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PubMed2006

Increasing use and associated harms of crystal methamphetamine injection in a Canadian setting.

BACKGROUND: There is a growing concern surrounding crystal methamphetamine use in Canada despite surprisingly little empirical data to support such claims. We evaluated the trends in crystal methamphetamine injection and factors associated with injection of the drug among a cohort of injection drug users (IDU) in Vancouver. METHODS: We conducted a prospective analysis of factors associated with crystal methamphetamine injection among participants enrolled in the Vancouver Injection Drug Users Study (VIDUS). Since serial measures for each individual were available, variables potentially associated with crystal methamphetamine injection were evaluated using generalized estimating equations (GEE) with logit link for binary outcomes. RESULTS: Overall, 1587 IDU were enrolled into the VIDUS cohort between May 1996 and December 2004. The proportion of IDU who reported injecting crystal methamphetamine during the last 6 months increased during the study period (Cochran-Armitage trend test, p<0.001). In multivariate GEE analyses, crystal methamphetamine injection was independently associated with younger age (adjusted odds ratio [AOR]: 4.77, 95% confidence interval [CI]=3.40-6.70), Caucasian ethnicity (AOR=2.21, 95% CI=1.57-3.12), syringe borrowing (AOR=1.62, 95% CI=1.22-2.13), and syringe lending (AOR=1.40, 95% CI=1.02-1.86). INTERPRETATION: There was a significant trend towards increasing crystal methamphetamine injection in this setting and elevated HIV risk behavior and younger age were independently associated with crystal methamphetamine injection. Given that banning precursor chemicals has had a limited effect on reducing methamphetamine supply in other jurisdictions, pragmatic and effective interventions are needed to address the growing use of this drug.

Adult↗
PubMed2005

Evaluation of different quantitative approaches for the determination of noneasily ionizable molecules by different atmospheric pressure interfaces used in liquid chromatography tandem mass spectrometry: abamectin as case of study.

The liquid chromatography tandem mass spectroscopy residue determination of compounds without any acidic or basic centers such as abamectin has been investigated. Several approaches regarding the interface used and adduct formation have been compared. The low acidity of the hydroxyl groups only made deprotonation feasible using the atmospheric pressure chemical ionization (APCI) interface. To obtain sufficient sensitivity for residue analysis, the Ion Sabre APCI interface was necessary. However, the sensitivity attained was lower than for monitoring adducts in positive ion mode. Using electrospray ionization, different adducts with Na+, NH4+, and Li+ were tested and compared. The best results were obtained for the ammoniated adduct in electrospray ionization (ESI) because of its high sensitivity and the presence of several product ions with similar abundance. The highest sensitivity was reached using an in-source fragment as precursor ion, leading to a limit of detection (LOD) of 2 microg/L with low relative standard deviation. The relatively high abundance of other transitions allowed abamectin confirmation at concentrations close to the LOD (6 microg/L). Alkali ions were found to be a suitable alternative to determine and confirm abamectin at residue levels. The [M + Na]+ also presented various product ions with similar abundance, which allowed confirmation at LOD levels. However, this LOD was found to be almost four times higher than with [M + NH4]+ because of the poor sensitivity of the transitions obtained. Although the use of Li+ facilitated the fragmentation of the adduct [M + Li]+, with similar sensitivity to [M + NH4]+, this fragmentation preferentially generated only one product ion, which did not allow confirmation at concentration levels lower than 15 microg/L. The use of APCI for monitoring adducts was also feasible, but with less sensitivity. The sensitivity increased with the Ion Sabre APCI, although it was still five times lower than with ESI. Other adduct formers such as Co2+ and Ni2+ also were tested with unsatisfactory results.

Algorithms↗
PubMed2001

Autoreactivity, backstimulation and reproducibility in a helper T lymphocyte precursor assay.

Helper T lymphocyte precursor (HTLp) frequencies determined by limiting dilution analysis (LDA) have a predictive value for alloreactivity in allogeneic bone marrow transplantation. Methodological problems in LDA include autoreactivity in the responder or stimulator cell populations and interleukin 2 (IL-2) production by the stimulator cells as a response to the responder cells (backstimulation). The extent and impact of these aspects for IL-2 production and HTLp frequency determination were studied by autologous and allogeneic mixed lymphocyte reactions with healthy volunteers and HTLp determinations from bone marrow transplantation donor/recipient pairs. We found that autoreactivity occurred in the unirradiated cells with a reproducible inter-individual variation. The immunogenicity of the stimulator cells was preserved after gamma irradiation with 50 Gy and the risks of autoreactivity and backstimulation were limited. Higher doses of irradiation decreased the immunogenicity. Immune reactions to antigens present in the serum supplement of the culture medium were seen with foetal calf serum and to a lesser extent with pooled human sera. This could be avoided by the use of autologous serum. We were unable to ensure satisfactory culture conditions in serum-free medium. The reproducibility of the HTLp frequency determinations was tested for intra- and inter-assay variation. The coefficients of variation were estimated as 24% and 35%, respectively. This was acceptable considering the range of the HTLp frequencies (1:10(2) to 1:10(7)). The influence of the extent of autoreactivity of the bone marrow donors was investigated in 28 HLA-identical sibling transplantations. We found no correlation between the autoreactivity of the donors and the HTLp frequencies. The extent of autoreactivity of the donor did not correlate with the clinical outcome in terms of acute graft-versus-host disease, treatment-related mortality, risk of relapse and overall survival. In spite of methodological difficulties and interference from autoreactivity and backstimulation, reproducible quantification of clinically significant alloreactivity can be attained.

Autoimmunity↗
PubMed2000

Cd4(+) T cell response to Leishmania spp. in non-infected individuals.

T cell mediated immunity is known to play a central role in the host response to control intra-cellular pathogens. This work demonstrates the presence of specific CD4(+) T cells to Leishmania spp. antigens in peripheral mononuclear cells of naïve individuals (normal volunteers from non-endemic regions). The responder population was expanded by generation of antigen-specific T cell lines, which were produced by repeated stimulation with fixed promastigotes and autologous irradiated PBMC as antigen presenting cells. The leishmania-T cell lines were shown to proliferate in response to different species of the parasite (L. amazonensis, L. braziliensis, and L. donovani), but not to other recall antigens such as Candida albicans or tetanus toxoid. A preferential expansion of IFNgamma and IL-2 producing Th1-like T cells was observed. The leishmania-reactive cells were distributed between CD4(+) CD45RA(+) ("naïve") and CD4(+) CD45R0(+) ("memory") populations. Although limiting dilution analysis showed a precursor frequency 3 times lower within the naïve compartment, similar numbers of T cell lines were derived from both purified subpopulations. This study using leishmania-specific CD4(+) T cell lines produced from normal individuals should provide information on cellular immune responses that are triggered by the parasite and how infection impacts the naïve T cell repertoire.

Animals↗
PubMed1998

Anti-viral immunity: spotting virus-specific T cells.

Historically, quantitation of virus-specific CD8+ T cells has been accomplished by limiting dilution analysis of cytotoxic precursor cells. Recent studies have shown that this technique greatly underestimates the actual number of antigen-specific cells and have provided new insight into anti-viral immune responses.

Animals↗
PubMed1988

Molecular mechanisms responsible for the drug-induced posttranscriptional modulation of ribonucleotide reductase levels in a hydroxyurea-resistant mouse L cell line.

Ribonucleotide reductase, which catalyzes the formation of deoxyribonucleotides from ribonucleoside diphosphate precursors, is the rate-limiting enzyme in DNA synthesis. The enzyme consists of two nonidentical subunits called M1 and M2, both of which are required for activity. Hydroxyurea, a specific inhibitor of DNA synthesis, acts by destroying the unique tyrosyl free radical of protein M2. Previously, we have described a mouse L cell line which exhibited a stable resistance to high concentrations of hydroxyurea. This mutant cell line contains elevated quantities of both proteins M1 and M2 as a result of corresponding increases in the levels of mRNAs for both subunits. Interestingly, both M1 and M2 protein levels were further elevated when mutant cells were cultured in the presence of hydroxyurea, and this elevation was not accompanied by increases in their corresponding mRNAs. These results indicated that hydroxyurea can modulate ribonucleotide reductase expression posttranscriptionally. In this report, we show that the level of both subunits of ribonucleotide reductase responds to hydroxyurea in a drug concentration dependent manner. Furthermore, results from kinetic studies indicate that protein M2 levels rise much more rapidly than protein M1. Pulse-chase experiments indicated that the half-lives of both the M1 and M2 polypeptides are increased by approximately 2-fold when the mutant cells are cultured in the presence of hydroxyurea. We also present evidence indicating that exposure of these cells to hydroxyurea leads to a relatively slow but specific increase in the rate of biosynthesis of both proteins M1 and M2, as assayed by pulse labeling.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2001

Disinfection byproduct relationships and speciation in chlorinated nanofiltered waters.

The formation and speciation of disinfection byproducts (DBPs) resulting from chlorination of nanofilter permeates obtained from various source water locations and membrane types are examined. Specific ultraviolet absorbance and bromide utilization are shown to decrease following nanofiltration. Both dissolved organic carbon (DOC) concentration and ultraviolet absorbance at 254 nm were found to correlate strongly with trihalomethane (THM), haloacetic acid (HAA), and total organic halide (TOX) concentrations in chlorinated nanofilter permeates, suggesting that they can be employed as surrogates for DBPs in nanofiltered waters. Because smooth curves were obtained for individual THM and HAA species as well as bromine and chlorine incorporation into THMs and HAAs as a function of Br-/DOC molar ratio, it is likely that mole fractions of these DBPs are more strongly influenced by chlorination conditions, Br-, and DOC concentrations than NOM source and membrane type. Mole fractions of mono-, di-, and trihalogenated HAAs were found to be independent of Br-/DOC. Even at a very low Br-/DOC of 2.9microM/mM, the mixed bromochloro- and tribromoacetic acids constituted 20% of total HAAs on a molar basis. This increased to approximately 50% as Br-/DOC increased to approximately 25microM/mM or more, proving that a large fraction of HAAs may not be covered under existing federal regulations. Total THM and HAA9 concentrations decreased in permeate waters with increasing Br-/DOC suggesting that nanofilter permeates are limited with respect to DBP precursors.

Absorption↗
PubMed2006

Kinetically controlled catalytic formation of zinc oxide thin films at low temperature.

We developed a unique method to produce ZnO thin films by kinetically controlled catalytic hydrolysis of a molecular precursor at low temperature, operating in conjunction with the vectorial control of crystal growth. Using a system in which the diffusion of a volatile catalyst into a solution of molecular precursor of the metal oxide limits the rate of hydrolysis and establishes a gradient of catalyst concentration, we investigated the nucleation of textured nanoparticles at the gas-liquid interface and characterized their subsequent growth. Use of this slow diffusion method combined with prediction of molecular species using a partial charge model enables a higher level of organizational control than obtained in other low-temperature synthesis methods, without the use of organic molecules. Various metal oxides and their morphologies and chemical compositions can be tailored for specific applications using this relatively simple approach.

Catalysis↗
PubMed2005

A novel single-step fabrication technique to create heterogeneous poly(ethylene glycol) hydrogel microstructures containing multiple phenotypes of mammalian cells.

In this study, a novel method for the one-step fabrication of stacked hydrogel microstructures using a microfluidic mold is presented. The fabrication of these structures takes advantage of the laminar flow regime in microfluidic devices, limiting the mixing of polymer precursor solutions. To create multilayered hydrogel structures, microfluidic devices were rotated 90 degrees from the traditional xy axes and sealed with a cover slip. Two discreet fluidic regions form in the channels, resulting in the multilayered hydrogel upon UV polymerization. Multilayered patterned poly(ethylene glycol) hydrogel arrays (60 mum tall, 250 mum wide) containing fluorescent dyes, fluorescein isothiocyanate, and tetramethylrhodamine isothiocyanate were created for imaging purposes. Additionally, this method was used to generate hydrogel layers containing murine fibroblasts and macrophages. The cell adhesion promoter, RGD, was added to hydrogel precursor solution to enhance fibroblast cell spreading within the hydrogel matrix in one layer, but not the other. We were able to successfully generate patterns of hydrogels containing multiple phenotypes by using this technique.

Animals↗
PubMed1994

Mutation in blood coagulation factor V associated with resistance to activated protein C.

Activated protein C (APC) is a serine protease with potent anticoagulant properties, which is formed in blood on the endothelium from an inactive precursor. During normal haemostasis, APC limits clot formation by proteolytic inactivation of factors Va and VIIIa (ref. 2). To do this efficiently the enzyme needs a nonenzymatic cofactor, protein S (ref. 3). Recently it was found that the anticoagulant response to APC (APC resistance) was very weak in the plasma of 21% of unselected consecutive patients with thrombosis and about 50% of selected patients with a personal or family history of thrombosis; moreover, 5% of healthy individuals show APC resistance, which is associated with a sevenfold increase in the risk for deep vein thrombosis. Here we demonstrate that the phenotype of APC resistance is associated with heterozygosity or homozygosity for a single point mutation in the factor V gene (at nucleotide position 1,691, G-->A substitution) which predicts the synthesis of a factor V molecule (FV Q506, or FV Leiden) that is not properly inactivated by APC. The allelic frequency of the mutation in the Dutch population is approximately 2% and is at least tenfold higher than that of all other known genetic risk factors for thrombosis (protein C (ref. 8), protein S (ref. 9), antithrombin10 deficiency) together.

Amino Acid Sequence↗
PubMed1990

Natural killer and lymphokine activated killer cell functions in Hodgkin's disease.

We report the natural killer (NK) and lymphokine activated killer (LAK) cell activities in peripheral blood lymphocytes (PBL) from untreated patients with Hodgkin's disease (HD) and from healthy donors. The frequency of LAK cell precursors was also studied using limiting dilution analysis (LDA). About 75% of the HD patients had normal NK activity. There was a higher percentage of low NK responders (mean percent NK activity of healthy donors--2 SD) in patients with lymphocyte depletion histologic grade of the disease and those who were in clinical stage IV, suggesting a correlation of decrease in NK activity with poor prognosis. We found efficient LAK activity against the NK-sensitive K562 cells and NK-resistant VIP (melanoma) and T-24 (bladder carcinoma) tumour targets in both low and normal NK responder HD patients, irrespective of the histopathological grade and clinical stage of the disease. In concordance with their good LAK cell activity, HD patients showed a frequency distribution of LAK cell progenitors in the PBL comparable to that of healthy donors.

Adolescent↗
PubMed2007

The adult human heart as a source for stem cells: repair strategies with embryonic-like progenitor cells.

Adequate cell-based repair of adult myocardium remains an elusive goal because most cells that are used cannot generate mature myocardium sufficient to promote large functional improvements. Embryonic stem cells can generate both mature cardiocytes and vasculature, but their use is hampered by associated teratoma formation and the need for an allogeneic source. The detection of sca-1(+), c-kit(+), or isl-1(+) cardiac precursors and the creation of cardiospheres from adult heart tissues suggest that a persistent population of immature progenitor cells is present in the mature myocardium. These cell populations probably represent stages along a continuum of cardiac stem cell development and differentiation. We report isolation from ventricle of uncommitted cardiac progenitor cells, which appear to resemble the more immature, common pool of embryonic lateral plate mesoderm progenitors that yield both myocardial and endocardial cells during normal cardiac development. Under controlled in vitro conditions and in vivo, these cells can differentiate into endothelial, smooth muscle, and cardiomyocyte lineages and can be isolated and expanded to clinically relevant numbers from adult rat myocardial tissue. In this article, we discuss the potential for autologous repair or even cardiac regeneration with cells that follow a developmental pathway similar to embryonic cardiac precursors but without the inherent limitations associated with undifferentiated embryonic stem cells.

Adult↗
PubMed2001

The predictive value of helper T lymphocyte precursor frequencies for graft-versus-host disease and graft-versus-leukaemia effects in allogeneic bone marrow transplantation.

Helper T lymphocyte precursor (HTLp) frequencies determined by limiting dilution analysis were studied in the graft-versus-host direction to assess the predictive value for outcome in allogeneic BMT. The HTLp frequencies correlated with the degree of HLA disparity. HTLp frequencies from 28 HLA-identical sibling BMT pairs had a median of 1:557 362 (range 1:9511 to <1:2 500 000). The HTLp frequencies from 20 HLA-matched unrelated and partially HLA-matched related BMT pairs had a median of 1:88 110 (range 1:4139-1:736 123). The HLA-identical sibling BMT pairs were split evenly into high and low HTLp frequency groups above and below 1:500 000. There was a trend towards a higher risk for acute GVHD > or =grade II (P = 0.075) in the high frequency group. There was no difference in TRM. The high HTLp frequency group had a significantly higher risk for chronic GVHD (P = 0.04), a significantly lower risk for relapse (P = 0.01), as well as a significantly better overall survival (P = 0.045) and leukaemia-free survival (P = 0.008). The HLA-matched unrelated and partially HLA-matched related BMT pairs were split evenly into high and low HTLp frequency groups above and below 1:90 000. There was a significantly higher risk for acute GVHD > or = grade II (P = 0.007) in the high HTLp frequency group. There was a trend towards a higher TRM in the high HTLp frequency group (P = 0.05). There were no differences in chronic GVHD, risk of relapse, overall survival and leukaemia-free survival. Analyzing all 48 patients the risk of acute GVHD > or = grade II and TRM was significantly higher (P = 0.012 and 0.021, respectively) with HTLp frequencies >1:100 000 and there was a trend towards a higher risk of relapse (P = 0.058) with low HTLp frequencies <1:400 000. Patients in the intermediate HTLp frequency group 1:100 000-1:400 000 had a trend towards improved survival (P = 0.059). The HTLp frequency seems to detect clinically significant differences in alloreactivity, that can be useful in donor selection and graft engineering.

Adolescent↗
PubMed1982

Decreased amino acids in various brain areas of patients with Lesch-Nyhan syndrome.

In an effort to further understand the pathogenesis of Lesch-Nyhan syndrome, an X-linked recessive disease of purine metabolism associated with a deficiency of hypoxanthine-guanine phosphoribosyltransferase, we have analyzed the amino acids in autopsy brain material obtained from five patients and six controls. The amino acids glycine and glutamine serve as substrates for the synthesis of purines in man. Amino acids were measured in the occipital cortex, limbic cortical area, cerebellar cortex, hippocampus and putamen. In general the amino acids were usually lower in concentration in brain material from affected individuals. Most dramatically decreased were threonine, serine, valine, isoleucine, lysine and arginine. Only glutamine and urea were higher than controls. Glutamate, gamma-aminobutyrate and cystathionine were essentially unaffected. The data reported here do not support a role for increased glycine in the pathogenesis of this disease as implied by findings previously reported in cultured cell lines (Skaper and Seegmiller 1976, 1977). The current findings suggest that individuals with Lesch-Nyhan syndrome have a generally lower concentration of free amino acids in brain. This decrease may be involved in the etiology of the disease or the decrease may be a result of the generally malnourished state of these individuals. These results imply that affected patients have a limited supply of amino acid precursors available for the synthesis of either proteins or neurotransmitters that the brain requires for normal function. Thus, the low amino acid pools could be an important factor in the brain dysfunction observed in patients with Lesch-Nyhan syndrome.

Adolescent↗
PubMed2005

Diagnosis of human prion disease.

With the discovery of the prion protein (PrP), immunodiagnostic procedures were applied to diagnose Creutzfeldt-Jakob disease (CJD). Before development of the conformation-dependent immunoassay (CDI), all immunoassays for the disease-causing PrP isoform (PrPSc) used limited proteolysis to digest the precursor cellular PrP (PrPC). Because the CDI is the only immunoassay that measures both the protease-resistant and protease-sensitive forms of PrPSc, we used the CDI to diagnose human prion disease. The CDI gave a positive signal for PrPSc in all 10-24 brain regions (100%) examined from 28 CJD patients. A subset of 18 brain regions from 8 patients with sporadic CJD (sCJD) was examined by histology, immunohistochemistry (IHC), and the CDI. Three of the 18 regions (17%) were consistently positive by histology and 4 of 18 (22%) by IHC for the 8 sCJD patients. In contrast, the CDI was positive in all 18 regions (100%) for all 8 sCJD patients. In both gray and white matter, approximately 90% of the total PrPSc was protease-sensitive and, thus, would have been degraded by procedures using proteases to eliminate PrPC. Our findings argue that the CDI should be used to establish or rule out the diagnosis of prion disease when a small number of samples is available as is the case with brain biopsy. Moreover, IHC should not be used as the standard against which all other immunodiagnostic techniques are compared because an immunoassay, such as the CDI, is substantially more sensitive.

Biopsy↗
PubMed1996

Costimulatory protein B7-1 enhances the cytotoxic T cell response and antibody response to hepatitis B surface antigen.

There is a need for more effective therapy for chronic virus infections. A principle natural mechanism for elimination of virus-infected host cells is activation of viral antigen-specific cytotoxic T lymphocytes (CTL). In an effort to develop methods of inducing virus-specific CTL responses that might be utilized in therapy of virus infections, we have investigated the effect of B7, a costimulatory factor for T-cell activation. In this study we show that delivery of genes encoding human B7-1 and a viral antigen in the same recombinant viral vector to cells of mice induces a greater viral antigen-specific CTL response than does similar delivery of the viral antigen gene alone. Two recombinant adenovirus vectors were constructed with the foreign genes inserted in the early region 3. One of them (Ad1312) directed expression of the surface antigen gene of hepatitis B virus (HBS); the other (Ad1310) directed coexpression of HBS and human B7-1 (CD80) by means of an internal ribosomal entry site placed between the two coding sequences. When inoculated into BALB/c mice, both vectors induced a viral surface antigen-specific CTL response. The response induced by Ad1310 was stronger than that by Adl312 as measured by a chromium release assay for CTL activity and limiting dilution analysis for CTL precursor frequency, indicating that the B7-1 gene co-delivered with the HBS gene had an enhancing effect on the CTL response against surface antigen. Ad1310 also induced a higher titer of antibody against surface antigen than did Ad1312. This result suggests that expression of a costimulatory protein and a viral antigen in the same cells in vivo induces stronger immune responses than expression of the antigen alone. This could be a novel strategy for development of both preventive and therapeutic vaccines against infectious agents.

3T3 Cells↗
PubMed1997

Relax promotes ectopic neuronal differentiation in Xenopus embryos.

We previously isolated a novel rat cDNA encoding a basic helix-loop-helix transcription factor named Relax, whose expression in the developing central nervous system is strictly limited to discrete domains containing precursor cells. The timing of Relax expression coincides with neuronal differentiation. To investigate the involvement of Relax in neurogenesis we tested whether Relax activated neural genes in the ectoderm by injecting Relax RNA into Xenopus embryos. We demonstrate that ectopic Relax expression induces a persistent enlargement of the neural plate and converts presumptive epidermal cells into neurons. This indicates that Relax, when overexpressed in Xenopus embryos, has a neuronal fate-determination function. Analyses both of Relax overexpression in the frog and of the distribution of Relax in the rat neural tube strongly suggest that Relax is a neuronal fate-determination gene.

Animals↗
PubMed1998

Characterization of the hematopoietic transcription factor NF-E2 in primary murine megakaryocytes.

Biochemical analysis of megakaryocytes, the precursors of blood platelets, is limited by their rarity in vivo, and studies on lineage-specific gene expression have been conducted exclusively in cell lines with limited megakaryocytic potential. Mice lacking the transcription factor NF-E2 display arrested megakaryocyte differentiation and profound thrombocytopenia. To study the heterodimeric NF-E2 protein in primary cells, we cultured mouse fetal livers with the c-Mpl ligand, obtained highly enriched megakaryocyte populations, and readily detected NF-E2 activity in nuclear extracts. As in erythroid cells, p45 NF-E2 is the only large subunit in primary megakaryocytes that dimerizes with distinct small Maf proteins to constitute a heterogeneous NF-E2 complex. Whereas p18/MafK is the predominant small Maf protein in erythroid cells, the related polypeptides MafG and/or MafF predominate in megakaryocytes. Although this represents the first example of differential small Maf protein expression among closely related blood lineages, the DNA-binding specificity of NF-E2 is similar in both cell types. Although the megakaryocyte protein preferentially binds an asymmetric AP-1-related motif, it also recognizes cAMP-responsive element-related sequences, albeit with lower affinity, and nucleotides outside the core sequence influence the DNA-protein interaction. These results demonstrate the feasibility of biochemical studies on primary murine megakaryocytes and provide a basis to dissect the critical functions of NF-E2 in megakaryocyte differentiation.

Animals↗