for people with diabetes was 7.0% of activity in financial year 1994/5 (of 115929 total in-patient and day case admissions). Patients with diabetes occupied 10.7 % of bed days and had a crude mean length of stay of 10.7 days vs 6.7 days for the non-diabetic group. The proportion of revenue used for their treatment was 8.7 %. This translated locally to 11.9 M. In year 2011 overall cost of in-patient care is predicted to increase by 9.4 %, however, the proportion of revenue used for the care of people with diabetes will increase by 15% because of age-related effects. The excess cost associated with treating diabetes is estimated to be 82% of admissions for the diabetic population, 88% of their bed days, and 86% of expenditure associated with their care. Most of this excess cost is associated with the recognised vascular complications of diabetes. We conclude that the cost of in-patient care for patients with diabetes is notably disproportionate to the population prevalence of diabetes-9 % compared to 1.36% in South Glamorgan-and will increase disproportionately with time. As much of the long-term morbidity is known to be preventable by earlier intervention, strategies should reflect the imperative to reduce the burden of diabetes.

Adolescent↗
PubMed1997

Assessing with CARE: an innovative method of testing the approach and casualty assessment components of basic life support, using video recording.

The resuscitation community is now moving towards a set of basic life support guidelines but different countries and training centres have their own individual methods of instruction. It would be advantageous if a universal testing method were available to facilitate intercentre comparison. This could lead to an international course which had been rigorously assessed and evaluated. Taking this as a starting point, the Cardiff Assessment of Response and Evaluation (CARE) was developed. CARE is an innovative assessment technique using video recording for testing the preliminary steps of life support as outlined by the European Resuscitation Council. The assessment was validated by testing 67 members of the public who had been trained in cardiopulmonary resuscitation, 27 shortly after instruction and 40 between 6 and 18 months after instruction. All subjects were tested without prior warning and video recorded for independent scoring by two researchers and a paramedic training officer. Scores were compared using the k correlation which showed a high level of agreement between observers. Video recording and marking using the CARE schedule and guidelines is a reliable method for assessing the preliminary steps in life support.

Cardiopulmonary Resuscitation↗
PubMed1997

Kindler syndrome: a rare cause of desquamative lesions of the gingiva.

Kindler syndrome is a rare syndrome with cutaneous and intraoral manifestations. It has been suggested that there is an overlap between this syndrome and another called Weary syndrome. Only 68 cases of Weary and Kindler syndromes have been reported, with fewer solely attributed to Kindler syndrome. The salient cutaneous features are neonatal bullae, poikiloderma, photosensitivity, and acral atrophy. This article presents the clinical intraoral findings of two siblings of consanguineous descent diagnosed as having Kindler syndrome. Both had an erythematous and erosive appearance of the gingiva; one sibling had poor oral hygiene and a rapidly progressive form of periodontal disease; the other, whose oral hygiene was acceptable, had no detectable bone loss.

Adult↗
PubMed1997

Patterns and costs of hospital care for coronary heart disease related and not related to diabetes.

OBJECTIVE: To describe the epidemiology and costs of coronary heart disease (CHD) requiring hospital admission, with particular reference to diabetes. SETTING: The former South Glamorgan Health Authority, South Wales. METHODS: Routine hospital activity data were record linked and all diabetic and non-diabetic individuals over a four year period (1991-95) were identified. A cost weight was included for each admission based on diagnosis related groups. RESULTS: There were 10,214 patients admitted with a primary diagnostic code for CHD, representing an incidence of 6.3 per 1000 per annum. Including all CHD and non-CHD admissions, these individuals were responsible for 17% of acute inpatient activity. Men had a consistently higher age specific prevalence of CHD than women. The age adjusted relative risk of CHD for patients with diabetes compared with those without was 4.1 for men and 5.5 for women. Patients with diabetes accounted for 16.9% of CHD related admissions and had a fourfold increased probability of undergoing a cardiac procedure. The total cost of CHD was estimated to be 6% of NHS revenue at 1994-95 pay and prices. Patients with diabetes were responsible for 16% of this expenditure. This translated to an estimated NHS acute hospital expenditure for CHD of 1.1 billion pounds per year at 1994-95 pay and prices. CONCLUSIONS: CHD was responsible for a larger proportion of NHS expenditure than had previously been reported. Nearly one in five acute hospital admissions were for patients whose condition included cardiac problems. The relation between diabetes and CHD was particularly evident, and may offer opportunities for disease prevention.

Acute Disease↗