Failure of azathioprine and steroids to augment one-day-pretransplant donor-specific transfusion-enhanced allograft survival.
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Animals↗
Biomedical subjects
J W Alexander
Publications and source records attributed to J W Alexander.
Effects of combination of tumor necrosis factor alpha and chemotactic peptide, f-Met-Leu-Phe, on phagocytosis of opsonized microspheres by human neutrophils.
Pretreatment of normal, human neutrophils with 8 units/ml of TNF-alpha followed by treatment with 10(-8) M FMLP resulted in a synergistic effect of the combination of the two mediators on the enhancement of the phagocytic capacity of the cells. This enhancement of phagocytosis occurred without an additional increase in the upregulation of C3b receptors (CR1) beyond that caused by each mediator alone. Pretreatment of the cells with 8 units/ml of TNF-alpha followed by 10(-6) M FMLP resulted in an additive effect of the mediators on neutrophil phagocytosis, again without an additional up-regulation of CR1. This additive effect resulted in an increase in phagocytic capacity of the neutrophils greater than that obtained by treatment of the cells with 10(-6) M FMLP alone, which heretofore has resulted in the greatest enhancement of phagocytic capacity obtained by any pretreatment condition. These synergistic and additive effects of the combination of mediators could be of great importance in host defense against bacterial infections and have important implications regarding the mechanisms of receptor upregulation and phagocytosis.
Humans↗
Effects of pre- and postengraftment donor-specific transfusions and cyclosporine on the enhancement of experimental allograft survival.
The tolerogenic effects of immediate pretransplant donor-specific transfusion (DST) with cyclosporine (CsA) have been well described. The purpose of this study was to determine if these effects could be improved upon by the administration of post-transplant DSTs. When added to a 29-day course of CsA, a single DST given 24 hr pretransplant improved graft survival compared to CsA alone (84.9 +/- 12.3 vs 40.0 +/- 8.8 days; P less than 0.05). The administration of an additional DST on post-transplant Days 7, 14, and 21 further improved this survival to 152 +/- 28 days, with 45% of grafts surviving greater than 200 days, until sacrifice. The donor specificity of this effect was demonstrated by the increased survival of second ACI grafts transplanted into Lewis recipients with existing "tolerant" ACI allografts (long-term survivors, or LTS); third-party Buffalo rat hearts transplanted into LTS rats in a similar manner were rejected normally. Loss of graft antigenicity was not seen, as retransplanted ACI hearts obtained from LTS Lewis rats were rejected in a first-order manner. From this we conclude that (1) the addition of multiple post-transplant DSTs improve the enhancement seen with preoperative DST and CsA, (2) loss of graft antigenicity does not contribute to this improved enhancement, and (3) this effect appears to be donor antigen specific.
Animals↗
Reduced expression of neutrophil CD11b and CD16 after severe traumatic injury.
Overwhelming sepsis continues to be a major source of morbidity and mortality in patients who have sustained severe traumatic injury. Recently, much interest has been focused on the role of the peripheral blood neutrophil (PMN) in infections in these patients. Two surface receptors, CD11b (CR3) and CD16 (Fc gamma RIII), are thought to participate in bacterial phagocytosis and are both present on greater than 85% of normal PMNs. We have previously shown that cells that lack both of these receptors have markedly reduced phagocytic function. The purpose of this study was to determine the effect of severe trauma on the expression of these PMN receptors. Twenty severe trauma patients, age 19-70 years, presenting with an initial APACHE II score of greater than or equal to 10 were arbitrarily divided into two groups to define severity of injury: Group A, initial APACHE II of 10-18 (n = 11) and Group B, initial APACHE II of 19-25 (n = 9). Blood was obtained on admission, on Day 3, and weekly thereafter. PMNs were stained with fluorochrome-labeled monoclonal antibodies directed against CD11b and CD16 and then analyzed by flow cytometry. Controls consisted of 14 normal adults, age 20-65 years. The percentage and absolute numbers of CD11b+/CD16+ PMNs were determined for each patient or control sample. ANOVA and multiple comparison of variables (P = 0.05) were performed for each week. Values for Group A were different from controls at Weeks 0, 1, and 3. Values for Group B were significantly lower than those of controls at all weeks.(ABSTRACT TRUNCATED AT 250 WORDS)
Antibodies, Monoclonal↗
Metabolic and immune effects of enteral ascorbic acid after burn trauma.
A burned guinea-pig model (30 per cent BSA) was used to study the effect of vitamin C on immune and metabolic responses following burn trauma. Thirty-six guinea-pigs received identical enteral diets (175 kcal/kg) except for the amount of vitamin C. Groups I, II, III and IV were given formulae delivering no vitamin C, (1 RDA) 15 mg/kg/day, 75 mg/kg/day or 375 mg/kg/day, respectively. Resistance to infection was evaluated by injecting each animal with 0.1 ml of 1 x 10(9) Staph. aureus 502A subcutaneously on day 10. On day 14, Staph. aureus abscesses were excised and the numbers of viable colonies were determined. Results showed no statistical differences between groups in the clearance of Staph. aureus. From days 2 to 12, animals in groups I, II and III had body weights of approximately 97 per cent of preburn body weight. Animals in group IV, however, had a body weight gain, 102 per cent of preburn body weight on day 12. Animals in group IV also had significantly lower metabolic rates on day 12 as compared to the animals in the other groups. These results suggest that large amounts of vitamin C have beneficial effects on the maintenance of body weight and metabolic rate following burn trauma.
Animals↗
The pathogenesis of canine hip dysplasia.
Dogs with CHD are born with normal hips that subsequently undergo varying degrees of subluxation of the coxofemoral joint. Although the etiology of CHD is multifactorial, the pathogenesis or stages of change within the affected coxofemoral joint(s) are similar regardless of cause. With the onset of the disease, there are progressive structural changes including joint laxity and femoral head subluxation; swelling, stretching, fraying, and eventual rupture of the teres ligament; a shallow, flattened acetabulum, deformity of the head; erosion of articular cartilage, eburnation of subchondral bone, DJD; and periarticular osteophyte formation.
Acetabulum↗
Impact of blood transfusion and burn injury on microbial translocation and bacterial survival.
The role of the immune system in microbial translocation must be clarified. In these studies, the effect of blood transfusion-related immunosuppression on translocation was investigated in a burn animal model previously known to increase the gut's permeability to 14C-radiolabeled Escherichia coli. In a first experiment, Balb/c mice underwent transfusion (T) with 0.2 mL per mouse of allogeneic C3H/HeJ mouse blood 5 days prior to undergoing 30-percent burn injury (B) and simultaneous gavage (G) with 10(9) E. coli bacteria labeled with 14C. An additional six groups of Balb/c mice underwent different combinations of T, B, and G procedures (TG, BG, TB, T, B, G). Survival rate was recorded for all groups on Day 10. This experiment suggested that B and T, to a lesser extent, were the factors affecting survival, although the combination of T, B, and G clearly showed a synergistic effect on mortality. In a second experiment, 18 Balb/c mice belonging to TBG, BG, TG, and G groups were sacrificed 1, 4, and 24 hours after burn or gavage. The residual radioactivity and the percentage of viable bacteria were computed for mesenteric lymph nodes, spleen, liver, lungs, blood, and peritoneal fluid. Statistical analysis of the radionuclide counts recognized B as the only variable able to enhance the magnitude of 14C E. coli translocation. The percentage of viable bacteria showed that T and, more moderately, B were the factors leading to the failure of bacterial clearance in the tissues.
Animals↗
Efficacy of a single pretransplant donor-specific transfusion and cyclosporin A administered 24 to 48 hours before one-haplotype-mismatched living related donor kidney transplant.
During the 7-year period from March 1984 to June 1991, 86 haploidentical living related kidney recipients were entered into one of three donor-specific transfusion (DST) and cyclosporine treatment protocols: (1) Multiple pretransplant DSTs with cyclosporine begun after transplant, n = 34; (2) Multiple pretransplant DSTs with cyclosporine begun pretransplant, n = 31; and (3) a single DST 24 to 48 hours before transplant with intravenous cyclosporine initiated after the transfusion, n = 21. Triple immunosuppression (prednisone, azathioprine, and cyclosporine) was continued in all groups after transplant. The 1-year patient (97%, 97%, and 93%, p = not significant) and graft (91%, 90%, and 87%, p = not significant) survival were similar for the three groups. No differences were seen in the incidence of rejection at 1 year (61%, 45%, and 60%, p = not significant) or in the incidence of infectious complications (26%, 42%, and 47%, p = not significant). It is concluded that a single DST given 24 to 48 hours before operation followed by pretransplant cyclosporine is as effective as classic DST conditioning of recipients using either pretransplant or post-transplant cyclosporine. The single DST protocol has the advantage of not eliminating any donors because of sensitization and was less costly and easier to administer.
Adult↗
The degree of bacterial translocation is a determinant factor for mortality after burn injury and is improved by prostaglandin analogs.
Bacterial translocation and related mortality rates were examined in previously transfused BALB/c mice that were gavaged with 14C radioisotope-labeled Escherichia coli before inflicting a 20% full-thickness flame burn. Radionuclide counts were measured in blood obtained by retro-orbital puncture 4 hours postburn, and survival was recorded for 10 days. Radionuclide counts in the blood correlated well with both radionuclide counts and numbers of viable bacterial in the tissues. Survivors had significantly less bacterial translocation as evidenced by blood radionuclide counts compared with nonsurvivors, and there was a significant inverse correlation between the degree of translocation and the length of survival. In the next experiment, the prostaglandin E (PGE) analogs misoprostol, enisoprost, or 16,16-dimethyl PGE2 were administered to transfused animals for 3 days before burn. Prostaglandin E analogs significantly reduced bacterial translocation as measured by blood radionuclide counts 4 hours postburn and improved survival. The data demonstrate that the intensity of bacterial translocation after burn injury is significantly associated with subsequent death. Improvement of survival by PGE analogs is associated with decreased bacterial translocation.
16,16-Dimethylprostaglandin E2↗
The effect of indomethacin on the febrile response following OKT3 therapy.
Fifty renal transplant recipients with histologically documented acute allograft rejection were treated with OKT3 monoclonal antibody therapy. Group 1 (n = 25) received standard premedication with steroids, acetaminophen, and diphenhydramine. Group 2 (n = 25) received these agents plus indomethacin in an attempt to minimize the early adverse effects associated with OKT3. At 1 hr prior to the first dose of OKT3, 50 mg of indomethacin was administered orally followed by 25 mg every 6 hr for the next 48 hr. Demographics were similar in the two groups. Reversal of rejection occurred in 23 of 25 (92%) in group 1, and in 22 of 25 (88%) in group 2. Graft survival rates at six months after the rejection were 88% in group 1 and 80% in group 2. There was a single patient death in group 2, due to a suicide in a patient with a functioning kidney and pancreas graft. The maximum temperature was significantly diminished in the group receiving indomethacin during the first three days of OKT3 therapy. The percentage of patients with a maximum temperature less than 100 degrees F was significantly higher in group 2: day 1--16% vs. 36%, day 2--12% vs. 48%, day 3--52% vs. 68% for group 1 and group 2, respectively. No serious side effects occurred in either group--however, subjective side effects were less common in group 2. Serum creatinine levels were similar in the two groups prior to rejection, at the start of OKT3 therapy, at the peak during OKT3 therapy, at the end of OKT3 therapy, and 30 days and 180 days post OKT3. The data indicate that the concurrent use of indomethacin with OKT3 appears to significantly decrease the initial febrile response without compromising renal function or the efficacy of OKT3 therapy.
Adolescent↗
The induction of immunologic hyporesponsiveness by preoperative donor-specific transfusions and cyclosporine in human cadaveric transplants. A preliminary trial.
A prospective randomized preliminary trial was performed in patients undergoing cadaveric renal transplantation to determine the potential benefits, disadvantages, and logistic problems associated with the administration of donor-specific transfusions and cyclosporine initiated 24 hr before transplantation. Ten patients received DST followed by continuous intravenous CsA approximately 24 hr before cadaveric renal transplantation from the same donor. Twelve patients receiving sequential therapy with Minnesota antilymphoblast globulin, azathioprine, and steroids with subsequent conversion to CsA served as controls. Patient demographics and the donor characteristics were evenly matched in the two groups. While the study group had longer cold ischemia time and more evidence of renal dysfunction within the first two weeks, subsequent renal function was identical in the groups and there were fewer episodes of severe rejection requiring treatment with OKT3 within the first six months in the DST group (5 vs. 0, P less than 0.05), which also had less reactivity in mixed lymphocyte cultures against preserved donor-specific lymphocytes than did the control group (stimulation index 9.0 +/- 3.0 vs. 25.3 +/- 6.0, respectively, P less than 0.05). The need for dialysis, incidence of infections and other complications, and subsequent immunosuppressive therapy were not different in the two groups. It is concluded that DSTs and intravenous CsA initiated 24 hr prior to transplantation are capable of inducing reduced immunologic responsiveness against the specific donor. Patients treated with this therapy should receive organs from "ideal" donors without risk factors and cold ischemia time should not exceed 30 hr. Further clinical studies of this approach are warranted.
Acquired Immunodeficiency Syndrome↗
Rapid whole-blood microassay using flow cytometry for measuring neutrophil phagocytosis.
A simple flow cytometric method (FCM) for measuring phagocytosis of Staphylococcus aureus by human neutrophils (polymorphonuclear leukocytes [PMNs]) is described. This assay utilizes 100 microliters of EDTA-anticoagulated whole blood and a simplified method of fluorescently labeling bacteria. A commercially available whole-blood lysing reagent allows for the removal of erythrocytes and the exclusion of external free or adherent bacteria. Phagocytized bacteria are unaffected by this reagent, so PMNs containing internalized bacteria can be easily identified by FCM. Advantages of this method include the following: (i) small sample size, (ii) no requirement for PMN separation, (iii) rapid reliable method of labeling the bacteria, (iv) ability to distinguish between adherent bacteria and those which are actually internalized, (v) avoidance of vital dyes as quenching agents, and (vi) ability to fix cells and store for future FCM analysis.
Adult↗
High-risk donors: diabetics, the elderly, and others.
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Age Factors↗
The effect of the prostaglandin analogues misoprostil and enisoprost on the synergy between donor-specific transfusion and cyclosporine in allograft survival.
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Administration, Oral↗
Primary appendiceal malignancies: rare but important.
The four main types of appendiceal neoplasms are carcinoid tumors (CT), mucinous cystadenocarcinomas, colonic adenocarcinomas (CAC), and adenocarcinoid tumors. They have different clinical features and require different therapy. They are rarely diagnosed before or during surgery and frequently require a secondary operation for proper treatment. A series of 14 patients treated between 1979 and 1989 at Harris Methodist Fort Worth Hospital are described. There are six important points of management. (1) A frozen section should be done whenever the appendiceal findings are atypical. Then a diagnosis of malignancy can be made during surgery and appropriate surgery can be done primarily. (2) All patients with appendiceal neoplasms should be followed because a second malignancy will develop in 15% to 20% of them. (3) Appendectomy is recommended for patients whose CT are less than or equal to 1.0 cm in diameter and for most patients whose tumors are between 1.0 and 2.0 cm in diameter. Right hemicolectomy is preferred for those patients whose CT are 2.0 cm or more in diameter or between 1.0 and 2.0 cm with heavy lymphatic and mesenteric invasion. (4) Mucinous cystadenocarcinomas are slowly progressive and are best treated by means of right hemicolectomy with aggressive debulking added if pseudomyxoma peritonei is present. (5) CAC require a right hemicolectomy and have the same prognosis as have other colon adenocarcinomas. (6) Adenocarcinoid tumors have a dual cell origin, a predilection for developing ovarian metastases, and a malignant potential between CT and CAC. They are best treated by means of right hemicolectomy with concomitant oophorectomy in postmenopausal women.
Adenocarcinoma↗
Incentives for organ donation? The United Network for Organ Sharing Ad Hoc Donations Committee.
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Adult↗
Increased gut permeability following burn trauma.
Twenty female Hartley guinea pigs, weighing 350 to 400 g, were given a 30% full-thickness burn injury. Gastrointestinal permeability was assessed before burn and on postburn days 1 through 3, 7, and 14 by administering 5 mL of an isotonic mixture of 8% lactulose and 1.15% L-rhamnose by gavage and measuring the urinary excretion for the next 7 hours. In normal guinea pigs, lactulose (molecular weight, 342d) is mostly absorbed by the paracellular route, whereas L-rhamnose (molecular weight, 164 d) is mostly absorbed by the transcellular route. Gut permeability to L-rhamnose did not increase after burn injury (211 micrograms before burn vs 230, 260, 180, 238, and 221 micrograms on days 1, 2, 3, 7, and 14, respectively, after burn). By contrast, gut permeability to lactulose increased significantly and was greatest in the first 48 hours after burn injury (60 micrograms before burn vs 380, 354, 203, 364, and 279 micrograms on days 1, 2, 3, 7, and 14, respectively, after burn). Gut permeability to low-molecular-weight compounds increases immediately after burn trauma, and this may be by a paracellular rather than transcellular mechanism.
Animals↗
Selection criteria for liver transplant donors.
As the number of successful liver transplants has increased, the demand for donors has outpaced the supply. Approximately 25% of patients die awaiting an appropriate donor. Current criteria for assessing potential donors need to be closely examined. Fifty-six potential donors were evaluated by our transplant team by utilizing standard liver function tests (LFT's)-SGOT, SGPT, bilirubin. Additionally, a lidocaine metabolism test was performed by giving a 1 mg/kg IV dose of lidocaine over 1 minute and measuring the accumulation of the major metabolite monoethylglycinxylidide (MEGX) at 15 minutes by fluorescent polarization immunoassay (Abbott Diagnostics, Abbott Park, IL). Previous work has suggested that a MEGX less than 50 ng/mL is associated with initial non-function. Thirty-four donors were transplanted (group I) and all had initial function (all MEGX values were greater than 50). Twenty-two donors (39%) were judged unacceptable (group II) by our transplant team and by outside centers based upon one of the following criteria: II A) elevated LFT's--8, 11 B) donor age--5, II C) donor instability--4, II D) no available recipient--3, II E) miscellaneous--2. Standard LFT's were not statistically different in the donors used and in those not used when excluding category II A. Six of seven donors excluded in group I had acceptable MEGX values indicating they may have been transplantable. Ten of 12 patients excluded in groups II B-D had normal LFT's and nine of 12 had acceptable MEGX values indicating they may have been transplantable also. In this era of organ shortage, a reevaluation of donor selection criteria utilizing new tests like MEGX may be necessary to meet the increased need.
Adolescent↗