Production of docosahexaenoic acid from microalgae and its benefits for use in animal feeds.
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Animal Feed↗
Biomedical subjects
C Weaver
Publications and source records attributed to C Weaver.
Characterization of a culture-derived CD15+CD11b- promyelocytic population from CD34+ peripheral blood cells.
Selected CD34+ cells from mobilized apheresis products were cultured in serum-free or serum-containing media supplemented with granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and stem cell factor (SCF; c-kit ligand). We examined the emergence of a CD15+CD11b- population, which appeared morphologically to be promyelocytes. This CD15+CD11b- population can be further expanded in culture into morphologically mature granulocytes. In an attempt to characterize this culture-derived CD15+CD11b- promyelocytic population, single cells were clone sorted into wells of a Terasaki plate containing various growth factors. We compared the growth factor requirements and kinetics of this apheresis culture-derived CD15+CD11b- population to the CD15+CD11b- population from fresh bone marrow samples. Our studies indicate that the CD15+CD11b- promyelocytic population from bone marrow and blood are equivalent in their ability to proliferate and in their requirements for growth factors. The CD15+CD11b- population in vitro shows a high proliferative capacity when compared with the other CD15/CD11b populations (CD15-CD11b-, CD15+CD11b+, CD15-CD11b+). Thus, we can manipulate CD34+ cells in vitro to proliferate and differentiate toward a mature neutrophil lineage. The CD15+CD11b- promyelocytic population derived from this culture may represent the most effective cultured cell population for therapeutic reduction of neutropenia in vivo based on both its stage of differentiation and its proliferative potential.
Antigens, CD↗
Magnesium kinetics in adolescent girls determined using stable isotopes: effects of high and low calcium intake.
Magnesium kinetics were measured in five adolescent girls who were participating in a calcium balance study. Two calcium levels were fed in a randomized crossover design. After an acclimation period, 26Mg was consumed orally and 25Mg was given intravenously, and then blood, urine, and feces were collected for 14 days. Total magnesium and percent enrichment were determined, and data were fitted to a eight-compartment model. There was no significant difference between high and low calcium intakes for any of the parameters examined. Mean values for control (800 mg/day) and high (1,800 mg/day) calcium intake were as follows: Mg intake, 305 +/- 30 and 286 +/- 9 mg/day; absorption (percent), 44 +/- 7 and 39 +/- 9; absorption (mg/day), 134 +/- 35 and 110 +/- 28; urinary excretion, 96 +/- 22 and 101 +/- 31 mg/day; fecal excretion, 175 +/- 32 and 200 +/- 11 mg/day; and magnesium balance, 13 +/- 35 and -34 +/- 48 mg/day, respectively. In conclusion, high calcium intake did not alter magnesium kinetics or balance in adolescent girls.
Absorption↗
Evaluation of pathologic criteria for acute renal allograft rejection: reproducibility, sensitivity, and clinical correlation.
This study was designed to evaluate the pathologic criteria used for acute renal allograft rejection that were developed by a panel of renal pathologists participating in the Cooperative Clinical Trials in Transplantation, a National Institutes of Health-supported, multicenter research group. The panel defined three categories of acute rejection. (1) Type I: mononuclear infiltrate in > or =5% of cortex, a total of at least three tubules with tubulitis in 10 consecutive high-power fields from the most severely affected areas, and at least two of the three following features: edema, activated lymphocytes, or tubular injury. (2) Type II: arterial, or arteriolar, endothelialitis with or without the preceding features. (3) Type III: arterial fibrinoid necrosis or transmural inflammation with or without thrombosis, parenchymal necrosis, or hemorrhage. Using these criteria, and without any knowledge of the clinical course or original diagnosis, a rotating panel of three pathologists agreed with the original study pathologist's diagnosis of the presence or absence of rejection in 259 of the 286 biopsies (91%) used for this analysis (kappa = 0.80). The sensitivity to establish the diagnosis of rejection was 91% for a single core and 99% for two cores. To validate the diagnostic criteria, the thresholds for number of tubules with tubulitis and the percent infiltrate were varied, and the pathologic diagnosis was compared with the clinical course. The greatest agreement occurred with a threshold of > or =1 tubule with tubulitis and > or =5% cortex with interstitial infiltrate (91%). Clinically severe rejection episodes were correlated with the type of rejection (type I, odds ratio [OR] 6.2; type II, OR 37.9). Type II rejection was more likely to be clinically severe than type I (OR 6.1). Analysis of other individual pathologic features revealed a correlation with clinical severity for endothelialitis (OR 13.2), interstitial hemorrhage (OR 13.2), and the presence of glomerulitis (OR 3.7) (all P < 0.05). The extent of tubulitis or of the interstitial infiltrate did not correlate with severity (P > 0.05). It is concluded that these criteria are simple, reproducible, and clinically relevant. These data should lead to further refinement of the diagnostic systems for renal allograft rejection.
Acute Disease↗
High-dose busulfan, melphalan, and thiotepa followed by autologous peripheral blood stem cell transplantation in patients with aggressive lymphoma or relapsed Hodgkin's disease.
The purpose of this study was to evaluate the efficacy of high-dose chemotherapy with busulfan (Bu), melphalan (Mel), and thiotepa (TT), and of autologous peripheral blood stem cell (PBSC) infusion in patients with aggressive non-Hodgkin's lymphoma (NHL) or relapsed Hodgkin's disease (HD). Forty patients, 23 with intermediate (n= 18) or high-grade (n=5) NHL and 17 with HD received Bu (12 mg/kg), Mel (100 mg/kg), TT (450-500 mg/m2) [corrected], and autologous PBSC infusion. Of 27 patients with more advanced disease, 16 had primary refractory disease, 8 were in refractory relapse, and 3 were in third remission. Of 13 patients with less advanced disease, 7 were in untreated or responding first relapse and 3 were in second remission, whereas 3 with high-grade NHL were in first remission. Twenty-nine patients (73%) had received prior radiotherapy (RT) prohibiting a total-body irradiation (TBI)-based conditioning regimen. The projected 2-year probabilities of survival, event-free survival, and relapse for all patients were 0.60, 0.46, and 0.31 (0.85, 0.85, and 0.15 for patients with less advanced disease and 0.48, 0.30, and 0.37 for patients with more advanced disease). The probability of nonrelapse mortality in the first 100 days was 0.17. Severe idiopathic pneumonia syndrome was not observed in any patients with less advanced disease and in only one patient with more advanced disease. A regimen of BuMelTT is well tolerated in patients with aggressive NHL or relapsed HD, and results obtained to date are at least equivalent to other published regimens, including TBI-based regimens. This regimen appears to be a particularly attractive alternative for patients who have already received dose-limiting RT and should be evaluated further in prospective, randomized studies.
Adolescent↗
Oral-antigen delivery by way of a multiple emulsion system enhances oral tolerance.
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Administration, Oral↗
Relationship between basal NO release and cyclooxygenase products in the normal rat kidney.
We investigated the physiological regulation of renal function by nitric oxide (NO) and its interactions with the endothelial cyclooxygenase products in the conscious, chronically catheterized rat. A subpressor dose of NO inhibitor nitro-L-arginine methyl ester (L-NAME) produced renal vasoconstriction that was unaffected by cyclooxygenase inhibition with indomethacin (Indo). Acute, high-dose L-NAME produced a pressor response of approximately 40 mmHg and marked renal vasoconstriction. Indo selectively amplified the renal vasoconstriction, whereas inhibition of the thromboxane-endoperoxide receptor had no effect. Chronic NO inhibition for 5 wk led to sustained hypertension and renal vasoconstriction; the latter was amplified by acute Indo. These data suggest that in the normal, conscious rat the kidney is under important NO-dependent tone. There is no obvious interaction between NO and the cyclooxygenase products in control of basal renal function. When systemic NO inhibition is produced with either acute or chronic high-dose L-NAME, the kidney is severely vasoconstricted. The renal vasoconstriction is not ameliorated by thromboxane-endoperoxide antagonism but is exacerbated by cyclooxygenase blockade, suggesting that vasodilator cyclooxygenase products compensate for the renal hypoperfusion because of severe NO deficiency.
Animals↗
Regulation of insulin secretion and blood glucose metabolism by adrenomedullin.
Adrenomedullin (AM), a recently discovered hypotensive peptide, is expressed in the endocrine pancreas of different species, as demonstrated by immunocytochemistry. Electron microscopic studies with double immunogold showed colocalization of AM and pancreatic polypeptide. A homogeneous expression of AM receptor was found throughout the islet using in situ hybridization. Six different insulin- producing cell lines have been analyzed by reverse transcription-PCR and showed expression of both AM and its receptor. Two experimental models have been used to study the effects of AM in pancreatic physiology. 1) Analysis of isolated rat islets shows that AM inhibits insulin secretion in a dose-dependent manner. The monoclonal antibody MoAb-G6, which neutralizes AM bioactivity, was able to increase insulin release 5-fold; this effect was reversed by the addition of synthetic AM. 2) Oral glucose tolerance tests showed that iv injection of AM reduces the levels of insulin in the bloodstream with a concomitant increase in circulating glucose. These studies implicate AM as a newly defined factor of the insulin regulatory system that could be involved in disorders such as diabetes and obesity.
Adrenomedullin↗
Factors that influence collection and engraftment of autologous peripheral-blood stem cells.
PURPOSE: To analyze factors that affect the collection of peripheral-blood stem cells (PBSC) before transplant and the tempo of engraftment after transplant. PATIENTS AND METHODS: A consecutive series of 243 patients with breast cancer (n = 87), malignant lymphoma (n = 90), multiple myeloma (n = 32), or other malignancies (n = 34) had PBSC collected following stimulation with colony-stimulating factors (CSFs) or after chemotherapy followed by CSF. Infusion of PBSC was performed following myeloablative chemotherapy with chemotherapy with or without total-body irradiation (TBI). Postinfusion CSFs were administered to 72 patients. An analysis of factors that influence CD34+ cell yield was performed by linear regression. Cox regression analysis was used to determine factors that affect the kinetics of granulocyte and platelet recovery following infusion of PBSC. RESULTS: Mobilization with chemotherapy followed by CSF, a diagnosis of breast cancer, absence of marrow disease, no prior history of radiation therapy, and fewer cycles of conventional-dose chemotherapy were associated with a higher average daily yield of CD34+ cells. In the multivariate analysis, the CD34 content of infused cells and the use of a posttransplant CSF influenced neutrophil recovery after infusion of PBSC. CD34 content was also important for predicting platelet recovery. The use of postinfusion CSF was associated with a significant delay in platelet recovery in patients who received less than 5.0 x 10(6) CD34+ cells/kg, but there was no discernable effect in patients who received greater than 5.0 x 10(6) CD34+ cells/kg. CONCLUSION: Disease status and prior treatment influence the ability to mobilize PBSC. CD34 cell dose is an important predictor of engraftment kinetics after PBSC transplant, regardless of disease or mobilization technique. The use of postinfusion CSF improves neutrophil recovery, but at low CD34 doses can delay platelet recovery.
Adolescent↗
Severe anemia: a risk factor for glomerular injury in sickle cell disease.
Approximately 15% to 20% of patients with sickle cell disease have proteinuria. Proteinuria, particularly albuminuria, is the hallmark of glomerular injury. This study examines risk factors for glomerular injury as indicated by urinary albumin excretion (UAE) 30 microgram/minute, directly related to sickle cell disease. A total of seven patients were enrolled between September 1992 and March 1993. Fasting blood chemistries, complete blood cell count, 24-hour urine for protein and creatinine clearance, and glomerular filtration rate determined by 125 I-iothalamate were obtained for each patient. The results indicated that the lower the hematocrit, the higher the UAE rate. Low hematocrits have served as a protective mechanism in sickle cell disease by reducing blood viscosity and thus decreasing the number of vaso-occlusive crises. However, severe anemia appears to have an indirect adverse effect on the kidney in sickle cell disease.
Adult↗
Engraftment of patients with lymphoid malignancies transplanted with autologous bone marrow, peripheral blood stem cells or both.
Forty six patients with lymphoid malignancies receiving autologous transplants using three different sources of hematopoietic stem cells were compared for engraftment parameters. Thirteen patients (five with multiple myeloma, seven with non-Hodgkin's lymphoma and one with Hodgkin's lymphoma) received autologous marrow with post-transplant growth factors (group 1). During the same time interval, 14 patients (five with multiple myeloma, six with non-Hodgkin's lymphoma and three with Hodgkin's lymphoma) were transplanted with autologous marrow plus recombinant granulocyte colony-stimulating factor (rhG-CSF)-mobilized peripheral blood stem cells (PBSC) and post-transplant growth factors (group 2). Nineteen patients (seven with multiple myeloma and 12 with non-Hodgkin's lymphoma) received rhG-CSF mobilized PBSC and post-transplant growth factors (group 3). All PBSC were collected after G-CSF mobilization (16 micrograms/kg/day s.c. for 6 days) without prior chemotherapy. After high-dose myeloablative chemotherapy or chemoradiotherapy, the median days to recovery of neutrophils to levels of 0.5 and 1.0 x 10(9)/l were 12 vs. 9 vs. 9 days (P = 0.0003 (group 1 vs. group 2) and P = 0.53 (group 2 vs. group 3)) and 13 vs. 10 vs. 10 days (P = 0.0003 (group 1 vs. group 2) and 0.92 (group 2 vs. group 3)) for groups 1, 2 and 3, respectively. The median day to platelet transfusion independence was 22 vs. 11 vs. 11 days (P = 0.001 (group 1 vs. group 2) and P = 0.50 (group 2 vs. group 3)) for groups 1, 2 and 3, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Failure of a single cycle of high dose cyclophosphamide followed by intensive myeloablative therapy and autologous stem cell transplantation to improve outcome in relapsed disease.
BACKGROUND: This study attempted to determine the use of a single cycle of high dose cyclophosphamide (60 mg/kg/day x 2) with (N = 16) and without granulocyte macrophage colony stimulating factor (GM-CSF) (N = 12) followed by intensive treatment and autologous stem cell transplantation (ASCT) in patients with relapsed disease. METHODS: Ten patients with multiple myeloma, eight with non-Hodgkin's lymphoma, three with Hodgkin's disease, six with breast cancer, and one with ovarian cancer were studied. Eighteen patients were in resistant relapse (RR) and 10 had sensitive relapses (SRs). All patients had marrow involvement with tumor and had received extensive prior therapy. RESULTS: When responses were assessed just before undergoing ASCT, none of the patients achieved a complete response (CR). Overall, 17 of 28 patients (61%) achieved a partial response (PR). Seven of 18 patients with RR achieved PR (39%). All 10 patients with SR achieved a PR. There were three early deaths. Sixteen patients underwent peripheral blood stem cell (PBSC) collection. Ten of 16 patients received cyclophosphamide plus GM-CSF, and 6 received cyclophosphamide alone. In patients treated with cyclophosphamide plus GM-CSF and cyclophosphamide alone, a median of 5.52 x 10(6) CD34+ cells/kg (range, 0.26-30.49) and 5.72 x 10(6) (range, 1.25-15.66) were collected, respectively. There was no apparent improvement in collection efficiency with GM-CSF. Twenty-two of 28 patients proceeded to ASCT irrespective of response, a median of 45 days (range, 21-203 days) after cyclophosphamide administration. After transplantation, 11 achieved a CR (50%) and 6 a PR (27%). To date, eight patients are alive (median, 679 days; range, 215-1190 days) and five remain in CR more than 6 months (median, 321 days; range, 215-1190 days). All eight surviving patients achieved a PR after high dose cyclophosphamide. CONCLUSIONS: High dose cyclophosphamide reduced the tumor burden by at least 50% in all patients with sensitive disease and in 39% of patients with refractory disease. However, only 5 of 22 patients (23%) remained in CR after ASCT, and all had sensitive disease before the administration of cyclophosphamide. These data suggest that high dose cyclophosphamide followed by intensive treatment and ABMT does not improve the fraction of long term disease free survivors in patients with refractory disease. Future trials would probably be required to demonstrate the utility of intensive treatment in patients with responsive relapse.
Adult↗
T cells of staphylococcal enterotoxin B-tolerized autoimmune MRL-lpr/lpr mice require co-stimulation through the B7-CD28/CTLA-4 pathway for activation and can be reanergized in vivo by stimulation of the T cell receptor in the absence of this co-stimulatory signal.
The CD28/CTLA-4 receptors on T cells interact with the B7 molecule on antigen-presenting cells (APC) to produce a co-stimulatory signal that determines the outcome of activation. The role of this co-stimulatory signal in T cell activation and loss of tolerance in autoimmune MRL-lpr/lpr mice has not been investigated previously. The present study examines the contribution of the CD28/CTLA-4 co-stimulatory pathway to the loss of T cell tolerance in V beta 8 transgenic MRL-lpr/lpr and (-)+/+ mice in which neonatal tolerance has been induced by the superantigen staphylococcal enterotoxin B (SEB). An artificial APC transfected with the murine B7 gene, and a CTLA-4-Ig fusion protein were used to analyze the significance of the CD28/CTLA-4 pathway in vitro. The CTLA-4-Ig fusion protein was also used to inhibit the pathway in vivo. Our results demonstrate that CD28 and CTLA-4 mRNA was overexpressed in the lymph nodes of lpr/lpr mice (MRL, C57BL/6, C3H and AKR), but not in +/+ mice of the same background strain. Lymph node T cells and thymocytes from SEB neonatally tolerized MRL-lpr/lpr mice that had undergone tolerance loss, proliferated when cultured with SEB and B7+ fibroblasts in vitro, but did not proliferate when the SEB was presented in the context of B7- fibroblasts. This in vitro tolerance loss could be prevented by blocking of B7 signaling by CTLA-4-Ig. This loss of tolerance did not occur in lymph node T cells from thymectomized MRL-lpr/lpr mice. SEB challenge of tolerized MRL-lpr/lpr mice in vivo led to weight loss, increased serum cytokine levels and depletion of V beta 8+ T cells. These effects were blocked by blocking of the co-stimulatory pathway by treatment with the CTLA-4-Ig fusion protein prior to and during challenge with SEB. T cells from thymus and lymph nodes of these mice did not proliferate later in response to stimulation in vitro with SEB even in the presence of B7+ APC. Nonresponsiveness was not due to deletion of V beta 8+ CD28+ T cells, as the number of these cells was increased after treatment with SEB and the CTLA-4-Ig fusion protein.(ABSTRACT TRUNCATED AT 250 WORDS)
Abatacept↗
Pancreatic changes elicited by chronic administration of excess L-arginine.
Male rats were injected daily ip (350 mg/100 g body weight) with L-arginine from 1 to 4 weeks. Weekly changes were assessed by glucose tolerance, pancreatic insulin, histology, immunohistochemistry, ultrastructure, and quantification of insulin mRNA by in situ hybridization. Following Week 1, light microscopy revealed areas of focal acinar cell degeneration and incipient disaggregation of exocrine cytoarchitecture. Ultrastructural changes revealed initial attenuation in endoplasmic reticulum and condensation and clumping of nuclear chromatin. Some mitochondria appeared swollen and the plasma membrane showed areas of focal disintegration. Islets appeared normal, although pancreatic insulin levels were lower than controls as was the quantified signal for insulin mRNA. At the end of Week 2, acinar necrosis was evident throughout most pancreatic lobules. Increasing numbers of acinar cells underwent progressive degeneration with further loss of plasma membrane integrity, the appearance of autophagic vacuoles, increased cytoplasmic debris, and mitochondrial disruption. At Week 4, only isolated single acinar cells remained within a fibrous connective tissue matrix contiguous with ducts, blood vessels, intrapancreatic nerves, and islets. Immunohistochemistry of islets and nerves revealed normal endocrine and neural components. Although nonfasted, arginine-treated rats were normoglycemic and no further significant changes in pancreatic insulin and mRNA were found between Weeks 2 and 4, some impairment of glucose tolerance was present throughout the 4-week period. Data support the hypothesis that excess arginine selectively destroys acinar cells. It is suggested that necrosis arises from attenuation in nucleoprotein synthesis which may result from amino acid imbalance and/or toxicity. Excess arginine-treated animals may serve as a model for the study of acute and chronic pancreatitis.
Animals↗
Peripheral blood stem cells (PBSCs) collected after recombinant granulocyte colony stimulating factor (rhG-CSF): an analysis of factors correlating with the tempo of engraftment after transplantation.
Factors affecting mobilization and engraftment were analysed in 54 patients undergoing transplant using autologous PBSCs mobilized with high-dose recombinant granulocyte stimulating factor (rhG-CSF). Patients received 5-7 d of rhG-CSF, 16 micrograms/kg/d, administered subcutaneously. PBSCs were harvested by leukapheresis using automated continuous-flow blood cell separators beginning on day 4 of rhG-CSF, processing 10 litres of whole blood, for 2-6 consecutive days. Transplants were performed for the following diseases: breast cancer (n = 22), non-Hodgkin's lymphoma (n = 18), multiple myeloma (n = 7) and other (n = 7). Engraftment was rapid with patients reaching a neutrophil count of 1 x 10(9)/l a median of 12 d (range 9-22) after transplant. Platelets > 20 x 10(9)/l independent of transfusion support were achieved a median of day 10 (range 7-60) after infusion. Multiple factors potentially influencing engraftment were examined using a Cox regression model. The number of CD34+ cells per kg was highly correlated with the time to achievement of granulocyte and platelet recovery (P < 0.012, 0.0001). The use of a post-infusion growth factor and a radiation preparative regimen was important for neutrophil recovery, and a diagnosis of breast cancer was important for platelet recovery. In an analysis by linear regression of the logarithm of CD34+ cells collected, lower age, marrow without disease, no prior radiation, and lower number of prior chemotherapy regimens, were important factors influencing larger numbers of CD34+ cells in collections.
Adolescent↗
Mature T cells of autoimmune lpr/lpr mice have a defect in antigen-stimulated suicide.
Antigen receptor-stimulated cell death of developing, immature T cells plays an important role in shaping the repertoire of antigens to which mature T cells will respond, but a role for receptor-stimulated death in controlling responses of mature T cells is controversial. Mutant lpr/lpr mice exhibit an autoimmune syndrome similar to systemic lupus erythematosus. Here we demonstrate that these mice have a defect in antigen-stimulated suicide of activated T cells in mature CD4+ and CD8+ T cell compartments. The defective suicide pathway is evident when the T cells are stimulated with antigen on antigen-presenting cells or with immobilized anti-CD3 in the absence of antigen-presenting cells. These studies, in concert with the work of others, suggest that antigen-stimulated death of mature cells may be important both in establishing peripheral tolerance and in limiting inflammation during normal immune responses.
Animals↗
Differential activation of antigen-stimulated suicide and cytokine production pathways in CD4+ T cells is regulated by the antigen-presenting cell.
Stimulation of the TCR of activated, mature T cells by an APC produces a spectrum of functional responses. Most of those responses positively promote immunity and inflammation. However, death of the responding T cell, which would limit subsequent inflammation, can also result from such stimulation. We compare the Ag threshold necessary to promote inflammation through cytokine production with the Ag threshold necessary to limit inflammation through T cell death. These two responses are independently regulated by the APC and this regulation is selective for both different APC products and different T cell subsets. The costimulator B7 selectively decreases the Ag threshold for cytokine production in Th1 cells with no effect on the Ag threshold for Th1 death. B7 has no effect on the Th2 Ag threshold for cytokine production or death. In contrast, IFN-gamma negatively modulates a macrophage product that selectively increases the threshold of Ag necessary to stimulate death in Th2 cells, but has no effect on cytokine production by Th2 cells or cytokine production or death of Th1 cells. This selective regulation of cytokine production and T cell death may play an important role in both shaping the quality of a given immune response and in providing a general mechanism for the regulation of the immune response by limiting inflammation and through peripheral deletion of inappropriate T cell specificities.
Animals↗
CHINs (community health information networks): infrastructure for the future.
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Comprehensive Health Care↗