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Biomedical subjects

C E Haisch

Publications and source records attributed to C E Haisch.

32 records · Page 2Linked to original sources

The nasogastric tube syndrome.

The nasogastric tube can produce sudden, life-threatening bilateral vocal cord paralysis and is often an unrecognized cause of this clinical entity. The pathophysiologic mechanism is thought to be paresis of the posterior cricoarytenoid muscles secondary to ulceration and infection over the posterior lamina of the cricoid. Since our initial report of this entity in 1981, several cases have been photo-documented. Study of whole organ sections of an involved larynx have demonstrated the histopathology. Diabetic renal transplant patients appear to be particularly susceptible to the condition, due to prolonged gastroparesis and requirement for nasogastric tube drainage. Esophagoscopy should be performed promptly in these patients when pharyngodynia, hoarseness, or evolving stridor present in the postoperative period.

Adult↗

The vascular endothelial cell is central to xenogeneic immune reactivity.

With the demand for organ transplants increasing, xenograft transplantation is being considered. A major obstacle to a solution to fulfilling this demand is xenograft rejection. Histologic evidence indicates that the vascular endothelial cell (VEC) is involved in both humoral and cellular aspects of xenograft rejection. To study this phenomenon murine VEC and splenocytes were used in a mixed lymphocyte/endothelial cell culture and in a mixed lymphocyte culture with human peripheral blood mononuclear cells as responders. The VEC is a much better stimulator than the splenocyte. Removal of macrophages and B cells from the human peripheral blood mononuclear cells has no effect on the response to the VEC. The VEC acts as a target for humoral responses in the complement-dependent cytotoxicity and the antibody-dependent cell-mediated cytotoxicity. The VEC is killed in these two assays, which indicates the importance of the VEC in humoral rejection. These data indicate that the VEC is an important cell in xenogeneic immune reaction and may be pivotal in xenograft rejection.

Animals↗

Long-term incompatible kidney survival in outbred higher primates without chronic immunosuppression.

Transplantation between non-identical humans has been limited by the requirement for chronic immunosuppression (CI). This study demonstrates in a nonhuman primate model that long-term acceptance of incompatible kidney allografts can be achieved without the use of CI. Following incompatible kidney transplantation, rhesus monkey recipients were given a 5-day course of clinical rabbit antithymocyte globulin (RATG). On day 12, unfractionated donor bone marrow (BM) was infused intravenously. Recipients were monitored for T-cell levels and T-cell subset levels with monoclonal antibodies and for responses in one way MLR. Graft survival in untreated control animals was 9.2 +/- 2.8 days. In six animals given RATG only, all died of rejection at a mean 35.8 +/- 5.7 days. Of five animals given RATG and donor BM (mean 2.5 RhLA mismatches, mean MLC 12.7), four are alive at 150 days, 248 days, 342 days, and 401 days (median 248 days). The ATG-BM infused group showed a prolonged imbalance of their OKT4/OKT8 cell ratio and cellular suppression of MLR responsiveness. The long-term survival obtained in these outbred primates is apparently due to a synergistic immunoregulatory effect induced by the RATG and donor BM. The model described is apparently the first report of long-term survival of outbred higher primates without CI and may represent a technique for producing tolerance without CI in the human.

Animals↗

Suppressor cells in rhesus monkeys treated with antithymocyte globulin.

Treatment of rhesus monkey skin allograft recipients with a brief course of rabbit antithymocyte globulin (ATG) produces an enduring immunosuppressive effect on the cellular immune system. Despite early recovery of circulating T cells, in vitro mitogen-induced lymphoproliferative responses of peripheral blood mononuclear cells (PBMCs) remain abnormally depressed for months. In this study we show that depressed mitogen-induced lymphoproliferative responses in these animals are attributable to regulatory effects of adherent PBMCs. Removal of the adherent fraction of PBMCs on Sephadex G-10 produced a significant restoration of the mitogen-induced lymphoproliferative responses in ATG-treated monkeys. Addition of the prostaglandin synthetase inhibitor indomethacin to cultures of unfractionated PBMCs from these animals also caused a significant recovery of the lymphoproliferative response. Indomethacin did not enhance the response of control animals or the response of the nonadherent PBMC fraction of ATG-treated animals. These data suggest that a prostaglandin-dependent mechanism is involved in the suppressive action of the adherent cells. PBMCs from ATG-treated monkeys cocultured with normal cryopreserved autologous cells induced a dose-dependent suppression in the response to both concanavalin A (Con A) and phytohemagglutinin (PHA). The suppressive activity depended upon the adherent cell fraction and was found to be resistant to low-dose gamma irradiation. These data indicate that administration of rabbit ATG induces nonspecific suppressor cells in the rhesus monkey. Preliminary characterization studies suggest the involvement of suppressor monocytes. The possible role of this suppressor cell system in the immunosuppressive action of rabbit ATG is discussed.

Animals↗

Effect of micropore filtration on pulmonary function after massive transfusion.

1. This study demonstrates a positive correlation between the number and size of infused microaggregates and the subsequent abnormality in pulmonary function as measured by oxygenation and dead space. 2. No such correlation between the severity of injury and the altered pulmonary function or transfusion volume was demonstrated. 3. We were unable to demonstrate an advantage to the use of a 40 mu micropore filter in preventing the adult respiratory distress syndrome (ARDS) or in improving pulmonary function in our patients. 4. One explanation for the failure to demonstrate such an advantage is the low efficiency of the filter used.

Adolescent↗

Potential of repairing ischemically damaged kidneys ex vivo.

Therapies that would accelerate recovery from ischemic injury could positively impact the number of kidneys procured from non-heart-beating donors. An acellular warm (32 degrees C) perfusion was used to deliver growth factors to canine kidneys damaged by 2 hours of warm ischemia. Fibroblast growth factors 1 and 2 were selected for activation of the tyrosine kinases because of their known receptor-specific binding in the kidney, metabolic regulation, and mitogenic effect. During 24 hours of ex vivo perfusion at near-normothermia, oxidative metabolism was sufficiently restored to the ischemically damaged tissue to support upregulation of cellular processes dependent on new synthesis. The junctional integrity protein, ZO-1 was used to determine recovery of cytoskeletal integrity. The upregulation of proliferating cell nuclear antigen was used as a marker for recovery of synthetic functions. This modulation of both injury and repair proteins in the damaged kidneys was dependent on new synthesis. The observed modulation resulting in normalization of the cytoskeletal integrity correlated with outcomes in that when the "repaired" kidneys were reimplanted, they provided life-sustaining function. In contrast, when warm ischemically damaged control kidneys without treatment, with subsequent hypothermic perfusion or warm perfused in the absence of growth factors, were reimplanted the result was nonviability. The results of this study suggest that the administration of growth factors during 24 hours of near-normothermic, acellular perfusion, in the absence of concordant inflammation, triggers pathways for new synthesis leading to cellular recovery rather than resulting in cell death.

Animals↗

Experience with renal transplantation in the nonhuman primate: a modified ureteroneocystostomy to prevent urologic complications.

Nonhuman primates provide an optimal model for the evaluation of tolerance in the preclinical setting. Transplantation and management of nonhuman primates are technically demanding, and the purpose of this article is to review our extensive experience in renal transplantation in non-human primates, with particular emphasis on modifications of surgical techniques on urologic complications. We retrospectively reviewed our results with 329 renal transplants in rhesus monkeys over an 18-year period. The surgical technique and, in particular, the ureteroneocystostomy have evolved over this period of time. This review extensively details our current technique, the surgical and urologic complications, and their management. There were 329 renal transplants performed. There were 85 early deaths, or animals euthanized, within 30 days of the transplant operation. In the first 15 years, there were 27 (10.68%) surgical complications that required euthanasia, and in the last 3 years the complication rate has been reduced to 5 (7.3%, p < .05). The routine use of microsurgical techniques has reduced the incidence of arterial thrombosis (6.2% vs. 2.9%, p < .05). The incidence of ureteral strictures (15 vs. 0, p < .005) has been reduced by a modification of the ureteroneocystostomy technique detailed in the text. Renal transplantation in small rhesus monkeys is technically demanding. The routine use of microsurgical techniques and a modified ureteroneocystostomy has reduced the incidence of surgical complications.

Animals↗

II: Ex vivo viability testing of kidneys after postmortem warm ischemia.

Future approaches to expand the organ donor pool with marginal and nonheartbeating donors, will be dependent upon prospective organ evaluation. Restoration of metabolism by preservation at warmer temperatures could potentially provide the window for such evaluation. Using a small bovine model, kidneys were subjected to either < 15, < 30 or < 60 minutes of warm ischemia (WI) followed by cold ischemia (CI) in ViaSpan. After WI and CI, kidneys were transitioned to a warm temperature perfusion (30 degrees C to 32 degrees C) using exsanguinous metabolic support (EMS) technology. Restored renal metabolism and function was assessed by oxygen consumption, glucose consumption, urine production, glomerular filtration rate, and hemodynamic characteristics. The results of this study suggest that it is feasible to distinguish viable from nonviable organs ex vivo by assessing renal metabolism and function during warm preservation using EMS technology.

Animals↗

Use of allogeneic bone marrow labeled with neomycin resistance gene to examine bone marrow-derived chimerism in experimental organ transplantation.

Posttransplant infusion of viable donor bone marrow cells (DBMC) has been shown in our previous studies to promote acceptance of incompatible kidney allografts in rhesus monkeys after treatment with polyclonal antithymocyte globulin to deplete peripheral T-lymphocytes. In this nonhuman primate model, the infusion of the DBMC is requisite for the induction of functional graft tolerance and specific MLR and CTLp unresponsiveness, although the relevant role and fate of bone marrow-derived chimeric cells is uncertain. Standard immunological and molecular techniques applied to this monkey model are unable to differentiate between chimeric cells derived from the infused DBMC and those derived from allograft-borne passenger leukocyte emigrants. To distinguish chimerism due to infused DBMC, we transduced DBMC with a functional neomycin resistance gene (Neo(r)) using the retroviral vector pHSG-Neo.Neo(r)-transduced BMC were infused into recipients approximately 2 wk after kidney transplantation and treatment with rabbit antithymocyte globulin. No maintenance immunosuppressive drugs were given. Genomic DNA isolated from peripheral blood leukocytes was used to monitor the presence ofNeo(r)-positive cells. Tissue samples obtained at necropsy also were assessed forNeo(r)-positive chimeric cells. The presence of DBMC-derived chimerism was assessed by polymerase chain reaction usingNeo(r) sequence-specific primers (PCR-SSP). Chimerism was detectable in recipient tissues at various times for up to 6 mo after DBMC infusion. These studies using gene transduction methodology indicate that a stable genetic marker can provide capability to examine DBMC-derived chimerism for prolonged periods in a nonhuman primate model. This approach should facilitate future studies in preclinical models to study the role and type of chimeric cell lineages in relation to functional allograft tolerance.

Animals↗