Biomedical subjects
Publications and source records attributed to R C Merrell.
Acute surgical abdomen is the object of urgent surgical attention. The objective of emergency operation is to interrupt a process that has a steadily worsening prognosis on a scale of hours unless effective surgical treatment is rendered. There are basically three processes to address: free or incipient sepsis and peritonitis, gastrointestinal soilage, and hemorrhage.
Opportunistic infection and neoplasia involving the gastrointestinal tract are common in AIDS patients. Life-threatening complications of this involvement may occur, requiring urgent diagnosis and therapy. We review the clinical presentation and approaches to management of AIDS-related gastrointestinal emergencies.
Combination therapy with one dose of 3 M KCl extracted donor-soluble antigen (Ag) and a short course of cyclosporine (CsA) has proven to prolong the survival of kidney allografts by enhancing specific T-suppressor populations. This regimen is tested in rat islet allografts in this study (Lewis to ACI). A 3-day perioperative course of 10 mg/kg/day CsA on Days -1, 0, and 1 did not prolong graft survival (MST = 10.7 +/- 2.5 days vs 9.4 +/- 1.2 days in controls). When this course of CsA therapy was combined with a single dose of donor antigen on Day -1, the survival time was prolonged slightly but significantly (MST = 14.0 +/- 5.8 days). Three cycles of a 3-day course of CsA therapy at 7-day intervals, a total of nine doses of 10 mg/kg/day CsA, were effective in delaying rejection of islet allografts (MST = 26.4 +/- 30.3). Moreover, combined therapy with donor antigen and three cycles of a 3-day course of CsA prolonged the survival of islet allografts (MST = 57.7 +/- 51.4 days) with 50% of recipients still normoglycemic at 60 days after transplantation. These findings indicate that the combination therapy of donor antigen with a short course of CsA has a powerful effect to prevent the rejection of islet allografts, as shown in kidney allografts, in rats.
Dissociated pancreatic islets form endocrine aggregates from single-cell suspension by rotation culture. Islet cell aggregates, or neoislets, can provide endocrine reconstitution for diabetic rats and enjoy prolonged graft survival when neoislets are transplanted across a major histocompatibility barrier (Lewis to ACI). Long-term survival of grafted neoislets was obtained in 71% of recipients without any immunosuppression and in 100% of recipients with minimal immunosuppression. As predicted by cell-cell recognition in rotation-mediated aggregation, neoislets apparently exclude mesenchymal cells that bear la antigens. Therefore, reduced immunogenicity is accomplished.
Cyclosporine (CyA) is toxic to the function of isolated islets and this toxicity may, in part, explain the failure of islet allografts as well as autografts with CyA immunosuppression. Not only do canine allografts fail despite CyA immunosuppression, but control autografts given CyA from the day prior to transplantation have a very high failure rate. In this study, we investigated CyA effects on established islet autografts. Twenty mongrel dogs underwent total pancreatectomy and successful intrasplenic islet autotransplantation. Ten served as control autografts (Group 1); five were started on oral CyA on the 5th postoperative day (Group 2) and 5 dogs were given CyA from the 10th day after grafting (Group 3). Intravenous glucose tolerance tests were performed before operation, before starting CyA and after 3 weeks. Plasma insulin was determined by radioimmunoassay. Control dogs remained normoglycemic throughout the study as did Group 3 animals. In Group 2, 2 of 5 dogs failed, both on the 4th day of CyA, while the other 3 were normoglycemic throughout the study. No significant difference was shown among the K values, fasting blood glucose and peak plasma insulin values following IVGTT before and after treatment with CyA. CyA begun the day before autografting gravely compromises graft success. However, after the graft is well established, an adverse effect of CyA on islet cell function is not evident.
Studies reported here indicate that an anti-Ia immunotoxin can eliminate the allostimulatory subpopulation of cells present within the islets of Langerhans without damaging the hormone-secreting cells. Such studies made use of an in vitro correlate of transplantation rejection, the mixed lymphocyte islet cell (MLIC) reaction. Using the MLIC, it was demonstrated that an anti-Ia immunotoxin removed cells capable of stimulating the MLIC in a dose-dependent fashion without altering the hormone-secreting functions of the remaining cells when challenged with glucose and theophylline. These studies suggest the feasibility of using such anti-Ia immunotoxins in islet allograft transplantation models to circumvent problems inherent in complement-mediated cytotoxicity, a previously documented effective form of inducing islet allotransplantation tolerance.
The possibility of vagal reinnervation to intrasplenic islet grafts was examined by measuring portal insulin response to electric stimulation of the dorsal vagus nerve in autografted dogs. Grafted islets responded appropriately to an exogenous cholinergic agent given intravenously. However, no insulin secretory response could be observed in grafted dogs after vagal stimulation, which markedly increased portal insulin levels in control dogs. Therefore, intrasplenic islets are not under direct vagal control. At the basal state, normal oscillatory release of insulin was observed in the animals with grafts, suggesting that the mechanism of rhythmic basal insulin release is intrinsic to the islet of Langerhans with no regulatory input from the vagus nerve or any element of pancreatic structure.
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Exposure of islets to high levels of glucose at a critical time leads to enhanced insulin release when later stimulated by glucose. Newly synthesized insulin is preferentially released with subsequent stimulation, implying the creation or enlargement of a separately regulated pool of insulin in response to the initial stimulus. Epinephrine via beta adrenergic receptors can trigger the discharge of the enhanced insulin pool via a beta adrenergic receptor response. Raising intracellular cAMP levels or stimulation by arginine also discharge the marked pool. The enhanced pool is accessible by several independent mechanisms.
The insidious presentation of intramesocolic perforation in diverticulitis has been reviewed, and two cases of intramesocolic perforation associated with pneumopylephlebitis have been reported. Review of the two previously reported cases of pneumopylephlebitis associated with diverticular perforation suggests that these may have been intramesocolic perforations as well. Exploratory laparotomy is clearly indicated in cases of pneumopylephlebitis. In patients with recurrent sepsis without a probable source, a water-soluble contrast enema is recommended. If conservative measures fail, an exploratory laparotomy should be performed to exclude intramesocolic abscess.
Bulk isolation of islets of Langerhans for biochemical studies or transplantation has generally been associated with significant or even prohibitive contamination by acinar tissue. High-purity islet preparations are associated with an extremely low yield. The acinar tissue can be ablated with d,l-ethionine, but previously, this tactic has been restricted to rodents because of toxicity problems in larger animals. A dosage regimen in dogs which reduces amylase content of the pancreas to 0.3% of normal with complete preservation of insulin content is reported. Ductal perfusion with collagenase permits the recovery of 45% of the islet cell mass as determined by extractable insulin. These islets prove functional in in vitro perifusion studies and in allografts.
Fixation of polypropylene (Marlex) mesh in the epigastrium and at the iliac crest can be ineffective because of insufficient local fascia; however, two techniques have been described to obtain firm and durable attachment of polypropylene grafts at these sites. Perichondral slips at the costal margin permit very satisfactory attachment with excellent long-term results. Stainless steel wire fixation of the mesh to the iliac crest has satisfied the need for osseous fixation in that area. Long-term repair of difficult and recurrent hernias has been described in three patients for whom other tactics for abdominal wall repairs were not available.
Molecular sieve membranes can protect pancreatic islets against immune recognition in diabetic patients treated by endocrine tissue replacement. These biocompatible membranes permit the passage of small peptides such as insulin, and preclude the diffusion of immunoglobulins and immunogenic molecules. However, the tissue must function indefinitely in an ultrafiltered environment determined by the sequestering membranes. The chronic perifusion of canine islet tissue was compared in ultrafiltered and microfiltered chambers. The biphasic pattern of insulin release by similar numbers of islets from the same pancrease preparation was not significantly different when tissue was cultured in a micro- or an ultrafiltered environment. The cumulative insulin output of the two systems was quite similar over 3 days of culture. Canine islet tissue can be sustained in an ultrafiltered environment with maintenance of insulin release to glucose stimulation, which is quantitatively similar to islet tissue maintained in chronic perifusion without ultrafiltration.
Successful intrasplenic islet autotransplantation in dogs requires an islet cell mass considerably greater than what might be expected based on studies of subtotal pancreatectomy. Grafts of marginal function ultimately fail, suggesting severe limitations in the capacity of an islet graft to adapt. Accommodation was tested in established intrasplenic grafts by either chronically stressing the graft with mild carbohydrate intolerance induced by exogenous corticosteroids or chronically suppressing the graft with exogenous insulin. After these manipulations, insulin output into the portal vein in response to intravenous (i.v.) glucose was measured and compared with that of normal dogs and dogs receiving islet autografts with no further treatment with either steroids or insulin. Transplanted islets tolerated the two manipulations well in that neither exogenous steroid nor insulin led to failure of the graft as a consequence of either stress or protracted diminished demand. The major determinant of successful islet grafting is the endocrine competence of the initial graft. If that competence is provided at the outset, the graft can adapt to a considerable range of demand for insulin secretion.
Rat islets were mechanically dissociated to single cells and allowed to form aggregates by rotation-mediated cell-cell interaction. The aggregates, or neoislets, demonstrated insulin release in response to 20 mM glucose and 10 mM theophylline that was comparable to that of intact islets cultured for a similar time. However, basal insulin release was considerably greater than that from freshly isolated islets. The microscopic structure of the neoislets revealed sorting into a B-cell domain at the surface with A-cells interior to the aggregate. The neoislets generated no mitogenic response in allogeneic lymph node lymphocytes. Reassociation of single islet cells provides stable, functional endocrine units with substantial reduction of immunogenicity.
Postoperative oliguria or anuria can rarely be attributed to an increase in intra-abdominal pressure. In this documented case, postoperative anuria responded to reduction in abdominal pressure by celiotomy. Actual abdominal pressure measurements are not available but probably would not be useful. However, hemodynamic measurements that were not consistent with diminished renal blood flow in a middle-aged patient were nevertheless associated with anuria, which responded to release of the abdominal pressure. Because of the association of regional pressure and acute renal decompensation, release of abdominal tension should be considered as a therapeutic option when hemodynamic measurements cannot explain a rapid decline in urine production.
Islet tissue was prepared by collagenase ductal perfusion in mongrel dogs and transplanted to the spleen as autografts following total pancreatectomy. The graft was introduced into the spleen by reflux through tributaries of the splenic vein. Total insulin output by the in situ islet cell mass and by the heterotopically transplanted islet cell mass was studied by measuring insulin in the portal vein prior to pancreatectomy and two weeks after grafting. Basal insulin as well as the insulin output in response to 0.5 gram per kilogram of intravenous glucose were measured. Normoglycemia was achieved immediately in all grafted dogs. The results of intravenous glucose tolerance testing suggested only a mild degree of carbohydrate intolerance in the grafted dogs. Insulin output in 60 minutes after glucose stimilation was similar for in situ and grafted islet cells. The results of glucose clamp studies did not reveal any significant change in the insulin sensitivity of grafted as opposed to normal dogs. Islets of Langerhans may be harvested by the ductal perfusion method to yield a completely adequate islet cell mass for grafting purposes in the canine model following total pancreatectomy.
Intrasplenic autotransplantation of islet fragments prepared by ductal perfusion constitutes a reproducible system for islet delivery to apancreatic dogs. The animals are normoglycemic from the time of grafting, and graft failure is rare. In this study, apancreatic dogs received islet autografts (controls), autografts plus oral cyclosporine, and allografts plus oral cyclosporine. Therapeutic blood levels of cyclosporine were documented by radioimmunoassay. However, allografts and autografts ceased to function after initial normoglycemia in all animals that received cyclosporine, and four out of six autografts failed. Normoglycemia persisted in the control-autografted animals for the duration of the study. Microscopic sections of the failed grafts demonstrated meager tissue survival but no evidence of rejection by cellular infiltration.