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Biomedical subjects

D L Dunn

Publications and source records attributed to D L Dunn.

At least 199 records · Page 11Linked to original sources
PubMed1991

Pancreas transplant pathology. A morphologic, immunohistochemical, and electron microscopic comparison of allogeneic grafts with rejection, syngeneic grafts, and chronic pancreatitis.

In an effort to establish diagnostic criteria for rejection and recurrent disease in transplanted pancreas, a comparative study was performed based on clinical diagnosis. Clinical rejection was diagnosed in patients who had decreased urinary amylase or increased blood glucose; they were treated for rejection and improved. A clinical diagnosis of recurrent diabetes was made in syngeneic transplant recipients with islet dysfunction. In addition, two control groups were used--nontransplant, nondiabetic pancreatitis patients and pretransplant normal biopsies from patients in the study. Morphologically, tissues were assessed for acinar inflammation, ductal changes, islet and nerve inflammation, and vascular changes. Immunohistochemical staining for insulin and glucagon was also performed to quantitate differences between the groups. Vascular changes (endothelialitis, vasculitis, obliterative endarteritis) were specific for rejection. Also, rejection was characterized by a lymphocytic or mixed infiltrate that involved the ducts. Recurrent diabetes was characterized by selective loss of beta cells with isletitis. Leukocyte common antigen and UCHL1 staining was helpful in identifying islet inflammation. An insulin/glucagon ratio of less than 1.0 appears to be specific for recurrent disease and in the absence of isletitis is a reasonable method for detecting recurrent disease at an early stage.

Adolescent↗
PubMed1990

Differential roles of Mac-1+ cells, and CD4+ and CD8+ T lymphocytes in primary nonfunction and classic rejection of islet allografts.

The high rate of persistent hyperglycemia, termed primary nonfunction, after islet allotransplantation in C57BL/6 mice recipients of B10.BR strain islets, as compared with B10.BR recipients of C57BL/6 islets, led to a series of experiments to determine whether islet allograft primary nonfunction was attributable to technical aspects of the transplant procedure or whether it was a consequence of alloimmunity. Primary nonfunction was prevented by systemic pharmacologic immunosuppression of the host with cyclosporine. Selective immunodepletion of host CD4+ and CD8+ T lymphocytes significantly extended the time of classic rejection but did not significantly affect the rate of primary nonfunction. However, modulation of macrophages by administration to the host of silica completely abolished primary nonfunction. These observations, in conjunction with the immunohistological findings of intense macrophage infiltration in islet allografts from recipients exhibiting persistent post-transplant hyperglycemia, support the hypothesis that primary nonfunction results from a cell-mediated host-immune response of rapid onset that is dependent on macrophages or macrophage byproducts as the main effectors.

Animals↗
PubMed1990

Decreased tumor necrosis factor production during the initial stages of infection correlates with survival during murine gram-negative sepsis.

Secretion of tumor necrosis factor (TNF)/cachectin occurs during gram-negative bacterial sepsis in response to macrophage stimulation by lipopolysaccharide (endotoxin) and may play an early pivotal role in the subsequent host response. We sought to determine whether administration of: (1) murine monoclonal antibody directed against endotoxin, (2) steroids, or (3) antimicrobial agents would abrogate TNF production and whether the protective capacity would correlate with TNF levels in an experimental model of murine gram-negative bacterial sepsis. Mice were pretreated with anti-lipopolysaccharide monoclonal antibody, gentamicin sulfate, hydrocortisone, or saline and were then challenged with a lethal dose of intraperitoneal Salmonella minnesota. Murine serum TNF levels were measured by the L929 fibroblast cytotoxicity assay. Both gentamicin and anti-lipopolysaccharide monoclonal antibody significantly enhanced survival, and TNF activity at 1.5 and 3 hours was significantly suppressed in animals receiving these agents compared with animals that received either steroids or saline. We conclude that agents such as gentamicin, which inhibits bacterial replication, or monoclonal antibodies, which may neutralize lipopolysaccharide, indeed enhance survival, and survival was correlated with a significant reduction in circulating TNF during the early stages of infection.

Animals↗
PubMed1990

Enterococcal sepsis and lung microvascular injury in sheep.

In a common bile duct contamination model, we studied the effect of Streptococcus faecalis compared with Escherichia coli in sheep with chronic lymph fistulas to investigate the role of enterococcus in acute lung injury and acute sepsis. Early pulmonary hypertension in the E coli group was not expressed in the S faecalis group, probably due to a failure of S faecalis to illicit a thromboxane A2 response. In the late period, E coli was associated with significantly greater lung microvascular damage compared with S faecalis. The lack of difference between groups with respect to complement activation suggests the action of chemotactic factors, in addition to complement, mediating granulocyte aggregation, and neutropenia. In this model, S faecalis demonstrated limited pathogenicity as expressed in lung microvascular injury compared with E coli.

6-Ketoprostaglandin F1 alpha↗
PubMed1990

Cross-reactive murine monoclonal antibodies directed against the core/lipid A region of endotoxin inhibit production of tumor necrosis factor.

Two murine monoclonal antibodies (mAbs) directed against the core/lipid A moiety of lipopolysaccharide (endotoxin, LPS) were derived from mice immunized with either Escherichia coli J5 or Salmonella minnesota Ra, Rb, Rc, or Re heat-killed organisms or LPS. These mAbs were selected on the basis of their ability to cross-react against a panel of gram-negative bacterial LPS using Western immunotransblot analysis. We hypothesized that these anti-LPS mAbs directed against the conserved core region of LPS would inhibit LPS-induced macrophage tumor necrosis factor (TNF) production by neutralizing LPS derived from different gram-negative bacteria. To test this hypothesis, unelicited peritoneal macrophages were treated with either mAb 5G11 (deep core/lipid A specificity, broad LPS cross-reactivity) or mAb 5B11 (intermediate core specificity, limited LPS cross-reactivity). Macrophages were then challenged with a panel of LPS, and TNF activity was measured by the use of the L929 cytotoxicity assay. MAb 5G11 significantly inhibited TNF production against a panel of different types of LPS, but mAb 5B11 did not. In addition, mAb 5G11 did not inhibit TNF production due to isolated lipid A stimulation, suggesting that mAb 5G11 neutralized LPS by binding primarily to the deep core region of LPS. MAb 5G11 was also able to inhibit TNF production if added within 10 min of LPS stimulation but had no effect at 30 min, suggesting that macrophage stimulation may be irreversible during even the early stages of the response to LPS.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

The process of microbial translocation.

The process of microbial translocation was studied using Candida albicans, Escherichia coli, or endotoxin instilled into Thiry-Vella loops of thermally injured guinea pigs and rats. Translocation of C. albicans occurred by direct penetration of enterocytes by a unique process different from classical phagocytosis. Translocation between enterocytes was not observed. Internalization was associated with a disturbance of the plasma membrane and brush border, but most internalized organisms were not surrounded by a plasma membrane. Passage of the candida into the lamina propria appeared to be associated with disruption of the basal membrane with extrusion of cytoplasm of the cell and candida. Organisms in the lamina propria were commonly phagocytized by macrophages but also were found free in lymphatics and blood vessels. Translocation of E. coli and endotoxin also occurred directly through enterocytes rather than between them, but translocated endotoxin diffused through the lamina propria and muscular wall of the bowel wall by passing between rather than through the myocytes. These descriptive phenomena provide new insight into the role of the enterocyte and intestinal immune cells in the translocation process.

Animals↗
PubMed1990

Development and potential use of antibody directed against lipopolysaccharide for the treatment of gram-negative bacterial sepsis.

Gram-negative bacterial sepsis remains a major cause of lethality in hospitalized patients, despite routine therapy consisting of antimicrobial agents, hemodynamic monitoring and fluid resuscitation, and metabolic support. Because a large body of evidence supports the concept that Gram-negative bacterial lipopolysaccharide (endotoxin, LPS) is responsible for many of the direct and host mediator-induced deleterious effects, recent work has been centered on the development and use of anti-LPS antibody preparations in order to ameliorate lethality. Both polyclonal and monoclonal antibody preparations directed against the common deep core/lipid A region of LPS are cross-reactive in vitro and cross-protective in vivo against a wide range of challenge organisms and LPS, and preliminary clinical trials indicate that a reduction in lethality may be possible. The precise endotoxin epitope against which antibody should be directed in order to maximize protection, however, has not been established. This modality most probably will become a standard form of adjunctive therapy within the next several years for the treatment of Gram-negative bacterial sepsis.

Animals↗
PubMed1990

Influence of preservation time on outcome and metabolic function of bladder-drained pancreas transplants.

The influence of cold storage preservation time on graft survival and metabolic function of pancreatic transplants was studied in 130 recipients of bladder-drained grafts (47 simultaneous with, 33 after, and 50 without a kidney transplant) between October 1, 1984 and May 1, 1989. The recipients were divided into four groups according to the preservation time: less than 6 hr (n = 11), 6-12 hr (n = 24), 12-24 hr (n = 75), and greater than 24 hr (n = 20). Twenty-six grafts were procured by other transplant teams and sent to us. Silica gel fractionated plasma was used for preservation in 104 cases and the University of Wisconsin solution in 25 (1 in the less than 6 hr, 2 in the 6-12 hr, 16 in the 12-24 hr, and 6 in the greater than 24 hr groups). The technical failure rate at 1 month was 13% (17 grafts), 1 (9%) in the less than 6 hr, 5 (21%) in the 6-12 hr, 9 (12%) in the 12-24 hr, and 2 (10%) in the greater than 24 hr groups. At 1 month, 107 (82%) of the grafts were functioning, 10 (91%) in the less than 6 hr, 18 (75%) in the 6-12 hr, 62 (83%) in the 12-24 hr and 17 (85%) in the greater than 24 hr groups, the longest preserved for 30 hr. The respective 1-year graft survival rates were 51%, 50%, 57%, and 70%. Ninety patients (10 in the less than 6 hr, 16 in the 6-12 hr, 51 in the 12-24 hr, and 13 in the greater than 24 hr groups) had metabolic studies between 2 and 6 weeks postransplant. The results of 24-hour profiles (14 blood glucose determinations) were similar in each preservation time group; the means of the mean (+/- SD) profile glucose (mg/dl) values were 130 +/- 19, 126 +/- 31, 130 +/- 24, and 129 +/- 30, respectively (P greater than 0.6). Mean plasma glucose levels at 2 hr during OGTT were 141 +/- 32, 145 +/- 43. 163 +/- 49, and 184 +/- 100 in the respective preservation groups (P greater than or equal to 0.064). According to the National Diabetes Data Group classification, 75% of recipients in the less than 6 hr, 50% in the 6-12 hr, 44% in the 12-24 hr, and 33% in the greater than 24 hr groups had normal OGTT results.(ABSTRACT TRUNCATED AT 400 WORDS)

Blood Glucose↗
PubMed1990

An increased incidence of late acute rejection episodes in cadaver renal allograft recipients given azathioprine, cyclosporine, and prednisone.

We studied the incidence of biopsy-proven, acute rejection episodes occurring after 1 year posttransplant in cadaver renal allograft recipients. The 328 patients evaluated were given three immunosuppressive drug protocols. Group I (transplanted 9/80-6/84) (n = 75) received azathioprine, prednisone (P), and antilymphoblast globulin; group II (transplanted 9/80-6/84) (n = 83) received cyclosporine and P; group III (transplanted 7/84-12/86) (n = 170) received ALG, AZA, CsA, and P (sequential therapy). The incidence of first acute rejection episodes occurring up to 1 year posttransplant was 55% in group I and 35% in groups II and III. The incidence of late (greater than 1 year) acute rejection episodes was 6.5% in group I, 2.5% in group II, and 9.5% in group III (group II vs. III, P = 0.02). In group III, 50% of the late rejections were first, 44% second, and 6% third. The primary etiologies of this increased incidence of late acute rejection may have included subtherapeutic CsA levels and lower P doses. Sequential immunosuppressive therapy has been shown to be advantageous in the first posttransplant year. However, unless adequate immunosuppression is maintained, this approach can be associated with a significantly increased incidence of late acute rejection.

Adult↗
PubMed1990

The impact of HLA matching on graft survival and on sensitization after a failed transplant--evidence that failure of poorly matched renal transplants does not result in increased sensitization.

There are costs (both financial and ethical) to distributing kidneys by HLA-match (time, transportation, repeat crossmatch; possibly bypassing a more deserving recipient). Arguments favoring matching include better short- and long-term survival, and decreased panel-reactive antibody (PRA) if a well-matched vs. poorly matched transplant fails. We studied these phenomena in a single institution. Since 1970, 1329 patients received cadaver (CAD) transplants; for those with defined antigens (n = 1316) there was no difference in 10-year graft survival in those with a less than or equal to 1 AB match vs. those with greater than 1 AB match or those with less than or equal to 1 AB mismatch (mm) vs. greater than 1 AB mm. Similarly there was no difference in those with less than or equal to 2 BDR mm vs. greater than 2 BDR mm. In fact, those with less than ABDR mm had worse 10-year graft survival (55%) than those with greater than or equal to 3 ABDR mm (61%) (P = .001). For patients with function greater than 6 months there was no difference in long-term outcome based on HLA match or mm. These findings were similar for patients both with and without CsA immunosuppression, and for primary and retransplants. A total of 382 patients transplanted since 1980 have lost their grafts (146 died with function). All had received pretransplant transfusions. Of 236 alive after graft loss, 64 had no postgraft failure PRAs (22 out of state, 23 chose to remain on dialysis, 19 died less than 3 months after graft loss); 172 had PRAs after failure; 106 (62%) have been retransplanted. Mean peak PRA in those retransplanted was 23 +/- 31 (range 0-100) vs. 46 +/- 39 (range 0-100) in those not retransplanted (P less than .05). Patients were stratified by PRA prior to first transplant (0%, 1-20%, greater than 20%). For recipients with 0% PRA, failure of a CAD transplant (n = 58) was no more likely to result in an increase of PRA than failure of a living-related donor (LRD) transplant (n = 49) (NS). For those with an increase, mean increase was 45% +/- 34 after LRD transplant and 41% +/- 28 after CAD transplant (NS). The proportion developing PRA greater than or equal to 60% was not different after a failed LRD (7/49) or CAD (11/58) transplant (NS). Other subgroups had similar results. AZA or CsA immunosuppression did not affect development of increased PRA after a failed graft.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibody Formation↗
PubMed1990

Detection of pancreatic fluid and urine leakage after pancreas transplantation: value of CT and cystography.

Leakage from the urinary bladder or duodenal stump after pancreas transplantation with urinary bladder drainage of the graft is difficult to diagnose clinically. We retrospectively reviewed our experience with fluoroscopic cystography and CT to determine their relative merit in the diagnosis of pancreatic fluid and urine leakage as documented by surgical exploration in pancreas transplant recipients. Thirteen leaks were diagnosed by fluoroscopic cystography or by CT in 11 patients after pancreas transplantation with urinary bladder drainage of pancreatic fluid. Conventional retrograde fluoroscopic cystography showed 11 leaks; CT with retrograde bladder opacification showed three leaks. Of the five CT studies that did not show a leak and that also were done within 7 days of a cystogram with abnormal findings, failure to use retrograde bladder opacification accounted for the majority (three cases) of missed diagnoses. Focal or free peritoneal abdominal fluid was seen in all CT examinations, with extravasation of contrast material seen into both walled-off collections and free ascites. Our experience suggests that retrograde bladder and duodenal stump opacification should be a routine part of the CT evaluation performed to detect leakage from the urinary bladder or duodenal stump after pancreas transplantation.

Anastomosis, Surgical↗
PubMed1990

Long-term follow-up of renal transplantation for Wegener's disease.

Eight patients with end-stage renal failure due to Wegener's granulomatosis underwent renal transplantation at the University of Minnesota. Seven patients were alive with a functioning graft 40 to 128 months posttransplant (mean follow-up: 91 months). One patient died 126 months posttransplant with a well-functioning graft. Posttransplant immunosuppression controlled primary disease in all but 1 patient, who presented with perisinusitis. Recurrent disease was not noted in any of the transplanted organs. We conclude that transplantation is an excellent treatment for renal failure secondary to Wegener's disease.

Adolescent↗
PubMed1990

Lessons learned and future hopes: three thousand renal transplants at the University of Minnesota.

1. The experience of 3,183 transplants between June 7, 1963 and September 30, 1990 at the University of Minnesota was reviewed. 2. Patients were divided into 4 historical periods-each era was associated with improved outcome. 3. As results have improved, the proportion of patients less than 5 years old and the proportion greater than 50 years old have increased. Type I diabetes has become the most common cause of renal failure in patients transplanted here. 4. The most important variable leading to improved outcome was donor source. Both HLA-identical and HLA-nonidentical LRD transplants have better outcome than CAD transplants (p less than 0.0001). 5. Multivariate analyses were done to determine risk factors for survival: a) in the first year, and b) in subsequent years. In the first year, age greater than 50, diabetes, and retransplantation had an adverse affect whereas LRDs and CsA immunosuppression were beneficial. Similar factors affected survival after the first year. HLA mismatch had no impact. 6. When death with graft function was excluded, diabetes and age greater than 50 were no longer risk factors, suggesting that the excess graft loss in these groups was due to patient death. 7. Chronic rejection and death with function remain the predominant causes of graft loss. 8. As protocols have evolved, results have improved, and previously "high-risk" patients are being successfully transplanted. Future efforts should be directed at decreasing graft loss from rejection and death with function.

Adult↗
PubMed1990

Solid organ transplantation. Where has it been, where is it going?

Current developments in the field of clinical transplantation have led to the proliferation and expansion of the indications for various surgical procedures. Elderly patients, individuals who are at high risk of developing complications during or after the transplant procedure, and extremely ill individuals whose only chance of survival is an immediate transplant increasingly are being considered as potential recipients. The often complex nature of the underlying disease of the transplant patient, the magnitude of the transplant procedure itself, and the potential severity of ensuing complications that are often unique to this group of patients frequently lead to examination and treatment of the patient in the intensive care unit. The preoperative evaluation, intraoperative monitoring, and postoperative care of such patients have become a critical mainstay to their recovery, and are the focus of other articles in this issue.

Female↗
PubMed1990

Problems related to immunosuppression. Infection and malignancy occurring after solid organ transplantation.

Renal transplantation is associated with many long-term complications caused by a combination of the patient's comorbid medical illnesses and the effects of the various maintenance immunosuppressive agents currently in use. Careful patient selection with an emphasis on adequate cardiovascular function and low maintenance doses of immunosuppression at a level compatible with graft acceptance should help to prevent significant long-term morbidity. Recurrence of the original renal disease is a common histologic finding but, except in a few diseases, rarely results in graft loss. Parenthood can be a reality for most patients who have excellent graft function.

Critical Care↗