Does human leukocyte antigen matching influence the outcome of lung transplantation? An analysis of 3,549 lung transplantations.

BACKGROUND AND OBJECTIVE: Human leukocyte antigen (HLA) compatibility has been shown to improve the outcome of renal and cardiac transplantation. However, its impact on outcome following lung transplantation is not clear, with several single-center studies reporting inconsistent results. We studied the influence of HLA matching on survival and the development of rejection and obliterative bronchiolitis after lung transplantation, using data from the United Network for Organ Sharing/International Society for Heart and Lung Transplantation registry. METHODS: The study population included adult patients who received cadaveric lung transplants between October 1987 and June 1997 for whom HLA data were available. Two cohorts were examined, depending on the era of transplantation: (1) October 1987 to June 1997 (n = 3,549): Differences in actuarial survival as stratified by either the total number of HLA mismatches or the number of mismatches at each HLA locus were determined using a log-rank test. Multivariate logistic regression models were developed to determine independent predictors of survival at 1, 3, and 5 years following lung transplantation. (2) April 1994 to June 1997 (n = 1,796): The association of HLA mismatching with acute rejection and obliterative bronchiolitis was determined using a chi-squared analysis. RESULTS: Only 164 patients (4.6%) received lung grafts with 2 or fewer HLA mismatches. Univariate analyses demonstrated a significant difference in post-transplant survival by mismatch level, with the total number of HLA mismatches (p = 0.0008) and mismatching at the HLA-A locus (p = 0.002) associated with worse survival. Multivariate logistic regression demonstrated that the number of mismatches at the HLA-A and HLA-DR loci predicted 1-year mortality (incremental odds ratios 1.18, p = 0.01, and 1.15, p = 0. 03, respectively). The total number of HLA mismatches predicted 3- and 5-year mortality (incremental odds ratios 1.13 at 3 years, p = 0. 0004, and 1.14 at 5 years, p = 0.0002). However, other covariates such as repeat transplantation, transplantation for congenital heart disease, advanced recipient age, and an early era of transplantation were stronger predictors of mortality. We found no significant association between HLA mismatching and the development of obliterative bronchiolitis, although there was an association between mismatching at the HLA-A locus and acute rejection episodes requiring hospital admission (p = 0.008). We also found no association between mismatching at the HLA-B locus and rejection episodes requiring either hospitalization or the alteration of anti-rejection medications (p = 0.034). CONCLUSION: Although the number of HLA mismatches at the HLA-A and HLA-DR loci predicted 1-year mortality and the total number of mismatches predicted 3- and 5-year mortality following lung transplantation, the effect of each covariate was small in this multicenter study of 3,549 patients. Further close follow-up of registry patients is necessary to determine the effect of HLA matching on long-term survival and freedom from obliterative bronchiolitis and rejection following lung transplantation. A prospective study of HLA matching for lung transplantation should not yet be considered in view of the small number of grafts with 2 or fewer mismatches and the modest effect of HLA matching on outcome.

Late presentation of an intra-abdominal foreign body.

Bowel obstruction by a foreign body is rare. The authors describe the case of a 77-year-old woman who had small-bowel obstruction due to a foreign body 40 years after a transabdominal hysterectomy. A loop of small bowel had herniated through a metal ring and had become necrotic. The ring and involved bowel were excised and the patient's clinical course was uncomplicated. The original purpose of the ring remains a mystery. The time frame between the introduction of a foreign body and the occurrence of symptoms in this case appears to be the longest ever reported.

Pharmacological response of quinidine induced early afterdepolarisations in canine cardiac Purkinje fibres: insights into underlying ionic mechanisms.

The purpose of these experiments was to study the pharmacological response of quinidine induced early afterdepolarisations to gain insights into underlying ionic mechanisms. Quinidine (8.5 microM) induced stable early afterdepolarisations at low activation frequencies in 80% of canine cardiac Purkinje fibres superfused with a modified Tyrode's solution. Early afterdepolarisations arose from a secondary plateau in the voltage range of -30 to -60 mV. Calcium channel blockers (verapamil, 1 microM, in 3/6 preparations; verapamil, 10 microM in 6/6 preparations; nifedipine, 0.1 microM in 5/5 preparations) completely eliminated early afterdepolarisations, despite continued quinidine superfusion, without altering the underlying action potential. Isoprenaline (0.2-1 microM) restored them in 75% of these preparations during continued calcium blocker superfusion. Tetrodotoxin (5/5 preparations) eliminated early afterdepolarisations by abbreviating action potentials and reducing or eliminating the quinidine induced secondary plateau. While low concentrations of isoprenaline favoured the occurrence of early afterdepolarisations, larger concentrations eliminated them by enhancing spontaneous automaticity. These experiments suggest that voltage dependent and/or receptor regulated slow inward current plays an important role in quinidine induced early afterdepolarisations. Beta receptor stimulation can enhance or suppress early afterdepolarisations, depending on whether effects on slow inward current (tending to favour them) or on automaticity (suppressing them) predominate.

Rat liver and intestinal mucosa differ in the developmental pattern and hormonal regulation of carbamoyl-phosphate synthetase I and ornithine carbamoyl transferase gene expression.

cDNA probes were employed to measure levels of carbamoyl-phosphate synthetase I (CPS) and ornithine carbamoyltransferase (OCT) mRNAs in fetal and neonatal livers and intestines. In the fetal liver, significant levels of OCT mRNA were present at 15-days gestation while CPS mRNA could not be detected until day 17 of fetal development. Apart from a small decline just after birth, amounts of both mRNAs increased steadily to reach adult levels in postnatal life. In contrast to the situation in liver, CPS and OCT mRNA levels in the fetal intestine rose rapidly to peak at day 21 of gestation and then declined steadily in the first seven days after birth. Using the methyl-sensitive restriction isoschizomeric pair, MspI/HpaII, the 5' ends of both the CPS and OCT genes were shown to undergo demethylation during development. In the case of the OCT gene, however, the hypomethylation characteristic of the adult liver and intestinal mucosa was not observed in the 15-day-old fetal liver, where significant levels of gene expression had already been established. Levels of CPS and OCT mRNA in livers of adults responded to glucagon in normal animals (1.5-fold and 2.2-fold increases, respectively) and to dexamethasone in experimentally induced diabetic animals (3-fold increase in CPS mRNA with no change in OCT mRNA). These treatments were all without effect on the levels of CPS and OCT mRNA in intestinal mucosa.