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Biomedical subjects

D Phelan

Publications and source records attributed to D Phelan.

At least 37 records · Page 2Linked to original sources
PubMed1996

Biochemical and immunological evaluation of donor-specific soluble HLA in the circulation of liver transplant recipients.

MHC antigens, normally expressed as integral membrane proteins, are also present in soluble form in the peripheral circulation. These soluble human leukocyte antigens (sHLA) are found at elevated levels in patients with a variety of infections as well as in organ transplant recipients. In liver transplant recipients, however, most of the circulating sHLA are of donor phenotype, especially during the early posttransplant period. Here we report the purification and characterization of sHLA of both recipient and donor origin from liver transplant recipients. It was observed that sHLA consisted of four major polypeptides having molecular mass of 44, 41, 35-37, and 12 kD complexed with IgM and IgG antibodies. Further analysis revealed that these immunoglobulins contained anti-HLA antibodies. Analysis of the affinity-purified materials by a number of approaches failed to detect any other fragment(s) of HLA class I heavy chain polypeptides smaller than 12 kD. No significant difference was observed in the biochemical nature of the sHLA of donor and recipient origin and they were similar to those found in normal individuals. Affinity-purified HLA-A3 inhibited the cytolytic activity of an HLA-A3-specific CD8+ T cell line, whereas, purified sHLA-A2 failed to inhibit anti-HLA-A3 CTL activity. Further, the proliferation of the T cell line was not inhibited by sHLA-A3. Thus, the inhibitory activity shown by sHLA was antigen-specific and directed against a functional subset of T lymphocytes. These results support the notion that sHLA may play an important regulatory role in the immune response to allograft in humans.

Adult↗
PubMed1995

The haemodynamic effect of prophylactic peri-operative dopexamine in coronary artery bypass patients.

Twenty-three low risk coronary artery bypass graft patients underwent a controlled study of the effects of prophylactic perioperative dopexamine hydrochloride on haemodynamic indices and peripheral perfusion. The infusion commenced following induction of anaesthesia and continued for 24 h postoperatively. The study demonstrated that dopexamine significantly increased cardiac index compared with the control group (P < 0.05) and that this effect was mediated through an increase in both left ventricular stroke volume index and heart rate (P < 0.05). This was associated with a significantly lower systemic vascular resistance (P < 0.05), without an increase in left ventricular stroke work index in the dopexamine group. Despite normal pre-operative left ventricular function, both groups exhibited a fall in pH (P < 0.05) relative to baseline levels. This fall in pH began prior to cardiopulmonary bypass and persisted in the early postoperative period in both groups, suggestive of tissue hypoperfusion and oxygen deficiency. These indices normalized more rapidly in the dopexamine group, suggesting a more rapid reversal of an intra-operative oxygen debt in this group. The study demonstrates the mechanism of action of dopexamine on cardiac function and peripheral perfusion during cardiac surgery and shows that the inodilator properties during cardiac surgery are useful haemodynamically and facilitate early reversal of tissue hypoperfusion and oxygen debt in this environment.

Adult↗
PubMed1994

Induction immunosuppression with antilymphocyte globulin or OKT3 in cadaver kidney transplantation. Results of a single institution prospective randomized trial.

Improved cadaver kidney allograft survival rates, shorter duration of acute tubular necrosis, and a reduction in the incidence of rejection have been achieved using "quadruple sequential therapy"--AZA, prednisone, and antilymphocyte globulin (ALG) induction followed by the delayed addition of CsA. OKT3 has been shown to be effective in preventing and treating rejection, including steroid- and ALG-resistant rejection episodes. A single institution prospective randomized trial comparing ALG and OKT3 prophylaxis in first cadaver kidney allograft recipients was performed to assess their relative advantages and disadvantages. First cadaver kidney allograft recipients were prospectively randomized to receive 7 days of either ALG (n = 58) or OKT3 (n = 59) as part of a quadruple therapy protocol that included AZA, prednisone, and oral CsA. Patient characteristics, patient survival and causes of death, graft survival and causes of graft loss, incidence of and time to rejection and response to treatment, incidence of infections and their type, renal function, and antibody formation to ALG and OKT3 were examined. The 1-, 2-, and 3-year actuarial patient survival rates were 96% in the ALG group and 98% in the OKT3 group. The graft survival rates were 81.1%, 78.4%, and 78.4% in the ALG group and 84.1%, 78.7%, and 78.7% in the OKT3 group. In ALG-treated patients, 63% never had rejection, compared with 49% in the OKT3 patients (P = NS). In the ALG group 31% had a single rejection, 6% had 2 rejections, and none had 3 rejections, compared with 37%, 12%, and 2% in the OKT3 group. In the ALG group, 43% were steroid responsive compared with 65% in the OKT3 group (P = 0.08). There were 1.44 infections per patient in the ALG group compared with 0.76 in the OKT3 group (P = 0.0004). In the ALG group, 37% of patients developed CMV disease compared with 10% in the OKT3 group (P = 0.001). In donor-positive/recipient-negative patients, 8/10 (80%) in the ALG group developed CMV infection, of which 6 (75%) had severe or moderate CMV disease, compared with 2/15 (13%) patients in the OKT3 group (P = 0.002), of whom only one (6.7%) developed moderate disease. In donor-positive/recipient-positive patients, 8/23 (35%) in the ALG group developed CMV infection, of whom 5/8 (62.5%) developed severe or moderate disease compared with 1/21 (4.8%) in the OKT3 group (P = 0.02). Antibody formation to ALG and OKT3 occurred in 11% and 8% of patients, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1993

Cardiopulmonary resuscitation skills in non consultant hospital doctors--the Irish experience.

We assessed the Cardiopulmonary Resuscitation (CPR) skills in 30 Non Consultant Hospital Doctors (N.C.H.D.'s) chosen randomly from a total of 110 on the staff of a university associated teaching hospital. The candidates filled out a questionnaire and were asked to perform initial assessment and CPR on a mannikin for two minutes. None of the candidates followed the recognised airway, breathing and circulation ABC sequence and only one provided effective CPR. We suggest there is a need for encouragement for doctors to undergo CPR training with subsequent certification and ongoing refresher courses during their career.

Attitude of Health Personnel↗
PubMed1993

Probable antibody-mediated failure of two sequential ABO-compatible hepatic allografts in a single recipient.

Two sequential ABO-compatible orthotopic liver allografts failed, despite excellent initial posttransplant function, in a patient with preformed donor-specific alloantibodies. There was no evidence of cell-mediated rejection. Retrospective crossmatching of recipient serum, obtained immediately prior to the first transplant, revealed the presence of lymphocytotoxic antibodies directed against donor class I HLA B17, at a titer of greater than 1:32,768. Similarly, lymphocytotoxic antibodies directed against the second donor's class I HLA A2 phenotype were detected on retrospective crossmatching utilizing both the three-wash Amos technique (TWA-CDC), and the anti-human immunoglobulin augmented technique (AHG-CDC), at a titer of greater than 1:32,768. Anti-class I specific alloantibodies were eluted from both failed liver grafts at titers of 1:256. The hepatic necrosis in zones 3 and 2 that were observed on histologic examination, and the profound refractory consumptive thrombocytopenia subsequent to each transplant may have been the result of antibody-mediated rejection by preformed lymphocytotoxic antibodies. Despite the liver's remarkable capacity to withstand antibody-mediated injury, primary humoral rejection following ABO compatible liver transplantation may occur if extremely high titers of performed allospecific lymphocytotoxic antibodies are present.

ABO Blood-Group System↗
PubMed1992

The relationship between a nutritional index and acute physiology score in critical illness.

Prognostic indices derived from available physiological data (SAPS), complex nutritional and biochemical tests (PNI), grip strength and serum albumin were calculated in 16 critically ill patients receiving intravenous nutrition over a six week period. The aim was to compare these independently derived prognostic indices, to assess their response to feeding, and to determine suitability for use in Irish intensive care units. Mean SAPS (7.6 +/- 0.92), PNI (3.1 +/- 0.29), serum albumin (30.3 +/- 1.03 g/l) and grip strength (17.9 +/- 1.3%) were all suggestive of an "at risk" group. Significant associations were found between the accepted SAPS index and both PNI (r = 0.6, p < 0.001, n = 35) and grip strength (r = -0.68, p < 0.001, n = 44) but not with serum albumin. No consistent improvement was seen in response to feeding in any of the derived indices. The close correlation between prognostic indices derived from either physiological, nutritional or grip strength data in this study and the failure of prognostic indices to improve during hyperalimentation would support a common mechanism, e.g. endogenous mediators, for metabolic and physiological disturbance in critical illness. It suggests that the role of hyperalimentation is supportive rather than therapeutic and re-iterates the importance of managing underlying disease processes. Simple grip strength may be a useful alternative to complex nutritional indices.

Critical Illness↗
PubMed1991

Antiidiotypic antibodies to HLA class I alloantibodies in normal individuals: a mechanism of tolerance to noninherited maternal HLA antigens.

Recent reports indicate that 25%-50% of transplant patients exhibit B-cell nonresponsiveness to their noninherited maternal HLA antigens (NIMAs). To test the hypothesis that tolerance of NIMAs is mediated by antiidiotypic antibodies, sera from seven normal human subjects were tested for the capacity to inhibit the reactivity of HLA alloantisera directed to NIMAs. Five of seven sera inhibited (50%-100%) the cytotoxicity of monospecific alloantisera directed to their NIMAs. This inhibition was specific in that antisera directed to third-party HLA antigens were not inhibited. Cytotoxicity inhibition by normal sera was selective for antisera directed to HLA-B locus antigens. Absorption with an antibody specific for an HLA class I framework determinant eliminated the inhibitory activity of three of the five sera, suggesting that the inhibition was mediated by soluble HLA antigens in these cases. However, two of the sera retained inhibitory activity following soluble antigen depletion, suggesting that, in these cases, inhibition is mediated by antiidiotypic antibodies. This hypothesis was confirmed by purifying the immunoglobulin (Ig) fraction of one of these sera by anti-Ig affinity chromatography; the column eluate (Ig fraction) but not the effluent (Ig-depleted serum) was capable of inhibition. These data are consistent with the hypothesis that tolerance of NIMAs is mediated, at least in part, by antiidiotypic antibodies.

Antibodies, Anti-Idiotypic↗
PubMed1990

Evaluation of putative cytoprotective properties of antiulcer drugs using quantitative histological techniques.

The capacity for cytoprotection has been claimed for a number of drugs that may have a place in the treatment of peptic ulcer disease. In this study we have used quantitative histological criteria to evaluate the ability of these drugs to be cytoprotective and have compared their effects with that of natural prostaglandin E2 (PG). The standard rat model, with injury by instillation of 1 ml of absolute ethanol, has been used. Putative cytoprotective agents were administered 15 min prior to ethanol. Each animal was sacrificed 15 min after ethanol exposure. The stomach was removed and studied using an established quantitative histological technique. This technique provides a measure of the surface area of mucosa damaged and of the volume of mucosa damaged. Ethanol alone caused damage to 76% of the area of the rat stomach and 14% of the volume of the rat gastric mucosa. Pretreatment by PG (25 micrograms/ml) resulted in reduction of the area of damage to 45% and reduction of the percentage volume damage to 2.2%. The synthetic analog of PGE2, Enprostil (1 microgram/ml) achieved similar protective effects. With pretreatment with colloidal bismuth subcitrate (10 mg/kg) or sucralfate (25 mg/kg), no protection against the surface area damaged by ethanol was seen, but there was a marked reduction of the volume of mucosa damaged. Indomethacin pretreatment augmented the damage caused by ethanol. The protective effects of colloidal bismuth subcitrate and sucralfate were not blocked by pretreatment with indomethacin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Lack of T-cell tolerance of noninherited maternal HLA antigens in normal humans.

Recent clinical reports of nonresponsiveness to noninherited maternal human leukocyte antigens have led to speculation that humans may acquire tolerance of noninherited maternal antigens through exposure to maternal cells neonatally or in utero. To test this hypothesis, we measured the responsiveness of normal subjects to their noninherited maternal and paternal antigens using cell-mediated lympholysis assays and mixed leukocyte reactions. All individuals exhibited cell-mediated lympholysis and mixed leukocyte reaction responses to the maternal cells that were comparable to those to the paternal cells. Limiting dilution analyses revealed significant cytotoxic T-lymphocyte precursor frequencies to both sets of parental antigens. To exclude the possibility that tolerance of individual noninherited maternal antigens was masked by the response to other antigens expressed on the same target cell, we raised cytotoxic T lymphocytes to the maternal cells and then tested for reactivity to a panel of targets that expressed single noninherited maternal HLA antigens. In all cases, each noninherited maternal antigen expressed on the maternal cells elicited a significant cell-mediated lympholysis response. An analysis of clinical data showed that pretransplant mixed lymphocyte reactions to maternal cells are not significantly lower than those to paternal cells. These data suggest that the reported B-cell tolerance of noninherited maternal antigens is not mediated by clonal deletion of T cells induced by exposure to the maternal cells neonatally or in utero.

Adolescent↗
PubMed1990

Septicaemia and the prevention of multiorgan failure--the intensive care perspective.

Septicaemia frequently presents without "classic" signs of infection--tachypnoea, hypotension and confusion are the commonest features. The mortality rate is 40 to 80% and in intensive care units, septicaemia accounts for 70% of all deaths. Despite the use of antimicrobial drugs to which the offending organism is sensitive, patients are still dying. Effects on distant organ systems are due to "Mediators". "Microvascular Failure" resulting in tissue hypoxia is the unifying hypothesis of multiple organ failure in septicaemia. Mortality is correlated with the number of organ system failures. Supportive management is aimed at prevention of organ failure--manipulation of the circulation being the central key. Intravascular volume expansion, vasoactive drugs, mechanical ventilation and invasive monitoring are the means. Antimicrobial therapy must be guided by 'best guess' approach with multiple agents until isolation of the offending organism can recommend specific therapy. Aggressive surgical drainage or excision, is particularly applicable in abdominal sepsis. Several adjunctive therapies aimed at mediators of sepsis, are as yet experimental.

Critical Care↗