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Biomedical subjects

J W Alexander

Publications and source records attributed to J W Alexander.

At least 109 records · Page 6Linked to original sources
PubMed1994

Effect of donor age on outcome of kidney transplantation. A two-year analysis of transplants reported to the United Network for Organ Sharing Registry.

The shortage of cadaveric donors coupled with a rapidly growing number of potential recipients has resulted in an increased use of older donors. In 1992, 10.7% of all cadaveric kidney transplants were from donors above the age of 55 compared with 5.4% in 1988. The present investigation serves as a follow-up of a prior study of the effect of donor age on outcome with a 2-year analysis of more than 30,000 cadaveric kidney transplants performed in the United States between October 1, 1987, and December 31, 1991, that were reported to the United Network for Organ Sharing. There was no difference between the graft survival at 1 and 2 years comparing donors aged 56-65 versus 65 and older, but the older donors (aged 56 and greater) had a 1- and 2-year graft survival that was approximately 10% and 14% less than that for recipients from the ideal age group of donors (16-45 years). There was no practical adverse interaction between donor age and recipient age, gender, diabetic status, peak PRA (panel reactive antibody activity) level of mismatch, cold ischemia time, or recipient race on outcome. The kidneys from older donors had poorer graft survival than the kidneys from younger donors when transplanted into recipients of repeat transplants, though the impact of repeat transplant and donor age on graft survival are independent of one another. These data suggest that kidneys from donors over the age of 55 overall have reduced functional reserve, which has an adverse effect on long-term function. Thus, attempts should be made to better estimate functional reserve among the older age group, but age alone should not be the sole factor for exclusion of a potential donor. The use of older donors appears to present an increased but acceptable risk of graft loss 2 years after transplant.

Adolescent↗
PubMed1994

The primary site of bacterial translocation.

OBJECTIVE: To establish the primary anatomic site of bacterial translocation in the intestinal tract. DESIGN: Prospective randomized experimental trials. SETTING: Laboratory. MATERIALS: Hartley guinea pigs. INTERVENTIONS: In guinea pigs, 10-cm closed loops of upper jejunum, distal ileum, or proximal colon were created. The animals then received intraluminal injections of Escherichia coli labeled with radioactive carbon (14C) before a 50% full-thickness burn was inflicted. Four hours after the burn injury, the animals were killed, and the intestinal loops, mesenteric lymph nodes, spleen, liver, and lung were harvested. Intestinal loops were irrigated and then treated with ethylenedinitroilotetraacetic acid to separate the enterocytes and colonocytes from the lamina propria. Radionuclide counts were determined in the effluents, the enterocytes (or colonocytes), lamina propria, and other organs. Colony-forming units of E coli were also determined in mesenteric lymph nodes, spleen, liver, and lung. MEASUREMENTS AND MAIN RESULTS: No significant differences were noted in the radionuclide counts in the lamina propria and epithelial cell fraction related to the type of loop. In addition, no significant differences were noted in the radionuclide counts in the mesenteric lymph nodes, liver, spleen, and lung related to the type of loop, but more viable bacteria were recovered when bacteria were injected into the jejunal loop. CONCLUSIONS: Translocation of bacteria occurred with similar intensity throughout the gut, but more bacteria were killed in the process of translocation across the lower part of the intestinal tract.

Animals↗
PubMed1994

Effects of antimurine interleukin-6 on bacterial translocation during gut-derived sepsis.

BACKGROUND: Recent studies have shown that interleukin-6 (IL-6) is involved in the systemic changes that are associated with infection and tissue injury and that there is a correlation between high levels of IL-6 and poor outcome during several pathologic conditions. OBJECTIVE: The effects of antimurine IL-6 antibody on survival and host defense were studied in a clinically relevant model of infection. METHODS: Balb/c mice were treated with 10 micrograms of antimurine interleukin-6, a nonspecific mouse IgG, or placebo 1 hour before they underwent bacterial challenge by gavage of 10(10) Escherichia coli and burn injury. Survival and the extent of translocation of E coli were determined as well as the correlation between the IL-6 levels and survival times. RESULTS: Survival after burn and gavage was 90% in animals treated with antimurine interleukin-6 vs 50% in animals treated with nonspecific IgG and 30% in saline-treated controls. A significant correlation between the levels of IL-6 and survival time was observed. Less translocation and better killing of bacteria were observed in the tissues of animals treated with antimurine interleukin-6. CONCLUSIONS: Interleukin-6 appears to play a major role in both the intensity of translocation of E coli from the intestine following burn injury and the host's ability to kill translocated organisms. Improved outcome was associated with a reduction of IL-6 levels by anti-IL-6 antibody.

Analysis of Variance↗
PubMed1994

IFN-gamma decreases translocation and improves survival following transfusion and thermal injury.

The effects of recombinant murine interferon-gamma (rmIFN-gamma) on survival and host defense were studied during gut-derived sepsis that included transfusion-induced immunosuppression. Balb/c mice (n = 153) were transfused with allogeneic blood and then treated with different doses of rmIFN-gamma: 10, 100, 1000, 10,000 U, or sterile saline as control once daily for 3 days. Five days after transfusion they were gavaged with 10(10) Escherichia coli and given a 20% TBSA burn injury. Survival was significantly higher in groups receiving 10 U compared to control and the group receiving 10,000 U (P < 0.0001 and P = 0.02, respectively). Groups receiving 100 or 1000 U also showed an improvement of survival compared to nontreated control animals (P = 0.02). The effect of rmIFN-gamma on the degree of translocation and the host's ability to kill translocated organisms was also investigated. Mice were treated as described above, except they were gavaged with 111In oxine-labeled E. coli and then subjected to a 20% TBSA burn. Mesenteric lymph nodes (MLN), liver, and spleen were harvested aseptically. Less translocation to the liver was observed compared to the nontreated group (P = 0.002) to the MLNs and spleen of the group treated with 100 U rmIFN-gamma compared to controls and the group treated with 10 U (P < 0.005). Animals receiving 1000 U showed fewer bacteria in the liver and spleen compared to the control group (P < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Heterogeneity of Kupffer cells and splenic, alveolar, and peritoneal macrophages for the production of TNF, IL-1, and IL-6.

Kupffer cells and alveolar, splenic, and peritoneal macrophages from normal rats were incubated for various periods of time in the presence of LPS, and the culture supernatants were analyzed for IL-6, IL-1, and TNF. There was very little difference in the amounts of the cytokines produced by the macrophages when stimulated with 0.01-10 micrograms/ml of LPS. The shapes of the time course curves for the production of the cytokines by the different types of macrophages were generally similar, although only Kupffer cells continued to produce IL-6 throughout the entire incubation period and splenic macrophages showed a lag period in the production of IL-1. Kupffer cells produced more IL-6 than that produced by the other populations of macrophages, and alveolar macrophages produced more IL-1 compared to that produced by splenic cells. Kupffer cells and peritoneal macrophages produced more IL-6 in 24 h than in 6 h of culture, and splenic macrophages produced more IL-1 in 24 compared to 6 h of culture. Alveolar macrophages produced more TNF than that produced by the other populations of cells but only when integrated over the entire incubation period. These results confirm and extend the observed functional heterogeneity of macrophages obtained from different tissues of the same animal. This study and future studies will lead to a better understanding of the role of cytokines in the inflammatory response.

Animals↗
PubMed1994

Posterior cruciate function following total knee arthroplasty. A biomechanical study.

The strain developed in the posterior cruciate ligament (PCL) of eight fresh cadaveric knees was measured before and after total knee arthroplasty using a loading technique that simulated stair ascent and descent. Each knee was instrumented with a Hall Effect strain gauge (Micro-Strain, Burlington, VT) in the PCL, a load cell in the quadriceps tendon, an electrogoniometer, and an array of linear displacement transducers to measure femoral rollback. Testing was undertaken with each knee in its normal state with the anterior cruciate cut and with a cruciate-retaining prosthesis, a cruciate-excising prosthesis, and a cruciate-substituting prosthesis. Normal PCL strain levels were produced in only 37% of the trials following implantation of the cruciate-retaining knee arthroplasties. With a cruciate-retaining prosthesis, femoral rollback decreased by an average of 36% and was associated with a 15% loss in extensor efficiency. In the procedures performed with excision of the PCL, rollback decreased by 70% and extensor efficiency by 19%. Cruciate substitution resulted in a 12% loss in rollback and an 11% decrease in extensor efficiency. The strain developed within the PCL during knee flexion was found to be extremely sensitive to the thickness of the polymeric tibial insert. In the majority of cases, it was not possible to restore normal ligament loading with flexion while simultaneously maintaining acceptable varus/valgus stability of the knee joint. Using a range of contemporary knee arthroplasties, the authors were unable to consistently reproduce normal function of the PCL.

Biomechanical Phenomena↗
PubMed1994

Granulocyte macrophage colony-stimulating factor improves survival in two models of gut-derived sepsis by improving gut barrier function and modulating bacterial clearance.

OBJECTIVE: The effect of recombinant murine granulocyte macrophage colony-stimulating factor (rmGM-CSF) on survival and host defense was studied using two clinically relevant models of infection that included transfusion-induced immunosuppression. SUMMARY BACKGROUND DATA: Granulocyte macrophage colony-stimulating factor improves resistance in several models of infection, but its role in transfusion-induced immunosuppression and bacterial translocation (gut-derived sepsis) has not been defined. METHODS: Balb/c mice were treated with 100 ng of rmGM-CSF or placebo for 6 days in a model of transfusion, burn, and gavage, or cecal ligation and puncture (CLP). Translocation was studied in the first model. RESULTS: Survival after transfusion, burn, and gavage was 90% in rmGM-CSF-treated animals versus 35% in the control group (p < 0.001). After CLP, survival was 75% in the rmGM-CSF group versus 30% in the control group (p = 0.01). Less translocation and better killing of bacteria was observed in the tissues in animals treated with rmGM-CSF. CONCLUSION: The ability of rmGM-CSF to improve gut barrier function and enhance killing of translocated organisms after burn injury-induced gut origin sepsis was associated with improved outcome. Granulocyte macrophage colony-stimulating factor also improved survival after CLP.

Animals↗
PubMed1994

Isolated pulmonary infection acts as a source of systemic tumor necrosis factor.

OBJECTIVE: To investigate the local secretion of tumor necrosis factor (TNF) in the lung as a source for systemic TNF. DESIGN: Prospective, randomized experimental trials. SETTING: Laboratory. SUBJECTS: Hartley guinea pigs. INTERVENTIONS: Female guinea pigs were challenged intratracheally with 10(3) to 10(9) Escherichia coli. Two and eight hrs after the bacterial challenge, colony-forming units of bacteria in the lung and blood, TNF and prostaglandin E2 (PGE2) in the bronchoalveolar lavage fluid, and serum TNF concentrations were determined. At the same time, alveolar macrophages were harvested and cultured in vitro, and TNF and PGE2 secretions were measured. MEASUREMENTS AND MAIN RESULTS: TNF and PGE2 concentrations were either not detected in bronchoalveolar lavage fluid or were found in very low levels in control animals. High concentrations of TNF and PGE2, however, were found in bacteria-challenged animals. Two hours after inoculation of bacteria, TNF in the bronchoalveolar lavage fluid had a significant correlation with TNF values in the serum. The TNF concentration in aortic blood was significantly higher than TNF concentration in right atrial blood. For comparable inocula, TNF in the bronchoalveolar lavage fluid after 8 hrs was significantly lower than at 2 hrs, but PGE2 levels remained high. Lipopolysaccharide-stimulated alveolar macrophage secretion of TNF in vitro was depressed in animals with high PGE2 levels in bronchoalveolar lavage fluid and high numbers of viable bacteria in the lungs. CONCLUSIONS: During pulmonary Gram-negative infection, the lungs may be a major source of TNF in the blood. The magnitude of TNF secretion by the lungs is highly dependent on the intensity of infection during its early stages. By 8 hrs after onset of infection, TNF secretion appears to downregulate, possibly by endogenous PGE2.

Animals↗
PubMed1994

Role of early enteral feeding and acute starvation on postburn bacterial translocation and host defense: prospective, randomized trials.

OBJECTIVES: To investigate the effect of: a) starvation during the preburn period and b) immediate postburn enteral nutrition on the permeability of the gut to microorganisms and the ability of the host to kill translocated bacteria. DESIGN: Prospective, randomized, experimental trials. SETTING: Laboratory. SUBJECTS: Balb/c mice and Hartley guinea pigs. INTERVENTIONS: In the first experiment, mice were starved for 0, 6, 12, 18, or 24 hrs before receiving gavage with 10(10) 14C-labeled Escherichia coli and a 20% burn injury. In the second experiment, guinea pigs received a 40% burn injury and were randomized to receive a complete enteral diet (175 kcal/kg/day) or infusion of an equal volume of lactated Ringer's solution via a previously placed gastrostomy for 6, 24, or 48 hrs. After each feeding period, 10(10) 14C Escherichia coli were infused intragastrically. In both experiments, the animals were killed 4 hrs after gavage, and mesenteric lymph nodes, spleen, liver, lungs, peritoneal fluid, and blood were harvested aseptically. MEASUREMENTS: For each tissue or fluid, the number of viable E. coli and radionuclide counts of the 14C E. coli were measured and the percentage of translocated bacteria that remained alive was calculated. MAIN RESULTS: In mice, 18 and 24 hrs of preburn starvation increased translocation only to the mesenteric lymph nodes, but it also enhanced bacterial killing in all tested tissues. Guinea pigs that were fed enterally for 6, 24, and 48 hrs postburn had significantly lower bacterial translocation in all tissues compared with animals infused with lactated Ringer's solution. Additionally, enhanced killing of translocating organisms was observed after 24 and 48 hrs of feeding. CONCLUSIONS: Starvation preburn has different consequences than starvation postburn on translocation and bacterial killing. Postburn enteral nutrition decreases the load of viable bacteria in the tissues via a double mechanism: an initial decreased translocation and a subsequent improved ability to kill bacteria that do translocate.

Acute Disease↗
PubMed1994

Heparan sulfate increases survival during gut-derived sepsis by decreasing bacterial translocation and enhancing host defense.

The effect of heparan sulfate (HS) on survival rate, bacterial translocation, and host defense was studied in a model of gut-derived sepsis that included transfusion-induced immunosuppression. Balb/c mice were treated pre- and postburn injury and bacterial challenge with HS, 5 mg/kg/day, or sterile phosphate-buffered saline. The HS pre- and postburn treated animals showed a significant improvement in survival compared to control animals (80 vs. 30%, p = .004, and 60 vs. 20%, p = .02, respectively). A lower amount of translocation was observed in the spleen (p < or = .001) of the HS group compared to control group. Quantitative colony counts and the calculated percentage of viable bacteria showed that the ability to kill translocated organisms was enhanced in all tissues of the animals receiving HS. These data suggest that treatment with HS positively affects the outcome in gut-derived sepsis. The beneficial effect was related both to an improved gut barrier function and to an enhanced host defense.

Analysis of Variance↗
PubMed1994

Time course of production of cytokines and prostaglandin E2 by macrophages isolated after thermal injury and bacterial translocation.

The relationship of translocation of bacteria from the gut of burned guinea pigs and the in vitro production of tumor necrosis factor (TNF), interleukin (IL)-1 and IL-6, and prostaglandin E2 (PGE2) by lipopolysaccharide (LPS)-stimulated mesenteric lymph node and splenic macrophages was investigated at two early times after thermal injury. Two hr postburn, there was a large number of translocated bacteria in the mesenteric lymph nodes and a large proportion was killed; at 24 hr postburn, there were fewer translocated bacteria, but a large proportion was viable. In some cases, there were very large differences compared to controls in the amounts of TNF, IL-6, and PGE2, but not of IL-1, produced by the macrophages at different times postburn and at different in vitro incubation times. The results suggest that the macrophages were primed by the burn or the translocated bacteria to produce in vitro different and sometimes large amounts of cytokines or PGE2 after further stimulation with LPS. Although there was no direct correlation between production of cytokines or PGE2 and time postburn, the early increased production of PGE2 by splenic macrophages could have depressed the animal's ability to kill translocated bacteria by 24 hr postburn, and could be one of the mechanisms of the cause of systemic infection after burn injury.

Animals↗
PubMed1993

The activation of bone marrow macrophages 24 hours after thermal injury.

We determined the effect of thermal injury on the in vitro production of the immunoactive substances tumor necrosis factor, interleukin 1, prostaglandin E2, and complement component C3 by lipopolysaccharide-stimulated guinea pig bone marrow macrophages and on the cytotoxicity of these cells. Macrophages from burned animals produced different amounts of these mediators compared with unburned animals at certain culture times, suggesting that thermal injury could program the bone marrow cells to respond differently from normal cells to in vitro stimulation with lipopolysaccharide. Also, the macrophages from burned animals displayed greater cytotoxicity towards L929 target cells. These results suggest that there is a complex interaction among cellular secretory products, especially after thermal injury, that may be important in host defense.

Animals↗
PubMed1993

Immunoenhancement via enteral nutrition.

Arginine, glutamine, the long chain polyunsaturated omega-3 and omega-6 fatty acids, and, to a lesser extent, ribonucleic acid and the vitamins E, C, and A have pharmacologic effects when given in amounts in excess of what is needed to prevent nutritional deficiency. These effects are exerted primarily via the immune system, and immunoenhancing diets that embody the recently developed principles of nutritional pharmacology have been shown to reduce infectious complications by approximately 75% in surgical patients and hospital stay by more than 20% in surgical patients and patients in the intensive care unit in three independent, prospective, randomized studies, two of which were double-blinded. These findings suggest that specialized diets can be designed that will be of benefit to patients with cancer, atherosclerosis, intestinal diseases, autoimmune diseases, infections, and trauma. However, the interaction of these nutrients in pharmacologic amounts with standard pharmacologic drugs is largely unknown, as are the effects of long-term administration of specialized diets to treat these conditions.

Adjuvants, Immunologic↗
PubMed1993

A comparison of hepatic, splenic, peritoneal and alveolar macrophages with respect to PGE2, TXB2, production and ADCC function.

The in vitro production of PGE2 and TxA2, measured as TxB2, and the antibody-dependent cellular cytotoxicity (ADCC) as well as spontaneous cellular cytotoxicity (SCC) displayed by hepatic, peritoneal, splenic, and alveolar macrophages from 12 rats was determined and compared. Kupffer cells, the fixed macrophages of the liver, were the most active cells in the production of PGE2. Kupffer cells and peritoneal macrophages released about equal amounts of TxB2 which was much higher than that released by splenic macrophages. Kupffer cells displayed the strongest ADCC activity, and alveolar macrophages had the lowest value. These results confirm the previously reported heterogeneity among different sources of macrophages and emphasize the enhanced activity of Kupffer cells with respect to eicosanoid production and ADCC function.

Animals↗