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Biomedical subjects

J W Alexander

Publications and source records attributed to J W Alexander.

At least 91 records · Page 5Linked to original sources
PubMed1996

Impact of first acute rejection episode and severity of rejection on cadaveric renal allograft survival.

A total of 504 renal transplants were performed between 1984 and 1993; 408 (81%) were cadaver grafts. This study evaluated the impact of a first acute rejection episode and the severity of the rejection on cadaveric allograft survival. Acute allograft rejection was based on clinical evaluation and confirmed by renal biopsy. Ten patients were excluded from this study due to early patient or graft loss. Patients were divided into Group I (n = 179), who never experienced acute rejection, and Group II (n = 219), who had an acute rejection episode. Group II patients were divided into IIA (n = 140), who had a mild first acute rejection episode treated with methylprednisolone, and IIB (n = 79), who had moderate or severe acute rejection treated with OKT3. The overall 1-, 2-, 3-, and 5-yr actuarial cadaveric renal allograft survival for Group I was 80%, 76%, 74%, and 68%. The corresponding graft survival for Groups IIA and IIB were 75%, 63%, 58%, and 50%; and 79% 71%, 65%, and 53% [p = 0.03 (I vs IIA), p = NS (I vs. IIB and IIA vs IIB)]. A similar pattern of survival was seen in primary kidney allograft recipients. In conclusion, long-term graft survival was superior in patients who never experienced acute rejection compared to those with rejection. Improvements in long-term graft survival can be accomplished in patients with severe rejection with OKT3 treatment resulting in comparable survival to those with mild rejection.

Actuarial Analysis↗
PubMed1996

Organizational development strategies on nursing units.

The organizational development process was evaluated on psychiatric units. Using a model of technostructural fit suggested by Alexander and Bauerschmidt, structural interventions were implemented. Insights on the use of organizational development in nursing are presented.

Clinical Nursing Research↗
PubMed1995

Nutritional immunomodulation enhances cardiac allograft survival in rats treated with donor-specific transfusion and cyclosporine.

The aim of this study was to assess the efficacy of an enteral diet fortified with arginine, RNA, and fish oil (Impact), alone and in combination with cyclosporine (CsA) and donor-specific transfusion (DST) on allograft survival in the ACI:Lewis rat cardiac transplant model. Animals were fed ad libitum with either standard rat chow or Impact diet. Six groups were studied; these consisted of untreated recipients fed either standard diet or Impact diet; recipients treated with CsA 10 mg/kg on the day prior to engraftment (day-1) followed by 2.5 mg/kg/d, day 0-->day+13 and fed with either standard diet or Impact; and animals given a DST (1 ml) on day-1, CsA as described previously and fed either standard diet or Impact. Untreated animals standard diet (group 1, n = 8) rejected their allografts at 7.0 +/- 0.0 days, while those fed Impact (group 2, n = 9) had graft survival of 12.8 +/- 2.1 days, (P = .01 versus group 1). Animals treated with CsA alone and standard diet (group 3, n = 9) rejected at 30.3 +/- 4.8 days, while the combination of CsA and Impact diet (group 4, n = 8) rejected at 33.0 +/- 9.5 days--minimally improved survival compared with group 3. Animals treated with DST/CsA and standard diet (group 5, n = 7) rejected at 72.1 +/- 6.8 days, while the substitution of Impact for standard diet (group 6, n = 8) led to a significant graft prolongation to 275 +/- 53 days, n = 8 (P < .015 vs. groups 1-5). These data suggest that Impact diet alone can have potent immunomodulatory properties but may require the addition of DST/CsA to realize its potential. These findings underscore the potential of dietary immunomodulatory therapy to prevent rejection and promote tolerance to solid organ allografts.

Adjuvants, Immunologic↗
PubMed1995

Administration of intragraft interleukin-4 prolongs cardiac allograft survival in rats treated with donor-specific transfusion/cyclosporine.

It has been hypothesized that immunoregulating cytokines produced by intragraft Th-2 cells may be important for prolonged allograft survival. ACI hearts transplanted into untreated Lewis rat recipients survived for 6.2 days, but they survived for 72.1 days in recipients treated with a donor-specific transfusion and low dose CsA for 14 days. In donor-specific transfusion/CsA-treated animals, intragraft infusion of IL-10 via a 14-day osmotic minipump had no effect on graft survival (75.6 days), but intragraft infusion of IL-4 prolonged graft survival to 149.2 days (P < 0.01). While the actual mechanism of this effect is unclear, it suggests that IL-4 may be important in the development of long-term graft survival.

Animals↗
PubMed1995

Indefinite allograft survival induced by the combination of multiple donor-specific transfusions, cyclosporine, and an anti-T cell monoclonal antibody in a protocol relevant to cadaveric organ transplantation. The importance of prolonged posttransplant cyclosporine coverage.

A single donor specific transfusion (DST) 24 hr pretransplant and Cyclosporine (CsA) are synergistic in inducing prolongation of allograft survival. This synergy was further potentiated by giving 3 additional DSTs at weekly intervals posttransplant, or by the additional administration of a small dose of the anti-T cell monoclonal antibody OX-52 24 hr pretransplant to the above protocol. This study determined whether indefinite survival can be achieved in the ACI-to-Lewis heart allograft model by combining an anti-T cell monoclonal antibody, 4 DSTs given once 24 hr pretransplant and weekly 3 times posttransplant, and CsA. CsA was given daily for 28 days or 60 days posttransplant. The dose consisted of CsA 5 mg/kg/day starting 24 hr pretransplant and continuing until day 7 posttransplant and followed by 2.5 mg/kg/day for either 21 more days (total CsA days = 28 days) or 53 days (total CsA days = 60 days). The anti-T cell monoclonal antibody OX52 (200 micrograms i.v.) was given once 24 hr pretransplant. DST (1 ml) was given 24 hr pretransplant and on days 7, 14, and 21 posttransplant. Low-dose CsA for 28 days never induced indefinite allograft survival. CsA for 60 days, however, resulted in the occasional indefinite allograft survival (> 1 year) even in this difficult model. The addition of DST 24 hr pre- and posttransplant on days 7, 14, and 21 to both 28 days and 60 days of CsA further prolonged allograft survival. The best survival was seen in the group given DST 24 hr pre- and on days 7, 14, and 21 posttransplant and 60 days of CsA, with all the allografts surviving beyond 100 days of CsA, with all the allografts surviving beyond 100 days and more than 50% surviving indefinitely (> 1 year). The addition of a single dose of OX52 24 hr pretransplant to the multiple DSTs and 28 days of CsA protocol significantly improved indefinite allograft survival but its influence was less dramatic when given to the multiple DSTs and 60 days of CsA protocol. This beneficial interaction between CsA, DST, and an anti-T cell MoAb offers a clinically applicable protocol for both living donor and cadaveric organ transplantation in inducing donor-specific hyporesponsiveness, and further investigations are warranted.

Animals↗
PubMed1995

Reduced inter- and intrasubject variability in cyclosporine pharmacokinetics in renal transplant recipients treated with a microemulsion formulation in conjunction with fasting, low-fat meals, or high-fat meals.

This cross-over study compared the pharmacokinetic parameters obtained from cyclosporine (CsA) concentration-time profiles after administration of the corn oil-based soft gel cap (CsA-GC) with those with the microemulsion (CsA-ME) gel cap. Neither the fasting state nor the coadministration of a low- or high-fat breakfast affected the pharmacokinetics of CsA presented in either formulation. Comparisons of the three sets of pharmacokinetic parameters--namely, after fasting or after low-fat or after high-fat diets--demonstrated the CsA-ME formulation to display greater intraindividual reproducibility of the C0 and C12 trough levels (TLs), Cmax, tmax, and area under the concentration-time curve (AUC) than the CsA-GC formulation. Although the degree of interindividual variation in AUC, Cmax and tmax after CsA-ME administration was slightly, but significantly, less than after CsA-GC administration, there was no difference between the two formulations in terms of the customarily monitored C0 or C12 TL values. CsA-ME showed higher correlation coefficients of drug exposure (AUC) with C12 than CsA-GC (0.910 versus 0.712). However, CsA-ME administration resulted in only modest improvement over CsA-GC administration in the relationships between drug dose and C0, C12, or AUC--namely, 0.645 versus 0.496, 0.611 versus 0.517, and 0.700 versus 0.501, respectively. Correlation analysis between individual timed samples and AUC determinations revealed that CsA-ME requires significantly less frequent blood monitoring for prediction of total drug exposure than does CsA-GC. Although the clinical utility of this reproducible pharmacokinetic behavior remains to be demonstrated in the de novo transplant setting, the markedly reduced intraindividual variation produced by administration of CsA-ME will likely improve the accuracy of pretransplant prediction of, and reduce the frequency of subsequent adjustments in, CsA doses.

Corn Oil↗
PubMed1995

Differential expression of intestinal and splenic cytokines after parenteral nutrition.

OBJECTIVE: To determine the effect of parenteral nutrition (PN) on the expression of message for inflammatory cytokines in the spleen and different segments of the intestine. DESIGN: Randomized controlled trial. PARTICIPANTS: Eleven adult male Sprague-Dawley rats weighing 250 to 300 g. INTERVENTIONS: All rats underwent central venous cannulation and were randomized to two groups. Group 1 (n = 6) received saline solution infusion and chow ad libitum; group 2 (n = 5) received lipid-free PN with no oral feeding. After 7 days, the animals were killed and the spleens and segments of small and large intestine were removed. MAIN OUTCOME MEASURES: The expression of message for tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and IL-1 in the spleen and intestine was determined using a semiquantitative reverse transcription polymerase reaction. Splenic macrophages were isolated and cultured for 24 hours with and without lipopolysaccharide. Production of TNF-alpha and IL-6 was determined by bioassay followed by enzyme-linked immunosorbent assay. RESULTS: After 7 days of infusion, messenger RNA (mRNA) expression for TNF-alpha, IL-1, and IL-6 was increased in the jejunum (P < .05), and TNF-alpha mRNA and IL-6 mRNA expression was decreased in the spleen (P < .01) of PN-fed animals when compared with saline/chow controls. In addition, TNF-alpha mRNA expression was increased in the cecum (P < .05), IL-1 mRNA expression was increased in the ileum (P < .05), and IL-6 mRNA expression was increased in the cecum (P < .05) and Peyer's patches (P < .007) in the PN-fed animals. Production of TNF-alpha and IL-6 by splenic macrophages was decreased following PN infusion in both lipopolysaccharide-treated and untreated cultures (P < .05). CONCLUSIONS: Infusion of lipid-free PN induces a differential mRNA expression for inflammatory cytokines in the spleen and intestine with an overall up-regulation of the expression of inflammatory cytokines in the intestine and a down-regulation in the spleen. These data provide evidence that the regulatory mechanisms for cytokine production are different in the intestine and the spleen. Further study is needed to elaborate the mechanism of this differential expression following lipid-free PN infusion.

Animals↗
PubMed1995

Anti-interleukin-6 antibody treatment improves survival during gut-derived sepsis in a time-dependent manner by enhancing host defense.

OBJECTIVE: To determine the in vivo neutralizing activities of anti-interleukin-6 (IL-6) antibody on survival rate and host defense in a clinically relevant model of infection. DESIGN: Prospective, randomized, experimental animal study. SETTING: University and Shriners Burns Institute research laboratories. SUBJECTS: Two hundred seventy-six adult, female Balb/c mice. INTERVENTIONS: Balb/c mice were treated with 10 micrograms of antimurine IL-6 antibody, nonspecific murine immunoglobulin G (IgG), or placebo at 2, 4, or 8 hrs after they underwent bacterial challenge by gavage of 10(10) Escherichia coli and thermal injury. The survival rate was determined. The number of viable translocated bacteria, the total amount of translocation, and the percentage of bacteria that survived were also studied in different tissues. MEASUREMENTS AND MAIN RESULTS: Survival rate after burn and gavage was significantly improved in animals treated with antimurine IL-6 antibody at 2 and 4 hrs but not at 8 hrs after injury compared with control animals treated with nonspecific IgG or saline. The IL-6 serum concentration was significantly lower after burn and gavage in the animals treated 2 and 4 hrs after injury compared with nontreated animals. Better killing of translocated bacteria was observed in the tissues of animals treated with antimurine IL-6 antibody 2 hrs after injury. CONCLUSIONS: Treatment with antimurine IL-6 antibody at 2 and 4 hrs after injury, but not at 8 hrs after injury, positively affects outcome during gut-derived sepsis. Moreover, the beneficial effect of treatment after 2 hrs was related to an enhanced clearance of translocated bacteria.

Animals↗
PubMed1995

Failure of local and systemic bacterial clearance in rats with acute pancreatitis.

These studies were designed to investigate the ability of rats to clear subcutaneous bacterial abscesses following acute pancreatitis. Animals underwent subcutaneous injection of 1 x 10(9) Escherichia coli and Staphylococcus aureus and, 24 h later, were randomized into four groups to receive (A) an intravenous (i.v.) infusion of cerulein, (B) saline i.v., (C) ligation of the pancreatic head, or (D) sham ligation. After 12 h, abscess sizes were measured and blood was withdrawn for culture and assay amylase and endotoxin level assay. Animals were observed for an additional 12 h to record mortality. Both E. coli and S. aureus abscesses were larger in group C vs. group D, while only the E. coli lesion was larger in group A vs. group B. Bacteremia was detected in 60% of the animals in group A, 40% in groups B and D, and 100% in group C. Mortality was 80% in group C vs. 10% in all other groups. Amylase and endotoxin levels were higher in group C vs. all groups. In the second experiment rats were injected with bacteria as above. Four, twelve, and twenty-four hours later the abscesses were removed for quantitation of bacteria and histologic evaluation. At 24 h rats underwent procedure A, B, C, or D and the abscesses were excised 12 h later. Group C had a significantly higher number of viable bacteria inside the lesion compared to group D. Histology showed tissue necrosis and cellulitis not observed in group D. It is concluded that acute pancreatis causes failure of local and systemic bacterial clearance and that the incidence of bacteremia and mortality is proportional to the severity of the disease.

Abscess↗
PubMed1995

The effect of aging on the shape of the proximal femur.

The design of cementless femoral prostheses is based on the assumption that age and gender do not affect the shape of the proximal femur. To test this hypothesis, standard anteroposterior and lateral radiographs were prepared of 4 sets of 20 femora, obtained from young (range, 40-60 years) and elderly (range, 60-90 years) donors of both genders. The intracortical and extracortical borders of each femur were digitized electronically, and key parameters were measured to define the shape and dimensions of the medullary canal and the position of the femoral head. Systematic differences were observed between the size and shape of male and female femora. Extracortical dimensions were larger in the male femora by 14% to 19%, and endosteal dimensions by 11% to 24%. However, there were no significant differences between the canal shape of young male and young female femora in the coronal, sagittal, or transverse planes. The male femora displayed no significant differences in canal shape or endosteal width as a function of age. Profound differences were observed in the endosteal shape and diaphyseal dimensions of the young and old female femora. The older female femora had wider canals at the level of the isthmus, with a significant reduction in the canal flare index (the ratio between the canal width proximal to the lesser trochanter and at the isthmus). This study demonstrates that cementless femoral prostheses of 1 standard shape cannot provide a close fit to the endosteal contours of young and elderly women.

Adult↗
PubMed1995

Bacterial translocation-related mortality may be associated with neutrophil-mediated organ damage.

Balb/c mice were transfused with .2 mL of C3H/HeJ mouse blood. 5 days later, the mice were gavaged with 10(10) 14C-labeled Escherichia coli, and a 20% full thickness flame burn was inflicted. Additional animals were treated with enisoprost (prostaglandin E1 (PGE1) analog) 200 micrograms/kg/day orally for 3 days before burn. Bacterial translocation was determined by both radionuclide counts (dpm) and viable colony counts 24 h post burn. Neutrophil accumulation was evaluated by the measurement of myeloperoxidase (MPO) in the liver. In addition, splenic macrophages were separated and cultured for 24 h with or without 10 micrograms/mL of LPS. Tumor necrosis factor, interleukin-1 (IL-1), IL-6, and PGE2 were measured in the cell culture supernatants. Consistent with previous work, enisoprost significantly reduced translocation. MPO in the liver was significantly greater in the control group compared to the enisoprost group. There was a significant correlation between MPO content and the degree of bacterial translocation (p < .05). Lipopolysaccharide-stimulated macrophage production of IL-1, IL-6, and PGE2 were significantly greater in the enisoprost group.

Alprostadil↗
PubMed1995

Effect of different regimens of gut decontamination on bacterial translocation and mortality in experimental acute pancreatitis.

OBJECTIVE: To assess the effect of four regimens of antibiotics (compared with a control regimen of distilled water) given orally on gut decontamination, bacterial translocation, and mortality in acute necrotising pancreatitis in mice. DESIGN: Randomised experimental study. SETTING: University hospitals, USA and Italy. MATERIALS: 150 young Swiss Webster mice. INTERVENTION: All mice were fed a diet deficient in choline and supplemented with ethionine. They were then randomised to be given by gavage (36 hours after starting the diet): distilled water (controls, group 1); aztreonam along (group 2); neomycin, erythromycin, metronidazole (group 3); polymyxin B and amikacin (group 4); polymyxin B, amikacin, amphotericin B (group 5). 20 Mice in each group were treated for 10 days, and the remaining 10 in each group were killed after 3 days. MAIN OUTCOME MEASURES: Survival, and qualitative and quantitative cultures of the liver, lungs, pancreas and caecum. RESULTS: The best survival rate during the first 7 days was in group 5, but by day 10 there was no difference among the groups. All the antibiotic regimens reduced the number of bacteria in the caecum and all but aztreonam alone (group 2) reduced the rate of translocation of both Gram negative and Gram positive bacteria to all organs studied. Translocation of yeast occurred in those animals in groups 2, 3, and 4 in which there was overgrowth of fungi in the caecum. CONCLUSION: Gram negative and Gram positive organisms and fungi may have an important role in infective morbidity and mortality in acute pancreatitis, and selective decontamination with polymyxin B, amikacin, amphotericin B reduced the incidence of translocation related infections and early mortality in mice with acute necrotising pancreatitis.

Acute Disease↗
PubMed1995

High doses of dietary arginine during repletion impair weight gain and increase infectious mortality in protein-malnourished mice.

There is considerable evidence for the beneficial effects of dietary arginine, a conditionally-essential amino acid that enhances anabolism and T-cell function. However, the safety and efficacy of higher doses of arginine supplementation following infection have not been investigated completely. These issues were explored therefore, in a murine model of malnutrition and infection. Severe protein malnutrition was induced by feeding mice for 6 weeks on an isoenergetic diet containing only 10 g protein/kg. Mice were then allowed to consume diets with normal amounts of protein (200 g/kg) with 50 g/kg provided as amino acid mixtures of glycine and arginine in which the arginine content ranged from 0 to 50 g/kg. During the repletion period a significant weight gain was noted in the groups fed on diets with either 10 or 20 g arginine/kg, but not in the group fed on the diet with 50 g arginine/kg, compared with the diet with 0 g arginine/kg. Mortality rates after infection with Salmonella typhimurium were not decreased by the addition of 10 or 20 g arginine/kg to the diet, and were in fact worsened by supplementation with 50 g arginine/kg. The results of the present study showed that not only are the beneficial effects of arginine supplementation after infection lost when high doses are administered, but also that these high doses become toxic. Mice fed on higher doses showed significant impairment of weight gain and an increase in mortality rates.

Animals↗
PubMed1995

[The intestine: a central organ in the pathogenesis of septic complications in acute pancreatitis].

Despite the array of new diagnostic and therapeutic tools, acute pancreatitis remains a critical condition with a high rate of septic morbidity and mortality. To date the main cause of death is still the occurrence of septic complications. In 80% the cases, the microorganisms responsible for infection are of enteric origin and in 30% of the patients with septic shock, no evident focus of infection is recognized. Bacterial translocation is increasingly accepted as the main cause of infection, sepsis and multiple organ failure in these critically ill patients. The mechanisms facilitating the loss of gut barrier function are overgrowth of enteric bacteria and damage to the intestinal mucosa. Pancreatitis-induced immunosuppression may allow the systemic spread of translocated organisms and subsequent severe septic sequelae.

Acute Disease↗
PubMed1994

Biomechanical testing of pars defect repairs.

STUDY DESIGN: Human lumbar vertebral bodies were used to biomechanically test three different pars interarticularis defect repair techniques. A posteriorly directed force was applied to the inferior facets so that a bending moment was created across the pars. OBJECTIVES: The stiffness and strength of each type of repair was measured and compared with the intact values. SUMMARY OF BACKGROUND DATA: The Buck screw provided both the stiffest and strongest repair overall and within each group of cadaveric specimens. This was followed by the Morscher hook screw. Both the screw and hook repair were statistically significantly stronger and stiffer than the wire repair. There was no statistical difference between the screw and hook repairs regarding strength or stiffness. METHODS: Using the intact L1 vertebral body as a control for each cadaver, the three surgical techniques for pars repair could be evaluated. RESULTS: The screw repair provided 64% of the intact stiffness and 58% of the intact strength. The hook repair provided an average of 52% of the intact stiffness and 40% of the intact strength. The wire provided only 3.5% of the intact stiffness and 12% of the intact strength. CONCLUSIONS: The screw repair technique is the stiffest and strongest pars repair method. The wire technique restores the least stiffness and strength.

Aged↗
PubMed1994

A new strategy for prolonging xenograft survival.

A new strategy based on a clonal reduction hypothesis has been developed for prolonging concordant cardiac xenograft survival. Splenocytes from Golden Syrian hamsters were transfused intravenously into Lewis rats 14 days before the time of a donor-specific heart transplant into the recipient. Cyclophosphamide was administered from days -11 to -7 to reduce or eliminate proliferating xenoreactive clones. Low dose CsA was administered after the cyclophosphamide to prevent emergence and expression of xenoreactive cells. Finally, rapamycin 1.0 mg/kg was given for 5 days after transplant as further immunosuppression since it acts synergistically with CsA. In the group that received no immunosuppression after day +8, mean graft survival was 33.2 +/- 7.0 days with 10 of 17 xenografts surviving > 28 days. Extending either CsA therapy or rapamycin therapy after day +8 did not prolong graft survival. Each component of the therapy was found to be necessary for the effect.

Animals↗