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Biomedical subjects

J W Alexander

Publications and source records attributed to J W Alexander.

At least 163 records · Page 9Linked to original sources
PubMed1991

The effects of in vivo administration of endotoxin on the functions and interaction of hepatocytes and Kupffer cells.

It was the purpose of this study to determine the effects of the in vivo administration of endotoxin on certain in vitro hepatocyte and Kupffer cell functions. An Alzet osmotic pump that contained endotoxin (LPS, 2.5 mg/100g) was implanted into the peritoneal cavity of 300g guinea pigs and delivered the endotoxin over a period of four days. In vivo administration of LPS did not cause a change in the in vitro release of albumin by isolated hepatocytes. However, when hepatocytes were co-cultured with Kupffer cells there was a significant decrease in albumin release for both control and LPS-treated animals. There was no difference between control and LPS-treated animals in the release of C3 by hepatocytes. However, there was a significant increase over the control group in C3 release by Kupffer cells from LPS-treated animals. When hepatocytes and Kupffer cells were cultured together, their release of C3 was not additive. Kupffer cells from LPS-treated animals released significantly greater amounts of PGE2 than control animals when stimulated in vitro with LPS. Thus, these Kupffer cells appeared to be primed to respond to an in vitro challenge of LPS. Kupffer cells from LPS-treated animals had significantly depressed antibody dependent cellular cytotoxicity (ADCC). This endotoxin model is useful for determining the in vivo effects of endotoxin on cellular function and gives some indirect evidence for the detrimental effects of LPS on the immune system and host defense.

Animals↗
PubMed1991

Distribution and survival of Escherichia coli translocating from the intestine after thermal injury.

The present investigation was performed to study the kinetics of tissue distribution and deposition of Escherichia coli and endotoxin translocating from the intestine after thermal injury. Escherichia coli was grown in the presence of 14C glucose and both labeled bacteria and endotoxin prepared from the labeled bacteria were used as translocation probes. Escherichia coli (10(8) to 10(10) bacteria) and E. coli endotoxin (100 micrograms per animal) were gavaged into the stomach immediately before a 30% burn injury was inflicted in mice. Animals were killed 1, 4 and 24 hours after burn injury. Translocation occurred extensively within 1 hour after burn injury. Expressed as amount of radioactivity per gram of tissue, translocation was greatest in the mesenteric lymph node (MLN) followed by spleen, lung, and liver. Translocation of endotoxin was similar to translocation of intact bacteria, with the exception that less radioactivity could be found in the peritoneal cavity and more in the liver. Both intact E. coli and endotoxin translocated directly through the intact bowel wall. Killing of bacteria was greatest in the MLN and spleen, approximating 95% to more than 99% of translocating bacteria. Killing efficiency was lowest in the lungs. It is concluded that estimation of translocation by viable bacterial counts in tissues grossly underestimates the extent of translocation of bacteria and ignores the extent of translocation of endotoxin. Translocation of endotoxin may have biologic significance that is independent of and in addition to translocation of intact bacteria.

Animals↗
PubMed1991

Composition of fat in enteral diets can influence outcome in experimental peritonitis.

An animal model of protracted acute peritonitis was used to study the effects on survival of different amounts and types of dietary fat. Guinea pigs (n = 132) were provided with gastrostomies and allowed to recover. Intraperitoneal osmotic pumps were then placed, allowing for effusion of viable bacteria during the next week. Three days after pump implantation, the animals were randomized to receive one of nine diets, differing only in fat content (3.5%, 14%, or 56% of total calories) and fat composition (100% Microlipid [primarily safflower oil, rich in linoleic acid], 100% MaxEPA [fish oil containing 35% omega-three fatty acids], or a 50:50 mixture of both oils). At the end of 2 weeks, survival rates were compared. Among all types of fat used, the level of fat did not affect outcome, with survival rates of 13% (6 of 45) at the low level of fat used, 30% (13 of 44) at the medium level, and 26% (11 of 43) at the high level (P greater than 0.10). However fat composition significantly influenced survival across all levels of fat, with a 39% (17 of 44) survival rate in the groups given equal amounts of Microlipid and MaxEPA, compared either to 21% (9 of 44) for the 100% Microlipid groups, or to 9% (4 of 44) for the 100% MaxEPA groups (p less than 0.05). A second experiment was performed with 58 animals fed five different mixtures of fats, all at 14% of total calories. Diets were made with fat ratios of 100:0, 75:25, 50:50, 25:75, and 0:100 Microlipid to MaxEPA. The survival rate in the 50:50 group was 83% (10 of 12), which is significantly higher than the survival rates with any of the others (p less than 0.05). It is concluded that the amount of fat in the diet does not strongly influence outcome in this model. However an equal mixture of safflower and fish oils significantly improves survival rates compared to diets made with single-oil preparations.

Acute Disease↗
PubMed1991

The use of "marginal" donors for organ transplantation. The influence of donor age on outcome.

The influence of donor age on outcome was studied in the recipients of 12,131 cadaveric renal allografts, 3026 heart allografts, and 2913 liver allografts with followup information in the UNOS data base for transplants performed between 10/1/87 and 12/31/89. For recipients of kidney transplants, donors of ages 6-15 had significantly better 1-year graft survival than donors of ages 56-65, but the difference was only 7.0%. Donors of age greater than 65 actually did better than donors ages 56-65, but donors less than or equal to 5 were less satisfactory. Kidneys from older donors survived as well as kidneys from younger donors in patients with repeat transplants, diabetes, black race, age over 45, O HLA or 5 and 6 HLA matches, delayed graft function, shared kidneys and PRA greater than 50. For kidney recipients, multifactorial analysis by Cox regression showed that donor age was less important than the use of ALG, donor race, diabetes or peak PRA in ages 16-45, delayed function, repeat transplant, and HLA match. Recipients of heart transplants from donors ages 45-55 had 1-year graft survival that was 8.4% less than recipients of hearts from donors age 16-45. However, 32.7% of heart patients died during the first 12 months after listing without benefit of a transplant. Liver transplant recipients of donor ages 16-45 had 10.8% better 1-year graft survival than recipients of donors greater than 45, but a greater percentage of older donors were transplanted to high risk and older recipients. Tragically, 24.3% of patients listed for liver transplantation died within 12 months without a transplant. This analysis shows that satisfactory graft survival can be achieved using older donors and that age in itself should not be a barrier to organ donation, providing that organ function is normal and that specific disease of the organ is absent.

Adolescent↗
PubMed1991

Cyclosporine dose reduction by ketoconazole administration in renal transplant recipients.

Cyclosporine metabolism occurs in the liver via hepatic cytochrome P-450 microsomal enzymes. Ketoconazole, an imidazole derivative, has been shown to inhibit the cytochrome P-450 enzyme system. Thirty-six renal transplant recipients receiving cyclosporine as part of a triple immunosuppressive drug regimen were started on 200 mg/day of oral ketoconazole. The dose of cyclosporine was reduced by 70% at the start of ketoconazole; this dose reduction was based on our previous experience with concomitant cyclosporine-ketoconazole therapy. Ketoconazole was started in patients who had been on cyclosporine for between 10 days and 74 months. The mean cyclosporine dose was 420 mg/day (5.9 mg/kg/day) before starting ketoconazole and 66 mg/day (0.9 mg/kg/day) one year after the addition of ketoconazole; this represents a cyclosporine dose reduction of 84.7% (P less than 0.0001). The mean trough whole-blood cyclosporine concentrations measured by HPLC, were 130 ng/mL preketoconazole and 149 ng/mL after 1 year of combination therapy. Mean serum creatinine and BUN levels were unchanged before and during ketoconazole administration, and no changes in liver function tests were noted. Cyclosporine pharmacokinetics were performed before and after at least three weeks of ketoconazole. Hourly whole-blood samples were measured by HPLC (parent cyclosporine only) and TDX (parent + metabolites). Combination therapy resulted in decreases in the maximum blood concentration and the steady-state volume of distribution divided by the fractional absorption, and increases in mean residence time and the parent-to-parent plus metabolite ratio (calculated by dividing the HPLC by the TDX value). The addition of ketoconazole to cyclosporine-treated patients resulted in a significant inhibition of cyclosporine metabolism and decrease in the dosage. There was minimal nephrotoxicity, and only four rejection episodes occurred on combined therapy. The concomitant administration of the two drugs was well tolerated, and there was no deleterious effect on the immunosuppressive activity of cyclosporine. This drug interaction provides a significant reduction in the costs associated with organ transplantation.

Adult↗
PubMed1991

Enhancement of allograft survival by donor-specific transfusion one day prior to transplant. Importance of timing and specificity when DST is given with cyclosporine.

Donor-specific transfusion effects were studied in the ACI-to-Lewis rat heterotopic heart allograft model using cyclosporine immunosuppression. Low-dose CsA for 1 week plus a single fresh or stored DST given 1 day before allografting significantly prolonged graft survival over CsA therapy alone (median survival time 23.5 days vs. 10 days, P less than 0.01), but third-party transfusion did not (11.5 vs. 10 days, NS). When CsA was started at the time of DST and continued for 2 weeks, maximal graft enhancement was achieved after just one DST. DST/CsA was equally efficacious if given on any day before transplantation, provided CsA was started on the same day as the transfusion. However, pretransplant DST given without CsA shortened subsequent graft survival of day -1 DST/CsA treatment (14.5 days, n = 6, vs. 60 days for controls, n = 10; P less than 0.01). The addition of methylprednisolone to the DST/CsA protocol had no effect on graft survival (51 vs. 53 days, P = NS), but extending the period of postoperative CsA therapy for 4 weeks at reduced dose (2.5 mg/kg/day) significantly prolonged median survival (111 days, n = 11) and resulted in 45% permanent engraftment (greater than 120 days survival). CsA permits graft enhancement with a single DST as early as 1 day before grafting. This avoids the risk of sensitization from DSTs and can extend DST use to cadaveric graft recipients.

Animals↗
PubMed1991

Recent contributions to transplantation at the University of Cincinnati.

1. Clinical investigations at the University of Cincinnati have focused primarily on infection control, methods to increase donor-specific unresponsiveness, improvement in immunosuppression, donor maintenance and evaluation, posttransplant monitoring, and reduced-size livers for children. 2. Donor specific unresponsiveness (DSU) can be achieved frequently in recipients of both cadaver donor and living related donor kidneys by giving a single donor specific transfusion and CsA only 24 hours preoperatively with continuing triple immunosuppressive therapy. 3. Prednisone can be withdrawn from almost all patients with no rejection by 1 year with significant improvement in blood pressure, daily insulin requirement in diabetics, total blood cholesterol, and low density lipoproteins (LDL). 4. Oral ketoconazole 200 mg/day can be used safely to block the hepatic metabolism of CsA and reduce the amount of CsA administered by an average of 77-88%. This is of great economic consequence to lower income patients and patients with poor drug absorption. 5. Eighteen patients with SLE who received 23 kidney transplantations had an increase in graft loss in the first 6 months but the rate of graft loss after 6 months was almost identical to other ESRD patients. 6. The Cincinnati Transplant Tumor Registry has data on about 8,000 patients. Except for those with CNS tumors, patients with active cancers should not be used as donors. However, donors with previous curative procedures should not be excluded automatically. Cancers arising in immunosuppressed transplant recipients that have a higher incidence than the general population (expressed as percentage of treated cancers) are: lymphomas (22% vs 5%), lip cancers (7% vs 0.3%), Kaposi's sarcoma (6% vs less than 0.1%), vulva and perineal cancers (4% vs 0.6%), hepatobiliary cancers (2.5% vs 1.0%) and sarcomas (1.8% vs 0.5%). Other cancers have about the same-distribution. 7. Immunologic monitoring during OKT3 therapy is particularly useful in re-treatment and treatment of pediatric liver patients when increased doses of the drug may be necessary. 8. The MEGX test has been found to be a major predictor of primary non-function of the transplanted liver, and it is also useful in predicting the risks of dying from liver disease. 9. Reduced-size livers have been used in 37 patients, representing almost half of all pediatric liver transplants. Survival with reduced-size grafts (91% at 1 year) compared favorably with survival of whole organs (79% at 1 year). The benefit is particularly dramatic in infants with biliary atresia (100% 1-year graft survival in 24 patients, median age 11 months).(ABSTRACT TRUNCATED AT 400 WORDS)

Actuarial Analysis↗
PubMed1991

Efficacy of induction therapy in cadaveric renal transplantation comparing rabbit antithymocyte serum and Minnesota antilymphoblast globulin.

From August 1986 to July 1989, 98 patients receiving primary cadaveric kidney transplants received either RATS (n = 50) or MALG (n = 48) during the induction phase of a quadruple immunosuppressive protocol. Patient groups were well matched. The duration of RATS and MALG treatment and the time of CyA induction were equivalent. Serum creatinine and rejection episodes up to 1 year were not statistically different. Hematologic side effects resulted in dose reduction of MALG in 42% of patients without adverse rejection results. In the RATS group, no dosage reductions were required. One-year patient survivals (96% to 100%), and 1-year graft survival (82% to 85%) were not significantly different in the 2 groups. Infectious complications were 30% higher in the MALG group and a significant factor in 2 deaths. Monitoring of lymphocyte subsets revealed insignificant differences in the percent of decrease of each cell population between MALG and RATS groups during induction.

Adult↗
PubMed1990

Neutral surface aminopeptidase activity of human tumor cell lines.

Seven human tumor cell lines were studied for their neutral surface aminopeptidase (AP) activity. The activity was shown to exist on all cell lines to varying degrees. The neutral AP activity of the cell lines had similar Km values and were affected by the same inhibitors as those reported for AP's of peripheral blood lymphocytes (PBL, Refs. 1 and 2). However, a difference was seen in the Vmax values of the various cell lines. These values were shown to correlate (r = 0.767, P less than 0.05) with cell surface area.

Aminopeptidases↗
PubMed1990

Failure of orthoclone OKT3 retreatment in a pancreas transplant recipient with antimurine antibodies.

Orthoclone OKT3 is a murine monoclonal antibody that blocks the generation and function of T lymphocytes. It has been shown to be effective in reversing acute cellular rejection in solid organ transplants. However, potential development of antimurine antibodies restricts the duration that the drug can be used and the ability to reuse the drug. The case reported in this article illustrates the failure of retreatment with OKT3 when high titer (1:3200) antimurine antibodies are present. Lack of efficacy of the drug was documented by virtually undetectable circulating OKT3 levels in plasma, no decrease in T3 lymphocytes, and organ rejection. OKT3 should only be reused when immune monitoring (antimurine antibody status, lymphocyte subsets, and OKT3 plasma levels) is performed before, during, and after its use. Patients with high-titer anti-OKT3 antibody should not be retreated with OKT3.

Adult↗
PubMed1990

Effects of chemotactic peptide f-Met-Leu-Phe (FMLP) on C3b receptor (CR1) expression and phagocytosis of microspheres by human neutrophils.

FMLP caused maximal upregulation of CR1 on neutrophils at a concentration of 10(-8) M but caused maximal enhancement of CR1-dependent phagocytosis of C3b.IgG-coated microspheres only at a concentration of 10(-6) M. There were positive correlations between FMLP-mediated upregulation of CR1 and FMLP-mediated enhancement of phagocytosis (correlation coefficient = 0.73, slope = 2.2) and between FMLP-mediated upregulation of CR1 and FMLP-mediated increase in total cell-associated microspheres (correlation coefficient = 0.88, slope = 1.3). The phagocytic capacity of both untreated and 10(-6) M FMLP-treated neutrophils was completely inhibited by fluid phase C3b and partially inhibited by aggregated IgG. The data suggest that CR1 upregulation is required but is not sufficient for maximal phagocytosis by the leukocytes. The data also suggest that FMLP at the higher concentrations may impart a phagocytic function to CR1, activate other phagocytic receptors, elicit phagocytosis-inducing mediators or may elicit a separate mechanism of phagocytosis. During the study, it was observed that there was considerable individual variation among different neutrophil preparations with respect to CR1 expression and binding and phagocytic capacity.

Humans↗
PubMed1990

Comparison of abilities of recombinant interleukin-1 alpha and -beta and noninflammatory IL-1 beta fragment 163-171 to upregulate C3b receptors (CR1) on human neutrophils and to enhance their phagocytic capacity.

Both recombinant IL-1 alpha and -beta caused an upregulation of C3b receptors (CR1) on human neutrophils and caused a receptor-mediated enhancement of phagocytosis of C3b.IgG-coated microspheres by these leukocytes. The alpha and beta forms of the recombinant cytokine were of comparable potency regarding CR1 upregulation, although both generally had less than 25% of the potency of FMLP in this respect. Recombinant IL-1 beta was slightly more potent than the alpha form of the cytokine regarding phagocytosis of opsonized microspheres and, again, both forms were less potent than FMLP in causing an enhancement of phagocytosis by neutrophils. The synthetic noninflammatory immunostimulatory nonapeptide corresponding to residues 163-171 of IL-1 beta was completely inert with respect to upregulation of CR1 on neutrophils and the enhancement of phagocytosis by these cells. Thus this domain in the intact IL-1 beta molecule apparently is not involved in CR1 upregulation and the ensuing enhancement in phagocytosis by neutrophils, although it is apparently important in the immunostimulatory activity regarding the proliferation of lymphocytes.

Antigens, CD↗
PubMed1990

Variable infection risk following allogeneic blood transfusions.

These studies address infection risk of allogeneic transfusion in an untraumatized, nonseptic rodent model. A' Segaloff Cancer Institute rats served as blood donors and Lewis rats as recipients. Lewis rats' delayed-type hypersensitivity (DTH) response and their ability to clear subdermal Staphylococcus aureus abscesses and Candida albicans pyelonephritis were measured as tests of the effect of transfusions. The effect of pharmacological immunosuppression with either cortisone acetate or cyclosporine provided a "yardstick" to measure the magnitude of transfusion effects. Repeated transfusions at 1-week intervals diminished DTH response to recall antigens (keyhole limpet hemocyanin), but otherwise they showed no evidence of immunosuppression in these experiments. In contrast, we found that transfusions by themselves produced mild immunostimulation. Subcutaneous Staphylococcus abscesses were smaller in animals receiving transfusions. The magnitude of immunostimulation from one transfusion was sufficient to reverse the immunosuppressive effect of cyclosporine by about 50% in a Candida pyelonephritis infection. These studies suggest that blood transfusions have complex interactions with different components of the immune response. T-cell function is impaired by repeated transfusions (diminished DTH response), but other inflammatory responses are accentuated. This suggests that blood transfusions may harm immune response in traumatized animals by causing excessive complement activation or cytokine release.

Abscess↗