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Biomedical subjects

C A White

Publications and source records attributed to C A White.

At least 19 recordsLinked to original sources
PubMed2006

Cost of applying the K/DOQI guidelines for bone metabolism and disease to a cohort of chronic hemodialysis patients.

Hyperphosphatemia is a common feature of advanced chronic kidney disease (CKD) and is treated routinely with oral calcium-based phosphate binders. In 2003, the National Kidney Foundation Kidney Disease Outcomes and Quality Initiative (K/DOQI) published Clinical Practice Guidelines (CPGs) for the treatment of Bone Metabolism and Disease in CKD. These advocate broad usage of expensive non-calcium-based phosphate binders such as sevelamer. This study was designed to determine the cost of implementation of the K/DOQI CPGs as they pertain to phosphate binding in a large Canadian hemodialysis (HD) unit. Laboratory and medication data for all chronic HD patients at the Ottawa Hospital were reviewed (n=416). Patients meeting each of the relevant K/DOQI guidelines were identified. Where guidelines would recommend a switch to non-calcium binders, equivalent sevelamer doses were estimated. The cost of implementing each guideline was then calculated individually and an estimate total cost of implementing all the guidelines was derived. Overall, 53% (222) patients fulfilled at least one criterion for sevelamer use. The yearly cost of implementation of the K/DOQI guidelines at this center was estimated at 500,605 dollars (American dollars). Given the significant cost, widespread adoption of the K/DOQI CPGs for Bone Metabolism and Disease should await the publication of compelling data demonstrating significant improved outcomes in patients treated with sevelamer.

Aged↗
PubMed2006

Effect of different forms of information produced for cancer patients on their use of the information, social support, and anxiety: randomised trial.

OBJECTIVE: To explore the hypothesis that different methods of selecting and printing information for cancer patients could improve emotional support by affecting interaction with others, and so lead to improved psychological wellbeing. DESIGN: Randomised trial with eight groups (three factors, 2x2x2). Data collected at recruitment and three month follow-up. PARTICIPANTS: 400 patients starting radiotherapy, of whom 325 with breast or prostate cancer and complete anxiety and depression data were included in the analysis. INTERVENTIONS: Printed booklets: half had only general information from CancerBACUP about each patient's cancer and half had personalised information from the patient's medical record plus selected general information; half were composed of information chosen interactively by the patient and half were produced automatically with a larger volume of material; and half had additional advice on anxiety management and half did not. MAIN OUTCOME MEASURES: Patients' views of the information, use of their booklets with others; change in reported social support; change in anxiety and depression. RESULTS: The larger booklets produced automatically were more likely to be found useful and to tell patients something new and less likely to be seen as too limited than the booklets produced interactively, but they were also more likely to overwhelm some patients. Personalised booklets were more likely than general booklets to tell patients something new. There was no difference in patients' perceived understanding of their cancer by any of the intervention factors. Patients with personalised information were more likely to show their booklets to others and to think it helped in discussing their cancer or its treatment. There were no major differences in social support, anxiety, or depression by any intervention factors. CONCLUSIONS: Patients were more likely to show personalised information to their confidants than general information. Further research is needed into the effects of sharing information on patients' social support and anxiety. Trial registration US Government Clinical Trials Database NCT00127465.

Adult↗
PubMed2005

Interleukin-11 inhibits expression of insulin-like growth factor binding protein-5 mRNA in decidualizing human endometrial stromal cells.

Differentiation of endometrial stromal cells into decidual cells is essential for successful embryo implantation. Interleukin (IL)-11 signalling is critical for normal decidualization in the mouse. The expression of IL-11 and its receptors during the menstrual cycle, and the effect of exogenous IL-11 on the decidualization of human endometrial stromal cells in vitro, suggests a role for this cytokine in human decidualization. As the downstream target genes of IL-11 are also likely to be critical mediators of this process, this study aimed to identify genes regulated by IL-11 in decidualizing human endometrial stromal cells in vitro. Stromal cells isolated from endometrial biopsies were decidualized with 17beta estradiol (E) and medroxyprogesterone acetate (EP) in the presence or absence of exogenous IL-11, and total RNA used for cDNA microarray analysis and real-time RT-PCR. Microarray analysis revealed 16 up-regulated and 11 down-regulated cDNAs in EP + IL-11-treated compared with EP-treated cells. The most down-regulated gene was insulin-like growth factor binding protein-5 (IGFBP-5) (3.6-fold). Using real-time RT-PCR, IL-11 was confirmed to decrease IGFBP-5 transcript abundance 102-fold (P = 0.016; n = 6). No difference in IGFBP-5 immunostaining intensity was detected in stromal cells decidualized in the presence or absence of IL-11, and there was no effect of exogenous IGFBP-5 on the progression of steroid-induced in vitro decidualization. Interactions between IL-11 and its target genes, including IGFBP-5, may contribute to the regulation of decidualization and/or mediate communication between the decidua and invading trophoblast at implantation.

Cell Differentiation↗
PubMed2005

Cytokines, chemokines and growth factors in endometrium related to implantation.

The complexity of the events of embryo implantation and placentation is exemplified by the number and range of cytokines with demonstrated roles in these processes. Disturbance of the normal expression or action of these cytokines results in complete or partial failure of implantation and abnormal placental formation in mice or humans. Of known importance are members of the gp130 family such as interleukin-11 (IL-11) and leukaemia inhibitory factor (LIF), the transforming growth factor beta (TGFbeta) superfamily including the activins, the colony-stimulating factors (CSF), the IL-1 system and IL-15 system. New data are also emerging for roles for a number of chemokines (chemoattractive cytokines) both in recruiting specific cohorts of leukocytes to implantation sites and in trophoblast differentiation and trafficking. This review focuses on those cytokines and chemokines whose expression pattern in the human endometrium is consistent with a potential role in implantation and placentation and for which some relevant actions are known. It examines what is known of their regulation and action along with alterations in clinically relevant situations.

Activins↗
PubMed2003

Mimicking the events of menstruation in the murine uterus.

Menstruation and endometrial regeneration occur during every normal reproductive cycle in women and some Old World primates. Many of the cellular and molecular events of menstruation have been identified by correlative or in vitro studies, but the lack of a convenient model for menstruation in a laboratory animal has restricted functional studies. In this study, a mouse model for menstruation first described by Finn in the 1980s has been modified for use in a commonly used inbred strain of mouse. A decidual stimulus was applied into the uterine lumen of appropriately primed mice and leukocyte numbers and apoptosis were examined over time following progesterone withdrawal. Endometrial tissue breakdown was initiated after 12-16 h, and by 24 h, the entire decidual zone had been shed. Re-epithelialization was nearly complete by 36 h and the endometrium was fully restored by 48 h. Leukocyte numbers increased significantly in the basal zone by 12 h after progesterone withdrawal, preceding stromal destruction. Stromal apoptosis was detected by TUNEL staining at 0 and 12 h but decreased by 16 h after progesterone withdrawal. This mouse model thus mimics many of the events of human menstruation and has the potential to assist in elucidation of the functional roles of a variety of factors thought to be important in both menstruation and endometrial repair.

Animals↗
PubMed2003

Altered placental development in interleukin-10 null mutant mice.

Placental morphogenesis and nutrient transfer function are regulated by growth factors at the foeto-maternal interface. Interleukin (IL)-10, expressed in the decidua and placenta, is implicated in regulating extravillous cytotrophoblast invasion through inhibiting matrix metalloproteinase expression and influencing the quality of the maternal immune response. Our laboratory has previously found that IL-10 deficiency in both the mother and foetus increases foetal weight at day 18 without altering placental weight suggesting that the placenta has a greater functional capacity when IL-10 is absent. The present study has used IL-10 null mutant (IL-10-/-) mice to investigate the role of IL-10 in placental development. Placental structure was assessed in adult virgin IL-10-/- or wild-type (IL-10+/+) mice mated with males of the same genotype and sacrificed at day 18 of gestation. Mid-sagittal cross sections of placental tissue were stained with Masson's trichrome or immuno-labelled with MTS-12 and pan-cytokeratin reactive antibodies to identify foetal endothelial cells and trophoblasts, respectively, and examined with video image analysis. IL-10 deficiency increased the total cross sectional area of the placenta by 28 per cent (IL-10-/- n=22 placentae from 8 dams, IL-10+/+n =21 placentae from 9 dams, P=0.026), principally through increasing the cross sectional area of placental labyrinth by 37 per cent (P=0.025). The proportion of maternal blood space in the labyrinth was increased by 26 per cent (P=0.001) and that of trophoblast was decreased by 16 per cent (P=0.001) in IL-10-/- placentae. The surface area of trophoblast per gram of labyrinth was increased by 41 per cent (P=0.0005) in IL-10-/- placentae. In the absence of IL-10, structural correlates of placental function are enhanced consistent with concomitant increases in foetal growth. These data indicate that IL-10 is a regulator of placental morphogenesis, acting to retard expansion of the placental labyrinth and to modify the architecture of the maternal blood sinuses. Since previous studies have paradoxically shown that postnatal growth is impaired in IL-10 null mutants, these observations are consistent with a role for IL-10 in regulating placental development and foetal programming.

Animals↗
PubMed2001

Determination of 3'-azido-2',3'-dideoxyuridine in maternal plasma, amniotic fluid, fetal and placental tissues by high-performance liquid chromatography.

3'-Azido-2',3'-dideoxyuridine (AZDU, Azddu, CS-87) is a nucleoside analog of 3'-azido-3'-deoxythymidine (zidovudine, AZT) that has been shown to inhibit human immunodeficiency virus (HIV-1). AZDU is a potential candidate for treatment of pregnant mothers to prevent prenatal transmission of HIV/AIDS to their unborn children. A rapid and efficient high-performance liquid chromatography (HPLC) method for the determination of AZDU concentrations in rat maternal plasma, amniotic fluid, placental and fetal tissue samples has been developed and validated. Tissue samples were homogenized in distilled water, protein precipitated and extracted using a C-18 solid-phase extraction (SPE) method prior to analysis. Plasma and amniotic fluid samples were protein precipitated with 2 M perchloric acid prior to analysis. Baseline resolution was achieved using a 4.5% acetonitrile in 40 mM sodium acetate (pH 7) buffer mobile phase for amniotic fluid, placenta and fetus samples and with a 5.5% acetonitrile in buffer solution for plasma at flow-rates of 2.0 ml/min. The HPLC system consists of a Hypersil ODS column (150x4.6 mm) with a Nova-Pak C-18 guard column with detection at 263 nm. The method yields retention times of 6.2 and 12.2 min for AZDU and AZT in plasma and 8.3 and 17.6 min for AZDU and AZT in amniotic fluid, fetal and placental tissues. Limits of detection ranged from 0.01 to 0.075 microg/ml. Recoveries ranged from 81 to 96% for AZDU and from 82 to 96% for AZT in the different matrices. Intra-day (n=6) and inter-day (n=9) precision (% RSD) and accuracy (% Error) ranged from 1.48 to 6.25% and from 0.50 to 10.07%, respectively.

Amniotic Fluid↗
PubMed2001

Quantitative analysis of myocardial perfusion changes with transmyocardial laser revascularization.

Transmyocardial laser revascularization (TLR) is a technique of creating left ventricular transmural channels in patients with refractory angina. We aimed to measure perfusion changes quantitatively using technetium-99m methoxyisobutyl isonitrile. Perfusion scans were performed on 94 TLRs and in 94 control patients at rest and during exercise at assessment, and 3-, 6-, and 12-month follow-up. A serial set of scans allowed direct comparison of each patient over all visits. Bull's-eyes were divided into 5 anatomic regions and a 20-region model. Severity values were calculated for rest, stress, and each cardiac region using a threshold of 1 for analysis. Higher scores indicated greater severity of ischemia and lower perfusion. At 3-month follow-up, the severity was significantly worse during TLR than in control patients both during stress (0.172 +/- 0.003 and 0.161 +/- 0.003, respectively, p = 0.007) and at rest (0.170 +/- 0.003 and 0.158 +/- 0.003, respectively, p = 0.002). At 6 months, severity during stress was 0.176 +/- 0.003 with TLR and 0.162 +/- 0.003 in controls (p = 0.001), with no significant difference at rest. At 12 months, there was no significant difference between TLR and control groups at stress and rest. Regional severity deteriorates during TLR compared with control patients anteriorly (p = 0.001, p = 0.0016, p = 0.005 at 3, 6, and 12 months), apically (p = 0.005, p = 0.0046, p = 0.032, respectively), and laterally (p <0.0001, p = 0.001, p = 0.002, respectively). An apparent improvement is observed in the inferoseptal region at 6- and 12-month follow-up-an area not lasered. Thus, TLR appears to produce deterioration in resting myocardial perfusion in lasered regions, and improvement in nonlasered regions, with no difference in exercise-induced myocardial ischemia compared with that in control patients.

Angina Pectoris↗
PubMed2001

Rapid entry and downregulation of T cells in the central nervous system during the reinduction of experimental autoimmune encephalomyelitis.

We investigated the mechanisms whereby a previous attack of experimental autoimmune encephalomyelitis (EAE) modifies a subsequent attack in the Lewis rat. Active immunization with myelin basic protein (MBP) and complete Freund's adjuvant 28 days after the passive transfer of MBP-sensitized spleen cells induced a second episode of EAE, which occurred earlier than in naive control animals, but was less severe overall. The pattern of neurological signs was also different in rechallenged rats, which had less severe tail and hindlimb weakness but more severe forelimb weakness. In rechallenged rats, inflammation was more severe in the cervical spinal cord, cerebellum, brainstem and cerebrum, but less severe in the lumbar spinal cord, than in controls. The early onset of EAE in rechallenged rats was explained by a memory T cell response to MBP(72-89) in the draining lymph node and spleen, and by the enhanced entry of T cells into the central nervous system (CNS). However, the number of alphabeta T cells in the spinal cord of rechallenged rats declined faster than in controls, especially in the lumbosacral cord, where the number of Vbeta8.2(+) T cells and the frequency of T cells reactive to MBP(72-89) rapidly decreased, indicating rapid downregulation of the immune response in the previously inflamed spinal cord. Apoptosis of inflammatory cells in the CNS was increased in the rechallenged rats and is likely to contribute to this downregulation. Furthermore, during the disease course the generation of encephalitogenic T cells in the peripheral lymphoid organs was limited compared with controls. Thus, a previous attack of EAE modifies a subsequent attack through the interaction of the following processes: a memory T cell response to MBP; facilitated T cell entry into the CNS; downregulation of the immune response in the CNS, including increased apoptosis of inflammatory cells; and a limited generation of encephalitogenic T cells in the peripheral lymphoid organs.

Adoptive Transfer↗
PubMed2001

Clearing of cells bearing the bcl-2 [t(14;18)] translocation from blood and marrow of patients treated with rituximab alone or in combination with CHOP chemotherapy.

PURPOSE: Patients who were PCR-positive for B-cell leukemia-lymphoma 2 (bcl-2) gene rearrangement [t(14;18)] were evaluated for responses to rituximab alone or combined with CHOP. PATIENTS AND METHODS: Patients had relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma (IWF: A-D). The single-agent trial used 375 mg/m2 weekly x 4; combination therapy included six cycles of CHOP and six 375 mg/m2 infusions of rituximab. Bcl-2 analyses of bone marrow (BM) and peripheral blood (PB) samples at base-line and following therapy were performed using a PCR assay. RESULTS: In the single-agent trial, of 70 patients whose peripheral blood (PB) was bcl-2 positive at baseline, 36 became bcl-2-negative, 13 remained positive, and 21 varied between positive and negative. The overall response rates (ORRs) were 72%, 31%, and 57%, respectively. Twelve of twenty-two patients with repeat bone marrow (BM) samples were bcl-2-negative three months post-treatment. Of 18 patients in the combination trial, 8 were bcl-2 positive in PB and/or BM. All of seven patients positive in PB at baseline and six of seven patients positive in BM were negative at the end of therapy; all patients responded to treatment (100% ORR). CONCLUSIONS: Rituximab, alone or combined with CHOP, eradicated bcl-2 positive cells from PB and BM in over half of the patients treated and was associated with a high overall clinical response rate. The impact on disease-free and overall survival awaits long-term follow up.

Adult↗
PubMed2001

Antibody-targeted immunotherapy for treatment of malignancy.

Despite testing since the mid-1900s, only in the past three years have some monoclonal antibodies provided sufficient efficacy and safety data to support regulatory approval as cancer therapy. Adjuvant-edrecolomab monoclonal antibody was approved in Germany after demonstration of a statistically significant 32% improvement over observation alone in the seven-year mortality rate for patients with colorectal cancer. Similarly, trastuzumab monoclonal antibody combined with chemotherapy prolonged the median time to the progression of breast cancer compared to chemotherapy alone. Unconjugated monoclonal antibodies investigated for the treatment of hematologic malignancies include anti-idiotype, CAMPATH-1, and rituximab. Rituximab was the first such therapy approved in the United States for relapsed or refractory low-grade or follicular B-cell non-Hodgkin's lymphoma after demonstration of an overall response rate of 48% and a duration of response of 11.7 months. The radioisotope-conjugated monoclonal antibodies tested as therapy include anti-B1, LYM-1, LL2, anti-CD33, and ibritumomab tiuxetan. Clearly, the full potential of immunotherapy still lies ahead.

Antibodies, Monoclonal↗
PubMed2001

Monoclonal antibodies: a new era in the treatment of non-Hodgkin's lymphoma.

Monoclonal antibodies (MAbs) have been used as therapeutic agents for many years. In 1997, Rituxan (IDEC-C2B8, rituximab, MabThera) became the first MAb to be approved by the FDA for a cancer indication. Rituxan served to heighten interest in the therapeutic applications of MAbs. Herceptin (for patients with breast cancer) and Mylotarg (for patients with acute myeloid leukemia) were approved shortly thereafter. Literally dozens of antibodies are currently under investigation for a variety of malignant and non-neoplastic indications. Rituxan is effective in patients with low-grade or follicular, relapsed or refractory non-Hodgkin's lymphoma (NHL). The response rate and time to progression (responders) are in the 50% and 13 months range, respectively. It is also active in intermediate-grade NHL where a large randomized study, in combination with CHOP chemotherapy, has shown a statistically significant increase in complete response (CR) rate (75% vs. 60%), prolongation of 1 year event-free survival (69% vs. 49%) and of overall survival (83% vs. 68%) as compared to CHOP alone. This marks the first time that any agent has shown results superior to CHOP, the curative gold standard for this type of NHL. Other promising antibodies under clinical investigation include: Hu1D10; Anti CD19, 22, 52, and anti-Id antibodies. The safety profile, clinical activity, and mechanism of action of these MAbs make them ideal candidates for combination with chemotherapy or biologicals. Over the next few years, we will see very significant therapeutic advances emerge as this important research yields additional clinical results.

Antibodies, Monoclonal↗
PubMed2001

Non-Hodgkin's lymphoma: review of conventional treatments.

The non-Hodgkin's lymphomas are a diverse groups of lymphoid neoplasms that collectively rank fifth in cancer incidence and mortality. Conventional treatment for patients with newly-diagnosed non-Hodgkin's lymphoma (NHL) includes radiation or chemotherapy. In addition, those with asymptomatic low-grade disease may follow a "watch and wait" approach. Single agent oral alkylating therapy and CVP (cyclophosphamide, vincristine, and prednisone) have become a mainstay of treatment for low-grade NHL. High intensity chemotherapy consisting of the anthracycline, doxorubicin along with cyclophosphamide, vincristine and prednisone (CHOP) is offered as standard treatment for intermediate-grade NHL. Following relapse, salvage therapy rarely results in long-term survival in patients with low-grade NHL. Up to 50% of patients die within five years of first relapse. For patients with intermediate-grade NHL who relapse after or do not respond to first-line treatment, a range of combination regimens can be offered, composed of non-cross resistant drugs not typically used during first-line treatment. However, less than half of patients with intermediate-grade disease achieve prolonged disease-free survival. With today's' conventional treatments, cure is only a possibility for a minority of patients with intermediate-grade disease and a limited group of patients with indolent NHL who are diagnosed at early stages. Novel approaches to treatment are therefore needed. Monoclonal antibodies may fulfill this need, administered either as single agents or in conjunction with conventional cytotoxic approaches. The task now lies in determining how best to use this new modality, with the hope of bringing a cure to a greater number of patients.

Animals↗
PubMed2000

Liquid chromatography--tandem mass spectrometry analysis of cocaine and its metabolites from blood, amniotic fluid, placental and fetal tissues: study of the metabolism and distribution of cocaine in pregnant rats.

The ability to simultaneously quantitate cocaine and its 12 metabolites from pregnant rat blood, amniotic fluid, placental and fetal tissue homogenates aids in elucidating the metabolism and distribution of cocaine. An efficient extraction method was developed to simultaneously recover these 13 components using underivatized silica solid-phase extraction (SPE) cartridges. The overall recoveries for cocaine and its metabolites were studied from pregnant rat blood (47-100%), amniotic fluid (61-100%), placental homogenate (31-83%), and fetal homogenate (39-87%). Extraction of the samples using silica is not classical SPE, but rather allows for the concentration of the sample into a small volume prior to injection and the removal of the proteins due to their strong interaction with the active silica surface. A positive ion mode electrospray ionization liquid chromatography-tandem mass spectrometry (LC-MS-MS) method was used and validated to simultaneously quantitate cocaine and 12 metabolites from these four biological matrices. A gradient elution method with a Zorbax XDB C8 reversed-phase column was used to separate the components. Multiple reaction monitoring (MRM) of a product ion arising from the corresponding precursor ion was used in order to enhance the selectivity and sensitivity of the method. Low background noise was observed from the complex biological matrices due to efficient SPE and the selectivity of the MRM mode. Linear calibration curves were generated from 0.01 to 2.50 ppm. The method also showed high intra-day (n =3) and inter-day (n=9) precision (% RSD) and accuracy (% error) for all components. The limits of detection (LODs) for the method ranged from 0.15 to 10 ppb. The LODs of cocaine and its major metabolites were less than 1 ppb from all four biological matrices. This method was applied to the study of the metabolism and distribution of cocaine in pregnant rats following intravenous infusion to a steady state plasma drug concentration. The following results were observed in the pregnant rat study: (1) the observations correlated strongly with the previous literature data on cocaine metabolism and distribution, (2) cocaine and norcocaine accumulated in the placenta, (3) arylhydroxylation of cocaine was a major metabolic pathway, (4) para-arylhydroxylation of cocaine was favored over meta-arylhydroxylation in rats and (5) accumulation of cocaine and its major metabolites was observed in the amniotic fluid.

Amniotic Fluid↗
PubMed2000

Mechanisms of the dose-dependent kinetics of trichloroethylene: oral bolus dosing of rats.

Trichloroethylene (TCE), a common contaminant of drinking water, is oxidized by high-affinity, low-capacity cytochrome P450 isozymes and subsequently converted to metabolites, some of which are carcinogenic in mice and rats. Although the initial oxidation step is known to be rate-limiting and saturable, the oral dosage-range over which saturation materializes is unclear. One objective of this study was to characterize the dose-dependency of gastrointestinal (GI) absorption of TCE and its kinetics over a wide range of oral bolus doses. A related objective was to investigate cause(s) of the apparent saturation kinetics observed. Cannulas were surgically implanted into a carotid artery and the stomach of male Sprague-Dawley rats. TCE was incorporated into a 5% aqueous Alkamuls emulsion and given in doses of 2 to 1200 mg/kg bw via the stomach tube. Serial blood samples were taken from the arterial cannula for up to 14 h postdosing and analyzed for TCE content by headspace gas chromatography. The rate of GI absorption of TCE diminished as the dosage increased. Pharmacokinetic analysis indicated that TCE was eliminated by capacity-limited hepatic metabolism, with incursion into nonlinear kinetics with bolus doses >/=8 to 16 mg/kg. Effects of p-nitrophenol, a competitive metabolic inhibitor, were manifest at a high, but not at a low TCE dose. Gavage bolus doses as high as 1200 mg/kg did not cause rapid elevation of serum enzyme levels, typical of the solvation of hepatocellular membranes observed after portal vein administration of TCE (Lee et al., Toxicol. Appl. Pharmacol. 163, 000-000, 2000). No evidence of cytochrome P4502E1 (CYP2E1) destruction was seen with oral doses up to 1000 mg/kg. Instead, CYP2E1 activity was induced as early as 1 h postdosing. Induction was maximal at 12 h, then returned toward controls during the next 12 h. Pretreatment with cycloheximide did not reduce CYP2E1 activity in rats given 432 or 1000 mg TCE/kg, suggesting that binding of TCE to CYP2E1 may stabilize the isozyme. Metabolic saturation, in concert with relatively slow GI absorption, are responsible for the prolonged elevation of blood TCE levels in rats given high TCE doses, while suicidal inactivation of CYP2E1 and hepatocellular injury apparently play little role.

Administration, Oral↗
PubMed2000

B cell apoptosis in the central nervous system in experimental autoimmune encephalomyelitis: roles of B cell CD95, CD95L and Bcl-2 expression.

The role and fate of B cells in the central nervous system (CNS) in experimental autoimmune encephalomyelitis (EAE) are unknown. Using enzyme-linked immunospot assays we now show that B cells reactive to myelin basic protein (MBP) accumulate in the CNS of Lewis rats with acute EAE induced by immunization with MBP and adjuvants. We also report that B cells are eliminated from the CNS by apoptosis during spontaneous recovery from this disease. Apoptotic B cells were identified by flow cytometry of inflammatory cells extracted from the spinal cord and by histological sections of the spinal cord using light and electron microscopic immunocytochemistry. B cell apoptosis occurred preferentially in the CNS rather than in the peripheral lymphoid organs and was maximal just prior to the onset of spontaneous clinical recovery. Three colour flow cytometry indicated that B cells expressing CD95 (Fas) or CD95 ligand (CD95L) were highly vulnerable to apoptosis, whereas B cells expressing Bcl-2 were relatively protected from apoptosis. We propose that B cells are eliminated from the CNS by the interaction of CD95L and CD95 on the same B cell and that this contributes to the spontaneous resolution of CNS inflammation and clinical recovery in acute EAE.

Animals↗
PubMed2000

Phase I/II 90Y-Zevalin (yttrium-90 ibritumomab tiuxetan, IDEC-Y2B8) radioimmunotherapy dosimetry results in relapsed or refractory non-Hodgkin's lymphoma.

Dosimetry studies in patients with non-Hodgkin's lymphoma were performed to estimate the radiation absorbed dose to normal organs and bone marrow from 90Y-Zevalin (yttrium-90 ibritumomab tiuxetan, IDEC-Y2B8) treatment in this phase I/II, multicenter trial. The trial was designed to determine the dose of Rituximab (chimeric anti-CD20, Rituxan, IDEC-C2B8, MabThera), the unlabeled antibody given prior to the radioconjugate to clear peripheral blood B cells and optimize distribution, and to determine the maximum tolerated dose of 90Y-Zevalin [7.4, 11, or 15 MBq/kg (0.2, 0.3, or 0.4 mCi/kg)]. Patients received (111)In-Zevalin (indium-111 ibritumomab tiuxetan, IDEC-In2B8 ) on day 0 followed by a therapeutic dose of 90Y-Zevalin on day 7. Both doses were preceded by an infusion of the chimeric, unlabeled antibody Rituximab. Following administration of (111)In-Zevalin, serial anterior/posterior whole-body scans were acquired. Major-organ radioactivity versus time estimates were calculated using regions of interest. Residence times were computed and entered into the MIRDOSE3 computer software program to calculate estimated radiation absorbed dose to each organ. Initial analyses of estimated radiation absorbed dose were completed at the clinical site. An additional, centralized dosimetry analysis was performed subsequently to provide a consistent analysis of data collected from the seven clinical sites. In all patients with dosimetry data (n=56), normal organ and red marrow radiation absorbed doses were estimated to be well under the protocol-defined upper limit of 20 Gy and 3 Gy, respectively. Median estimated radiation absorbed dose was 3.4 Gy to liver (range 1.2-7.8 Gy), 2.6 Gy to lungs (range 0.72-4.4 Gy), and 0.38 Gy to kidneys (range 0.07-0.61 Gy). Median estimated tumor radiation absorbed dose was 17 Gy (range 5.8-67 Gy). No correlation was noted between hematologic toxicity and the following variables: red marrow radiation absorbed dose, blood T(1/2), blood AUC, plasma T(1/2), and plasma AUC. It is concluded that 90Y-Zevalin administered at nonmyeloablative maximum tolerated doses results in acceptable radiation absorbed doses to normal organs. The only toxicity of note is hematologic and is not correlated to red marrow radiation absorbed dose estimates or T(1/2), reflecting that hematologic toxicity is dependent on bone marrow reserve in this heavily pretreated population.

Antibodies, Monoclonal↗