Effect of different combinations of dietary additives on bacterial translocation and survival in gut-derived sepsis

BACKGROUND: Dietary arginine, glutamine, and fish oil each have been shown to improve resistance to infection. The purpose of this study was to assess the potential benefit of different combinations and amounts of these components on bacterial translocation and related mortality during gut-derived sepsis. METHODS: Balb/c mice were fed for 10 days with an AIN-76A diet supplemented with different combinations and percentages of arginine, glutamine, glycine, fish oil, and medium-chain triglycerides. Controls were fed a complete AIN-76A diet or chow. After 10 days of feeding, all animals were transfused. On day 15, the animals were gavaged with 10(10) 111In-radiolabeled or unlabeled Escherichia coli and given a 30% burn injury. Animals gavaged with unlabeled bacteria were observed for survival (n = 317). Groups that showed the best survival as well as control groups were gavaged with labeled bacteria and killed 4 hours postburn (n = 60) for harvest of mesenteric lymph nodes, liver and spleen. RESULTS: Mice fed diets enriched with 5% fish oil + 2% arginine, 2% arginine + 2% glutamine, or 5% fish oil + 2% glutamine had higher survival than control groups. The animals fed fish oil+glutamine had significantly reduced translocation to the liver and spleen. Animals fed arginine+glutamine had an enhanced ability to kill translocated organisms in the liver compared with other groups. Fish oil+arginine improved both barrier function and microbial killing. CONCLUSIONS: Feeding with arginine+glutamine, fish oil+arginine, or fish oil+glutamine supplemented diets positively affects the outcome in a gut-derived sepsis model.     

Burn variables influencing survival: a study of 144 patients

This review assess the influence of burn variables on patients' survival using epidemiological analysis of 144 patients admitted over a 2-year period, the overall mortality rate was 9.7 per cent. The risk of mortality in patients with 30-50 and 50-80 per cent total body surface area (TBSA) burns was 16 and 86 times that in patients with less than 30 per cent TBSA burns respectively. The risk of mortality was multiplied by five when burns were full skin thickness or arrival was delayed for between 2 and 5 h. The increases in burn size, burn depth and arrival delay significantly raised the mortality rate (P < 0.0001, P = 0.02 and P = 0.01 respectively). When burn surface area (BSA) exceeded 30 per cent TBSA, the effect of the other two variables on survival were reinforced. When the patients' age was under 6 years and BSA was above 85 per cent TBSA, the risk of mortality was increased five times but insignificantly raised its rate.     

Recombinant human erythropoietin in the anemia associated with multiple myeloma or non-Hodgkin's lymphoma: dose finding and identification of predictors of response

Previous phase I-II clinical trials have shown that recombinant human erythropoietin (rHuEpo) can ameliorate anemia in a portion of patients with multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL). Therefore, we performed a randomized controlled multicenter study to define the optimal initial dosage and to identify predictors of response to rHuEpo. A total of 146 patients who had hemoglobin (Hb) levels < or = 11 g/dL and who had no need for transfusion at the time of enrollment entered this trial. Patients were randomized to receive 1,000 U (n = 31), 2,000 U (n = 29), 5,000 U (n = 31), or 10,000 U (n = 26) of rHuEpo daily subcutaneously for 8 weeks or to receive no therapy (n = 29). Of the patients, 84 suffered from MM and 62 from low- to intermediate-grade NHL, including chronic lymphocytic leukemia; 116 of 146 (79%) received chemotherapy during the study. The mean baseline Hb level was 9.4 +/- 1.0 g/dL. The median serum Epo level was 32 mU/mL, and endogenous Epo production was found to be defective in 77% of the patients, as judged by a value for the ratio of observed-to-predicted serum Epo levels (O/P ratio) of < or = 0.9. An intention-to-treat analysis was performed to evaluate treatment efficacy. The median average increase in Hb levels per week was 0.04 g/dL in the control group and -0.04 (P = .57), 0.22 (P = .05), 0.43 (P = .01), and 0.58 (P = .0001) g/dL in the 1,000 U, 2,000 U, 5,000 U, and 10,000 U groups, respectively (P values versus control). The probability of response (delta Hb > or = 2 g/dL) increased steadily and, after 8 weeks, reached 31% (2,000 U), 61% (5,000 U), and 62% (10,000 U), respectively. Regression analysis using Cox's proportional hazard model and classification and regression tree analysis showed that serum Epo levels and the O/P ratio were the most important factors predicting response in patients receiving 5,000 or 10,000 U. Approximately three quarters of patients presenting with Epo levels inappropriately low for the degree of anemia responded to rHuEpo, whereas only one quarter of those with adequate Epo levels did so. Classification and regression tree analysis also showed that doses of 2,000 U daily were effective in patients with an average platelet count greater than 150 x 10(9)/L. About 50% of these patients are expected to respond to rHuEpo. Thus, rHuEpo was safe and effective in ameliorating the anemia of MM and NHL patients who showed defective endogenous Epo production. From a practical point of view, we conclude that the decision to use rHuEpo in an individual anemic patient with MM or NHL should be based on serum Epo levels, whereas the choice of the initial dosage should be based on residual marrow function.     

Foreign residency: specialist candidate in the United States

OBJECTIVE: Endotoxin as the inciting agent of cytokines and other mediators, whose high level expression correlates with the septic shock and MOF, has been the one of leading causes of death in ICU. METHODS: For treating sepsis and MOF caused by endotoxin, the anti-lipid A of LPS antibody was used, 19 burned patients whose TBSA varied from 50% to 100% were divided into anti-LPS treatment group and nontreated group. RESULTS: The levels of serum endotoxin, IL-6, IL-8, TNF and soluble IL-2R were lower obviously in patients of anti-LPS group than those of nontreated group (P < 0.05). CONCLUSION: Clinical study surggests that anti-lipid A of LPS antibody can act as an therapeutic agent against gram-negative bacterin infection in burned patients.     

Effect of lysostaphin on phagocyte function in burn mice

The ability of lysostaphin to prevent immunosuppression of phagocyte was assessed in burn mice. A full thickness burn covering 20% of TBSA was created on back of mouse, Lysostaphin was given intraperitoneally (400 micrograms/kg/day) for 3 days in treatment group. The results showed that lysostaphin treatment could restore the depression of phagocytosis of chick RBC by peritoneal macrophages. In the group treated by lysostaphin, peritoneal macrophage chemiluminescence expressed much greater peak value than that in both burn and normal groups. The a-value, which is a criterion of carbon clearance, was 1.63 x 10(-2) in lysostaphin treated mice, while that in burn and normal mice were 8.13 x 10(-4) and 2.76 x 10(-3), respectively. Results of the study indicated that lysostaphin was effective in improving phagocytosis by phagocytes.     

Apolipoprotein E-deficient mice have impaired innate immune responses to Listeria monocytogenes in vivo

Apolipoprotein E (apoE) influences both innate and acquired immunity in cultured cells. To determine whether apoE affects the immune system in vivo, Listeria monocytogenes (LM) was administered intraperitoneally (10(4) c.f.u.) to congenic C57BL/6 apoE-/- and +/+ mice (n = 12 in each group). Survival was assessed daily for 5 days. Deficiency of apoE significantly increased death by day 5 (P = 0.03). The majority of deaths occurred at day 4. Extent of infection after LM administration was assessed at day 3 by determining colony counts in hepatic and splenic extracts. ApoE+/+ mice had very low colony counts in both spleen and liver [mean +/- SE: 2.0 +/- 0.5 and 0.7 +/- 0.2 (x 10(4)), respectively, n = 8 in each group]; while apoE-/- mice had significantly increased counts in both spleen and liver [64 +/- 51 and 98 +/- 93 (x 10(4)), P = 0.05 and 0.03]. Serum concentrations of TNF-alpha were significantly increased in apoE-/- mice at day 3 compared to apoE+/+ mice (127 +/- 43 pg/ml versus 20 +/- 17, P = 0.003). LM induced more hepatic damage in apoE-/- mice compared to apoE+/+ mice as judged by increased serum concentrations of alanine aminotransferase at day 1 (apoE-/- 301 +/- 45 U/ml, apoE+/+ 101 +/- 9 U/ml, P = 0.01). The increased proliferation and mortality from LM in apoE-/- mice occurred prior to the initiation of acquired immune responses. Therefore, apoE-deficient mice have an impaired innate response to infection by LM.     

Allogeneic peripheral blood stem cell transplantation in patients with advanced hematologic malignancies: a retrospective comparison with marrow transplantation

Allogeneic peripheral blood stem cell (PBSC) transplants from HLA-identical siblings were performed in 37 patients with advanced hematologic malignancies. Outcomes were compared to a historical group of 37 similar patients with advanced hematologic malignancies receiving bone marrow (BM) transplants from HLA-identical donors. The PBSC group and historical BM group were well matched for diagnosis, disease stage, age, and graft-versus-host disease (GVHD) prophylaxis. Patients received PBSC transplants between 1993 to 1995 while BM patients were treated between 1989 to 1994. Engraftment, measured by the time to reach a peripheral neutrophil count > 500/L and platelet count > 20,000/microL without transfusions, occurred on days 14 and 11 in the patients transplanted with PBSC compared to days 16 and 15 in the patients receiving BM (P = .00063, .00014). The PBSC group required a median of 8 U of red blood cells and 24 U of platelets compared to 17 U of red blood cells and 118 U of platelets for BM transplant recipients (P = .0005, .0001). The estimated risks of developing grades 2 to 4 acute GVHD were 37% for the PBSC group and 56% for the BM group (P = .18), while the estimated risks of grades 3 to 4 acute GVHD were 14% for the PBSC group and 33% for the BM group, P = .05). Chronic GVHD occurred in 7 of 18 evaluable patients receiving PBSC and 6 of 23 evaluable patients receiving BM, P = .5. The estimated risks of transplant-related mortality at 200 days were 27% versus 45% (P = .33) relapse were 70% versus 53% (P = .27) and of overall survival were 50% and 41% (P = .39) for patients transplanted with PBSC or BM, respectively. This retrospective comparison suggests that compared to marrow transplantation from HLA-identical donors, allogeneic PBSC transplantation from HLA-identical donors is associated with faster engraftment, fewer transfusions, and no greater incidence of acute or chronic GVHD.     

Serum enzymatic changes modulated using trypsin: chymotrypsin preparation during burn wounds in humans

The levels of marker enzymes for liver function, namely transaminases (SGPT, SGOT), creatine phosphokinase (CPK), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) were estimated in the sera of burn patients by administering trypsin: chymotrypsin preparation and comparing with an untreated group. Neutrophil proteolytic activity was also measured by assaying the lysosomal enzymes, namely neutrophil elastase and cathepsin D. Our earlier studies have already proved the efficacy of the above enzyme preparation to burn patients on the enhancement of vascular responses during the acute phase of the burn injury. These beneficial responses were brought about by the modulation of acute phase proteins expressed in the liver. Hence, it is of interest to study the changes in the above mentioned liver enzymes and certain lysosomal enzymes in the serum during the first 10 days of burn injury. The levels of liver and lysosomal enzymes markedly decreased in the treated group when compared with the untreated group. The enzyme studies clearly indicated that the initial rise in the liver enzymes was minimized in the treated group when compared with the untreated group and this helped in reducing the stress to the liver in the treated cases. The increase in the activity of alpha 1-antitrypsin and alpha 2-macroglobulin and decreased levels of C-reactive protein are attributed to the reduction of proteolytic enzyme levels in the treated group and minimizing the degradative changes during wound repair.     

Recombinant human erythropoietin in transfusion-dependent anemic patients with multiple myeloma and non-Hodgkin's lymphoma--a randomized multicenter study. The European Study Group of Erythropoietin (Epoetin Beta) Treatment in Multiple Myeloma and Non-Hodgkin's Lymphoma

One hundred twenty-one anemic, transfusion-dependent patients with multiple myeloma (MM) or low-grade non-Hodgkin's lymphoma (NHL) were randomly allocated to receive (a) recombinant human erythropoietin (rhEPO) 10,000 U/d subcutaneously 7 days a week (fixed dose group) (n = 38), or (b) rhEPO 2,000 U/d subcutaneously for 8 weeks followed by step-wise escalation of the rhEPO dose (titration group) (n = 44), or (c) no rhEPO therapy (control group) (n = 39). The total treatment period was 24 weeks. There were no differences between the three groups with regard to baseline clinical, demographic, or health status measures. The cumulative response frequency, defined as elimination of the transfusion need in combination with an increase in the hemoglobin concentration by >20 g/L, was 60% in both rhEPO treatment groups and 24% in the control group (P = .01 and .02, respectively, log rank test). For patients in the titration group the response rate on the first dose level (2,000 U/d) was only 14%. Cox's univariate regression analysis revealed that an inadequately low endogenous erythropoietin concentration in relation to the degree of anemia and a baseline platelet concentration > or = 100 x 10(9)/L were significant predictors for response to rhEPO therapy (P < .01). Multivariate regression analysis showed that relative erythropoietin concentration was the most important factor and the platelet count had no additional influence on response. Treatment with rhEPO was well tolerated. We conclude that treatment with rhEPO may be indicated in anemic MM and NHL patients with a relative erythropoietin deficiency. An initial dose of 5,000 U/d subcutaneously may be recommended.     

The role of splenic macrophages in plasma tumor necrosis factor levels in endotoxemia

We investigated the function of splenic macrophages (M phi s) with respect to changes in plasma tumor necrosis factor (TNF) in lethally endotoxemic rats treated with gadolinium chloride (GdCl3), which blocks the phagocytosis of large liver M phi s. We also carried out an immunohistochemical study to investigate the change of populations of liver and splenic M phi s under the condition of dysfunction of liver M phi s with or without splenectomy. Twenty-four-hour survival rates were 100% in the GdCl3-treated group (n = 6) and 0% in the nontreated group (n = 6). These rates did not change with splenectomy. Immunohistochemical examination with the primary monoclonal antibodies ED1, ED2 and ED3 revealed that large liver M phi s were eliminated after GdCl3 injection, and that this was not related to splenectomy. The splenic M phi s were not affected by GdCl3 treatment. Plasma TNF levels did not differ between the GdCl3-treated and the nontreated groups, irrespective of whether splenectomy was performed. It was suggested that plasma TNF levels are not affected by the splenic M phi s and that they do not compensate for dysfunction of liver M phi s after GdCl3 treatment.     

Visceral leishmaniasis in the BALB/c mouse: a comparison of the efficacy of a nonionic surfactant formulation of sodium stibogluconate with those of three proprietary formulations of amphotericin B

In this study, treatment efficacies of a nonionic surfactant vesicle formulation of sodium stibogluconate (SSG-NIV) and of several formulations of amphotericin B were compared in a murine model of visceral leishmaniasis. Treatment with multiple doses of AmBisome, Abelcet, and Amphocil (total dose, 12.5 mg of amphotericin B/kg of body weight) resulted in a significant suppression of parasite burdens in liver (P < 0.0005) and spleen (P < 0.0005) compared with those of controls, with Abelcet having the lowest activity. Only AmBisome and Amphocil gave significant suppression of parasites in bone marrow (compared to control values, P < 0.005). In the acute-infection model, single-dose treatments of SSG-NIV (296 mg of SbV/kg), SSG solution (296 mg of SbV/kg), or AmBisome (8 mg of amphotericin B/kg) were equally effective against liver parasites (compared to control values, P < 0.0005). SSG-NIV and AmBisome treatment also significantly suppressed parasites in bone marrow and spleen (P < 0.005), with SSG-NIV treatment being more suppressive (>98% suppression in all three sites). Free-SSG treatment failed to suppress spleen or bone marrow parasites. Infection status influenced treatment outcome. In the chronic-infection model, the AmBisome single-dose treatment was less effective in all three infection sites and the SSG-NIV single-dose treatment was less effective in the spleen. The results of this study suggest that the antileishmanial efficacy of SSG-NIV compares favorably with those of the novel amphotericin B formulations.     

Effect of octreotide on dynamic excretion of bile in Chinese acromegalic patients assessed by [99mTc]EHIDA hepatobiliary scan

We used [99mTc]EHIDA hepatobiliary scintigraphy to determine whether both hepatic bile secretion and gallbladder contractility are suppressed in acromegalic patients receiving long-term treatment with the somatostatin analogue octreotide. We studied three groups of patients: group 1, untreated patients; group 2, average dose of octreotide 500 +/- 100 micrograms/day for 33 +/- 4 months; and group 3, 1000 +/- 200 micrograms/day for 33 +/- 4 months. Images were taken at specified time intervals during the 120-min period following injection of EHIDA. After a single injection of octreotide, group 1 patients demonstrated delayed visualization of the radioisotope in the liver, gallbladder, and duodenum. At the end of long-term treatment, group 2 patients showed a delay in appearance of maximal radioactivity in the gallbladder. Two weeks following discontinuation of octreotide, this parameter had decreased significantly (P < 0.001). In group 3, visualization of the liver, gallbladder, and duodenum were prolonged, with delayed visualization of the gallbladder persisting two weeks after withdrawal (P < 0.005). These results indicate that gallbladder contractility is decreased after a single injection of octreotide and that during chronic octreotide therapy the rate of bile secretion is reduced. Impaired gallbladder contractility normalizes more rapidly after discontinuation of octreotide in patients receiving low doses of the analog.     

Nitric oxide production is increased in patients after burn injury

OBJECTIVE: Human burn injury is associated with an inflammatory response and related hyperdynamic cardiovascular profile. Increased production of nitric oxide (NO), a potent endogenous vasodilator, has been reported in patients with inflammatory states, including sepsis, but not after trauma other than burns. We studied whether plasma levels of the stable byproducts of NO, nitrite (NO2-) and nitrate (NO3-), are increased in burn patients. DESIGN: Prospective controlled study. PATIENTS AND METHODS: In consecutive patients admitted to the intensive care unit of the burn center at the Queen Astrid Military Hospital in Brussels, plasma was drawn daily from day 1 to day 5 postadmission for determination of NO2-/NO3- levels (Griess' reaction). In a control group of nonseptic inpatients from the department of neurology in Erasme University Hospital who were matched for nutrition (30 to 40 kcal/kg/day of a standard enteral solution), plasma was drawn once for NO2-/NO3- determination. MEASUREMENTS AND MAIN RESULTS: The burn group included 16 patients (age 35 +/- 18 years, total burn surface area (TBSA) 37 +/- 19%) and the control group included six patients (age 64 +/- 18 years). For each comparison between the groups, NO2-/NO3- plasma levels were higher in those patients with burns than in the control group. In the burn group, there was no correlation between NO2-/NO3- plasma levels and TBSA, age, TBSA x age, blood pressure or time. However, in a subgroup of five burned patients who became septic during the study period, NO2-/NO3- plasma levels were slightly higher than in the non-infected patients (177 +/- 131 vs. 83 +/- 48 micromoles/L, NS). CONCLUSION: Human burn injury is associated with an increase in NO production. In this small-size study, NO production was not proportional to burn area, and seemed to be further enhanced in septic patients.     

Prevention of corticosteroid-induced suppression of human polymorphonuclear leukocyte-induced damage of Aspergillus fumigatus hyphae by granulocyte colony-stimulating factor and gamma interferon

Neutrophils (PMNs) are a critical line of defense against Aspergillus fumigatus infection. Increased frequency of invasive aspergillosis has been observed in patients receiving corticosteroids, suggesting a deleterious effect of these compounds on PMN antifungal function. To investigate this hypothesis and to determine the potential preventive utility of granulocyte colony-stimulating factor (G-CSF) and gamma interferon (IFN-gamma), the effects of hydrocortisone (HCS) and dexamethasone (DXS) on PMN-induced damage of Aspergillus fumigatus hyphae were studied with or without pretreatment of PMNs with G-CSF and IFN-gamma. PMNs treated with HCS (> or = 3,000 microM) or DXS (> or = 10 microM) during a 2-h colorimetric tetrazolium metabolic assay (using methylthiotetrazolium) showed suppressed percentage of hyphal damage (P < 0.02). In addition, both HCS (> or = 30 microM) and DXS (> or = 1 microM) significantly suppressed oxidative burst measured as superoxide anion release by PMNs in response to opsonized and nonopsonized hyphae as well as to N-formylmethionyl leucyl phenylalanine. Pretreatment of PMNs with G-CSF (4,000 U/ml) and/or IFN-gamma (100 and 1,000 U/ml) for 90 min prevented the suppression of hyphal damage that occurred in the presence of HCS (3,000 microM; P < 0.01) or DXS (10 microM; P < or = 0.001). G-CSF (4,000 U/ml) and IFN-gamma (100 U/ml) combined had an additive effect on increasing the antifungal activity of HCS-treated but not of DXS-treated PMNs compared with IFN-gamma alone (P = 0.015). Thus, these findings reveal that corticosteroids impair PMN function in response to A. fumigatus and that G-CSF and IFN-gamma prevent this impairment.     

An essential role for free radicals and derived species in signal transduction

OBJECTIVE: To examine whether there is generation of oxygen free radicals (OFR) and lipid peroxidation of cell membrane after volume replacement for burn shock, and to study the relationship between OFR injury and enterogenous endotoxemia. METHODS: Forty-seven burn patients were involved in this study. Among them, 18 had delayed fluid resuscitation (DR) and the others had early fluid resuscitation (ER) within 6 hours postburn. Sixty-six gnotobiotic rats were used in a collaborating experiment as burn models. They were divided into 4 groups: sham injury (n = 6), early resuscitation (n = 24), late resuscitation (n = 24) and vitamins E and C treatment group (n = 12). All the rats, except those in the sham injury group, were inflicted with 40% total body surface area (TBSA) third-degree burns. OFR was determined in the blood of patients with electron spin resonance (ESR). S/W ratio and tau c values of patients' erythrocytes were measured with ESR spectrometer. Blood superoxide dismutase (SOD) and glutathione peroxidase (GSHPx) activities, malondialdehyde contents and plasma endotoxin levels were assayed. Rats were sacrificed at the 12th, 24th, 48th and 72nd hour after injury. Plasma endotoxin levels, mucosal SOD, GSHPx and malondialdehyde (MDA), as well as diamine oxidase activity of ileum were determined. Cultures of mesenteric lymph nodes (MLN), liver, spleen, heart, lung, kidney and blood were done. RESULTS: A significant increase in blood OFR contents and plasma MDA, and a significant decline in blood SOD and GSHPx were found after resuscitation in DR group as compared with those in ER group. Both strong to weak spectra component (S/W) ratio and tau c value were higher in DR group in contrast with those in ER group. Higher elevation in plasma endotoxin level in DR group was seen. In DR group, plasma MDA content was correlated with S/W ratio, tau c value and plasma endotoxin level. In rats, the level of mucosal MDA, plasma endotoxin and incidence of bacterial translocation (BT) were significantly higher. Mucosal SOD, GSHPx and diamine oxidase (DAO) activity were significantly lower in DR group as compared with those in ER group. In DR group, mucosal MDA content was negatively correlated with mucosal DAO activity, while the latter was negatively correlated with BT. After treatment with vitamins E and C, mucosal MDA content decreased, plasma endotoxin and BT significantly declined and mucosal DAO heightened. CONCLUSIONS: Tissue reperfusion might induce the production of OFR, resulting in lipid peroxidation injury, especially to intestinal mucosa, and resulting in disruption of mucosal barrier function followed by endotoxemia and BT.     

Heparin prevents postischemic endothelial cell dysfunction by a mechanism independent of its anticoagulant activity

PURPOSE: Heparin may have protective effects on postischemic vascular endothelial cell function that are distinct from its anticoagulant, antiplatelet, or anticomplement activity. We tested this hypothesis in isolated rat hindlimbs. METHODS: Isolated rat hindlimbs underwent 60 minutes of normothermic ischemia and 10 minutes of reperfusion. Potential heparin interaction with plasma-based proteins or cells was eliminated by perfusion of the hindlimbs with a nonrecirculated albumin-enriched crystalloid buffer. Endothelial function was assessed by measurement of endothelium-derived relaxing factor (EDRF) activity. Limbs perfused at constant pressure were subjected to increasing log dose infusions of acetylcholine and nitroprusside to measure endothelial-dependent (EDRF-mediated) and endothelial-independent vasoreactivity, respectively. Fifty limbs were divided into seven groups: two nonischemic groups (one with heparin) and five ischemia/reperfusion groups treated with increasing doses of heparin (0 to 1.0 U/ml perfusate). RESULTS: The nontreated ischemia/reperfusion group (n = 12) had a 46.2% reduction in endothelial-dependent vasodilation of the rat hindlimb when compared with the nonischemic control (n = 7, p < 0.05). Treatment with heparin 0.5 U/ml (n = 6) nearly abolished this attenuation of endothelial-dependent vasodilation (4.3% reduction, p = not significant vs nonischemic control). The endothelial protective effect of heparin was dose-dependent: groups treated with 0.25 U/ml (n = 6) and 0.1 U/ml heparin (n = 7) showed progressive impairment in postischemic EDRF-mediated vasodilation. Endothelial-independent vasodilation induced by nitroprusside was unchanged by ischemia/reperfusion or heparin treatment, which confirmed that the postischemic damage and its protection by heparin were specific to the endothelium. CONCLUSIONS: Heparin prevented postischemic endothelial cell dysfunction by a mechanism independent of its interactions with plasma-based proteins or cells. This nonanticoagulant protective effect may contribute to the salutary effects of heparinization during acute ischemic events.     

Conjugated estrogen reduces transfusion and coagulation factor requirements in orthotopic liver transplantation

We conducted a prospective, randomized study to determine the efficacy of conjugated estrogen in reducing blood product transfusion during orthotopic liver transplantation (OLT). Patients undergoing OLT were included in the study. Only those having a reaction time of more than 30 mm or 15 min (19 -28 mm) on computed thromboelastography (CTEG) at the beginning of surgery were enrolled in the study. Patients were randomized to receive either conjugated estrogen (CE) or placebo. Every patient received a first dose of CE (100 mg i.v.) (20 mL) or placebo (20 mL of isotonic sodium chloride solution) at the beginning of the procedure and a second dose of CE (100 mg i.v.) or 20 mL of placebo (20 mL of isotonic sodium chloride solution) just after reperfusion of the new graft. The two groups were similar in age, weight, requirement for veno-veno bypass, time on veno-veno bypass, CTEG measurement, and preoperative hemoglobin and platelet values. Blood products were given in relation to hematocrit and coagulation (CTEG) variables, which were measured every hour during the surgery. The amount of transfused blood products did not differ in terms of units of cryoprecipitate, but the intraoperative requirements for red blood cells (6 +/- 3 vs 9 +/- 6 U; P = 0.05), platelets (12 +/- 8 U vs 18 +/- 10 U; P = 0.05) and fresh-frozen plasma (3 +/- 3 U vs 6 +/- 4 U; P = 0.001) was significantly less in the estrogen group than in the control group. We conclude that CE is associated with a significant decrease in use of fresh-frozen plasma, platelets, and red blood cells during OLT. Implications: In this study, we prospectively investigated whether i.v. conjugated estrogen could decrease blood product transfusion during orthotopic liver transplantation. Conjugated estrogen-treated patients received less fresh-frozen plasma, red blood cells, and platelets. In this population of patients, conjugated estrogen can be a useful addition in coagulation management during orthotopic liver transplantation.     

Prostate cancer: 4. Screening

OBJECTIVES: To evaluate the association between tamoxifen (TAM) treatment and rate of bone fractures in older, nursing home residents. PARTICIPANTS: A total of 93,031 women, aged 65 years and older, whose data were part of the 1993 New York State MDS and for whom there was documentation of treatment with at least one medication. SETTING: New York State long-term care facilities. DESIGN: Cross-sectional study via secondary analysis of 1385 matched sets of residents. Each set included one resident who was receiving TAM treatment and up to four residents who were not. MEASUREMENTS: Measurements included age, ethnicity, TAM treatment, hormone replacement therapy, vision impairment, any bone fractures, and, specifically, hip fractures. RESULTS: During the 1.5-year period for which bone fractures are documented in the 1993 MDS, the fracture rates were: 7.62% in women not treated with TAM, 3.20% in women receiving 10 mg TAM daily, and 6.73% in women receiving 20 mg TAM daily. The odds ratio (OR) for bone fractures among women receiving 20 mg TAM daily compared with nontreated women was 0.916 (95% confidence interval (CI): 0.720-1.164; P = .472), and was 0.312 (95% CI: 0.112-0.865; P = .025) for those receiving 10 mg daily. The rates of hip fracture were 4.98%, 2.40%, and 4.57% for controls and women receiving 10 mg and 20 mg TAM daily, respectively. Whereas the hip fracture rate for women receiving 20 mg daily was statistically similar to that of the controls (OR = .963; 95% CI: 0.718-1.291; P = .800), the difference between the controls and those receiving 10 mg daily approached significance (OR: 0.313; 95% CI: 0.096-1.018; P = .054). CONCLUSION: Although standard treatment of 20 mg TAM daily offers no apparent protection against bone fracture in older nursing home residents, a daily 10 mg dose seems to be protective.     

The influence of antenatal corticosteroids on hypoglycemia in newborn rats with intrauterine growth retardation

This study examines the effect of maternally injected glucocorticoid on the pattern of hypoglycemia exhibited by rat pups with intrauterine growth retardation (IUGR). The majority of surgical procedures designed to produce small-for-gestational age (SGA) newborns for biochemical studies were carried out on days 18 and 19 of gestation because of favorable vields of pups with IUGR at those operative days. At birth, normal controls showed a mean +/- SE plasma glucose value of 63 +/- 2 mg/dl; mean glucose for the group with IUGR was significantly lower at 43 +/- 2 mg/dl. There was a further decrease in the plasma glucose concentration of pups with IUGR at 2-4 hr of age, whereas values in the control littermates did not fall during this interval. Through the first 2 hr of neonatal life, 46% of the pups with IUGR exhibited plasma glucose values less than 40 mg/dl, whereas only 18% of the control littermates manifiested hypoglycemia. During the 2-4-hr interval, the incidence of hypoglycemia in animals with IUGR increased to 91%; however, the incidence in control remained at 18% from 2-4 hr and fell to 4% at 4-6 hr of age. At birth, the pups with IUGR had a lower mean liver weight compared to their control littermates, but glycogen concentration of liver was similar to the control mean +/- SE of 25.7 +/- 1.8 (IUGR = 22.2 +/- 1.3 mg/g wet weight). Total hepatic glycogen stores, however, were markedly lower in dysmature rat pups (IUGR = 2.96 +/- 0.17 mg; control = 7.23 +/- 0.43 mg). Concentrations of plasma glucose at birth of individual control and IUGR animals were found to correlate significantly (r = 0.64, p less than 0.001) with total liver glycogen content. The decline in plasma glucose values in pups with IUGR was not present in animals whose dams received glucocorticoid injection 24 and 48 hr before delivery. At 4-6 hr of age, for instance, the mean plasma glucose concentration in the corticoid-treated IUGR group (70.1 +/- 6.9 mg/dl) approximated that of the control group. Instead on the 91% incidence of hypoglycemia noted in the nontreated dysmature pups, an incidence of 55% was found at 2-4 hr of age in offspring of mothers given glucocorticoid. At 4-6 hr, the treated group showed an incidence of 18% compared to a 67% figure in the nontreated IUGR animals. The concentration of liver glycogen in these animals also differed in that the treated IUGR pups showed significantly higher values (26.9 +/- 1.7 mg/g wet weight, mean +/- SE) than nontreated progeny. It is concluded that antenatally administered corticosteroid influence the development of neonatal hypoglycemia in the dysmature rat pup and that the major effect is not at birth, but during the 2-4-hr period of neonatal life.     

Combined in vitro and in vivo T lymphocyte depletion for the control of graft-versus-host disease following haploidentical marrow transplant

Most patients requiring allogeneic bone marrow transplantation (BMT) lack a human leukocyte antigen genotypically identical sibling and require an alternative donor. This carries an increased risk of graft failure and acute graft-versus-host disease (GVHD). We sought to overcome these problems with transplants by using grafts obtained from the most readily available source: the haploidentical, partially mismatched, related donor. This study of 40 patients used a novel approach combining in vitro and in vivo T cell depletion with T lymphocyte targeted monoclonal antibodies (mAb) and intensified conditioning therapy, including fractionated total body irradiation before etoposide, cytoside arabinoside, cyclophosphamide, and methylprednisolone. Grafts were treated with T10B9.1A-31 mAb, directed against the alpha-beta heterodimer of the T cell receptor, and rabbit complement. In vivo depletion was attempted with an anti-CD5 mAb-Ricin A-chain (H65-RTA) immunotoxin (IT). Study patients were compared with a historical control group of 17 patients not given H65-RTA. Rates of engraftment were not significantly different (93% vs. 100%, P=0.12), although patients receiving IT engrafted more rapidly. The incidence of > grade I GVHD was significantly lower in the study group (36% vs. 100%, P=0.0001), as well as for severe grade III-IV GVHD (19% vs. 92%, P=0.0001). Five-year survival tended to be improved in the study group (40% vs. 18%, P=0.21). Transplant from haploidentical family members is indicated for patients without a matched sibling in whom allogeneic BMT offers the best opportunity to achieve cure.