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Biomedical subjects

J W Alexander

Publications and source records attributed to J W Alexander.

At least 127 records · Page 7Linked to original sources
PubMed1993

Reduction of bacterial translocation with oral fibroblast growth factor and sucralfate.

The aim of this study was to evaluate the ability of basic fibroblast growth factor (bFGF) and sucralfate to prevent bacterial translocation after burn injury. Four groups of Balb/c mice (n = 10/group) were treated by gavage with bFGF (10 micrograms/kg/d), sucralfate (15 mg/kg/d), bFGF plus sucralfate, or saline for 4 days prior to receiving a gavage with 1 x 10(10) 14C-radiolabeled Escherichia coli and a 20% full-thickness burn. Four hours after burn, the mesenteric lymph nodes, liver, spleen, and blood were harvested aseptically. For each tissue, the number of viable bacteria and radionuclide counts of the translocated 14C-labeled E. coli were measured, and the percentage of translocated organisms that remained alive was calculated. The results indicated that treatment with either bFGF or sucralfate alone had a partial effect on translocation, whereas the combined treatment with bFGF plus sucralfate significantly decreased the magnitude of translocation in all tested tissues (p < 0.05, ANOVA), which was associated with complete preservation of gut mucosal integrity. None of the treatments affected the ability of the host to kill translocated bacteria when the results were compared with those of the controls. The additive effect of the combined therapy may be due to the high affinity of sucralfate for bFGF, decreasing the degradation of bFGF by gastric acid.

Animals↗
PubMed1993

Identification of the blood component responsible for increased susceptibility to gut-derived infection.

It has previously been reported that the transfusion of allogeneic whole blood increases sepsis-related mortality and decreases the ability of the host to kill bacteria that have translocated from the intestinal tract. To determine which blood component contributes to this adverse effect, the impact of the transfusion of white cells (WBCs), red cells (RBCs), and plasma on microbial translocation, bacteria killing, and mortality rate was studied. Blood from C3H/HeJ mice was separated into WBCs, RBCs, and plasma, and these fractions were transfused to Balb/c mice. Controls received sterile saline. Five days after transfusion, all Balb/c mice underwent a 20-percent burn and gavage with 1 x 10(10) Escherichia coli labeled with 14C-glucose. Mortality was observed for 10 days. Four additional groups, receiving the same treatment as above, were sacrificed 4 hours after the burn, and mesenteric lymph nodes, liver, kidney, and blood were harvested aseptically. For each tissue, quantitative colony counts, radionuclide counts, and percentage of translocated bacteria that remained alive were calculated. By radionuclide counts, no difference was observed in the degree of 14C E. coli translocation among the groups. In contrast, the percentage of viable bacteria and the mortality rate were significantly higher in the group receiving allogeneic WBCs than in all other groups (p < 0.05). It is concluded that WBCs are the component in transfused blood that has an adverse effect on host resistance to gut-derived infection.

Animals↗
PubMed1993

Arginine-supplemented diets improve survival in gut-derived sepsis and peritonitis by modulating bacterial clearance. The role of nitric oxide.

OBJECTIVE: The effect of arginine on survival rates and host defense mechanisms was studied using two clinically relevant models of infection that included transfusion-induced immunosuppression. SUMMARY BACKGROUND DATA: Dietary arginine will improve resistance to infection but its role in transfusion-induced immunosuppression and bacterial translocation (gut-derived sepsis) has not been defined. METHODS: Balb/c mice were fed for 10 days with either a defined AIN-76A diet, an AIN-76A diet supplemented with 2% arginine, an AIN-76A diet supplemented with 4% glycine, or standard laboratory chow. In most experiments, the mice were then transfused with allogeneic blood and allowed to feed for an additional 5 days before undergoing either cecal ligation and puncture (CLP) or gavage with 10(10) Escherichia coli and a 20% burn injury. Additional animals fed with the arginine supplemented diet were treated with the nitric oxide inhibitor N omega-Nitro-L-arginine (NNA) before gavage and burn. The effect of these diets and NNA on the degree of translocation of 14C-radiolabeled E. coli from the intestine and the ability of the host to kill translocated organisms was also investigated. Mice were fed and received transfusion, gavage, and burn as above. Mesenteric lymph nodes (MLN), liver and spleen were harvested 4 hours postburn. RESULTS: Survival after CLP was 56% in the arginine-supplemented group versus 28% in the AIN-76A group and 20% in the chow group (p < 0.02). After gavage and burn, survival was 100% in the arginine-supplemented group versus 50% in both the glycine-supplemented and chow groups and 35% in the AIN-76A group (p < 0.01). In animals receiving the arginine-supplemented diet, treatment with NNA decreased survival from 95% to 30.5% (p < 0.0001). Greater translocation, as measured by radionuclide counts, was observed to the MLN of the AIN-76A group. However, there was no difference in translocation to the liver and spleen related to dietary group. Quantitative colony counts and the calculated percentage of remaining viable bacteria showed that the ability to kill translocated organisms was significantly enhanced in animals receiving arginine. Treatment with NNA reversed the beneficial effects of arginine on immune defense. CONCLUSIONS: The benefit of arginine appears to be mediated by improved bactericidal mechanisms via the arginine-nitric oxide pathway.

Animals↗
PubMed1993

Clinical correlations of cyclosporine-specific and -nonspecific assays in stable renal transplants, acute rejection, and cyclosporine nephrotoxicity.

Accurate and early diagnosis of the cause of renal transplant dysfunction is important in successful patient management. Controversy exists as to whether a cyclosporine-specific or -nonspecific method is more predictive of clinical events. In an attempt to answer this question, all episodes of acute renal dysfunction were reviewed in 322 stable renal transplant recipients over a 20-month period. To diagnose the cause of each episode of renal dysfunction, an analysis was made of patient demographics; weight; serum creatinine; cyclosporine dose; cyclosporine level, using a specific method--high-performance liquid chromatography (HPLC)--and a nonspecific method--fluorescent polarization immunoassay (FPIA); changes in cyclosporine dose; renal biopsy; and response to any therapeutic intervention. There were 138 patients, who developed 279 episodes of renal dysfunction. Causes of renal dysfunction were cyclosporine-related (n = 103), acute rejection (n = 63), extracellular fluid volume depletion (n = 27), other (n = 59), and unknown (n = 27). The mean HPLC cyclosporine level was significantly different in patients with acute cyclosporine toxicity (p < 0.001) and patients with acute rejection (p < 0.001) when compared to those with stable renal function; the mean FPIA cyclosporine levels were not significantly different between the three groups. However, a larger percentage of patients with rejection were subtherapeutic when measured by HPLC, while a higher proportion of patients with nephrotoxicity were above the therapeutic range measured by FPIA.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1993

Effect of a short course of rapamycin, cyclosporin A, and donor-specific transfusion on rat cardiac allograft survival.

The interactions of rapamycin (Rapa), CsA, and donor-specific transfusion (DST) were examined in an ACI to Lewis rat heterotopic cardiac allograft model. Survival data were truncated at 175 days for the purpose of statistical comparisons. Vehicle (Veh)-treated animals rejected at a mean of 7.3 +/- 0.2 days. Treatment with a DST on the day before transplantation (d-1) resulted in a decreased survival of 5.5 +/- 0.3 days (P < 0.05). An 8-day course of low-dose CsA (d-1 to d6) in Veh-treated animals prolonged allograft survival to 10.3 +/- 0.5 days (P < 0.05). The addition of a DST d-1 to the Veh/CsA-treated animals resulted in a synergistic prolongation of survival to 45.7 +/- 12.5 days (P < 0.05). Rapa proved to be a potent immunosuppressive agent in this model, with an 8-day course of Rapa (d-1 to d6) at 0.5 mg/kg/day (R1) or 1.5 mg/kg/day (R2), resulting in mean allograft survivals of 24.2 +/- 5.0 and 67.3 +/- 20.9 days, respectively (P < 0.05 vs. Veh or Veh/CsA). Rapa demonstrated synergy with CsA by further prolonging allograft survival to 115.9 +/- 27.9 days (R1/CsA, P < 0.05 vs. Veh/CsA, R1) and 164.6 +/- 10.4 days (R2/CsA, P < 0.05 vs. Veh/CsA). The extended graft survival using a combination of Rapa and DST, compared to Rapa alone, did not prove to be statistically significant. When all three treatments were combined (Rapa/DST/CsA), no significant benefit to survival was seen over Veh/DST/CsA (45.7 +/- 12.5 days vs. R1/DST/CsA, 81.9 +/- 18.4 days; R2/DST/CsA, 98.5 +/- 21.3 days; P > 0.05). If Rapa was withheld until postoperative day 1 (Rapa, 1.5 mg/kg/day on d1 to d6/DST/CsA), enhancement of the DST/CsA effect was seen with a mean survival of 170.2 +/- 4.8 days (P < 0.05). This suggests that the timing of Rapa administration may significantly impact its interaction with DST/CsA treatment and merits further investigation.

Animals↗
PubMed1993

Reduced PMN beta 2 integrins after trauma: a possible role for colony-stimulating factors.

The beta 2 integrins are composed of a common 95-kD beta-subunit (CD18) and one of three possible alpha-subunits: CD11a, CD11b, or CD11c. These molecules are involved in neutrophil adhesion, diapodesis, chemotaxis and phagocytosis. In this study, the effects of traumatic injury on neutrophil expression of these alpha-subunits were investigated. Neutrophils from patients with severe trauma (n = 30) were stained with fluorescent anti-CD11a, -CD11b, or -CD11c. The percentage of positive neutrophils and the mean channel fluorescence were assayed by flow cytometry. In 10 patients and 10 normals, the effects of granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) on alpha-subunit expression were evaluated. Ninety-four +/- 2% (s.e.m.) of normal neutrophils were CD11a+, 89 +/- 1% were CD11b+ and 89 +/- 8% were CD11c+. Only 65 +/- 2% of patient neutrophils were CD11a+, 45 +/- 5% were CD11b+ and 8 +/- 1% were CD11c+. Culture of normal neutrophils without colony-stimulating factors resulted in reduced expression of CD11a and CD11c, but up-regulation of CD11b. Down-regulation of CD11a and CD11c was partially reversed by colony-stimulating factors (30 U/ml). CD11b receptor density was further up-regulated by GM-CSF and G-CSF. Treatment of patient neutrophils with colony-stimulating factors in culture resulted in up-regulation of alpha-subunits as well. GM-CSF appeared to have the greater effect. These results indicate that colony-stimulating factors may have a clinical role in improving beta 2 integrin expression, and suggest a use in these infection-prone patients.

Adolescent↗
PubMed1993

Histological, biochemical, and ultrastructural studies on hyperpigmented human skin xenografts.

The mechanisms for hyperpigmentation observed in human cutaneous xenografts placed on athymic nude mice was investigated. Histologic, biochemical, histochemical, and ultrastructural examinations were performed on human skin prior to grafting and at various times ranging from 2 weeks to 30 weeks post-grafting (PG). Hyperpigmentation was macroscopically visible on the graft as early as 4-6 weeks. The number of Dopa-positive melanocytes per unit area was increased at 2 weeks PG and remained elevated until 20 weeks PG. The surface area of the melanocytes, a measure of the activity of the cells, also increased significantly and remained above the pre-grafting size throughout the study. Western blot analysis using tyrosinase specific antibody (alpha Ty-SP) revealed the presence of tyrosinase exclusively in the grafted skin from 2 weeks to 12 weeks PG tested. Histological and ultrastructural observations revealed the presence of numerous dendritic melanocytes, indeterminant clear cells suggestive of Langerhans cells, and dermal melanophages. The results of this study suggest that the observed hyperpigmentation in grafted tissue is caused by an increase in the number of Dopa-positive melanocytes and probably from enhanced melanin production. Extracts of proteins from the xenografts exhibited prominent differences in low and high molecular proteins between pre- and post-grafted skin. Among them, the exclusive appearance of a protein doublet with apparent mw approximately 14 kDa was found in grafted skin, and subsequent studies indicate it has potent effects on melanocyte function.

Animals↗
PubMed1993

Sociotechnical professional perspectives for a nursing administration curriculum.

The curriculum as described was implemented four years ago. We have not yet been able to test and fully evaluate the model. What has been demonstrated is an ability by the students to articulate the philosophical principles of the sociotechnical/professional perspective in comprehensive examinations. These exams and students' papers also demonstrate the students' ability to apply the principles. The curriculum is essentially a philosophical overlay, thus a limitation of the curriculum is that the faculty must truly be committed to and believe in the administrative roles of facilitation, coordination, and integration. Because this view of administration is new, time is needed to orient faculty who have learned and taught from a more traditional framework. This new view is a strength from the student perspective. Many come to graduate school seeking new ways. A sociotechnical/professional perspective for nursing administration reflects the most current nursing and management literature and is considered to be very contemporary and future-oriented.

Curriculum↗
PubMed1993

Prednisone withdrawal in HLA identical and one haplotype-matched live-related donor and cadaver renal transplant recipients.

Prednisone withdrawal was attempted in 121 of 915 renal transplants recipients between 1967 to 1992. There were 57 males, 64 females. Age range was 21 to 62 (mean 39.2 years). Etiology of renal failure was chronic glomerulonephritis (54), diabetic nephropathy (36), interstitial disease (17), hypertensive nephrosclerosis (6), and other (8). Kidney source was from HLA-identical living-related donors (LRD) in 54 (Group I), one haplotype-matched LRD in 23 (Group II), and cadaver in 44 (Group III). Prior to the introduction of cyclosporin A (CsA) in 1984, prednisone withdrawal was attempted only in Group I. After 1984, prednisone withdrawal was also attempted in patients in Groups II and III, selected on the basis of having had no rejection episodes during the six months after transplantation. Forty-five patients in Group I were treated with azathioprine (Aza) and prednisone, and the remaining patients in Groups I to III were treated with Aza, prednisone and CsA. Mean follow-up was 93 months (6 to 207). Prednisone was gradually tapered and withdrawn in 94 of 121 patients after a mean period of 22.5 months (9 to 60). In 27 other patients, the prednisone dosage has been tapered to 5 mg/day or less with the aim of discontinuing the drug. There were seven episodes of acute rejection (3 during taper, and 1 each at 6, 7, 24 and 114 months after prednisone withdrawal); all seven were successfully reversed. Four other patients developed chronic vascular rejection (2 during taper and 2 after withdrawal).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Bacterial translocation: a potential source for infection in acute pancreatitis.

Infections from enteric bacteria are a major cause of morbidity and mortality during acute pancreatitis (AP), but the pathways by which these organisms reach distant organs remains speculative. Experiments were conducted to determine if bacterial translocation could be a mechanism for infection during this disease. AP was induced in Lewis rats by i.v. infusion of caerulein (experiment I) or ligation of the head of the pancreas (experiment II). In a third experiment, rats were gavaged with 1 x 10(8) 14C-radiolabeled Escherichia coli and pancreatitis was induced with caerulein. Results in all three experiments showed that AP increased the number of viable bacteria recovered in peritoneal fluid, mesenteric lymph nodes (MLN), liver, lungs, and pancreas. Radionuclide counting indicated that AP enhanced the gut permeability to 14C E. coli. To estimate the impact of AP on the magnitude of translocation and on the ability of the host to clear bacteria, the nuclide and colony-forming units (CFU) ratios were calculated between animals with and without AP. Blood, peritoneal fluid, and MLN had the highest nuclide ratio. During AP, these tissues may be the principal routes for bacterial spreading from the gut lumen. Peritoneal fluid, pancreas, and lung were the tissues with the highest CFU ratio. Bacterial killing ability of these tissues is likely impaired during AP.

Acute Disease↗
PubMed1993

Prostaglandin E1 analogues misoprostol and enisoprost decrease microbial translocation and modulate the immune response.

The aim of this study was to investigate the ability of two prostaglandin E1 (PGE1) analogues, misoprostol and enisoprost, to alter bacterial translocation following burn injury. Balb/c mice were treated with misoprostol (n = 36) or enisoprost (n = 36) for 3 days with different doses (20 or 200 micrograms/kg/day) prior to receiving a 20% full-thickness burn and simultaneous gavage with 1 x 10(10) 14C-Escherichia coli. Animals were sacrificed 4 and 24 hr postburn, and blood, peritoneal fluid, mesenteric lymph nodes, spleen, liver, and lungs were harvested aseptically. Radionuclide counts, number of viable bacteria, and percentage of translocating bacteria remaining alive in each tissue suggested that the high doses of misoprostol or enisoprost decreased the magnitude of 14C-E. coli translocation, while the low dose of both drugs enhanced bacterial clearance. Therefore, both misoprostol and enisoprost reduce bacterial translocation, and modulate bacterial clearance in a dose-dependent manner.

Alprostadil↗
PubMed1993

Translocation of Candida albicans is related to the blood flow of individual intestinal villi.

Splanchnic ischemia is associated with increased bacterial translocation, but previous observations showed that translocation of Candida albicans did not occur uniformly among individual intestinal villi. This study was performed to investigate the relationship between the degree of Candida translocation and the microcirculation of individual villi. Thiry-Vella intestinal loops were created in eight guinea pigs. One week later, the distal aorta and right carotid artery were cannulated, and systemic blood pressure was recorded throughout the entire experiment. C. albicans (1 x 10(10)) was introduced into the Thiry-Vella loop, and the animals underwent a 40% full-thickness burn. Systolic hypotension was observed in the first 75 minutes postburn; then the systemic blood pressure returned to a normal range. Four hours after burn, 8 x 10(7) microspheres (10 microns) were injected into the aorta. The animals were sacrificed, and the Thiry-Vella loops were harvested and processed for light microscopy. At the microscopic level, within each villus, both the number of beads trapped in the arterioles and the number of Candida translocated into the enterocytes were counted. An inverse linear correlation between number of beads and number of translocated yeast per individual villus was found (r = -0.78; P < 0.005). These data provide further evidence that blood flow is an important determinant of the magnitude of microbial translocation, even within individual villi.

Animals↗
PubMed1993

Cyclosporine-ketoconazole interaction. Long-term follow-up and preliminary results of a randomized trial.

Forty-three renal transplant recipients receiving cyclosporine were started on 200 mg/day of oral ketoconazole 10 days to 75 months posttransplant. The cyclosporine dose was reduced by 70% when ketoconazole was started. The mean cyclosporine dose was 5.6 mg/kg/day preketoconazole, and 0.9, 0.8, and 0.7 mg/kg/day at one, two, and three years after addition of ketoconazole (cyclosporine dose reduction 84%, 86%, and 88% at one, two, and three years, respectively). Two patients died after two years of combination therapy, six patients returned to dialysis, and ketoconazole was discontinued in four. Renal function in patients on ketoconazole remained stable (serum creatinine 1.8, 1.7, 1.7, and 1.8 mg/dl preketoconazole and at one, two, and three years, respectively). In a second study, 52 patients were randomized to standard doses of cyclosporine (n = 28), or reduced doses of cyclosporine with ketoconazole (n = 24); seven of the patients were not started on ketoconazole. In 28 patients on standard-dose cyclosporine, there were two deaths and one graft loss. In 17 patients receiving ketoconazole there were two deaths and no graft losses. Renal function and the frequency of rejection episodes was similar in the two groups. In the ketoconazole group, the cyclosporine dose was < 20% of that in the patients on standard doses. In both studies addition of ketoconazole to cyclosporine-treated patients resulted in significant inhibition of cyclosporine metabolism and decrease in dosage in patients followed for up to four years. This drug interaction provides a significant reduction in cost of immunosuppressive therapy in organ transplant recipient.

Adult↗
PubMed1993

The effects of antibiotic-impregnated autogeneic cancellous bone graft on bone healing.

Autogeneic cancellous bone graft has been recommended as a vehicle for local antibiotic delivery. Its effect on graft incorporation, however, is unknown. The healing of defects grafted with tobramycin-impregnated cancellous bone were compared with those grafted with cancellous bone alone. Plane roentgenographs, microradiographs, bone density analyses, histologic examination, and biomechanical testing were performed on specimens throughout the course of healing. The presence of large concentrations of local tobramycin does not appear to affect the normal healing characteristics of cancellous bone graft.

Animals↗