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David Simpson

Publications and source records attributed to David Simpson.

At least 91 records · Page 5Linked to original sources
PubMed2003

Use of mobile phase 18-crown-6 to improve peak resolution between mono- and divalent metal and amine cations in ion chromatography.

It is difficult to quantify NH4+ by ion chromatography in the presence of high concentrations of Na+ due to peak overlap. The Dionex IonPac CS15 column, which contains phosphonate, carboxylate, and 18-crown-6 functional groups, was originally developed to overcome this problem. We have found that the addition of 18-crown-6 to the eluent promotes improved peak resolution between Na+ and NH4+ even at concentrations as high as 60,000 to 1 using this column. Its use also improves the separation of alkali and alkaline earth metal and amine cations. Mobile phase 18-crown-6 increased the retention times of CH3NH3+, NH4+, and K+, and decreased the retention time of Sr2+. The retention times of Li+, Na+, Mg2+, Ca2+, (CH3)2NH2+, and (CH3)3NH+ were not affected. This method makes possible the direct analysis of ammonia from nitrogenase, the enzyme responsible for biological nitrogen fixation. The resolution of the NH4+ peak from the Na+ and Mg2+ peaks improved from zero resolution to values of 6.19 and 5.65, respectively. This technique considerably reduces the analysis time of NH4+ in the presence of high concentrations of Mg2+ and Na+ over traditional indophenol measurements.

Amines↗
PubMed2003

A multi-center 1H MRS study of the AIDS dementia complex: validation and preliminary analysis.

PURPOSE: To demonstrate the technical feasibility and reliability of a multi-center study characterizing regional levels of the brain metabolite ratios choline (Cho)/creatine (Cr) and myoinositol (MI)/Cr, markers of glial cell activity, and N-acetyl aspartate (NAA)/Cr, a marker of mature neurons, in subjects with AIDS dementia complex (ADC). MATERIALS AND METHODS: Using an automated protocol (GE PROBE-P), short echo time spectra (TE = 35 msec) were obtained at eight sites from uniformly prepared phantoms and from three brain regions (frontal white matter, basal ganglia, and parietal cortex) of normal volunteers and ADC and HIV-negative subjects. RESULTS: A random-effects model of the phantom and volunteer data showed no significant inter-site differences. Feasibility of a multi-center study was further validated by detection of significant differences between the metabolite ratios of ADC subjects and HIV-negative controls. ADC subjects exhibited significantly higher Cho/Cr and MI/Cr in the basal ganglia and significantly reduced NAA/Cr and significantly higher MI/Cr in the frontal white matter. These results are consistent with the predominantly subcortical distribution of the pathologic abnormalities associated with ADC. CONCLUSION: This is the first study to ascertain and validate the reliability and reproducibility of a short echo time (1)H-MRS acquisition sequence from multiple brain regions in a multi-center setting. It should now be possible to examine the regional effects of HIV infection in the brain in a large number of subjects and to study the metabolic effects of new therapies for the treatment of ADC in a clinical trial setting.

AIDS Dementia Complex↗
PubMed2003

Does lower-body BMD develop at the expense of upper-body BMD in female runners?

PURPOSE: Evidence suggests that exercise plays an important role in stimulating site-specific bone mineral density (BMD). However, what is less well understood is how these benefits dissipate throughout the body. Hence, the purpose of the present study was to compare the levels of, and the correlation between, BMD recorded at 10 sites in female endurance runners, and to investigate possible determinants responsible for any inter-site differences observed. METHODS: Repeated measures ANOVA was used to compare the BMD between sites and factor analysis was used to describe the pattern of intersite correlations. Allometric ANCOVA was used to identify the primary determinants of bone mass and how these varied between sites. RESULTS: The ANOVA and factor analysis identified systematic differences in BMD between sites, with the greatest BMD being observed in the lower-body sites, in particular the legs. An investigation into the possible mechanisms responsible for these differences revealed "distances run" (km.wk-1) as a positive, and "years of training" as a negative determinant of bone mass (P < 0.001). However, the effect of a number of determinants varied between sites (P < 0.05). Specifically, the ANCOVA identified that running further distances resulted in higher bone mass in the arms and legs. In contrast, training for additional years appeared to result in lower bone mass in the arms and lumbar spine. Calcium intake was also found to be positively associated with bone mass in the legs but negatively associated at all other sites. CONCLUSIONS: A combination of running exercise and calcium intake would appear to stimulate the bone mass of women endurance runners at lower-body sites but at the expense of bone mass at upper-body sites.

Adult↗
PubMed2003

T-cell depleting antibodies: new hope for induction of allograft tolerance in bone marrow transplantation?

Graft versus host disease (GVHD) remains the main barrier to successful allogeneic bone marrow transplant outcomes. Depletion of graft T cells is an effective way of reducing the incidence of acute and chronic GVHD, and a variety of methods have been used to achieve this depletion. Donor CD8+ T cells seem to be the critical effector cells; GVHD is reduced when the depletion process eliminates these cells, but not when CD4 cells are targeted alone. However, despite the successful reduction in GVHD, transplant outcomes are usually inferior with T-cell depleted transplants, because of increased graft failure, infections and relapse. Alternative approaches are needed. In vivo T-cell depletion, using antithymocyte globulin (ATG) as part of the conditioning regimen, seems an attractive option. Pre-transplant ATG lingers in the bone marrow to deplete engrafting donor T cells, but also depletes host T cells to prevent graft rejection and allow de-escalation of the conditioning regimen. It also avoids the need for graft manipulation with its associated costs, need for expertise and CD34+ cell loss. The efficacy of pre-transplant horse ATG remains anecdotal but it has been reported to modestly lower GVHD in single arm studies. Rabbit ATG has been studied in prospective randomised trials. There is evidence of a dose-response effect in reducing GVHD; however, there was no improvement in outcome, because of increased mortality associated with infection. In contrast, pre-transplant alemtuzumab (campath-1H) or an earlier version of this molecule (campath-1G), which target CD52+ cells, do appear to be effective in reducing both acute and chronic GVHD. There is speculation that this is not solely due to the effect of campath on T cells but that it may also be due to the elimination of host antigen-presenting cells (APC), which seem to be important in GVHD pathogenesis. Host APC are more efficient at expressing endogenous and exogenous host antigens on class I MHC to donor CD8+ cells than donor APC, which need to cross-prime exogenous antigen. Campath-1G eliminates host dendritic cells by the time of graft infusion, supporting this as a possible mechanism of action. Pre-transplant alemtuzumab has not yet been studied in a prospective randomised study, and this is required to quantify any benefit on outcome; despite this, published studies do show cause for optimism.

Alemtuzumab↗
PubMed2002

Safety, tolerability, and pharmacokinetic effects of thalidomide in patients infected with human immunodeficiency virus: AIDS Clinical Trials Group 267.

Thalidomide is used to treat human immunodeficiency virus (HIV)-associated conditions, including aphthous ulcers and wasting syndrome. The safety, tolerability, and pharmacokinetics of a formulation of thalidomide with improved bioavailability in HIV-infected persons was examined in a placebo-controlled, dose-escalating phase 1 study. Subjects with CD4 cell counts of 200-500 cells/mm(3) were enrolled and randomized 3:1 in groups of 12 to receive 50, 100, or 150 mg of thalidomide or matching placebo. Two subjects who received 150 mg of drug and 2 subjects assigned placebo experienced dose-limiting toxicity. Concentrations of thalidomide in the blood increased with escalating dose, but the time to maximum concentration and clearance did not differ across dose cohorts. Previous suggestions of autoinduction of drug metabolism were not confirmed by this study. At the doses studied, thalidomide was tolerated well and had linear pharmacokinetics.

Adult↗
PubMed2002

In vivo purging with rituximab prior to collection of stem cells for autologous transplantation in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) cells express the CD20 antigen, and monoclonal antibodies against CD20 have resulted in remissions. We hypothezised that the anti-CD20 antibody rituximab (Rituxan) may be useful in reducing the number of contaminating CLL cells in stem cell collections for use in autologous transplantation. A pilot study in 5 patients was designed using rituximab 375 mg/m(2) as an in vivo purging step following cyclophosphamide 4 gm/m(2) and granulocyte colony-stimulating factor/granulocyte-macrophage colony-stimulating factor (G-CSF/GM-CSF) mobilization therapy for patients with advanced-stage CLL undergoing autologous stem cell transplantation. Eligible patients had 0-30% marrow involvement prior to mobilization. A single pre-rituximab leukapheresis product was obtained after the white blood cells (WBC) reached 800/mm(3) to serve as a control but was not reinfused. Rituximab was administered the following day and subsequent leukaphereses were commenced 48 h later to reach a total of >2 x 10(6) CD34(+) cells/kg. Dual-color flow cytometry CD5/CD19 and consensus PCR using primers to the joining region and FR3 of the variable region of the immunoglobulin heavy chain (IgH) were used to evaluate the degree of contaminating CLL cells in the leukapheresis product and to monitor disease status post transplant. All 5 patients were informative for the consensus PCR assay. Four of 5 patients mobilized >2 x 10(6) CD34(+) cells/kg and proceeded to cyclophosphamide 120 mg/kg and total body irradiation (6 x 200 cGy) with stem cell rescue. All leukaphereses products were positive by PCR for the IgH rearrangement and 4/5 contained CD5/CD19 dual-positive cells. Comparing the pre- and post-rituximab leukapheresis products, a reduction in the percentage of CD5(+)/CD19(+) cells was seen in 4/5 patients. All patients engrafted at a median of 13.5 days to ANC > 500/mm(3) and 11 days to platelets >20,000/mm(3). No regimen-related mortality was seen. Although 2 patients tested positive on PCR for the IgH rearrangement early after transplant, all patients had absence of the IgH gene rearrangement at 1 year and no CD5/CD19 dual-positive cells were could be detected in the bone marrow. This includes 1 heavily pretreated patient who received stem cells containing up to 30% CD5(+)/CD19(+) cells. We conclude that purging with Rituximab 48 h prior to stem cell collection was able to reduce significantly (but not eliminate) the percentage of CLL cells in the leukaphereses. However, despite the infusion of CD5(+)/CD19(+) cells in the stem cell coions, patients were able to obtain durable complete molecular remissions, implying that the PCR-positive cells in the leukaphereses may not have long-term clonogenic potential. The results also support the recommendation to test if rituximab should be part of a maintenance regimen after transplant to prevent disease recurrence in high-risk patients.

Antibodies, Monoclonal↗