Biomedical subjects
Publications and source records attributed to J S Thompson.
Increasing experience with intestinal transplantation has led to the refinement of techniques to detect and treat rejection and infectious complications. Improved outcome has led to a broadening of the indications for intestinal transplantation, particularly solitary intestinal transplantation.
Gastrointestinal surgical procedures have the potential to disrupt motor activity in various organs of the gastrointestinal tract or, indeed, throughout the entire alimentary canal. Several of these motor effects have important clinical consequences and have also served to advance our understanding of the regulation of gastrointestinal motor activity. This review will focus, in particular, on the effects of surgery on the small intestine, and will attempt to emphasize the implications of these studies for our understanding of small intestinal motility, in general.
Allogeneic bone marrow transplantation (BMT) from an HLA-matched sibling appears to improve survival and diminish some of the physiologic derangements seen in children with mucopolysaccharidosis (MPS)-I (Hurler Syndrome), an inherited metabolic storage disease resulting from the lack of alpha-L-iduronidase enzyme activity. Death is usually expected in the first decade of life. Unfortunately, most patients lack an HLA-matched sibling donor and alternative donors have been identified for transplant. This study reports on a five-year median follow-up (range: 985-2,355 days) in 11 Hurler Syndrome patients who underwent allogeneic BMT from partially mismatched related donors (PMRDs). The median age was 20 months (range: 11-44 months). The overall survival rate was 64% (95% CI 34-94%). The overall graft failure rate (36%) was higher than reported with matched sibling BMT. All patients with sustained engraftment experienced improvement in physical manifestations, such as corneal opacity, gum and tongue hypertrophy, hepatosplenomegaly and joint mobility. Skeletal abnormalities, such as dysostosis-multiplex, were stabilized but not reversed. Some patients have continued to show decline in neuropsychometric testing, while others appear to stabilize and one has demonstrated improvement. Until better methods for replacing enzyme activity are developed, BMT from a matched sibling of alternative donors can be considered a viable intervention for Hurler Syndrome patients to achieve partial improvement or stabilization from the deterioration caused by substrate storage, particularly in minimally affected patients early in life.
Wound-related complications are common after incisional hernia repair. Prophylactic antibiotic use, placement of subcutaneous drains, and technical factors such as mesh implantation reportedly influence the incidence of these complications. Our aim was to study the incidence of wound complications in incisional hernia repairs and to determine whether use of antibiotics, drains, or mesh influence these rates. Two hundred fifty hernias were repaired in 206 patients over a 14-year period. Simple repair was performed in 151 patients while mesh was used in 99 repairs. Mesh repair was used in larger hernias, required longer operating time, and had greater blood loss than simple repair. Twenty-eight per cent of repairs with mesh were for recurrent hernias compared with 14 per cent for simple repair (P < .05). Overall, 34 per cent of patients had wound-related complications. Chronic obstructive pulmonary disease, obesity, steroid therapy, and previous wound infection were not associated with increased risk for wound complications. The use of mesh and hernia defect > 10 cm were associated with significantly more wound complications. The incidence of seroma was increased in mesh repairs (21% vs 7%), as were total wound complications (44% vs 26%; P < 0.05). A suprafascial onlay mesh technique resulted in more frequent seroma formation. Patients undergoing mesh repair were more likely to receive antibiotics (91% vs 71%) and have subcutaneous drains placed (57% vs 25%; P < 0.05) compared to simple primary repair. Neither antibiotics nor drains had an effect on the incidence of wound complications within each group. Overall, wound infections were more frequent when drains were placed. We conclude that repair of incisional hernias is associated with substantial risk of wound-related complications. Mesh is used for repair of larger and more complex hernias and is associated with increased risk of wound complications. Abnormal fluid collections are the most frequent problem, but the use of drains does not reduce the incidence of these complications.
BACKGROUND: Treatment of acute renal allograft rejection with the monoclonal antibody (mAb) OKT3 has been shown to be superior to treatment with polyclonal antisera. To date, only OKT3 has demonstrated consistent efficacy in reversing rejection crisis. METHODS: From 1989 to 1993, a phase II trial comparing the mAb T10B9.1A31 (T10B9) with OKT3 for treatment of acute cellular rejection in renal allograft recipients was done at the University of Kentucky. We collected data from 178 patients potentially eligible to enter the study; 48 never rejected, 9 refused, 13 could not be biopsied, 16 received methylprednisolone, and 11 received antithymocyte globulin or OKT3. Altogether, 81 patients entered the study, 76 of whom were able to be evaluated. Patients with biopsy-confirmed acute rejection were randomly assigned to T10B9 or OKT3 for at least 10 days. RESULTS: Demographically, there was no difference between the T10B9 or OKT3 cohorts. Actuarial graft survival at 4 years was 87% for patients receiving T10B9, 79% for those receiving OKT3, and 89% for those receiving both mAbs (P=0.55). Patient survival at 4 years was 94% for T10B9, 100% for OKT3, and 89% for both mAbs (P=0.45). Mean creatinines of the cohorts were no different at 1, 6, 12, 24, and 36 months. There was less cytokine nephropathy (P<0.001) observed in patients receiving T10B9. Untoward gastrointestinal, neurological, respiratory, and febrile effects were significantly more frequent in the OKT3 cohort after the first dose (day 0) and with later (day 1-9) administration. Cytokine levels (tumor necrosis factor alpha and interferon gamma) measured 2 hr after the first dose were three to six times higher in patients treated with OKT3 than in those treated with T10B9 (P<0.005). Infectious complications were not significantly different, although serious infections occurred only in patients receiving OKT3. No cases of posttransplant lymphoproliferative disorder were seen in either cohort. Human anti-mouse antibody development was as follows: titer 1:100, 30% T10B9, 42% OKT3; titer 1:1000, 3% T10B9, 3% OKT3. There was no cross-reactivity with OKT3 in patients treated with T10B9, and there was only 9.7% cross-reactivity to T10B9 in patients treated with OKT3. CONCLUSIONS: T10B9 provides treatment for renal allograft acute cellular rejection as effective as that of OKT3 with fewer untoward effects, less cytokine release and nephropathy, fewer serious infections, and without increased development of human anti-mouse antibody. The lack of cross-reactivity offers an alternative therapy should the first mAb fail or re-rejection occur. A phase III trial should be initiated in renal allograft recipients, and phase I and phase II trials should be initiated in other solid-organ transplantations.
BACKGROUND: We have previously reported that delaying histoincompatible transplantation after total body irradiation (TBI) conditioning markedly decreased the mortality of acute graft-versus-host disease (GVHD) in severe combined immunodeficiency mice. However, it was not clear whether the delayed transplantation would affect the final engraftment and acute GVHD mortality in normal hosts. METHODS: BALB/c mice (H2d) were lethally irradiated with 8.5 Gy TBI and transplanted with C57BL/6 (H2d) bone marrow plus spleen cells on the same day (TBI+day 0) or 4 days after TBI conditioning (TBI+day 4). RESULTS: We again demonstrated that delaying transplantation by 4 days after TBI conditioning markedly reduced acute GVHD mortality in normal hosts after major histoincompatible transplantation. The survival rates were 66% in TBI+day 4 vs. 0% in TBI+day 0 allogeneic transplanted animals by day +60 (P<0.001). Further analysis demonstrated that the 4-day rest between the TBI and allogeneic transplantation broke the interaction of cell/inflammatory tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-6 cytokine reactions stimulated by TBI and incompatible transplantation. Flow cytometry revealed 97% donor cells in host marrow by 2 weeks in TBI+day 0 transplantation versus 57% in TBI+day 4 transplantation. There was no difference in percentage of donor CD3+ T-cell engraftment between the TBI+day 0 and TBI+day 4 allogeneic transplanted animals. In TBI+day 4 transplantation, the percentage of donor cells in host marrow steadily increased to 74% by day +60 and 93% by day +100. CONCLUSIONS: This 2- to 3-month early mixed chimerism in TBI+day 4 transplanted animals might be related to lower levels of tumor necrosis factor-alpha and IL-6 both of which have been shown to stimulate lymphohematopoiesis and was associated with lower acute GVHD mortality. The data again demonstrated in immunologically normal BALB/c mice that delaying allogeneic transplantation after TBI is a simple and effective way to reduce acute GVHD mortality, achieve satisfactory engraftment and significantly increase overall survival.
BACKGROUND: The new microemulsion formulation of cyclosporine (CsA-ME) is more bioavailable than cyclosporine (CsA) in de novo renal transplant patients. Therefore, it was of interest to compare the safety profile of each formulation in such patients. METHODS: In a multicenter, double-blind, parallel-group study, 101 renal transplant recipients were randomized after transplantation to receive either CsA (n=50) or CsA-ME (n=51) capsules twice daily for 2 years. Of these patients, 54 (CsA, n=26; CsA-ME, n=28) completed 1 year of the study and entered the second-year, double-blind extension. Initial dose at the time of transplantation was 5 mg/kg b.i.d.; doses were titrated to target trough levels. METHODS: The mean (+/- SD) doses at the end of 2 years were 4.6 +/- 1.8 and 3.8 +/- 1.1 mg/kg per day for CsA- and CsA-ME-treated patients, respectively. The mean (+/- SD) CsA trough levels at end point were 187 +/- 63 and 210 +/- 95 ng/ml for CsA- and CsA-ME-treated patients, respectively. At least one adverse event was reported by 25/26 (96%) of CsA- and 27/28 (96%) of CsA-ME-treated patients. No patient discontinued the study because of adverse events. No deaths occurred during the study. Renal function, as measured by serum creatinine levels, and blood pressure were comparable over time in both treatment groups. CONCLUSIONS: There was no significant difference in safety and tolerability between CsA- and CsA-ME-treated kidney recipients for 2 years after transplantation.
Genomic imprinting is an epigenetic modification in the germline leading to parental allele-specific gene expression in somatic cells. We have previously found that imprinted genes can be abnormally expressed or silenced in tumors and that the cyclin-dependent kinase inhibitor (CKI) CDKN1C (p57KIP2) is normally imprinted, with preferential expression of the maternal allele. Here we analyze the imprinting status of three additional CKIs, the abnormal expression and/or chromosomal localization of which has been implicated in human malignancy: CDKN1A, CDKN1B, and CDKN2C. Allele-specific expression was examined by reverse transcription-PCR, using primers that span transcribed polymorphisms as well as exon/intron boundaries, to distinguish cDNA products from genomic DNA. Biallelic expression was observed for all three genes in both fetal and adult tissues. Thus, genomic imprinting is not a generalized feature of CKIs.
Explore the source record for details and available documents.
We have investigated the action of the product of the enzyme NADPH oxidase; hydrogen peroxide (H2O2), on the first phase of the hypoxic contraction, prostaglandin F2 alpha (PGF2 alpha)-induced contractions and potassium chloride (KCl)-induced contractions, in isolated rat pulmonary arteries in a wire myograph. Both concentrations of H2O2 (0.03 and 0.5 mM) produced initial contractions, and the higher concentration of H2O2 produced a significant inhibition of both the priming concentration of PGF2 alpha (5 microM) and the hypoxic contraction (P < 0.01 for both contractions). These effects were shown to be reversible, with contractions of a similar size to control values being seen to both PGF2 alpha (5 microM) and hypoxia following washout of H2O2 (P > 0.1 for both contractions). H2O2 (0.03 mM) was shown to have no significant effect upon either contraction (P > 0.1 for both contractions). H2O2 (0.5 mM) was also shown to have a significant inhibitory effect upon the efficacy (Emax) of the PGF2 alpha and KCl concentration-response curves (P < 0.01 for both contractions). This inhibition was again shown to be reversible. The higher concentration of H2O2 (0.5 mM) is clearly shown to be having a dual action, producing an initial contraction followed by inhibition of contractions to both PGF2 alpha and KCl. The mechanism by which H2O2 produces vasoconstriction is unclear, but it is suggested that H2O2 may inhibit the release of Ca2+ ions from intracellular stores as this is a common link between the modes of action of these two contractile agents. In addition to this, as an elevation in intracellular Ca2+ from intracellular stores appears to be a prerequisite for hypoxic pulmonary vasoconstriction (HPV), then this apparent mode of action of H2O2 could play an important role in the regulation of HPV and suggests a possible role for NADPH oxidase or a similar oxidoreductase as an oxygen sensor.
1. The pulmonary vasculature is normally in a low resting state of tone. It has been hypothesized that this basal tone is actively maintained by the continuous release of a vasodilator in the resting state. However, evidence for basal release of nitric oxide (NO) is inconclusive. 2. We studied the release of NO in arteries from the pulmonary circulation of male Wistar-Kyoto rats by examining the effects of the L-arginine analogue NG-nitro-L-arginine methyl ester (L-NAME) on resting pulmonary arteries and on vessels pre-contracted with prostaglandin F2(alpha) (PGF2 alpha). 3. Rats (n = 21) were killed by an overdose with pentobarbitone. Pulmonary arteries were dissected (mean internal diameter 459 +/- 11 microns) and mounted in a small vessel wire myograph. Resting tensions were to set to stimulate transmural pressures of 17.5 mmHg. 4. L-NAME (100 microM) was found to produce a contraction of 0.64 +/- 0.09 mN mm-1 in resting pulmonary arteries when added alone to the myograph bath. This contraction was not produced following removal of the endothelium. Vessel contraction to PGF(2 alpha) (100 microM) was found to be significantly greater when carried out in the presence of L-NAME (100 microM) -1.37 +/- 0.15 mN mm-1 compared with 1.96 +/- 0.17 mN mm-1. Dilation following acetylcholine (ACh) (1 microM) was abolished in the presence of L-NAME (100 microM). 5. Rat pulmonary artery contraction in response to the addition of L-NAME and the absence of contraction upon removal of the endothelium provides supportive evidence of the active release of nitric oxide for the maintenance of resting tone.
The results of partially matched related donor (PMRD) marrow transplantation for 82 patients with leukemia are reported, including 45 who received two antigen disparate grafts. Following intensive radiochemotherapy, patients received grafts which were partially depleted of T cells by the monoclonal antibody T10B9 and complement. Actuarial probability of engraftment was 86% (95% CI = 78-93%). The median day to engraftment was similar among recipients of grafts disparate at one, two or three antigen loci. The incidence of severe (grades III and IV) acute graft-versus-host disease and extensive chronic graft-versus-host disease was 13% and 6%, respectively. The probability of disease-free survival for the entire cohort of patients is 31% at 3 years. Age < or = 30 years, early or intermediate stage disease and a graft disparate at one or two loci predicted longer disease-free survival in multivariant analysis. Moreover, 47% of patients receiving PMRD grafts disparate at two loci who had both these favorable pretransplant characteristics were alive and free of disease 3 years after transplantation. We believe that the utilization of PMRDs, especially those with two antigen disparate grafts, can extend allogeneic transplantation to additional leukemic patients lacking a histocompatible donor, with acceptable results.
Explore the source record for details and available documents.
Nitroglycerin (NTG) produces vasodilation by releasing nitric oxide (NO) at the cellular level. Other studies have suggested that NO may directly alter vascular permeability and may alter the development of tissue injury. We therefore examined the effects of NTG on vascular permeability in the buffer-perfused rabbit lung under normal conditions and during lung injury. Vascular permeability was assessed by measurement of the capillary filtration coefficient (Kf,c). In normal lungs, NTG did not alter Kf,c or the rate of weight gain. Oxidant lung injury was produced by the addition of purine and xanthine oxidase and resulted in increased Kf,c and increased weight gain. However, NTG did not alter these effects of oxidant lung injury. We conclude that NTG does not alter pulmonary vascular permeability in either normal or oxidant-injured lungs.
Atrial natriuretic peptide (ANP) is a vasodilator secreted by the heart in response to right atrial stretch. We have hypothesized that ANP may be released to attenuate pulmonary hypertension due to hypoxia. We have examined whether ANP inhibits hypoxic pulmonary vasoconstriction (HPV) in isolated pulmonary resistance vessels (PRV) from chronically hypoxic (CH) rats, compared to air-breathing, control (C) rats. After at least 17 days of chronic hypoxia, vessels (n = 29) were dissected from CH and C littermates and mounted in an automated myograph. The inhibitory effect of ANP on the rapid first contractile phase of HPV, and the relaxant effect of ANP on vessels tonically contracted in the second phase of HPV, were studied. ANP caused concentration-dependent inhibition of HPV in both C and CH vessels (p < 0.001), whilst vehicle had no effect (mean maximum inhibition was 88 and 101%, respectively, at 17 nM ANP). ANP also caused significant concentration-dependent relaxation of the second contractile phase of HPV, which was similar in C and CH vessels (mean maximum relaxation of 89 and 94%, respectively; median effective concentrations were 2.4 and 2.0 nM, respectively). We conclude that atrial natriuretic peptide is a potent antagonist of both contractile phases of hypoxic pulmonary vasoconstriction in isolated rat pulmonary resistance vessels at concentrations similar to those observed in hypoxic pulmonary hypertension in life. There was no difference between vessels from chronically hypoxic and control animals.
Cytolytic induction therapy of heart transplantation with OKT3 (immunoglobulin G2a isotype, anti CD3 idiotype) or T10B9.1A-31 (immunoglobulin MK isotype, anti-T-cell receptor alpha beta idiotype) was done in an open-label trial to determine the safety and efficacy of the latter monoclonal antibody. A total of nine patients undergoing orthotopic heart transplantation received a 10-day course of either T10B9.1A-31 (T10B9) (n = 4) 18 mg on bypass and 6 mg intravenously every 12 hours or OKT3 (n = 5) 10 mg on cardiopulmonary bypass and 5 mg intravenously daily. Endomyocardial biopsy surveillance revealed no rejection during induction therapy with T10B9, and one OKT3 induction failure was successfully treated with T10B9, all without significant side effects. T10B9 effectively prevented the onset of early acute rejection in heart transplantation with minimal side effects. T10B9 reversed rejection in one patient whose OKT3 induction failed. Results are encouraging and warrant further investigation.
A chimeric severe combined immunodeficient mouse engrafted with human peripheral blood (hu-PBL-SCID) model has been developed to test anti-T-cell monoclonal antibody (mAb) effects on systemic symptoms of the host and the survival of human skin grafts. To obtain consistent engraftment without lethal acute graft-versus-host disease (GVHD), SCID mice were pretreated with a combination of total body irradiation (2.5 Gy, day 0) and anti-asialo GM1 (anti-mouse natural killer cell) antiserum (50 micrograms i.p., day 3) before the intraperitoneal injection of 40-50 X 10(6) human PBL on day 4. With this protocol, the engraftment rate was 82% with 5-98% human CD45-positive cells in the peripheral blood. Mortality at 30 days was 0% in the mice bearing 5-50% human cells compared with 70% in those with more than 50%. Using hu-PBL-SCID mice with 5-50% human cells in their peripheral blood, we demonstrated the following results: 1) Human T cells isolated from these mice proliferated in response to immobilized OKT3 stimulation in vitro. 2) Hu-PBL-SCID mice but not normal SCID mice were able to reject human skin grafts in vivo 16-21 days after grafting. 3) Both OKT3 (anti-human CD3 mAb) and T10B9 (anti-human alpha beta T-cell receptor mAb) treatment prevented human skin graft rejection in hu-PBL-SCID mice. 4) OKT3 but not T10B9 induced first dose reactions characterized by hypothermia and hypoactivity which were consistently observed within 90 min of intravenous injection into hu-PBL-SCID mice. 5) Human cytokines were detected in the serum of the hu-PBL-SCID mice treated with anti-T-cell mAbs. The close similarity of these responses to human clinical mAb immunosuppressive therapy suggests that the hu-PBL-SCID mouse model may be an excellent tool for investigating the immunosuppression, side effects, and mechanism of action of agents that are specific for human and higher apes and not reactive with lower animals.
We have previously shown that the p57KIP2 gene, which encodes a cyclin-dependent kinase inhibitor, undergoes genomic imprinting and lies within a 700-kb domain of imprinted genes on 11p15, including IGF2 and H19. Loss of heterozygosity and loss of imprinting (LOI) of this region are frequently observed in Wilms' tumor (WT) and other embryonal malignancies. Although LOI of p57KIP2 was observed in some WTs (approximately 10%), allele-specific expression was preserved in most tumors examined. Because our initial studies were inconclusive concerning the absolute expression level of p57KIP2 in WT, we developed a sensitive and quantitative RNase protection assay to determine if changes in p57KIP2 expression play a role in WT. Expression of p57KIP2 was found to be virtually absent in 21 of 21 WTs compared to matched normal kidney from the same patients, as well as compared to fetal kidney. We also examined p57KIP2 expression in the normal kidney and tongue of patients with Beckwith-Wiedemann syndrome (BWS), which predisposes to WT and also involves LOI of IGF2 and H19. Although p57KIP2 was undetectable in BWS tongue, similar results were also observed in postnatal non-BWS tongue samples. Most primary skin fibroblast cultures of BWS cell lines exhibited normal imprinting of p57KIP2. However, one BWS patient did show LOI of p57KIP2 in skin fibroblasts. Thus, p57KIP2 is part of a domain of genes on 11p15 that show altered expression and, in some cases, altered imprinting in WT and BWS.